TWI328585B - Oxazol derivatives - Google Patents
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- TWI328585B TWI328585B TW91109889A TW91109889A TWI328585B TW I328585 B TWI328585 B TW I328585B TW 91109889 A TW91109889 A TW 91109889A TW 91109889 A TW91109889 A TW 91109889A TW I328585 B TWI328585 B TW I328585B
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1328585 A7 B7 五、 站術範圍 本發明係關於新穎°号唑衍生物、其製造及以其作為藥品 的用途。本發明特別係關於式(I)化合物1328585 A7 B7 V. Scope of the station The present invention relates to novel azole derivatives, their manufacture and their use as pharmaceuticals. The invention relates in particular to compounds of formula (I)
及其醫藥上可接受之鹽類和酯類,其中 R1 係芳基或雜芳基; R2、R3、R4及R6係彼此獨立是氫、羥基、低碳埽基、鹵 素、低碳烷基或低碳烷氧基,其中R2、R3、R4及R6 的至少其中之一不是氫,或 將R3與R4彼此結合,和與彼附著的碳原子一起形成 環’並且 R3 及 R4—起是-CH=CH-S-、-S-CH=CH-' -CH=CH-0- > -0-CH=CH-、-CH=CH-CH=CH· 、-((:Η2)3·5-、-〇-(cH2)2.3-或-(CH2)2.3-0-,以及 R2及R6係如以上的定義; R5 係低碳烷氧基、低碳烯氧基、And pharmaceutically acceptable salts and esters thereof, wherein R1 is aryl or heteroaryl; R2, R3, R4 and R6 are independently of each other hydrogen, hydroxy, lower sulfhydryl, halogen, lower alkyl or a lower alkoxy group, wherein at least one of R2, R3, R4 and R6 is not hydrogen, or R3 and R4 are bonded to each other, and together with the carbon atom to which they are attached form a ring' and R3 and R4 are -CH =CH-S-, -S-CH=CH-' -CH=CH-0- > -0-CH=CH-, -CH=CH-CH=CH·, -((:Η2)3·5 -, -〇-(cH2)2.3- or -(CH2)2.3-0-, and R2 and R6 are as defined above; R5 is lower alkoxy, lower alkoxy,
R R- 或 ΪR R- or Ϊ
R 10 -5 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(2 R7 係氫或低碳烷基 R8 係氫或低碳烷基 R9 係氫或低碳烷基 R10 係芳基: η 係1、2或3 ; 其中在碳原子<^與碳原子Cbi間的鍵係碳碳單鍵或雙鍵。 以過氧物酶體增殖劑活化之受體(Peroxisome Proliferator Activated Receptors) (PPAR's)係核激素受體超級族系的成 員,其係以配體活化之轉錄因子調節基因表現。已經證實 及選殖彼的各種副型。這些包括PP AR a、PP AR /3 (也稱為 PPAR 5 )及PPAR r。彼以至少兩種PPAR 7的主同型物存 在。雖然PPAR r 1表現在遍存的大部份組織中,但是在脂 肪細胞中幾乎只發現較長的同型物PPAR τ 2。相對之下, PPAR α以優先表現在肝、腎及心中。以PPAR's調整各種身 體反應,包括葡萄糖-及脂質-體内平衡、細胞分化、發炎 反應及心血管事件。 糖尿病係一種病患控制在血中的葡萄糖值的能力受損的 疾病,因為病患已喪失部份適當反應胰島素作用的能力。 在常稱為非姨島素依賴型糖尿病(NIDDM)的II型糖尿病中 (T2D),在已開發國家中有80-90%的所有糖尿病病患受其 所苦,在胰臟中的蘭氏小島仍會產生胰島素。但是,標的 is耳、主要肌肉、肝及脂肪组織會展現冗全的抗肤島素刺 激作用,並以產生非生理學上的高胰島素值補償身體。但 是,在疾病的後期,由於胰臟枯竭而使胰島素分泌作用降 _- R -_ 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585 A7 . B7__ 五、發明説明( ) 3 ’ 低。除此之外,T2D係代謝性心血管疾病徵候群。其中與 丁2 D有關連的合併症是抗胰島素症、血脂異常、高血壓、 血管内皮機能異常及發炎性動脈粥樣硬化症。 糖尿病現行的第_線治療通常包含低脂-及低葡萄糖飲食 及運動。服從可使疾病的進度緩和’但是,疾病的進度變 成需要以低血糖葯物治療,例如’磺醯尿素或葉德香。目 前已引入有希望的新類型藥物,使病患對彼自身的胰島素 再敏感(胰島素敏感劑),藉以使血液葡萄糖及三酸甘油酯 量逆轉至正常,並因此廢止或至少降低對外源胰島素的需 求。派爾吉利它容(pioglitazone) (ActosTM)及若西格利它 容(rosiglitazone) ( AvandiaTM)屬於 PPAR r ·促動劑的。塞唑 烷二酮(TZD)類型,並已是許多國家核准為NIDDM的第一 個代表藥物。但是,這些化合物蒙受副效應所害,包括罕 見,但是嚴重的肝毒素(如以托格利它容(troglitazone)的體 驗)’並會使人類體重增加。因此’急需要新、好及更有效 的NIDDM治療藥物。最近的研究提供ppARa與PPAR 7的 共促動作用可能使得化合物具有增強治療潛力的證據,即 改進加之正¥化葡為糖-及姨島素值的脂質分布效應(孰勒 (Keller)及(華利(Wahli) : Trends Endocrin. Metab. 1993, 4:291-296, Macdonald and Lane: Current Biology v〇l.5 pp 618-621(1995))。 - 本發明的新賴化合物超越在本技藝中已知的化合物,由 於彼等會結合及同時且非常有效活化PPAr α與ppar 丫兩 者。因此,以這些化合物组合PPART活化作用的抗血糖效 本紙張尺度適用中國國家標準(CNS) Α4規格(210X 297公釐) 1328585 A7 B7 五、發明説明( 應與PPAR 〇:活化作用的抗血脂異常。結果會降低血衆葡萄 糖及腺島素(=胰島素敏感作用)、降低三酸甘油酯及增加 HDL膽固醇(=改進脂質分布)。此外,這些化合物也可以 降低LDL膽固醇、增加血壓及抗發炎性動脈粥樣硬化症。 因為以PPAR α與PPAR 7的共促動劑追求丁2D疾病徵候群的 多面性,故與在本技藝中已知的化合物比較,希望彼等具 有增強的治療潛力》 本發明的化合物尚展現與已-知化合物比較上改進的藥理 特性。 - 裝 除非有另外其它的指示,由以下陳述的定義例證及定義 用於說明本發明的各種術語的意義及範圍。 在本說明書中,使用”低碳,•術語代表由丨至7個碳原子所 構成的基團’以1至4個碳原子較佳。 以"鹵素”術語表示氟、氯、溴及块。 訂 線 以"保護基"術語表示如例如醯基、烷氧羰基、芳氧羰 基、甲矽烷基或亞胺衍生物之類的基團,使用其暫時封閉 g旎基的反應性。熟知的保護基係例如可用於保護胺基之 第三丁氧羰基、笮氧羰基、芴基甲氧羰基或二苯亞甲基’ 或用於保護.致基之低碳烷基·、点_三甲基甲矽烷基乙基及 /3 -三氣乙基-酯類》 單獨或與其它基團組合的”烷基,,術語表示丨至2〇個碳原子 之支化或直鏈單價飽和脂肪族烴基,以丨至16個碳原子較 佳,以1至10個碳原子更佳。可將烷基例如以由素羥基、 低碳烷氧基、低碳烷氧羰基、NH2、N (H,低碳烷基)及, 1328585 A7 ______B7 五、發明説明(c ) 或N (低碳烷基)2取代。 單獨或與其它基團組合的"低碳烷基„術語表示1至7個碳 原子之支鏈或直鏈單價烷基,以1至4個碳原子較佳。將該 術語進一步以如甲基'乙基、正丙基、異丙基、正丁基、 第二丁基' 第三丁基及類似物之類的基團為實例說明。低 碳烷基可以具有如結合先前說明的,,烷基"術語之取代樣 式。 ’’烷氧基"術語表示R|_〇_基…,其中R,係烷基。以"低碳烷 氧基"術語表示R1 - 〇-基,其中R,係低碳烷基。低碳烷氧基 的實例係例如甲氧基、乙氧基、丙氧基、異丙氧基、丁氧 基、異丁氧基及己氧基。 單獨或組合的"低碳埽基"術語表示含有烯烴鍵及多達8個 碳原子(以多達6個較佳,以多達4個特別佳)之直鏈或支鏈 烴殘基基。烯基的實例係是乙烯基、卜丙烯基、2_丙缔 基、異丙埽基、1-丁烯基、2_丁烯基、3_丁烯基及異丁烯 基。以2 -丙締基係較佳的實例。 以’’低碳烯氧基,,術語代表R"_〇基,其中R"係低碳烯 基。”低碳缔氧基”的實例係丁晞氧基,特別是丁·3•烯氧 基。 芳基術语係關於苯基或茶基,以苯基較佳,可將其視 需要以自素、經基、CN、CF3、Ν〇2、ΝΑ、N (H,低碳,境 基)、N(低碳烷基h、羧基' 胺羰基、低碳烷基、低碳烷氧 基' 芳基及/或芳氧基經單-或多·取代,特別是單·或二取 代。較佳的取代基係自素、Ch '低碳烷基及/或低碳烷氧 本纸張尺度適用中g @家標準(CNS) A4規格(21Q χ 297^爱) 心〇:>谷5 A7R 10 -5 - This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (2 R7 hydrogen or lower alkyl R8 hydrogen or lower alkyl R9 Hydrogen or lower alkyl R10 aryl: η system 1, 2 or 3; wherein the bond between the carbon atom <^ and the carbon atom Cbi is a single bond or a double bond of a carbon-carbon. Proliferation by peroxidase Peroxisome Proliferator Activated Receptors (PPAR's) are members of the nuclear hormone receptor superfamily, which regulate gene expression by ligand-activated transcription factors. Various subtypes have been identified and selected. These include PP AR a, PP AR /3 (also known as PPAR 5 ) and PPAR r. They exist as major isoforms of at least two PPAR 7. Although PPAR r 1 is expressed in most tissues that are ubiquitous, Almost only the long isoform PPAR τ 2 is found in fat cells. In contrast, PPAR α is preferentially expressed in the liver, kidney and heart. PPAR's regulate various body reactions, including glucose- and lipid-body balance, cell differentiation. , inflammatory response and cardiovascular events. Diabetes is a patient control A disease in which the ability to make a glucose value in the blood is impaired because the patient has lost some of the ability to respond appropriately to insulin. In type 2 diabetes (T2D), often referred to as non-supplementation-dependent diabetes mellitus (NIDDM) In all developed countries, 80-90% of all diabetic patients suffer from it, and the island of Lang's in the pancreas still produces insulin. However, the target is, the main muscle, liver and fat tissue will show A cumbersome anti-skin stimulating effect and compensates for the body by producing non-physiologically high insulin values. However, in the later stages of the disease, insulin secretion is reduced due to pancreatic depletion _ R - _ This paper scale applies China National Standard (CNS) A4 Specification (210X 297 mm) 1328585 A7 . B7__ V. Invention Description ( ) 3 ' Low. In addition, T2D is a metabolic cardiovascular disease syndrome. Among them, it is related to Ding 2 D. The comorbidities are insulin resistance, dyslipidemia, hypertension, vascular endothelial function abnormalities, and inflammatory atherosclerosis. The current first-line treatment for diabetes usually involves a low-fat- and low-glucose diet and exercise. The progress of the disease has eased 'But the progress of the disease has become a need for treatment with hypoglycemic drugs, such as 'sulfonate urea or YE Dexiang. A promising new type of drug has been introduced to re-sensitize the patient's own insulin (insulin sensitizer) ), in order to reverse the amount of blood glucose and triglyceride to normal, and thus abolish or at least reduce the demand for exogenous insulin. Pioglitazone (ActosTM) and Josigliazone (rosiglitazone) ( AvandiaTM) belongs to PPAR r ·activator. It is a type of thiazolidinedione (TZD) and has been approved by many countries as the first representative drug for NIDDM. However, these compounds suffer from side effects, including rare, but severe hepatotoxins (such as the experience of troglitazone) and cause weight gain in humans. Therefore, there is an urgent need for new, better and more effective NIDDM treatments. Recent studies have provided evidence that the co-promoting action of ppARa and PPAR 7 may lead to evidence that the compound has enhanced therapeutic potential, namely improved lipid profile effects with positive glucose and valerin values (Keller and (Keller) Wahli: Trends Endocrin. Metab. 1993, 4:291-296, Macdonald and Lane: Current Biology v〇l.5 pp 618-621 (1995)) - The novel compound of the present invention goes beyond the skill Known compounds, because they combine and simultaneously and very effectively activate both PPAr α and ppar 。. Therefore, the anti-glycemic effect of these compounds combined with PPART activation is applicable to the Chinese National Standard (CNS) Α4 specification. (210X 297 mm) 1328585 A7 B7 V. Description of the invention (should be associated with PPAR 〇: activation of anti-lipidemia. The result will reduce blood glucose and adenosine (= insulin sensitivity), reduce triglyceride and increase HDL cholesterol (= improved lipid profile). In addition, these compounds can also lower LDL cholesterol, increase blood pressure and fight inflammatory atherosclerosis. Because of the common agonist pursuit of PPAR α and PPAR 7 The multifaceted nature of the 2D disease syndrome is expected to have enhanced therapeutic potential compared to compounds known in the art. The compounds of the present invention exhibit improved pharmacological properties as compared to known compounds. There are other indications, which are exemplified and defined by the definitions set forth below to illustrate the meaning and scope of the various terms of the invention. In this specification, the use of "low carbon," terminology represents from 丨 to 7 carbon atoms. The group 'preferably has 1 to 4 carbon atoms. The term "halogen" means fluorine, chlorine, bromine and a block. The order line is expressed in terms of "protecting group" such as, for example, a mercapto group, an alkoxycarbonyl group, an aryloxy group. a group such as a carbonyl group, a methoxyalkyl group or an imine derivative, which is used to temporarily block the reactivity of the g thiol group. A well-known protecting group can be used, for example, to protect the amine group, the third butoxycarbonyl group, the fluorenyloxy group, the hydrazine. Methoxycarbonyl or dibenzylidene' or a lower alkyl group for use in protecting the group, a p-trimethylformamidoethyl group and/or a tris-ethyl-ethyl ester, alone or in combination with Other group combinations of "alkyl," A branched or linear monovalent saturated aliphatic hydrocarbon group having from 2 to 5 carbon atoms, preferably from 16 to 16 carbon atoms, more preferably from 1 to 10 carbon atoms, and the alkyl group may be, for example, a hydroxyl group. Lower alkoxy, lower alkoxycarbonyl, NH2, N (H, lower alkyl) and 1,328585 A7 ______B7 V. Inventive description (c) or N (lower alkyl) 2 substituted. Separately or in combination with others The "lower alkyl" term of the group combination means a branched or straight-chain monovalent alkyl group of 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. The term is further illustrated by a group such as methyl 'ethyl, n-propyl, isopropyl, n-butyl, t-butyl 't-butyl and the like. The lower alkyl group may have a substitution pattern of the alkyl group " as described in connection with the previously stated. The term 'alkoxy' refers to R|_〇_ group..., wherein R is an alkyl group. The term "lower alkoxy" refers to R1 - fluorenyl, wherein R is lower alkyl. Examples of the lower alkoxy group are, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group and a hexyloxy group. The term "low carbon thiol", alone or in combination, means a straight or branched hydrocarbon residue containing an olefinic bond and up to 8 carbon atoms (up to 6 preferably up to 4 particularly preferred). base. Examples of the alkenyl group are a vinyl group, a propylene group, a 2-propyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group and an isobutenyl group. A preferred example is 2-ethyl-propyl group. By ''lower carbyloxy,' the term stands for R" hydrazino, wherein R" is a lower olefin. An example of a "lower carbon epoxide group" is a butoxy group, especially a butyl 3 oxy group. The aryl term is phenyl or tea based, preferably phenyl, which can be self-primed, trans-based, CN, CF3, Ν〇2, ΝΑ, N (H, low carbon, environmental). , N (lower alkyl h, carboxy 'amine carbonyl, lower alkyl, lower alkoxy ' aryl and / or aryloxy group by mono- or poly-, especially mono- or di-substituted. Good substituents are self-priming, Ch 'lower alkyl and/or lower alkoxylated. This paper is suitable for use in the g @家标准(CNS) A4 specification (21Q χ 297^爱) 心〇:>谷5 A7
B7 基。 以_芳基"術語表示芳族5 ·或6-員環,其可以包含丨、2 或3個選自氮、氧及/或硫之原子,如咬喃基、吡啶基、1, 、1,3-及丨,4-二嗉基、嘧嗯基 '異呤唑基、σ号唑基、咪唑基 或吡咯基。以"雜芳基"術語進—步表示含有兩個5_或6-員 衣之雙%系芳族基團,其中丨或2個環可以包括丨、2或3個選 自氮、氧及/或硫之原子,如例如啕哚或喹啉基;或部份氫 化之雙%系芳族基團,如例如吲哚滿基。雜芳基可以具有 如結合先W說明的”芳基•,術語之取代樣式。較佳的雜芳基 係例如嘍嗯基及呋喃基,可將其視需要如上述方式取代, 以鹵素、CFS、低碳烷基及/或低碳烷氧基較佳。 以•'在醫藥上可接受之鹽類"術語包含具有有機酸(如氫氣 酸' 氫溴酸、硝酸、硫酸、磷酸、檸檬酸、甲酸、馬來 骹、醋酸、富馬酸、琥珀酸、酒石酸、甲烷磺酸、對-甲苯 %酸及類似物)之式(I)化合物的鹽類,其對活的有機體沒 有母性。較佳的具有酸的鹽類係甲酸鹽、馬來酸鹽、檸檬 酸鹽、氫氣酸鹽、氫溴酸鹽及曱烷磺酸鹽類。進一步將式j 化合物以在醫藥上可接受之鹼類形成鹽類,如以鹼鹽類(例 如Na-及Κ-鹽)、鹼土鹽類(例如,Ca及Mg•鹽)及按或經 取代之銨鹽類(如例如三甲基銨鹽)。"在醫藥上可接受之鹽 類"術語也關於這些鹽類。_ 也可將式I化合物溶合,即水合。以製造過程期間可以完 成溶合,或例如由於初期無水的式丨化合物的收濕特性而發 生溶合(水合)。在醫藥上可接受之鹽類術語也包括在醫藥 —-- *10-本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) ΓΙ328585 Α7B7 base. The term "aryl" refers to an aromatic 5 or 6-membered ring which may contain fluorene, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur, such as a thiol group, a pyridyl group, 1, 1,3- and oxime, 4-didecyl, pyrimido-isoxazolyl, σ-zolyl, imidazolyl or pyrrolyl. The "heteroaryl" terminology refers to a double % aromatic group containing two 5 or 6-membered garments, wherein the or two rings may include hydrazine, 2 or 3 selected from nitrogen, An atom of oxygen and/or sulfur, such as, for example, an anthracene or a quinolinyl group; or a partially hydrogenated double % aromatic group such as, for example, an indanyl group. The heteroaryl group may have the substitution pattern of the term "aryl group" as described in conjunction with the above, and the preferred heteroaryl group such as fluorenyl and furyl groups may be substituted as described above, with halogen, CFS. , a lower alkyl group and/or a lower alkoxy group is preferred. The term 'medicinally acceptable salt' includes organic acids (eg hydrogen acid 'hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, lemon). Salts of the compounds of formula (I) of acids, formic acid, maleic acid, acetic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluene acid and the like, which have no maternity to living organisms. Preferred are acid salts of formate, maleate, citrate, hydrochloride, hydrobromide and decane sulfonate. Further compounds of formula j are pharmaceutically acceptable The base forms salts such as alkali salts (for example, Na- and sulfonium salts), alkaline earth salts (for example, Ca and Mg• salts), and substituted or substituted ammonium salts (such as, for example, trimethylammonium salts). ). "The pharmaceutically acceptable salt " terminology is also about these salts. _ can also be combined with Formula I Hydration, ie hydration. The solvation can be completed during the manufacturing process, or hydrated (hydrated), for example due to the hygroscopic nature of the initially anhydrous hydrazine compound. The pharmaceutically acceptable salt term is also included in the medicine. -- *10- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) ΓΙ328585 Α7
1328585 A7 B7 五、發明説明(8 ) 其中 R1 係芳基或雜芳基,_ R2、R3及R4係彼此獨立是氫、鹵素、低碳烷基或低碳烷氧 基,其中R2、R3及R4的至少其中之一不是氫,或 將R3與R4彼此結合,和與其附著的碳原子一起形成 環,並且R3 及R4—起是-CH=CH-S-、-S-CH=CH-、-CH=CH-0- 、 -0-CH=CH- 、-CH=CH-CH=CH-或-(CH2)3-5-,以及R2係如以上的定義, R5 係低碳烷氧基或 -N Η 〇1328585 A7 B7 V. INSTRUCTION DESCRIPTION (8) wherein R1 is an aryl or heteroaryl group, and _R2, R3 and R4 are independently of each other hydrogen, halogen, lower alkyl or lower alkoxy, wherein R2, R3 and At least one of R4 is not hydrogen, or R3 and R4 are bonded to each other, and together with the carbon atom to which they are attached, form a ring, and R3 and R4 are -CH=CH-S-, -S-CH=CH-, -CH=CH-0-, -0-CH=CH-, -CH=CH-CH=CH- or -(CH2)3-5-, and R2 is as defined above, R5 is lower alkoxy Or -N Η 〇
及其醫藥上可接受之鹽類。 在特別佳的具體實施例中,本發明係關於以式(Ibb)為特 徵之式(I)化合物And pharmaceutically acceptable salts thereof. In a particularly preferred embodiment, the invention relates to a compound of formula (I) characterized by formula (Ibb)
(Ibb) -12 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1328585(Ibb) -12 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1328585
其中R 、R、R3、R4及R5係如以上的定義,及其醫藥上可 接文之鹽類。根據Cahn-Ingold-Prel〇g_ Convention ,式(11?13) 代表非對稱性碳原子C *具有S組態。 此外’以如以上定義其中R丨係視需要以1至3個獨立選自 由鹵素、CF3、低碳烷基及低碳烷氧基所構成的群組之取代 基取代的苯基之化合物較佳,以未經取代之苯基特別佳。 而且,以如以上定義其中R丨係視需要以i至3個獨立選自由 鹵素、CF;、低碳烷基及低碳烷氧基所構成的群組之取代基 取代的4嗯基之化合物較佳,以未經取代之π塞嗯基特別 佳β 也以其中將R3與R4彼此結合,和與其附著的碳原子一起 形成環’並且R3及R4一起是_CH=CH-CH=CH-,以及R2及 R係虱之式(I)化合物較佳β這些化合物因此包含以下部份Wherein R, R, R3, R4 and R5 are as defined above, and a pharmaceutically acceptable salt thereof. According to Cahn-Ingold-Prel〇g_Convention, the formula (11?13) represents an asymmetric carbon atom C* with an S configuration. Further, a compound having a phenyl group as defined above wherein R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, CF3, lower alkyl group and lower alkoxy group is preferred. It is especially good with an unsubstituted phenyl group. Further, a compound of the formula wherein R is substituted with i to 3 substituents independently selected from the group consisting of halogen, CF;, lower alkyl and lower alkoxy as defined above Preferably, the unsubstituted π thiol group is particularly preferably β in which R 3 and R 4 are bonded to each other, and together with the carbon atom to which they are attached, form a ring ' and R 3 and R 4 together are _CH=CH-CH=CH- And the compounds of formula (I) of R2 and R are preferably β. These compounds therefore comprise the following
裝 訂Binding
線 再者,其中將R3與R4彼此結合,和與其附著的碳原子一 起形成環,並且R3及R4—起是_CH=CH-S-,以及R2及R6係 氫之式(I)化合物較佳。這些化合物因此包含以下部份 —^— ------ 13 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) j 『1328585 A7Further, wherein R3 and R4 are bonded to each other, together with the carbon atom to which they are attached, form a ring, and R3 and R4 together are _CH=CH-S-, and R2 and R6 are hydrogen compounds of formula (I). good. These compounds therefore contain the following parts —^— ------ 13 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) j 『1328585 A7
裝 此外^其巾r2、r3&r4係彼此獨立是氫或低碳燒基之 如以上定義的化合物較佳,以那些其中R2及R3係甲基,〆 及R4係ft的化合物特別佳。其-它特別佳的式⑴化合物係: 些其中R2係甲基,以及r3&r4係氫的化合物。更特別佳的 式(I)化合物係那些其中R4係甲基,以及尺2及尺3係氫的化合 物。以那些其中R6係甲基的式I化合物特別佳。 。 訂 以其中R係低碳烷氧基之式(〖)化合物代表本發明較佳的 具體實施例,以那些其中R5係甲氧基、乙氧基 '丙氧基、 丁氧基或己氧基之式(1)化合物代表本發明特別佳的具體實 施例。其它較佳的化合物係那些其中R5係Further, the towels r2, r3 & r4 are each independently hydrogen or a lower carbon group. The compound as defined above is preferred, and those wherein R2 and R3 are methyl, ruthenium and R4 are particularly preferred. It is a particularly preferred compound of the formula (1): those in which R2 is a methyl group and r3&r4 is a hydrogen. More particularly preferred compounds of formula (I) are those wherein R4 is methyl, and quaternary 2 and amp 3 are hydrogen. Those compounds of formula I in which the R6 is methyl are particularly preferred. . The formula (") wherein R is a lower alkoxy group represents a preferred embodiment of the invention, wherein those wherein R5 is methoxy, ethoxy 'propoxy, butoxy or hexyloxy The compound of formula (1) represents a particularly preferred embodiment of the invention. Other preferred compounds are those in which the R5 system
以根據本發明的式I化合物及其醫藥上可接受之鹽類較 佳。以式I化合物特別佳。 本發明較佳的觀點係根據式〗的化合物,其中 的化合物。 · 本纸張尺度適財目s家標準(CNS) Α4規格(21GX 297公爱) A7 -— _— B7 五、發明説明(~~) R2、R3及R4係彼,獨立是氫、齒素、低碳烷基或低碳烷氧 基’其中R、R3及IV»的至少其中之一不是氫或 將R與R彼此結合,和與其附著的碳原子_起形成 環,並且R3及R4-起是_(:]^=(;^冬、^心^ ' -CH=CH-°- ' -〇-CH=CH- ^ -CH=CH-CH=CH- 或-(CH2)3,5·,以及其中尺2係如以上的定義; R5 係低碳烷氧基或The compound of the formula I according to the invention and its pharmaceutically acceptable salts are preferred. Compounds of formula I are especially preferred. A preferred aspect of the invention is a compound according to the formula, wherein the compound. · This paper scale is suitable for the standard of financial assets (CNS) Α 4 specifications (21GX 297 public) A7 - _ - B7 V. Invention description (~~) R2, R3 and R4 are independent, hydrogen and fang a lower alkyl group or a lower alkoxy group wherein at least one of R, R3 and IV» is not hydrogen or R and R are bonded to each other, and a carbon atom attached thereto forms a ring, and R3 and R4 It is _(:]^=(;^冬,^心^ ' -CH=CH-°- ' -〇-CH=CH- ^ -CH=CH-CH=CH- or -(CH2)3,5 ·, and where the rule 2 is as defined above; R5 is lower alkoxy or
R6 是氫; R7 是甲基; η 是2 ; 其中在竣原子(:3與碳原子cbt間的鍵係碳碳單鍵; 及其醫藥上可接受之鹽類。 以其中Ri係視需要以一或多個(以1至3個較佳)獨立選自 三氟曱基、.芳基、烷基 '烷氧基及函素之取代基取代的苯 基或噻嗯基之式I化合物較佳。以其中Ri係苯基或以1至3個 獨立選自燒氧基及三氟甲基之取代基取代的苯基之根據 的化合物特別佳。 本發明另一個較佳的觀點係式I化合物, 其中R2、R3、R4及R6係彼此獨立是氫、羥基、低碳烷基或 ____- 15 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585 A7 B7 12 五、發明説明( 低碳烷氧基,其中R2、R3、R4及R0的至少其中之一 不是氫,或 將R3與R4彼此結合’和與其附著的碳原子―起形成 環’並且 R3 及 R4—起是_(:11=〇^_3 、_3^=^^- CH CH 〇、_0-CH=CH-或-CH=CH-CH=CH-, 以及其中R2及R6係如以上的定義。 以其中r2、r3、Rm系彼此獨立是氫、羥基 '低碳烷基 或低碳烷氧基,及其中汉2、Ri、“及尺6的至少其中之一不 是氫之根據^1的化合物特別佳”x其中將r3#r4彼此結 合,和與附著的碳原予—起形成環,並且R3及R4—起是 -CH=CH-S-、_S_CH=CH.、_CH=CH 〇、_〇 ch=ch•或 -CH=CH-CH=CH·,以及其tR\R6係如以上的定義之式【 化合物更特別佳。以那㈣係氫的式!化合物同樣特別佳。. 以其中R2及R6係氫,以及^r3#r4彼此結合,和與 著的碳原子一起形成環,並且…及尺4—起是_ch=ch -S-CH^CH-之根據式丨的化合物更佳。 -或 以其中R3W 一起是之报據式!的化合物特別 佳。這些化合物因此具有以下的化學式R6 is hydrogen; R7 is methyl; η is 2; wherein a bond between a ruthenium atom (:3 and a carbon atom cbt is a single carbon-carbon bond; and a pharmaceutically acceptable salt thereof) One or more (1 to 3 preferred) compounds of formula I substituted independently of a phenyl or thiol group substituted with a substituent selected from the group consisting of a trifluoromethyl, an aryl, an alkyl 'alkoxy and a functional group Preferably, the compound is based on a compound wherein Ri is a phenyl group or a phenyl group substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy groups and trifluoromethyl groups. Another preferred aspect of the invention is Formula I a compound in which R2, R3, R4 and R6 are independently of each other hydrogen, hydroxy, lower alkyl or ____-15 - The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7 12 5. Description of the invention (lower alkoxy, wherein at least one of R2, R3, R4 and R0 is not hydrogen, or R3 and R4 are bonded to each other' and the carbon atom to which they are attached - forms a ring' and R3 and R4 The starting point is _(:11=〇^_3, _3^=^^-CH CH 〇, _0-CH=CH- or -CH=CH-CH=CH-, and wherein R2 and R6 are as defined above.Wherein r2, r3, and Rm are each independently hydrogen, hydroxy 'lower alkyl or lower alkoxy, and at least one of the intermediates of the Chinese 2, Ri, and the ruler 6 is not hydrogen.佳"x where r3#r4 is bonded to each other, and forms a ring with the attached carbonogen, and R3 and R4 are -CH=CH-S-, _S_CH=CH., _CH=CH 〇, _〇 Ch=ch• or -CH=CH-CH=CH·, and its tR\R6 is as defined above. [The compound is more particularly preferred. The compound of the formula (4) is hydrogen. The compound is also particularly preferred. And R6 is hydrogen, and ^r3#r4 is bonded to each other, and forms a ring together with the carbon atom, and ... and the ruler 4 is _ch=ch -S-CH^CH-, and the compound according to the formula is better. - or a compound in which R3W is a report together! These compounds therefore have the following chemical formula
本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、 發明説明(13 本發明另一個較佳的觀點係根據式j的化合物,其中R5係 低碳烷氧基或This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of the invention (13) Another preferred aspect of the invention is a compound according to formula j, wherein R5 is a lower alkane Oxyl or
.以其中R5係低碳烷氧基的那-些式丨化合物特別佳。以其中 R5係曱氧基、乙氧基或丙氧基之根據式化合物更特別 佳。 本發明進一步較佳的觀點係式〗化合物,其中R7係烷基。 以其中R係甲基之根據式〗的那些化合物特別佳。 以其中R8係低碳垸基,特別是甲基的式“匕合物也較佳。 以其中R9係氫的式】化合物也較佳。以其中r9係低碳院基 的式I化合物更佳。 以其中R係、苯基或以低碳燒基取代之笨基的幻化合物更 佳。以其中r1g係苯基的那些合物特別佳。 以其中…的式ί化合物較佳。以其中〇是2或3的式!化合 物更佳。以其中η是2的那些式!化合物特別佳。 式Η匕合物可以包括許多不對稱中心,並可以旋光性純對 U例如外消旋物)、旋光 性純非對陕異構物、非對晚異構物的;昆合 外消旋物或非對映異構外消旋物的混合二 如外消旋物的解離作用、不對稱合成作用或不對稱色廣^ 14五、 發明說明 A7 B7 離,〆 I (以對掌性吸附劑或溶離劑之色層分離法 先活性物形式。 忖從 以 碳 以 。不對稱碳原予,,(C*)代表具有4個不同的取代基之 根據 Cahn-Ingold-Prelog· Convention ,不對稱碳原子可 具有"R"或"S"組態。 以式(la)為特徵之式(I)的對掌性化合物較佳 R1- N-The compounds of the formula wherein R5 is a lower alkoxy group are particularly preferred. A compound according to the formula wherein R5 is a decyloxy group, an ethoxy group or a propoxy group is more preferred. A further preferred aspect of the invention is a compound wherein R7 is alkyl. Those compounds in which the R-form methyl group is based on the formula are particularly preferred. The compound of the formula wherein R8 is a low carbon fluorenyl group, particularly a methyl group, is also preferred. The compound of the formula wherein R9 is hydrogen is also preferred. The compound of formula I wherein r9 is a low carbon compound is preferred. It is more preferable to use a compound having a R system, a phenyl group or a stupid group substituted with a low carbon group. Among them, those having a phenyl group of phenyl group are particularly preferred. Among them, a compound of the formula ί is preferred. It is a formula of 2 or 3. The compound is more preferable. Those compounds in which η is 2 are particularly preferred. The compound of the formula may include many asymmetric centers, and may be optically pure to U such as a racemate, Optically pure non-parallel isomers, non-isomeromers; a mixture of quinone racemates or diastereomeric racemates, such as dissociation of racemates, asymmetric synthesis Or asymmetry of color ^ 14 5, invention description A7 B7 away, 〆I (in the form of the active layer for the separation of palmar adsorbents or leaching agents. 忖 from carbon to asymmetric carbon, (C*) stands for Cahn-Ingold-Prelog Convention with 4 different substituents, asymmetric carbon atoms Has a "R" or "S" configuration. The palm-like compound of formula (I) characterized by formula (la) is preferred R1-N-
CT -(CH2)CT -(CH2)
(la) = RI、r2、r3、r4、r5、r6Wwui a)代表不對稱碳原子c*具有s組態。 》 R1- 〇-(la) = RI, r2, r3, r4, r5, r6Wwui a) represents an asymmetric carbon atom c* with s configuration. 》 R1- 〇-
(la) 以其中 R1、R2、R3、r4、r6、 5 R R及n係如以上的定義及並 中R代表低碳職基之根據式(Ia)的化合物特別佳。- 以其中在碳原子匸3與硬; 又你于C之間的鍵係碳碳雙鍵(根據 -18 - 本纸張尺度適种国國家標準(CNS) A4規格 1328585 A7 B7 五、發明説明(15 )(la) A compound according to formula (Ia) wherein R1, R2, R3, r4, r6, 5 R R and n are as defined above and wherein R represents a lower carbon group is particularly preferred. - a carbon-carbon double bond in which the carbon atom is 匸3 and hard; and you are between C (according to -18 - this paper size is suitable for national standards (CNS) A4 specification 13258585 A7 B7 V. Description of invention (15)
Cahn- Ingold-Prelog-Convention 的或 E-或 Z-組態)之式1化合 物較佳。因此,那些化合物具有以下化學式(Ic)Formula 1 compounds of Cahn-Ingold-Prelog-Convention or E- or Z-configuration are preferred. Therefore, those compounds have the following chemical formula (Ic)
以E-組態较佳。以Z-組態特·別佳.。 ·! k 再者’以其中在碳原子ca與碳原子cb之間的鍵係碳碳單 鍵之式I化合物特別佳。因此,那些化合物具有以下化學式 (Id)It is better to use E-configuration. With Z-configuration special. · k Further is particularly preferred as the compound of the formula I in which the bond between the carbon atom ca and the carbon atom cb is a single bond of carbon. Therefore, those compounds have the following chemical formula (Id)
〇/\R7 R_ FT 訂〇/\R7 R_ FT order
線 較佳的通式(1)化合物係那些選自以下群組的化合物: 1. 2 -甲氧基-3-{4-[2-(5·甲基-2-苯基-崎唑-4-基)-乙氧 基]-苯并[b]嘍吩-7-基}_丙酸; 2. 2 -乙氧基- 3- {4-[2-(5 -甲基-2-苯基-°号〇生-4-基)-乙氧 基]-苯并[b]〇墓吩-7-基}-丙酸; 3. 3-{4-[2-(5 -甲基-2-苯基-崎唑-4-基)-乙氧基]-苯并 [15]"塞吩-7-基}-2-丙氧基_丙酸; 4 . 2 -丁氧基- 3- {4-[2-(5 -甲基-2-苯基-哼唑-4 -基)-乙氧 ---- - 19 -_______ 本紙張尺度適用中國國家標準(CNS) A4规格(210X 297公爱) 1328585 A7 B7 五、發明説明(16 ) 基]-年并[b]B塞吩-7-基}-丙自父, 5. 2 -異丁氧基- 3- {4-[2-(5 - T基-2-各基-°号β坐-4-基)-乙 氧基]-私并[b]pj吩-7-基}-丙酸; 6. 2 -己氧基-3-{4-[2-(5 -曱基-2-苯基-哼唑-4-基)-乙氧 基]-苯并[b]4吩-7-基}-丙酸; 7. 2 -曱氧基- 3- {4-[2-(5 -甲基-2-苯基-哼唑-4 -基)-乙氧 基]奈-1-基}_丙故> 8. 2 -乙氧基-3-{4-[2-(5 -甲-基-2-苯基-哼唑-4-基)-乙氧 基]-奈'-1-基}-丙@艾, 9. 3-{4-[2-(5 -甲基-2-苯基-吟唑-4-基)-乙氧基]-莕-l- 基} - 2 -丙氧基丙酸: 10. 2-丁氧基-3-{4-[2-(5 -甲基-2-、苯基-哼唑-4-基)-乙氧 基]-萘-1 -基}-丙酸: 11. (S)-2 -甲氧基-3-{4-[2-(5 -甲基-2-苯基-吟唑-4-基)-乙氧基]-苯并[b]嘍吩-7-基}-丙酸; 12. (S)-2 -乙氧基-3-{4-[2-(5 -甲基-2-苯基-呤唑-4-基)-乙氧基]-苯并[b]4吩-7-基}-丙酸; 13. (S)-2 -曱氧基-3-{4-[2-(5 -甲基-2-苯基-咩唑-4-基)-乙氣基]基}-丙酸; 14. (S)-2 -乙氧基-3-{4-[2-(5 -甲基-2-苯基-噚唑-4-基)-乙氧基]-各-1-基}-丙酸, 15· 2-(2-苯醯基-苯基胺基)-3-{4-[2-(5 -甲基-2-苯基-咩 唑-4 -基)-乙氧基]-莕-1 -基}-丙酸; 16. 2-(2 -苯醯基-苯基胺基)-3-{4-[2-(5 -甲基-2-苯基-呤 _ - 20 -__ 本故張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7Preferred compounds of the formula (1) are those selected from the group consisting of: 1. 2-Methoxy-3-{4-[2-(5.methyl-2-phenyl-s-zole- 4-yl)-ethoxy]-benzo[b]porphin-7-yl}-propionic acid; 2. 2-ethoxy-3-{4-[2-(5-methyl-2- Phenyl-[#]-4-yl)-ethoxy]-benzo[b]indole -7-yl}-propionic acid; 3. 3-{4-[2-(5-methyl) -2-phenyl-oxazol-4-yl)-ethoxy]-benzo[15]"cephen-7-yl}-2-propoxy-propionic acid; 4 . 2 -butoxy - 3- {4-[2-(5 -Methyl-2-phenyl-indazol-4-yl)-ethoxy---- - 19 -_______ This paper size applies to the Chinese National Standard (CNS) A4 specification. (210X 297 public) 1328585 A7 B7 V. Description of invention (16) Base]-year and [b]B thiophene-7-yl}-propyl from the father, 5. 2 -isobutoxy- 3- {4 -[2-(5-T-yl-2-yl-[beta]-S--4-yl)-ethoxy]-private [b]pj-phen-7-yl}-propionic acid; 6. 2 - Hexyloxy-3-{4-[2-(5-fluorenyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]4-phen-7-yl}-prop Acid; 7. 2-methoxyl-3-{4-[2-(5-methyl-2-phenyl-indazol-4-yl)-ethoxy]na-1-yl}-propyl > 8. 2-Ethoxy-3-{4-[2-(5-methyl-yl-2- Phenyl-oxazol-4-yl)-ethoxy]-naphtho-1-yl}-propane@艾, 9. 3-{4-[2-(5-methyl-2-phenyl-oxime) Zyridin-4-yl)-ethoxy]-indole-l-yl}-2-propoxypropionic acid: 10. 2-butoxy-3-{4-[2-(5-methyl-2) -, phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-propionic acid: 11. (S)-2-methoxy-3-{4-[2-(5 -methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]porphin-7-yl}-propionic acid; 12. (S)-2-ethoxy- 3-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]4-phen-7-yl}-propionic acid; (S)-2-indolyl-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethane group]-}-propionic acid; S)-2-ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-yl-1-yl}-propionic acid , 15· 2-(2-Benzyl-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-indazol-4-yl)-ethoxy]-荇-1 -yl}-propionic acid; 16. 2-(2-phenylhydrazino-phenylamino)-3-{4-[2-(5-methyl-2-phenyl-indole--20) -__ The national standard (CNS) A4 specification (210 X 297 mm) 1328585 A7
全-4-基)-乙氧基]_笨并[b]p塞吩·7·基卜丙酸; 17· 3-{3,)-二甲基·4_[2(5·甲基·2·苯基·呤唑_4·基卜乙 氧基]-笨基}-2 -乙氧基丙酸; H 2 -乙氧基_3_{3_曱基_4_[2_(5 -甲基_2_苯基-咩唑·4· 基)·乙氧基]-笨基}_丙酸; 19. 2-(2-笨醯基_苯基胺基)_3_{3,5_二甲基_4 [2 (5甲 基-2-苯基·巧唑·4_基)·乙氧基]-苯基卜丙酸: 2〇. 2-(2-苯醯基-苯基胺基)--3-{3.-甲基-4-[2-(5 -甲基·2_ 苯基号唑_4·基)_乙氧基]-苯基}-丙酸; 21. (S)-2-甲氧基·3_(4_{2·[5_甲基_2 (4三氣甲基苯基) 巧峻-4-基]乙氧基}莕·丨-基)丙酸; 22. (S)-2-乙氧基·3_(4_{2·[5•甲基·2·(4_三氟甲基苯基) 吒唑-4-基]乙氧基}^-i•基)丙酸; 23. (S)-2 -甲氧基_3·(4_{2[5甲基_2(4三氟甲基苯基) 喝唑-4-基]乙氧基}苯并[b](>塞吩_7•基)丙酸; 24. =)-2-乙氧基_3·(4·{2_[5_甲基_2 (4三氟甲基苯基) °可唑-4-基]乙氧基}苯并[b]嘍吩·7基)丙酸; 25. (S)-3-{4-[2-(2·聯苯-4-基_5_甲基呤唑_4•基)乙氧基] 某· 1 -基.} - 2-乙氧基丙酸; 26. (S)-3-{4-[2-(2-聯苯·4·基·5·甲基吟唑_4-基)乙氧基] 茶-1-基}-2 -丙氧基丙酸; 27. (S)-3-{4-[2-(2-聯苯-4_基·5·甲基咩唑_4•基)乙氧基] 苯并[b]-塞吩-7 -基丨-2·丙氧基丙酸; 8· (S) 3 {4-[2-(2 -聯苯_4 -基-5·甲基°号吃-4-基)乙氧基]All-4-yl)-ethoxy]-p- and [b]p-sept.7·kibpropionic acid; 17·3-{3,)-dimethyl·4_[2(5·methyl· 2·Phenyl·carbazole_4·yl ethoxy]-styl}-2-ethoxypropionic acid; H 2 -ethoxy _3_{3_ fluorenyl _4_[2_(5-A Base 2_phenyl-carbazole·4·yl)·ethoxy]-styl}_propionic acid; 19. 2-(2-stupyl-phenylamino)_3_{3,5_two Methyl _4 [2 (5-methyl-2-phenyl-pyrazole·4-yl)·ethoxy]-phenyl-propionic acid: 2〇. 2-(2-Benzyl-phenylamine ))--3-{3.-Methyl-4-[2-(5-methyl.2_phenyloxazol-4-yl)-ethoxy]-phenyl}-propionic acid; S)-2-methoxy·3_(4_{2·[5_methyl_2(4trimethylmethylphenyl) qiaojun-4-yl]ethoxy}anthracene-yl)propionic acid ; (S)-2-Ethoxy·3_(4_{2·[5•methyl·2·(4_trifluoromethylphenyl)oxazol-4-yl]ethoxy}^- i•yl)propionic acid; 23. (S)-2-methoxy_3·(4_{2[5methyl_2(4)trifluoromethylphenyl)oxazol-4-yl]ethoxylate }Benzo[b](>cetin-7(7)-propionic acid; 24. =)-2-ethoxy-3-3((4·{2_[5_methyl_2(4trifluoromethyl) Phenyl) °oxazol-4-yl]ethoxy}benzo[b]porphin-7-propionic acid 25. (S)-3-{4-[2-(2·Biphenyl-4-yl-5-methylcarbazole_4•yl)ethoxy] +1-yl.} - 2-B Oxypropionic acid; 26. (S)-3-{4-[2-(2-biphenyl·4·yl·5·methylcarbazole-4-yl)ethoxy]tea-1-yl} -2 -propoxypropionic acid; 27. (S)-3-{4-[2-(2-biphenyl-4-yl·5·methylcarbazole-4)ethoxy]benzo [b]-cerebral-7-ylindole-2·propoxypropionic acid; 8·(S) 3 {4-[2-(2-diphenyl-4-yl-5-methyl) 4-yl)ethoxy]
1328585 A7 ______B7 五、發明説明(18 ) 莕-1 -基} - 2 -甲氧基丙酸: 29. (S)-3- {4-[2-(2-聯苯-4-基-5 -甲基。号唑-4-基)乙氧基] 莕-1-基}-2-(2,2,2-三氟乙氧基)丙酸; 3〇_ (S)-3-{4-[2-(2-聯苯-4-基-5 -甲基呤唑-4·基)乙氧基] 苯并[b]〇塞吩-7-基}-2 -乙氧基丙酸; 31· (S)-3-(4-{2-[2-(4-異丙基苯基)-5 -甲基呤唑-4-基]乙 氧基}苯并[b]嘍吩-7-基)-2 -甲氧基丙酸; 32. (S)-3-(4-{2-[2-(4-異丙朞苯基)-5 -甲基哼唑-4-基]乙 氧基}笨并[b]嘍吩-7-基)-2-(2,2,2 -三氟乙氧基)丙 酸; 33. (S)-3-(4-{2-[2-(3,5-二甲基苯基)-5 -甲基咩唑-4-基] 乙氧基}笨并[b μ塞吩-7-基)-2 -甲氧基丙酸: 34. (S)-3-(4-{2-[2-(3,5-二曱氧基苯基)-5 -曱基咩唑-4-基]乙氧基}苯并[b]。塞吩-7-基)-2 -甲氧基丙酸; 35. (S)-3-(4-{2-[2-(3,5-二甲基苯基)-5-甲基。号唑-4-基] 乙乳基}^-1-基)-2 -甲氧基丙酸; 36. [外消旋性]-3 - (4 - { 2 - [ 2 - (3,5 -二氣苯基)-5 -甲基噚唑-4 -基]乙氧基}苯并[b]噻吩-7-基)-2 -甲氧基丙酸; 37. [外消旋.性]-3 - (4 _{ 2 - [ 2 - ( 3 , 5 -二氟苯基)-5 -甲基呤唑· 4 -基]乙氧基}苯并[b]嘍吩-7-基)·2 -甲氧基丙酸; 38_ [外消旋性]-2 - 丁氧基- 3-(4 - {2-[2-(3,5 -二氟苯基)· 5 -甲基哼唑-4-基]乙氧基}苯并[b]噻吩-7-基)丙酸; 39.[外消旋性]-2 - 丁氧基-3 - ( 4 - { 2 - [ 2 - ( 3,5 -二甲氧基苯 基)-5 -甲基噚唑-4 -基]乙氧基}笨并[b]嘧吩-7 -基)丙 ___-22 -__ ^纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明( 酸; 40. [外消旋性]-2 - 丁氧基_ 3 - (4 - { 2 - [ 2 - ( 3,5 -二甲基苯基)· 5 -甲基。号唆-4-基]乙氧基}苯幷[b]e塞吩-7_基)丙酸; 41. [外消旋性]-3 - ( 4 - { 2 - [ 2 - ( 3,5 -二氟苯基)-5 -甲基噚唑- 4- 基]乙氧基}苯并[b]P塞吩-7-基)_2_乙氧基丙酸; 42. [外消旋性]-2 -甲氧基-3 - (4 - { 3 - [ 2 - (4 -甲氧基苯基)- 5- 甲基呤吐-4-基]丙氧基丙酸; 43. [外消旋性]_ 3 - ( 4 - { 3 - [ 2 乂4 -氯苯基)· 5 _甲基哼唑-4 _ 基]丙氧基}莕-1-基)-2 -甲氧基丙酸; 44. [外消旋性]-2 -甲氧基-3 - (4 - { 3 - [5 -甲基-2 - (4 -三氟甲 基苯基)17亏哇-4 -基]丙氧基}苯并[b]e塞吩_7-基)丙酸; 45. [外消旋性]-2 -乙氧基-3 - (4 - { 3_- [ 5 -甲基-2 -(4 -三氟甲 基苯基)。号吐-4-基]丙氧基}笨并[b]噻吩_7-基)丙酸; 46. [外消旋性]-3 - ( 4 - { 3 - [ 2 - (4 -氯苯基)_ 5 -甲基崎唑_ 4 _ 基]丙氧基}萬-1-基)-2 -異丙氧基丙酸: 47_ (S)-2 -甲氧基-3-(4-{3-[5 -甲基_2_(4·三氟甲基笨基) 亏0主-4 -基]丙氣基基)丙酸; 48. [外消旋性]-3-(4 - { 3-[2-(4 -氣苯基卜5_甲基„号唑_4. 基]丙氧.基}表并[b] 4吩-7-基)·2_甲氧基丙酸; 49. [外消旋性]-2 -乙氧基-3-(4-{3-[2-(4 -甲氧基苯基)· 5-甲基》号唑-4-基]丙氧-基}萘-丨_基)丙酸; 〕〇.[外消旋性]-2 -乙氧基-3-(4-{3_[2-(4_異丙基苯基卜 5-甲基呤唑-4-基]丙氧基}莕-丨·基)丙酸; 51.[外消旋性]-3 - ( 4 - { 3 - [ 2 - ( 4 -氣苯基)_ 5 _甲基呤唑_ 4 _ -23 -1328585 A7 ______B7 V. INSTRUCTIONS (18) 荇-1 -yl} - 2 -methoxypropionic acid: 29. (S)-3- {4-[2-(2-biphenyl-4-yl-5) -methyl.oxazol-4-yl)ethoxy]indol-1-yl}-2-(2,2,2-trifluoroethoxy)propionic acid; 3〇_ (S)-3-{ 4-[2-(2-biphenyl-4-yl-5-methyloxazol-4yl)ethoxy]benzo[b]dexh-7-yl}-2-ethoxypropane Acid; 31· (S)-3-(4-{2-[2-(4-isopropylphenyl)-5-methyloxazol-4-yl]ethoxy}benzo[b]pyrene Benz-7-yl)-2-methoxypropionic acid; 32. (S)-3-(4-{2-[2-(4-isopropylphenyl)-5-methylcarbazole-4 -yl]ethoxy} benzo[b] porphin-7-yl)-2-(2,2,2-trifluoroethoxy)propionic acid; 33. (S)-3-(4-{ 2-[2-(3,5-Dimethylphenyl)-5-methyloxazol-4-yl]ethoxy}bromo[b μcephen-7-yl)-2-methoxy Propionic acid: 34. (S)-3-(4-{2-[2-(3,5-Dimethoxyphenyl)-5-indolyloxazol-4-yl]ethoxy}benzo [b].cephen-7-yl)-2-methoxypropionic acid; 35. (S)-3-(4-{2-[2-(3,5-dimethylphenyl)-5 -methyl. oxazol-4-yl]ethyl lactyl}^-1-yl)-2-methoxypropionic acid; 36. [racemic]-3 - (4 - { 2 - [ 2 - (3,5 - two gas (5)-methyl-oxazol-4-yl]ethoxy}benzo[b]thiophen-7-yl)-2-methoxypropionic acid; 37. [racemic.]-3 (4 _{ 2 - [ 2 - ( 3 , 5 -difluorophenyl)-5 -methylcarbazole · 4 -yl]ethoxy}benzo[b]porphin-7-yl)·2 - Methoxypropionic acid; 38_ [racemic]-2-butoxy-3-(4-(2-[2-(3,5-difluorophenyl))-5-methylcarbazole-4 -yl]ethoxy}benzo[b]thiophen-7-yl)propanoic acid; 39. [racemic]-2 -butoxy-3 - ( 4 - { 2 - [ 2 - ( 3, 5-Dimethoxyphenyl)-5-methyloxazol-4-yl]ethoxy} benzo[b]pyrimidin-7-yl)propene___-22 -__ ^paper scale for China National Standard (CNS) A4 Specification (210 X 297 mm) 1328585 A7 B7 V. Description of the Invention (Acid; 40. [Rapex]-2 - Butoxy_ 3 - (4 - { 2 - [ 2 - (3,5-Dimethylphenyl)·5-methyl.唆-4-yl]ethoxy}phenylhydrazine [b]e-sept-7-yl)propionic acid; 41. [racemic]-3 - ( 4 - { 2 - [ 2 - ( 3, 5-difluorophenyl)-5-methylcarbazole-4-yl]ethoxy}benzo[b]P-sept-7-yl)_2-ethoxypropionic acid; 42. [racemic -2 -Methoxy-3 -(4 - { 3 - [ 2 - (4-methoxyphenyl)- 5-methylindole-4-yl]propoxypropionic acid; 43. [ Racemic]_ 3 - ( 4 - { 3 - [ 2 乂 4 -chlorophenyl)· 5 _methylcarbazole-4 _yl]propoxy}pyridin-1-yl)-2-methoxy Propionate; 44. [Racea]-2-methoxy-3 - (4 - { 3 - [5 -methyl-2 - (4-trifluoromethylphenyl) 17 -propyl]propoxy}benzo[b]eseptene-7-yl)propanoic acid; 45. [Racemic]-2 -ethoxy-3 - (4 - { 3_- [ 5 - A -2 -(4-trifluoromethylphenyl). oxime-4-yl]propoxy} benzo[b]thiophene-7-yl)propanoic acid; 46. [racemic]-3 - ( 4 - { 3 - [ 2 - (4 - chlorophenyl)_ 5 -methyl oxazol _ 4 _ yl] propoxy octenyl-1- yl)-2 -isopropoxypropionic acid: 47_ (S)-2-methoxy-3-(4-{3-[5-methyl_2_(4.trifluoromethyl)-based 2-hydroxy-4-yl]propenyl)propionic acid 48. [Outside Cyclosyl]-3-(4 - { 3-[2-(4 - phenylphenyl) 5_methyl oxime _4. yl] propyloxy] yl) and [b] 4 phen-7-yl 2·methoxypropionic acid; 49. [racemic]-2 -ethoxy-3-(4-{3-[2-(4-methoxyphenyl)· 5-methyl " oxazol-4-yl]propoxy-yl}naphthyl-fluorenyl-propionic acid; 〕 〇. [racemic]-2 -ethoxy-3-(4-{3_[2-(4 _isopropylphenyl b 5-methyloxazol-4-yl]propoxy} 荇-丨·yl)propionic acid; 51. [racemate]-3 - ( 4 - { 3 - [ 2 - (4-Phenylphenyl)_ 5 _methylcarbazole _ 4 _ -23 -
基]丙乳基}茶-1-基)-2 -乙氧基丙酸; 3 2 [外消旋性]-3 - (4 - { 3 - [ 2 - (4 -異丙基苯基)-5 -甲基呤唑_ 4- 基]丙氧基}莕-1_基)_2·甲氧基丙酸; 53,[外消旋性]-3-(4 - {2-[2-(3,5 -二甲基苯基)-5 -甲基哼 唆-4-基]乙氧基}苯并塞吩·7 -基)_2_乙氧基丙酸: 54.[外消旋性]-3-(4-{2-[2-(3,5·二甲氧基苯基)-5 -甲基 °亏吐-4-基]乙氧基}苯并[b]lI塞吩_7_基)_2_乙氧基丙 酸; - 55·[外消旋性]-2 -乙氧基- 3-(4-{3-[2-(4 -甲氧基苯基)- 5- 甲基吟唑-4-基]丙氧基}苯并[b]嘧吩-7·基)丙酸; %·[外消旋性]-2 -甲氧基- 3-(4-{3-[2-( 4 -甲氧基苯基)- 5-甲基。号吐_4_基]丙氧基}苯并[b]噻吩-7·基)丙酸; 57.[外消旋性]-2 -乙氧基-3 - (4 - { 3 - [ 2 - (4 -異丙基苯基)-5 -甲基呤唑-4-基]丙氧基}苯并[b]P塞吩_7_基)丙酸; 58-[外消旋性]-3-(4-{3-[2-(4-異丙基苯基)-5-甲基咩唑-4 -基]丙氧基}苯并[b]噻吩-7-基)_2 -甲氧基丙酸; 59. [外消旋性]-3-(4-{3-[2-(4-氣苯基)-5-甲基呤唑-4-基]丙氧基}苯并[b]嘍吩-7-基)-2 -乙氧基丙酸; 60. [外消旋性]-3 - ( 4 - { 3 - [ 2 - ( 4 -氣苯基)-5 -甲基β号唑-4 -基]丙氧基}苯并[b]»塞吩-7-基)-2 -甲氧基丙酸: 61. [外消旋性]-2 -乙氧基- 3-(4-{3-[2-(4 -甲氧基苯基)-5-甲基嘮嗅-4-基]丙氧基广凑-^基)丙酸; 62-[外消旋性]-2 -乙氧基-3 - ( 4 - { 3 - [ 2 - ( 4 -異丙基苯基)-5-甲基嘮唑-4-基]丙氧基丙酸; 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公嫠) 1328585 A7 B7 五、發明説明(21 63.[外消旋性]-3 - (4 - { 3 - [ 2 - (4 -氯苯基)-5 ·曱基呤唑-4 - 基]丙氧基}某-1-基)-2 -乙氧基丙酸; 64·[外消旋性]-2 -乙氧基_3_(4_{2_[2_(4•異丙基苯基)_ 5-甲基。号唑-4-基]乙氧基}苯并[b]嘧吩·7·基)丙酸; 65. (5)-2-丁-3-烯氧基-3-(4_{2-[2_(4_異丙基苯基)_5_ 甲基^号。坐-4-基]乙氧基}苯并[b]。塞吩·7_基)丙酸; 66. [外消旋性]-3 - (4 - { 2 - [ 2 - (4 -異丙基苯基卜5 _甲基哼唑_ 4-基]乙氧基}苏-1-基)_2 --否氧基丙酸; 67. [外消旋性]-2-乙氧基-3-(4-{2-[2-(4-異丙基苯基)-5 -甲基嘮唑-4-基]乙氧基}莕-丨_基)丙酸; 68. [外消旋性]-3-(4-{2-[2-(3,5-二甲氧基苯基)_5_甲基 °号唑-4-基]乙氧基}苯并[b]噻吩_7-基)·2_異丙氧基丙 酸; 69. (5)-3-(4-{2-[2-(3,5-二甲氧基苯基).5_甲基„号唑_4_ 基]乙氧基}苯幷[b]°塞吩-7-基)-2 -異丙氧基丙酸; 70. [外消旋性]-3 - (4 - { 3 - [ 2 - (4 -異丙基苯基)_ 5 _甲基崎唑-4 -基]丙氧基}苯幷[b]。墓吩-7-基)-2 -丙氧基丙酸; 71. [外消旋性]-3 - (4 - { 2 - [ 2 - (3,5 ·二曱氧基苯基)_ 5 -甲基 呤吐-4-.基]乙氧基}莕-1_基)-2_乙氧基丙酸; 72. [外消旋性]-3-(4-{2-[2-(3,5-二甲氧基苯基)·5 -甲基 呤唑-4-基]乙氧基}莕-1-基)-2-丙氧基丙酸; 73. [外消旋性]-3 - (4 - { 2 - [ 2 - ( 3,5 -二甲氧基苯基)-5 -甲基 <7亏°坐-4-基]乙乳基}各-1-基)-2-異丙氧基丙酸; 74_ [外消旋性]-2 -異丙氧基-3 - (4 - { 2 - [ 2 - ( 4 -異丙基苯基)- _- 25 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(22 ) 5 -甲基》号唑-4-基]乙氧基}茶-1-基)丙酸’ 75. 2Z-乙氧基·3-{2_甲基_4_[2-(5-甲基_2_苯基号唑-4- 基)-乙氧基]-苯基}-丙晞酸; 76. [外消旋性]· 2 -乙氧基_ 3 - { 2 -甲基-4 - [2 · ( 5 -甲基_ 2 _苯 基·噚唑·4 -基)_乙氧基]•苯基}-丙酸; 77. 2(S)-乙氧基-3-{2·曱基·4_[2-(5 -甲基-2.苯基-喝唑_ 4-基)-乙氧基]-苯基卜丙酸; 78. 2 (R)-乙氧基_3_{2_甲基—·4_[2-(5-甲基-2-苯基-呤 唑-4-基)-乙氧基卜苯基丨·丙酸; 79. 3-{2,3-二甲基-4_[2-(5·甲基-2-苯基号唑-4-基)-乙 氧基]-笨基}-2Ζ·乙氧基丙烯酸;’ 80. [外消旋性]-3 - { 2,3 -二甲基-4 2 - (5 -甲基-2 -苯基-呤 唑-4-基)-乙氧基;]·苯基卜2 -乙氧基丙酸; 81. 3-{2,6-二甲基-4_[2_(5_甲基-2-苯基-哼唑-4-基)-乙 乳基]-年'基}·2Ζ·乙氧基丙稀酸; 82. [外消旋性]-3-{2,6-二甲基-4-[2-(5·甲基-2-苯基号 吐-4-基)-乙氧基]_苯基卜2·乙氧基丙酸; 83. 2Ζ -乙乳基- 3- {4-[2-(5 -甲基-2·苯基-σ号峻-4-基)-乙 氧基]-苯并吱喃-7-基}-丙婦酸; 84. 2Ε -乙氧基- 3- {4-[2-(5 -甲基-2-苯基号吐-4-基)-乙 氧基]-苯并呋喃-7 -基}-丙烯酸; 85. [外消旋性]-2 -乙氧基_ 3 - { 4 - [ 2 - ( 5 -甲基-2 -苯基-噚唑· 4_基)_乙乳基]-冬并ρ夫喃-7-基}-丙酸; 86. [外消旋性]-2 -乙氧基· 3 - { 4 - [ 2 - ( 5 -甲基-2 -苯基-嘮唑· 本紙張尺度適用中國囡家標竿(CNS) Α4規格(21〇Χ297公釐) 1328585 A7]]propyl aryl}tea-1-yl)-2-ethoxypropionic acid; 3 2 [racemic]-3 - (4 - { 3 - [ 2 - (4-isopropylphenyl) -5-methylcarbazole-4-yl]propoxy}indole-1_yl)_2-methoxypropionic acid; 53,[racemic]-3-(4 - {2-[2- (3,5-Dimethylphenyl)-5-methylindol-4-yl]ethoxy}benzoxeno-7-yl)_2-ethoxypropionic acid: 54. [Rectone -3(4-{2-[2-(3,5.dimethoxyphenyl)-5-methyl~deoxy-4-yl]ethoxy}benzo[b]lI _7_yl)_2_ethoxypropionic acid; - 55·[racemic]-2-ethoxylated 3-(4-{3-[2-(4-methoxyphenyl) - 5-methyloxazol-4-yl]propoxy}benzo[b]sulfon-7-yl)propionic acid; %·[racemic]-2-methoxy- 3-(4 -{3-[2-(4-methoxyphenyl)- 5-methyl. oxime _4_yl]propoxy}benzo[b]thiophen-7-yl)propanoic acid; 57. Racemic]-2 -ethoxy-3 -(4 - { 3 - [ 2 - (4-isopropylphenyl)-5 -methyloxazol-4-yl]propoxy} benzo [b]Pcetin-7-yl)propionic acid; 58-[racemic]-3-(4-{3-[2-(4-isopropylphenyl)-5-methylcarbazole -4 -yl]propoxy}benzo[b]thiophen-7-yl)_2-methoxypropionic acid 59. [Racecycline]-3-(4-{3-[2-(4-Phenylphenyl)-5-methyloxazol-4-yl]propoxy}benzo[b]pyrene Benz-7-yl)-2-ethoxypropionic acid; 60. [racemic]-3 - ( 4 - { 3 - [ 2 - ( 4 - phenyl)-5 -methyl β azole -4 -yl]propoxy}benzo[b]»cephen-7-yl)-2-methoxypropionic acid: 61. [Racemic]-2 -ethoxy- 3-(4 -{3-[2-(4-Methoxyphenyl)-5-methyloxime-4-yl]propoxy-polyalkyl-propionic acid; 62-[racemic]-2 -Ethoxy-3 - ( 4 - { 3 - [ 2 - ( 4 -isopropylphenyl)-5-methyloxazol-4-yl] propoxypropionic acid; This paper scale applies to China Standard (CNS) A4 size (210X 297 mm) 1328585 A7 B7 V. Description of invention (21 63. [Racecyclin]-3 - (4 - { 3 - [ 2 - (4-chlorophenyl)-5 · mercaptoin-4 -yl]propoxy}-1-yl)-2-ethoxypropionic acid; 64·[racemic]-2 -ethoxy_3_(4_{2_[ 2_(4•isopropylphenyl)_ 5-methyl. Zyzol-4-yl]ethoxy}benzo[b]sulfonyl-7-yl)propionic acid; 65. (5)-2-but-3-enyloxy-3-(4_{2-[ 2_(4_isopropylphenyl)_5_methyl^.#-4-yl]ethoxy}benzo[b].sept.7-yl)propionic acid; 66. [racemic] -3 - (4 - { 2 - [ 2 -(4-isopropylphenyl) 5 -methylcarbazole-4-yl]ethoxy}su-1-yl)_2-nooxypropionic acid 67. [Racecycline]-2-ethoxy-3-(4-{2-[2-(4-isopropylphenyl)-5-methyloxazol-4-yl]ethoxylate Propionate; 68. [Racecycline]-3-(4-{2-[2-(3,5-dimethoxyphenyl)-5-methyl]carbazole 4-yl]ethoxy}benzo[b]thiophene-7-yl)-2-isopropoxypropionic acid; 69. (5)-3-(4-{2-[2-(3, 5-dimethoxyphenyl).5-methyl oxime _4_yl]ethoxy}phenylhydrazine [b]°cephen-7-yl)-2-isopropoxypropionic acid; [Racea]-3 - (4 - { 3 - [ 2 - (4-isopropylphenyl) _ 5 _methyl oxazol-4-yl] propoxy} phenyl hydrazine [b]. Tomb Benz-7-yl)-2-propoxypropionic acid; 71. [Racemic]-3 - (4 - { 2 - [ 2 - (3,5 · Dimethoxyphenyl)_ 5 - Methyl oxime 4-.yl]ethoxy} oxime-1 _)-2 ethoxy propyl 72. [Racecycline]-3-(4-{2-[2-(3,5-dimethoxyphenyl)·5-methyloxazol-4-yl]ethoxy}荇-1-yl)-2-propoxypropionic acid; 73. [racemic]-3 - (4 - { 2 - [ 2 - ( 3,5 -dimethoxyphenyl)-5 - Base <7 ° 坐-4-yl]ethyl keto}}-1-yl)-2-isopropoxypropionic acid; 74_ [racemic]-2 -isopropoxy-3 - ( 4 - { 2 - [ 2 - ( 4 -isopropylphenyl)- _- 25 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (22 5 -Methyl"oxazol-4-yl]ethoxy}tea-1-yl)propionic acid '75. 2Z-ethoxyl 3-{2_methyl_4_[2-(5-A Base 2_phenyloxazol-4-yl)-ethoxy]-phenyl}-propionic acid; 76. [racemic]· 2 -ethoxy-3- 3 - { 2 -methyl- 4-(2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid; 77. 2(S)-ethoxy-3-{ 2·曱基·4_[2-(5-methyl-2.phenyl-oxazolyl-4-yl)-ethoxy]-phenylpropanoic acid; 78. 2 (R)-ethoxy _ 3_{2_methyl-.4_[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxyphenyl phenylpropanoid; 79. 3-{2,3 - Methyl-4_[2-(5.methyl-2-phenyloxazol-4-yl)-ethoxy]-p-styl}-2Ζ·ethoxyacrylic acid; '80. [racemic] -3 - { 2,3 -Dimethyl-4 2 -(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy;]·Phenyl-2-ethoxypropionic acid 81. 3-{2,6-Dimethyl-4_[2_(5-methyl-2-phenyl-oxazol-4-yl)-ethyl lactyl]-year's base}·2Ζ·ethoxy Acetyl acid; 82. [racemic]-3-{2,6-dimethyl-4-[2-(5-methyl-2-phenyl- -4-yl)-ethoxy ] _ 2 2 · ethoxy propionic acid; 83. 2 Ζ - ethyl lactyl - 3- {4-[2-(5 -methyl-2·phenyl-σ)-4-yl) Ethoxy]-benzopyran-7-yl}-propanoid; 84. 2Ε-ethoxy-3--{4-[2-(5-methyl-2-phenyl) -4- ()-ethoxy]-benzofuran-7-yl}-acrylic acid; 85. [Racemic]-2-ethoxy-3-(5-[4-[2-(5-methyl-2-) Phenyl-carbazole·4_yl)-ethylidyl]-winter-p-pentan-7-yl}-propionic acid; 86. [racemic]-2-ethoxy·3 - { 4 - [ 2 - ( 5 -Methyl-2-phenyl-carbazole · This paper scale applies to China National Standard (CNS) Α 4 specifications (21〇Χ297 mm) 1328585 A7
4-基)乙氧基]-2,3-二氫苯并吱喃小基}•丙酸; 87. 2Z-乙氧基-3_{7-[2_(5_甲基_2•苯基,哼唑4基卜乙 氧基]-苯并呋喃-4-基卜丙烯酸; 88. 2E-乙氧基-3-{7_[2.(5_甲基_2_笨基斗主·4基卜乙 氧基]-苯并吱喃基卜丙烯酸; 狄[外消旋性]-2_乙氧基_3-{7_[2 (5甲基_2_苯基·呤唑 4-基)-乙氧基]-笨并呋喃-4_基}丙酸; 90.[外消旋性]-2-乙氧基.3-{2_[2_(5_甲基-厂苯基“号唑 4-基)乙氧基]_2,3·二氫苯并咬喃_4_基}_丙酸; 9L [外消旋性]-2-乙氧基_3.{7·[2·(5甲基小苯基气七 4 -基)乙氧基]eji滿-4 -基卜丙酸; 92. 卜消旋性]乙氧基_3_(4 {2 [2_(5甲基_2苯基, 口亏吐-4-基)乙氧基]·5,6,7 8四氯茶·卜基卜丙酸; 93. -(4-{2-[2-(4-^ ).5_ f 基]乙氧基}苯并[b]口塞吩_7_基)·2·乙氧基丙酸; 94. [外消旋性]·2 -乙氧基.3_(4_{2_[2_(4_氟苯基)5_甲 基唑-4 -基]乙氧基}笨并[b ]噻吩_ 7 ·基)丙酸; 95. [外消旋性]-2 -乙氧基_ 3 _ (4 - { 2 - [ 2 - (2 -乙氧基-4 _氟苯 基)-5 -甲基咩唑-4_基]乙氧基}苯并[b]p塞吩·7_基)丙 酸; 96_ [外消旋性]-2 -乙氧基—-3 - (4 - { 2 - [ 2 - ( 4 -甲氧基苯基)_ 5 -甲基。号唑-4-基]乙氧基}苯并[b]p塞吩-7-基)丙酸;97.[外消旋性]-2 -乙氧基-3 - ( 4 - { 2 - [ 2 - (4 -異丙氧基苯基)_ 5 -甲基°号。坐-4 -基]乙氧基}苯并[b]p塞吩-7 -基)丙酸; ___- 27 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)4-yl)ethoxy]-2,3-dihydrobenzopyranyl}}propionic acid; 87. 2Z-ethoxy-3_{7-[2_(5-methyl_2•phenyl , carbazole 4 kibethoxy]-benzofuran-4-yl acrylic acid; 88. 2E-ethoxy-3-{7_[2.(5_methyl_2_ 笨基斗主·4基 ethoxy]-benzopyranyl acryl; Di [racemic]-2_ethoxy_3-{7_[2 (5-methyl-2-phenyl]carbazole-4-yl )-ethoxy]- benzofuran-4_yl}propionic acid; 90. [racemic]-2-ethoxy. 3-{2_[2_(5-methyl-phenyl) Oxazide 4-yl)ethoxy]_2,3·dihydrobenzobenzoin_4_yl}-propionic acid; 9L [racemic]-2-ethoxy-3-.{7·[2· (5 methyl small phenyl gas s-7-yl) ethoxy]eji full-4 - kipropropanoic acid; 92. Cyclonic] ethoxy _3_(4 {2 [2_(5 methyl _ 2 phenyl, benzoate-4-yl)ethoxy]·5,6,7 8 tetrachlorocha·bubupropionic acid; 93. -(4-{2-[2-(4-^) .5_ f ethoxy] benzo[b] phenanthrene _7_yl)·2·ethoxypropionic acid; 94. [racemic]·2-ethoxylated.3_(4_{ 2_[2_(4-fluorophenyl)5-methyloxazol-4-yl]ethoxy} benzo[b]thiophene-7-yl)propanoic acid; 95. [Racemic]-2-B Oxy _ 3 _ (4 - { 2 - [ 2 -(2-ethoxy-4 fluorophenyl)-5-methyloxazol-4-yl]ethoxy}benzo[b]p-sept.7-yl)propionic acid 96_ [racemic]-2 -ethoxy--3 - (4 - { 2 - [ 2 - ( 4 -methoxyphenyl) - 5 -methyl. oxazol-4-yl] Oxy}benzo[b]p-cephen-7-yl)propanoic acid; 97. [Racemic]-2-ethoxy-3 - (4 - { 2 - [ 2 - (4-isopropyl) Oxyphenyl) 5-methyl-methyl. Sodium-4-yl]ethoxy}benzo[b]p-cetin-7-yl)propionic acid; ___- 27 - This paper scale applies to China Standard (CNS) A4 size (210X 297 mm)
裝 訂Binding
線 1328585 A7 B7 五、發明説明(24 ) 98.(5)-2-曱氧基-3-{7-[2-(5-曱基-2-苯基-。号唑-4-基)-乙氧基]-苯并[b]·»塞吩:4-基}-丙酸; 99_ 2Z -乙氧基-3-{7-[2-(5 -甲基-2 -苯基-哼唑-4 -基)乙氧 基]印滿-4 -基}-丙埽酸: 100. (S)-2 -曱氧基-3-{7-[2-(5 -甲基-2-苯基-哼唑-4-基)乙 氧> 基]印滿-4-基}•-丙@父, 101. [外消旋性]-3-(4 - {2-[2-(2 -乙氧基-4-氟苯基)-5 -甲 基哼唑-4-基]乙氧基}莕-1-二基)-2-甲氧基丙酸; 102. [外消旋性]-2 -曱氧基-3-(4-{2-[2-(4 -甲氧基苯基)-5 -曱基。号唑-4-基]乙氧基}莕-1-基)丙酸; 103.2Z -乙氧基- 3- {7-[2-(5 -甲基-2-苯基-崎唑-4 -基)-乙 氧基]-私并[b]p塞吩-4-基}-丙缔_酸, 104. [外消旋性]-2 -乙氧基-3 - { 7 - [ 2 - ( 5 -甲基-2 -苯基-哼唑-4 -基)-乙氣基]-苯并[b]>»j吩-4-基}-丙酸; 105. [外消旋性]-2 - [ 1 -甲基-3 -氧基-3 -苯基-(Z)-丙烯胺 基]-3-{4-[2-(5 -甲基-2-苯基-哼唑-4 -基)-乙氧基]-苯 幷[b]p塞吩-7-基}-丙酸; 106. [外消旋性]-2-[ 1-甲基-3 -氧基-3-(4 -三氟甲基苯基)-(Z) -丙烯胺基]-3-{4-[2-(5 -甲基-2-苯基-哼唑- 4-基)-乙氧基]-私并[b]!1塞吩-7-基}-丙酸; 107. [外消旋性]-3 - { 4 - [ 2 - ( 5 -甲基-2 -苯基-噚唑-4 -基)-乙 氧基]-苯并[b]4吩-7-基卜2-[3 -氧基-3-苯基-1-三氟 甲基-(2)-丙締胺基]-丙酸; 108. [外消旋性]-2 -乙氧基- 3-{4-[2-(4 -異丙基苯基)-5 -甲 __-28 -_ 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) (· 裝 訂Line 1328085 A7 B7 V. Description of the invention (24) 98. (5)-2-decyloxy-3-{7-[2-(5-mercapto-2-phenyl-.oxazol-4-yl) -ethoxy]-benzo[b]»»cephene: 4-yl}-propionic acid; 99_ 2Z-ethoxy-3-{7-[2-(5-methyl-2-phenyl- (oxazol-4-yl)ethoxy]indan-4-yl}-propionic acid: 100. (S)-2 -decyloxy-3-{7-[2-(5-methyl-2) -Phenyl-oxazol-4-yl)ethoxyl> base]indan-4-yl}•-propyl@parent, 101. [racemic]-3-(4 - {2-[2- (2-ethoxy-4-fluorophenyl)-5-methyloxazol-4-yl]ethoxy}indole-1-diyl)-2-methoxypropionic acid; 102. Cyclos]-2-oxooxy-3-(4-{2-[2-(4-methoxyphenyl)-5-fluorenyl. oxazol-4-yl]ethoxy} oxime-1 -yl)propionic acid; 103.2Z-ethoxy-3-(7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-private [b] P-cephen-4-yl}-propanoid-acid, 104. [racemic]-2 -ethoxy-3 - { 7 - [ 2 - ( 5 -methyl-2-phenyl-carbazole -4 -yl)-ethane group]-benzo[b]>»j-phen-4-yl}-propionic acid; 105. [racemic]-2 - [1-methyl-3-oxo 3-phenyl-(Z)-acrylamido]-3-{4-[2-(5-methyl-2-phenyl-indazol-4-yl)-B Oxy]-benzoquinone [b]p-cephen-7-yl}-propionic acid; 106. [Racemic]-2-[1-methyl-3-oxo-3-(4-trifluoro) Methylphenyl)-(Z)-acrylamido]-3-{4-[2-(5-methyl-2-phenyl-indazol-4-yl)-ethoxy]-private b]!1 phene-7-yl}-propionic acid; 107. [Racemic]-3 - { 4 - [ 2 - ( 5 -methyl-2-phenyl-carbazol-4-yl) -ethoxy]-benzo[b]4phen-7-ylbu 2-[3-oxo-3-phenyl-1-trifluoromethyl-(2)-propyl-amino-propionic acid]-propionic acid 108. [Racea]-2 -ethoxy- 3-{4-[2-(4-isopropylphenyl)-5-甲__-28 -_ This paper size applies to China Standard (CNS) A4 size (210 X 297 mm) (· Binding
1328585 A7 B7 五、發明説明(25 ) 基哼唑-4 -基甲氧基]-5,6,7,8 -四氫莕- l-基}-丙酸; 109. [外消旋性]-2 -乙氧基-3 - [ 4 - ( 5 -甲基-2 -苯基-呤唑-4 -基甲氧基)-5,6,7,8 -四氫萘-1-基]-丙酸; 110. [外消旋性]-2 -乙氧基-3 - ( 4 - { 2 - [ 2 - (2 -乙氧基-4 -氟苯 基)-5 -甲基哼唑-4-基]乙氧基}-5,6,7,8 -四氫莕-1-基) 丙酸; 111. [外消旋性]-2 -乙氧基- 3-(4 - {2-[2-(4 -氟苯基)-5 -曱 基呤唑-4 -基]乙氧基} - 5,6丄7,8 -四氫莕-1 -基)丙酸; 112. [外消旋性]-2 -乙氧基- 3-(4 - {3-[2-(4 -曱氧基苯基)-5_甲基吟唑-4·基]丙氧基}-5,6,7,8 -四氫茬-1-基)丙 酸; 113. [外消旋性]-2 -乙氧基-3-(4 - {2_-[5 -甲基-2-(4-三氟甲 基苯基)哼唑-4 -基]乙氧基}-5,6,7,8 -四氫萘-1-基)丙 酸; 114. [外消旋性]-2 -曱氧基-3 - { 3 -甲基-4 - [ 2 - ( 5 -曱基-2 -苯 基-崎唑-4-基)-乙氧基]-苯基}-丙酸; 115. [外消旋性]-2 -曱氧基-3 - { 3 -甲氧基-4 - [ 2 - ( 5 -甲基-2 -•^基-°亏°坐-4 -基)-乙氧基]-本基}-丙酸, 116. [外消旋性]-2 -乙氧基- 3- {3 -甲氧基- 4- [2-(5 -甲基- 2-苯基-哼唑-4-基)-乙氧基]-苯基}-丙酸鋰; 117. [外消旋性]-3 - { 3,5 -二甲基- 4-[ 2-(5 -曱基-2 -苯基-哼 唑-4·基)-乙氧基]-苯基}-2-甲氧基丙酸; Π8.[外消旋性]-3 - { 2 -羥基-4 - [ 2 - ( 5 -甲基-2 -苯基-哼唑-4 -基)-乙乳基]-苯基}-2 -曱氧基丙酸; _-29 -_ 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) k 訂1328585 A7 B7 V. Description of the invention (25) carbazol-4-ylmethoxy]-5,6,7,8-tetrahydroindole-l-yl}-propionic acid; 109. [racemic] -2 -ethoxy-3-[4-(5-methyl-2-phenyl-indazol-4-ylmethoxy)-5,6,7,8-tetrahydronaphthalen-1-yl] -propionic acid; 110. [racemic]-2 -ethoxy-3 - ( 4 - { 2 - [ 2 - (2-ethoxy-4-fluorophenyl)-5 -methylcarbazole 4-yl]ethoxy}-5,6,7,8-tetrahydroindol-1-yl)propionic acid; 111. [racemic]-2-ethoxylated 3-(4 - { 2-[2-(4-Fluorophenyl)-5-mercaptoindazole-4-yl]ethoxy}-5,6丄7,8-tetrahydroindol-1-ylpropionic acid; 112. [Racecyclin]-2 -ethoxy-3-(4 - {3-[2-(4-oxophenyl)-5-methylcarbazol-4yl]propoxy}- 5,6,7,8-tetrahydroindol-1-yl)propionic acid; 113. [Racemic]-2 -ethoxy-3-(4 - {2_-[5-methyl-2- (4-trifluoromethylphenyl)oxazol-4-yl]ethoxy}-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid; 114. [racemic]- 2-methoxy-3-({3-methyl-4-[2-(5-fluorenyl-2-phenyl-soxazol-4-yl)-ethoxy]-phenyl}-propionic acid; 115. [Racea]-2 -decyloxy-3 - { 3 -methoxy-4 - [ 2 - ( 5 -Methyl-2 -•^------------ 4-ethoxy)-ethoxy]-benzyl}-propionic acid, 116. [Racemic]-2-Ethoxy 3- 3-[3-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid lithium; 117. [Racecyclin]-3 - { 3,5 -Dimethyl- 4-[2-(5-fluorenyl-2-phenyl-oxazol-4yl)-ethoxy]-phenyl} -2-methoxypropionic acid; Π 8. [racemate]-3 - { 2 -hydroxy-4 - [ 2 - ( 5 -methyl-2-phenyl-oxazol-4-yl)-B乳基]-phenyl}-2 -decyloxypropionic acid; _-29 -_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) k
1328585 A7 B7 五、發明説明(26 ) 119. [外消旋性]-3·{3·甲基·4·[2_(5 -甲基·2_苯基-p号唑_ 4 -基)-乙氧基卜苯|厂2_(1-甲基_3 -氧基·3_笨基· (Ζ) -丙烯胺基)丙酸; 120. [外消旋性]-2 -乙氧基-3-[4-(5 -甲基-2 -苯基·呤唑.4_ 基甲乳基)私并咬喃-7-基]-丙酸; 121. [外消旋性]-2 -乙氧基-3-[4-(5 -甲基-2-4吩-2·基,号 咬-4 -基甲氧基)苯并呋喃-7 -基]-丙酸; 122. [外消旋性]_ 2 -乙氧基· 3 -_{—4 - [_2 - (4 -乙基苯基)-5 -甲基 °号。坐-4 -基甲氧基]苯并呋喃_ · 7 -基}-丙酸; 123. [外消旋性]_3_{4-[2-(4 -第三丁基苯基)·5 -甲基呤唑_ 4 -基甲氧基]苯并呋喃-7-基}-2 -乙氧基丙酸; 124. [外消旋性]-2·乙氧基-3-{4-[2·-(4-異丙氧基苯基)_5_ 甲基嘮唑-4-基甲氧基]苯并呋喃-7-基}-丙酸; 125. [外消旋性]·2 -乙氧基-3-[4-(5 -甲基-2-苯基-喝吐_4_ 基曱氧基)-2,3 -二氫苯并呋喃-7-基]-丙酸; 126. [外消旋性]·2 -乙氧基-3-{4-[2-(4 -乙基苯基)-5·甲基 哼唑-4-基甲氧基]-2,3 -二氫苯并呋喃-7-基}-丙酸; 127. [外消旋性]-3 - { 4 - [ 2 - (4 -第三丁基苯基)-5 -甲基〇号。坐· 4 -基甲氧基]-2,3 -二氫苯并呋喃-7·基}-2·乙氧基丙 酉父, 128. [外消旋性]-2 -乙氧基-3-{4-[2-(4 -異丙氧基苯基)·5_ 甲基。号唑_4 -基甲氧基]·2,3 -二氫苯并呋喃-7-基卜丙 酸; 129. [外消旋性]-2 -乙氧基- 3- [2 -甲基- 4- (5 -甲基-2-笨基· ___- 30 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明( °号峻-4-基曱氧基)苯基]•丙酸; 130. [外消旋性]-2 -乙氧基_ 3 _[ 2 -甲基-4 - ( 5 -曱基-2 · b塞吩_ 2-基4峻-4-基甲氧基)苯基卜丙酸; 131. [外消旋性]-2 -乙氧基-3-{4-[2 _ (4 -乙基苯基)-5 -甲基 °号°坐·4·基甲氧基]-2-甲基苯基}-丙酸; 132. [外消旋性]-3-{4-[2-(4 -第三丁基苯基)-5 -甲基。号唑-4-基甲氧基]-2 -甲基苯基卜2-乙氧基丙酸: 133. [外消旋性]-2 -乙氧基_ 3 [ 2 - (4 -異丙氧基苯基)-5 - 甲基呤唑-4-基甲氧基]_2_甲基苯基}-丙酸; 134. (S)-2- 丁- 3-烯氧基·3-{3,5 -二甲基-4-[2-(5 -甲基-2- 苯基-噚唑_4_基)_乙氧基]•苯基丙酸; 135. 3-{3,5-二甲基-4-[2-(5-甲基-2-苯基-哼唑-4-基)-乙 氧基]-苯基}-2Z -乙氧基丙晞酸; 136. [外消旋性]-3 - { 4 - [ 2 - (4 -氯苯基)-5 -甲基咩唑-4 -基甲 氧基]苯并呋喃-7-基}-2 -乙氧基丙酸: 137. [外消旋性]-3- {4-[2-(4 -氯苯基)-5 -甲基哼唑-4 -基甲 氧基]-2 -甲基苯基}-2 -乙氧基丙酸; 138. [外消旋性]-3 - { 4 - [ 2 - (3 , 5 -二甲氧基苯基)-5 -甲基哼 唑-4 -基.甲氧基]苯并呋喃-7 _基} _ 2 -乙氧基丙酸; 139. 2Z -乙氧基-3-{4-[2-(4 -異丙基苯基)-5 -甲基吟咬-4-基甲氧基]-2 -甲基苯基}-丙歸r酸; M0.[外消旋性】-2 -乙氧基-3 - [ 3 -曱基-4 - (2 -苯基-哼唑-4 -基甲氧基)苯基]-丙酸; 141_(5)-3-{3,5-二甲基-4-[2-(5-甲基-2-苯基-哼唑-4- ___- 31 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585 A7 ____B7 _____ 五、發明説明(28) 基)-乙氧基]-笨基}-2 -丙氧基丙酸; 142. 2Z -丁- 3-烯氧基·3-{3,5 -二甲基·4-[2-(5 -甲基-2 -苯 基-哼唑-4-基)-乙氧基卜苯基卜丙烯酸; 143.2E - 丁-3·烯氧基-3-{3,5·二甲基-4-[2-(5 -甲基-2 -苯 基-咩唑-4 -基)-乙氧基]-苯基卜丙烯酸: 144.[外消旋性]-3-{4-[2-(2 -氯苯基)-5 -曱基哼唑-4 -基甲 氧基]-2 -甲基笨基卜2 -乙氧基丙酸; I45·[外消旋性]-3 - { 4 - [ 2 _( 3 _惠苯基)-5 -甲基崎唑·4 -基甲 氧基]-2 -甲基苯基卜2 -乙氧基丙酸; 146.[外消旋性]-2 -乙氧基-3 - { 2 -甲基-4 - [ 3 - ( 5 -甲基-2 -苯 基-哼唑-4-基)丙氧基]苯基卜丙酸; 147_ [外消旋性]· 2 -乙氧基-3 - { 4 - [ 2 --(4 -氟基-3 -甲基苯基)-5 -甲基呤唑-4-基甲氧基]-2 -甲基苯基}-丙酸; 148. [外消旋性]-2 -乙氧基-3 - { 4 - [ 2 - (2 -曱氧基苯基)-5 -甲 基噚唑-4-基甲氧基]-2-甲基苯基卜丙酸; 149. [外消旋性]-3 - (4 - { 2 - [ 2 - (4 -氯苯基)-5 -甲基呤唑-4 -基]乙氧基}-5,6,7,8 -四氩莕-1-基)-2 -乙氧基丙酸; 150. [外消旋性]-2 -乙氧基-3 - [ 4 - ( 5 -甲基-2 -苯基-咩唑-4 -基甲氧基)萘-1-基]-丙酸; 151. [外消旋性]-2 -乙氧基-3 - [ 7 - ( 5 -甲基-2 -苯基-哼唑-4 -基甲氧基)苯并[b]·»塞吩-4-基]-丙酸; 152_ [外消旋性]-2 -乙氧基-3 - { 7 - [ 2 - (4 -異丙氧基苯基)-5 -甲基呤唑-4-基甲氧基]苯并[b] «塞吩-4-基}-丙酸; 153.〖外消旋性]-2 -乙氧基-3 - ( 7 - { 2 - [ 2 - (2 -乙氧基-4 -氟苯 _-32 -___ 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) 1328585 A7 B7 五、發明説明(29 基)-5 -甲基呤唑_4 -基]乙氧基}苯幷[b]p塞吩-4 -基)丙 Ιέ ; 154. [外消旋性]-3 - ( 7 - { 2 - [ 2 - (4 -氣苯基)-5 -甲基哼唑-4 _ 基]乙氧基}笨并[b]噻吩-4-基)-2 -乙氧基丙酸; 155. [外消旋性]-3 - { 7 - [ 2 - (4 -第三丁基苯基)-5 -甲基哼唑-4-基曱氧基]苯并[b]〇塞吩_4-基}-2·乙氧基丙酸; 156. (S)-2-乙氧基-3-{3 -甲基-4-[2-(5 -甲基-2-苯基号吐-4 -基)-乙氧基]-苯基卜丙酸_; _ 157. (2S)-3-{ 3,5-二甲基_4_ [2_(5 -甲基-2-苯基-口号唑-4- 基)-乙氧基]-笨基}-2 -乙氧基丙酸; 158. [外消旋性]-2 -乙氧基-3 - { 3 -氟基-4 - [ 2 - ( 5 -甲基-2 ·苯 基号唑-4-基)-乙氧基卜苯基}·丙酸; 159. [外消旋性]-2 -乙氧基-3 - { 4 - [ 2 - ( 5 -甲基-2 -苯基-»号唑-4 -基)乙氧基]-3 -丙基苯基}·丙酸; 160. (2S)-2-乙氧基-3-{3 -曱氧基-4-[2-(5 -甲基-2-苯基· 吟唑-4-基)-乙氧基卜苯基卜丙酸; 161. (2S)-2-乙氧基-3-{2 -甲氧基-4-[2-(5 -甲基-2-苯基· 哼唑-4-基)-乙氧基]-苯基卜丙酸; 162. [外消旋性]-2-異丙氧基-3-{4-[2-(5 -甲基-2 -苯基-噚 唑-4-基)-乙氧基]-苯并[b]4吩_7-基}-丙酸: 163. (5)-2-異丙乳基-3-{4-[2-(5-甲基-2-苯基-°号也-4· 基)-乙氧基]-笨并[b ]噻吩-7 -基}-丙酸; 164. [外消旋性]-3-{3 -稀丙基- 4- [2-(5 -甲基表基-^号。坐_ 4 -基)-乙氧基]-茶-1-基}_2 -乙氧基两酸, ___- 33 - 本紙張尺度逋用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(30 ) 特別佳的式(1)化合物係選自以下群組: 2- 甲氧基- 3- {4-[2-(5-甲基- 2- +基、。号^坐_4 -基)-乙氧基]_ 苯并[b ]嘧吩-7 -基卜丙酸: 3- { 4-[2-(5-曱基-2-苯基-崎唑-4-基)-乙氧基]-苯并[b]噻 吩-7-基} - 2-丙氧基丙酸; (S)-2-甲氧基-3-{4-[2-(5-甲基-2-苯基-哼唑-4-基)-乙氧 基]-苯并[b]·1塞吩-7-基}-丙酸; (S)-3-(4-{ 2-[2-(3,5-二曱氧良苯基)-5-甲基11号唑-4-基]乙 氧基}苯并[b]〇塞吩-7-基)-2-甲1基丙酸; (8)-2-曱氧基-3-(4-{3-[5-甲基-2-(4-三氟甲基笨基)》号唑-4 -基]丙氧基}萬-1-基)丙酸; 2Z-乙氧基_3-{2-甲基-4-[2-(5-甲基-2-苯基号唑·4-基)-乙氧基]-苯基}-丙烯酸; 2(S)-乙氧基-3-{ 2-甲基-4-[2-(5-甲基-2-苯基-哼唑- 4· 基)-乙氧基]-苯基}-丙酸; 2Z-乙氧基-3-{4-[2-(5-甲基-2-苯基号唑-4 -基)_乙氧基卜 笨幷呋喃-7-基卜丙烯酸; [外/肖旋性]-2-[l -甲基-3-氧基-3-苯基- (Z) -丙埽胺基]_3_ {4-[2-(5-曱基-2-苯基·呤唑-4-基)-乙氧基卜苯并[b]噻吩_ 7 -基}-丙酸; [外消旋性]-3-{2-羥基-4-[2-(5-曱基-2·苯基-气吐·4_基)· 乙氧基]-苯基}-2-甲氧基丙酸Γ [外消旋性]-3-{3-甲基-4-[2-(5-甲基-2-笨基-呤嗅_4_基)_ 乙氧基卜苯基}-2-(1-曱基-3-氧基-3-苯基-U)-丙締胺基) ____ - 34 - 本紙敢从通財g g家料(CNS) A4規格(2lQX297公爱) ~ - - 1328585 A7 B7 五、發明説明(31 ) 丙酸; [外消旋性卜2-乙氧基-3-(2-曱基_4-( 5-曱基-2-苯基号唑_ 4-基曱氧基)苯基]-丙酸; [外消旋性]-2-乙氧基-3-{ 4-[2-(4-異丙氧基笨基)_5_甲基 °号唑-4-基甲氧基]-2-甲基苯基卜丙酸; (2S)-3-{3,5 -一曱基-4-[2-(5-曱基-2-苯基号嗅基)_ 乙 氧基]-苯基}-2-乙氧基丙酸;及 (2S)-2-乙氧基-3-{3-甲氧基气]2_(5-甲基_2_苯基-呤唑_ 4 -基)-乙氧基]-苯基}-丙酸。- 以(S)-2-甲氣基- 3·{4-[2-(5-曱基-2-笨基-呵唑_4_基)_ 乙氧基]-苯并[b]喵吩-7-基}-丙酸及其醫藥上可接受之鹽 類和酯類更特別佳。以(S)-2-曱氧基·3-{4-[2-(5-甲基-2- 苯基-哼唑-4_基)_乙氧基]-苯并[b]嘧吩_7_基卜丙酸最 佳。 式(I)化合物可以具有一或多個不對稱碳原子,並可以旋 光性純對映異構物形式或成為外消旋物存在。本發明包含 所有這些形式。 應認知的是可在官能基上衍生在本發明中的通式(1)化合 物,以提供能夠在活體内轉換成母體化合物的衍生物。 本發明進一步的觀點係式I化合物之製造方法,其包含式 II化合物的去保護作用1328585 A7 B7 V. INSTRUCTIONS (26) 119. [Racecyclic]-3·{3·Methyl·4·[2_(5-methyl·2_phenyl-p-azol-4-yl) -ethoxy benzene|factor 2_(1-methyl-3-oxy-3_phenyl)(propenyl)-propenyl)propionic acid; 120. [racemic]-2 -ethoxy -3-[4-(5-methyl-2-phenyl-2-carbazole.4-yl-methyl), acetyl- 7-yl]-propionic acid; 121. [racemic]-2 - Ethoxy-3-[4-(5-methyl-2-4-phen-2-yl, keto-4-ylmethoxy)benzofuran-7-yl]-propionic acid; 122. Racemic] _ 2 -ethoxy 3 -_{- 4 - [_2 - (4-ethylphenyl)-5-methyl °. Sodium-4-ylmethoxy]benzofuran_·7-yl}-propionic acid; 123. [Racecyclic]_3_{4-[2-(4-tributylphenyl)·5- Methylcarbazole _ 4-methoxymethoxy]benzofuran-7-yl}-2-ethoxypropionic acid; 124. [Racemic]-2·Ethoxy-3-{4-[ 2·-(4-Isopropoxyphenyl)_5-methyloxazol-4-ylmethoxy]benzofuran-7-yl}-propionic acid; 125. [Racemic]·2 - B Oxy-3-[4-(5-methyl-2-phenyl-sodium benzo-4-yloxy)-2,3-dihydrobenzofuran-7-yl]-propionic acid; 126. [ Racemic]·2-ethoxy-3-{4-[2-(4-ethylphenyl)-5-methyloxazol-4-ylmethoxy]-2,3-dihydro Benzofuran-7-yl}-propionic acid; 127. [Racemic]-3 - { 4 - [ 2 - (4-tributylphenyl)-5-methyl oxime. Sodium 4-methyloxy]-2,3-dihydrobenzofuran-7-yl}-2.ethoxypropanol, 128. [racemic]-2-ethoxy-3 -{4-[2-(4-isopropoxyphenyl).5-methyl. Isoazol-4-yl-methoxy]·2,3-dihydrobenzofuran-7-ylpropanoic acid; 129. [Racemic]-2-ethoxy-3- [2-methyl - 4- (5 -Methyl-2-phenyl] ___- 30 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Invention description (°号峻-4 -yloxy)phenyl]•propionic acid; 130. [racemate]-2 -ethoxy_3 _[ 2 -methyl-4 - ( 5 -mercapto-2 · b-septene _ 2-(4-cyclo-4-ylmethoxy)phenylpropanoic acid; 131. [Racemic]-2 -ethoxy-3-{4-[2 _ (4-ethylphenyl) -5 -methyl °°°4·ylmethoxy]-2-methylphenyl}-propionic acid; 132. [racemic]-3-{4-[2-(4 - Tributylphenyl)-5-methyl.oxazole-4-ylmethoxy]-2-methylphenyl-2-ethoxypropionic acid: 133. [racemic]-2 - B Oxy-3 [2-(4-isopropoxyphenyl)-5-methyloxazol-4-ylmethoxy]_2-methylphenyl}-propionic acid; 134. (S)-2 - But-3-enyloxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-carbazole-4-yl)-ethoxy]benzene Propionate; 135. 3-{3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-B ]]-phenyl}-2Z-ethoxypropionic acid; 136. [Racemic]-3 - { 4 - [ 2 - (4-chlorophenyl)-5 -methylcarbazole-4 - Methoxy]benzofuran-7-yl}-2-ethoxypropionic acid: 137. [Racemic]-3-{4-[2-(4-chlorophenyl)-5-A Ketrazole-4-ylmethoxy]-2-methylphenyl}-2-ethoxypropionic acid; 138. [Racemic]-3 - { 4 - [ 2 - (3 , 5 - Dimethoxyphenyl)-5-methyloxazol-4-yl.methoxy]benzofuran-7-yl} _2-ethoxypropionic acid; 139. 2Z-ethoxy-3- {4-[2-(4-isopropylphenyl)-5-methylindole-4-ylmethoxy]-2-methylphenyl}-propanyl r-acid; M0.[racemic -2 -ethoxy-3 - [ 3 -mercapto-4 - (2-phenyl-oxazol-4-ylmethoxy)phenyl]-propionic acid; 141_(5)-3-{ 3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-indazole-4- ___- 31 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 ____B7 _____ V. Description of the invention (28) yl)-ethoxy]-styl}-2-propoxypropionic acid; 142. 2Z-but-3-enoxy-3-{3,5 -Dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy bphenyl Acene acid; 143.2E - butyl-3·alkenyl-3-{3,5·dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-B Oxy]-phenyl-acrylic acid: 144. [racemic]-3-{4-[2-(2-chlorophenyl)-5-mercaptoindazole-4-ylmethoxy]-2 -methyl stupid ibu- 2 -ethoxypropionic acid; I45 ·[racemic]-3 - { 4 - [ 2 _( 3 _ phenylene)-5 -methyl succinyl 4 - yl Oxy]-2-methylphenyl- 2-ethoxypropionic acid; 146. [racemate]-2 -ethoxy-3 - { 2 -methyl-4 - [ 3 - ( 5 - Methyl-2-phenyl-oxazol-4-yl)propoxy]phenylpropionic acid; 147_ [racemic]·2-ethoxy-3 - { 4 - [ 2 --(4 -fluoro-3-methylphenyl)-5-methyloxazol-4-ylmethoxy]-2-methylphenyl}-propionic acid; 148. [Racemic]-2 - B Oxy-3 - { 4 - [ 2 - (2-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]-2-methylphenylpropionic acid; 149. Racemic]-3 - (4 - { 2 - [ 2 - (4-chlorophenyl)-5 -methylcarbazol-4-yl]ethoxy}-5,6,7,8-tetrahydrogen荇-1-yl)-2-ethoxypropionic acid; 150. [racemic]-2 -ethoxy-3 - [ 4 - ( 5 -methyl-2-phenyl-carbazole-4 - 基甲Naphthyl-1-yl]-propionic acid; 151. [racemic]-2 -ethoxy-3 - [ 7 - ( 5 -methyl-2-phenyl-oxazol-4-yl) Oxy)benzo[b]·»cephen-4-yl]-propionic acid; 152_ [racemic]-2 -ethoxy-3 - { 7 - [ 2 - (4-isopropoxy) Phenyl)-5-methyloxazol-4-ylmethoxy]benzo[b] «cephen-4-yl}-propionic acid; 153. [racemic]-2-ethoxy- 3 - ( 7 - { 2 - [ 2 - (2-ethoxy-4-fluorobenzene_-32 -___) This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V , Description of the invention (29-)-5-methylcarbazole-4-yl]ethoxy}phenylhydrazine [b]p-cephen-4-yl)propanoid; 154. [Racemic]-3 - ( 7 - { 2 - [ 2 - (4-Phenylphenyl)-5-methylcarbazole-4 _yl]ethoxy} benzo[b]thiophen-4-yl)-2-ethoxypropane Acid; 155. [Racecycline]-3 - { 7 - [ 2 - ( 4 -th-butylphenyl)-5 -methyloxazol-4-yl decyloxy]benzo[b]pyrene塞 _ 4-yl}-2·ethoxypropionic acid; 156. (S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-benzene) Base No. 4 -yl)-ethoxy]-phenylpropionic acid _; _ 157. (2S)-3-{ 3,5-dimethyl_4_ [2_(5 - Methyl-2-phenyl-oxazolyl-4-yl)-ethoxy]-phenyl}-2-ethoxypropanoic acid; 158. [Racemic]-2-ethoxy-3 { 3 -Fluoro-4 - [ 2 - ( 5 -methyl - 2 -phenyloxazol-4-yl)-ethoxyphenyl]-propionic acid; 159. [Racemic]-2 -ethoxy-4-({4-[2-(5-methyl-2-phenyl-]oxazolyl-4-yl)ethoxy]-3-propylphenyl}-propionic acid; 160. (2S)-2-ethoxy-3-{3-decyloxy-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxyphenylphenyl Propionic acid; 161. (2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy ].-Phenylpropionic acid; 162. [Racecycline]-2-isopropoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl) )-ethoxy]-benzo[b]4 phen-7-yl}-propionic acid: 163. (5)-2-Isopropyl-3-{4-[2-(5-methyl- 2-phenyl-# is also -4 yl)-ethoxy]- benzo[b]thiophen-7-yl}-propionic acid; 164. [racemic]-3-{3 - isopropyl Base - 4- [2-(5-methyl-phenoxy-^). Sit _ 4 -yl)-ethoxy]-tea-1-yl}_2-ethoxy diacid, ___- 33 - This paper scale is based on the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. INSTRUCTION DESCRIPTION (30) Particularly preferred compounds of formula (1) are selected from the group consisting of 2-methoxy-3-(4-[2-(5-methyl-2-yl), No.^Sit_4-yl)-ethoxy]_benzo[b]sulfon-7-kibpropionic acid: 3-{4-[2-(5-mercapto-2-phenyl-saki (oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-2-propoxypropionic acid; (S)-2-methoxy-3-{4-[2- (5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]·1 ceto-7-yl}-propionic acid; (S)-3-(4 -{ 2-[2-(3,5-Dioxalyl-phenyl)-5-methyl-11-oxazol-4-yl]ethoxy}benzo[b]deceno-7-yl)- 2-methyl-1-propionic acid; (8)-2-decyloxy-3-(4-{3-[5-methyl-2-(4-trifluoromethylphenyl)-oxazole-4 - (1,4-methoxy-4-[2-(5-methyl-2-phenyloxazole·4-yl) )-ethoxy]-phenyl}-acrylic acid; 2(S)-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-carbazole-4) · yl)-ethoxy]-phenyl}-propionic acid; 2Z-ethoxy- 3-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)-ethoxy bromoxyfuran-7-ylbu-acrylic acid; [external/cyclonic]-2- [l-Methyl-3-oxo-3-phenyl-(Z)-propionylamino]_3_ {4-[2-(5-fluorenyl-2-phenyl-oxazol-4-yl) -ethoxy benzo[b]thiophene-7-yl}-propionic acid; [racemic]-3-{2-hydroxy-4-[2-(5-fluorenyl-2.phenyl- Breathing ·4_yl)· Ethoxy]-phenyl}-2-methoxypropanoic acid 外 [racemic]-3-{3-methyl-4-[2-(5-methyl) -2- stupyl-oxime _4_yl)_ethoxy bphenyl}-2-(1-indolyl-3-oxy-3-phenyl-U)-propyl-aminoamine) ____ 34 - The paper dare to pass the GG family material (CNS) A4 specifications (2lQX297 public) ~ - 1328585 A7 B7 V. Description of invention (31) Propionic acid; [racemicity 2-ethoxy-3- (2-mercapto-4-(5-fluorenyl-2-phenyloxazole-4-ylindoleoxy)phenyl]-propionic acid; [racemic]-2-ethoxy-3- {4-[2-(4-Isopropoxy)]-5-methyl-[oxazol-4-ylmethoxy]-2-methylphenylpropanoic acid; (2S)-3-{3 ,5-monodecyl-4-[2-(5-fluorenyl-2-phenylphonyl)-ethoxy]-phenyl}-2-ethoxypropionic acid; and (2S)-2 -ethoxy-3-{3-methoxy gas]2_(5-methyl_2_ Phenyl-carbazole-4-yl)-ethoxy]-phenyl}-propionic acid. - (S)-2-Methane-3·{4-[2-(5-fluorenyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]pyrene The phen-7-yl}-propionic acid and its pharmaceutically acceptable salts and esters are more particularly preferred. (S)-2-decyloxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]pyrimidine _7_Kippropionic acid is the best. The compound of formula (I) may have one or more asymmetric carbon atoms and may exist as an optically pure enantiomer or as a racemate. The present invention encompasses all of these forms. It is to be understood that the compound of the formula (1) which can be derivatized in the present invention on a functional group to provide a derivative which can be converted into a parent compound in vivo. A further aspect of the invention is a process for the manufacture of a compound of formula I, which comprises deprotection of a compound of formula II
____- 35 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(& ) 其中R1、R2、R3、R4、R5、R6、"及以系如以上的定義,以 及PG係保護基》 本發明也關於如以上定義之式(!)化合物的製造方法,該 方法包含除去在式(Ila)化合物中的去保護基____- 35 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Inventions (& ) where R1, R2, R3, R4, R5, R6, " The present invention also relates to a process for the production of a compound of formula (!) as defined above, which process comprises removing a deprotecting group in a compound of formula (Ila).
其中R、R2、R3· ' R4及R5係如以上的定義,以及pG係保護 基,並視需要將所得式(I)化合物轉化成醫藥上可接受之鹽 類。 在式(II)化合物中可能的保護基PG係例如低碳烷基-、点_ 二甲基甲>5夕虎基乙基-及/3-三氯乙基-酯類,可以使用其保 護對應的羧基。可在鹼存在下(如例wLi0H或Na〇H)的有機 溶劑中(如例如hO、乙醇、四氫呋喃或二咩烷)或這些溶劑 的混合物中以例如丨〇_ 501的溫度範圍下除去低碳烷基-酿 保理基。可在Zn存在下的醋酸中以例如1 〇· 5〇的溫度範圍 下除去万-二氣乙基-g旨保護基》可在氣化四丁基錄存在下 的四氫呋喃中以例如20-651的溫度範圍下除去点_三甲基 甲矽烷基乙基-酯保護基。在本技藝中已知將如以上定義的 式(I)化合物轉化成醫藥上可接受之鹽類的方法。 本發明進一步係關於在根據如以上定義的方法製造如以 _____- 36 - 本紙银尺度適用中國圉家標準(CNS) A4規格(210X 297公釐) 1328585Wherein R, R2, R3, 'R4 and R5 are as defined above, and a pG-based protecting group, and the resulting compound of formula (I) is converted to a pharmaceutically acceptable salt as needed. Possible protecting groups PG in the compound of the formula (II) are, for example, lower alkyl-, p-dimethylamino>5-thyl-ethyl- and /3-trichloroethyl-ester, which can be used Protect the corresponding carboxyl group. The low carbon can be removed in a temperature range such as 丨〇 501 in an organic solvent such as, for example, hO, ethanol, tetrahydrofuran or dioxane, or a mixture of these solvents in the presence of a base (e.g., wLiOH or Na〇H) Alkyl-bulk factor. The protecting group can be removed in the presence of Zn in the presence of Zn at a temperature of, for example, 1 〇·5 》. In the tetrahydrofuran in the presence of vaporized tetrabutyl, for example, 20-651 The point-trimethylformamidoethyl-ester protecting group is removed at a temperature range. Methods of converting a compound of formula (I) as defined above into a pharmaceutically acceptable salt are known in the art. The invention further relates to the application of the Chinese Standard (CNS) A4 specification (210X 297 mm) according to the method as defined above, such as _____- 36 - the paper silver scale 1328585
上定義的式(i)化合物時的該化合物。 如以上的說明,可以#用太 爲使用本發明的式Π)化合物作為治療 及/或預防以PPAR α另/弋dd a η · „ .. „ “及/或PPAR^K動劑調節之疾病的藥 劑。這些疾病的實例是搣 ]头 尿病)、血壓上升、脂質及膪 ,土糖 负及膽固%值降低、動脈粥樣硬化 疾病及代謝性徵候群。以作A ,.A & 以作為治療及/或預防非胰島素 型糖尿病之藥劑使用較佳。 句瓦依賴 本發明因此也關於包含如(上定義的化合物及在醫藥上 可接受之載體及/或佐劑之醫藥組合物。 本發明進-步係關於以如以上定義的化合物作為治療活 性物質的用途,特別作為治療及/或預防以ppARQ/或 PPARr促動劑調節之疾病的治療活性物質。這些疾病 例是糖尿病(特別是非姨島素依賴型糖尿病)、血壓上升、 脂質及膽固醇值降低、動脈粥樣硬化症疾病及代謝性徵候 群,以非胰島素依賴型糖尿病較佳。 在另-個具體實施例中,本發明係關於治療及/或預防以 PPARa及/或PPARr促動劑調節之疾病的方法該方法包 含以式I化合物投予人類或動物《這些疾病較佳的實例是糖 尿病(特別是非胰島素依賴型糖尿病)、血壓上升、脂質及 膽固醇值降低、動脈粥樣硬化症疾病及代謝性徵候^ ,以 治療及/或預防非胰島素依顇型糖尿病較佳。 本發明進一步係關於以如以上定義的化合物治療及/或預 防以PPARa及/或PPARt促動劑調節之疾病的用途。這些 疾病較佳的實例是糖尿病(特別是非胰島素依賴型^尿 _ -37 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X 297公釐) 裝 訂 線 34 1328585 五、發明説明( 病)、血壓上升、脂質及膽固醇值降低 '動脈粥樣硬化症疾 祸及代謝性徵候群,以非姨島素依賴型糖尿病較佳。 此外纟發明係關於以如以上定義的化合物製備藥劑的 用途’以供治療及/或預防以ppARa及βρρΑΐ^促動劑調 即《疾病。這些疾病較佳的實例是糖尿病(特別是非姨島 素依賴型糖尿病)、血壓上升、脂質及膽固醇值降低、動脈 粥樣硬化症疾病及代謝性徵候群,以非姨島素依賴型糖尿 病較佳。這些藥劑包含如以上苳義的化合物。 可由以下提供的方法'以在實例中提供的方法或以類似 的方法製造式⑴化合物1悉本技藝的人已知各個反應步 驟適當的反應條件。原料或是市售商品,或可以類似於以 下或在實例中提供的方法或以本技藝中已知的方法製備, 例如,從 wo 94/27995、w〇98/427〇4及Ερ 1〇78923和在本 文中引證的參考文及在以下文中引證的參考文。 可以例如根據在方程式1、方程式2及方程式3中描述的方 法或以類似的方法合成式⑴化合物6勺外消旋物(在方程式^ 中的化合物Η ’在方程式2中的化合物8,在方程式3中的化 合物外消旋性-6)與具有烷氧基取代基R5的非對掌性烯烴化 合物(在方程式1中的化合物1丨)。 可以例如根據在方程式3中描述的方法或以類似的方法合 成具有胺基取代基R 5的式(ί)化合物的外消旋物及旋光性純 的類似物(在方程式3中的化合物6)。 可以根據在方程式4中描述的方法或以類似的方法製備具 有烷氧基取代基R5的式(1)的單對掌性化合物(在方程式4 ^ -38 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公爱) 1328585 A7 B7The compound of the formula (i) above. As explained above, it is possible to use the compound of the formula 本) of the present invention as a treatment and/or prevention of a disease modulated by PPAR α / 弋 dd a η · „ .. „“ and/or PPAR^K kinetics. Pharmacy. Examples of these diseases are 搣 头 头 头 、 、 、 、 、 、 头 头 头 头 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 脂质 头 头 头It is preferred to use as an agent for the treatment and/or prevention of non-insulin type diabetes. The invention accordingly also relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant. The present invention relates to the use of a compound as defined above as a therapeutically active substance, in particular as a therapeutically active substance for the treatment and/or prevention of a disease modulated by a ppARQ/ or PPARr agonist. These diseases are diabetes ( In particular, non-insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, blood pressure, lipid and cholesterol, atherosclerotic disease, and metabolic syndrome are preferred. In an embodiment, the invention relates to a method of treating and/or preventing a disease modulated by a PPARa and/or PPARr activator, the method comprising administering a compound of formula I to a human or an animal. A preferred example of such a disease is diabetes (particularly Non-insulin-dependent diabetes mellitus, elevated blood pressure, decreased lipid and cholesterol levels, atherosclerotic disease, and metabolic signs are preferred for treating and/or preventing non-insulin-dependent diabetes mellitus. The present invention further relates to The use of a compound as defined above for the treatment and/or prophylaxis of diseases mediated by PPARa and/or PPARt agonists. A preferred example of these diseases is diabetes (especially non-insulin dependent urinary _37). Standard (CNS) A4 size (210X 297 mm) Gutter 34 1328585 V. Description of the invention (disease), increased blood pressure, decreased lipid and cholesterol values 'Atherosclerosis and metabolic syndrome, non-Island Dependent-type diabetes is preferred. Further, the invention relates to the use of a medicament for the preparation of a medicament as defined above for treatment and/or prevention. ppARa and βρρΑΐ 促 促 促 《 《 《 《 《 《 《 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Groups, preferably non-alked-dependent diabetes mellitus. These agents comprise a compound as defined above. The method of the present invention can be produced by the method provided below by the method provided in the examples or by a similar method. Suitable reaction conditions for each reaction step are known. The starting materials are either commercially available or can be prepared analogously to the methods provided below or in the examples or by methods known in the art, for example, from wo 94/27995, w 〇98/427〇4 and Ερ 1〇78923 and the references cited therein and the references cited in the following. The racemate of the compound of formula (1) can be synthesized, for example, according to the method described in Equation 1, Equation 2 and Equation 3 or in a similar manner (compound 在 in equation ^, compound 8 in equation 2, in the equation The compound in 3 is racemic-6) and the non-p-palphatic olefin compound having an alkoxy substituent R5 (compound 1 in Formula 1). The racemate and optically pure analog (compound 6 in Equation 3) of the compound of the formula (I) having an amino substituent R 5 can be synthesized, for example, according to the method described in Equation 3 or in a similar manner. . A single pair of palm compounds of formula (1) having an alkoxy substituent R5 can be prepared according to the method described in Equation 4 or in a similar manner (in Equation 4^-38, this paper scale applies to the Chinese National Standard (CNS)). Α4 specifications (210X297 public) 1328585 A7 B7
1328585 A7 B71328585 A7 B7
1328585 A7 ____B7 五、發明説明(37 ) 已知酚1及/或醛6,或可以在本技藝中已知的方法合成。 在万程式5- 1 0中提供這些酚及醛可能的合成實例。根據已 知的步驟濃縮芳基-呤唑化合物2(如方程式丨丨—^陳列的方 式製備)與酚1或醛6,如果R12代表羥基,則經由以三苯膦 及偶氮二羧基二第三丁基_、二異丙基或二乙基-酯作為試 劑的Mitsunobu-反應,以在如甲笨或四氫呋喃之溶劑中以 室溫進行Mitsunobu-反應較佳。或者如果代表齒化物、 甲磺醯酸酯或甲苯磺醯酸酯部-曾時,則可將芳基号唑化合 物2與酚1或醛6在如碳酸铯或破酸鉀之弱鹼的存在下的如 Ν,Ν·二甲基甲醯胺 '丙酮或甲乙酮之溶劑中以從室溫至14〇 C的溫度範圍(以約50°C較佳)反應,因此獲得醚化合物3或 醛5(步驟a)。接著將前者加以滇基甲基化作用,例如,以在 惰性溶劑中(以二氣甲烷較佳)的三吟烷及HBr(以62%水性 HBr較佳)在〇。(;下(較佳)處理,以得到高反應性及時常非常 不穩定的親電子物4(步驟b)。親電予物4適合使烷氧基-醋酸 酿7 ( Ru=低碳烷基)的烯醇化物烷基化,以在如四氫呋喃 之洛劑中的如二異丙基醯胺鋰之強的非親核性鹼在· 781下 處理7所製得的締醇化鋰。為了增加缔醇化親電子物之反應 性,故以在如六曱基磷醯胺二甲基·3,4,5,6· 四氫- 2(1Η) -嘧啶酮(DMPU)之共溶劑的存在下進行反應較 佳’以得到酯9(步驟d)。或者將也可以vnsmeier甲醯化作 用或經由在四氯化鈦存在下的甲醯化作用(以在介於_ 78。〇 與/谷劑的回泥溫度之間的溫度下的二氣甲垸中較佳)取得的 醛化合物5(步驟c)與烷氧基-醋酸酯(7)的烯醇化物(以在如 ----- 41 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 13285851328585 A7 ____B7 V. INSTRUCTION DESCRIPTION (37) Phenol 1 and/or aldehyde 6 are known or can be synthesized by methods known in the art. Examples of possible synthesis of these phenols and aldehydes are provided in Million 5-10. The aryl-carbazole compound 2 (prepared as shown in the formula )-^) and phenol 1 or aldehyde 6 are concentrated according to known procedures, and if R12 represents a hydroxyl group, via triphenylphosphine and azodicarboxydi The Mitsunobu-reaction of tributyl-, di-isopropyl or diethyl-ester as a reagent is preferably carried out at room temperature in a solvent such as methyl or tetrahydrofuran. Or if it represents a tooth, a sulfonate or a toluene sulfonate-previously, the presence of the aryl azole compound 2 and the phenol 1 or aldehyde 6 in a weak base such as cesium carbonate or potassium hydride The solvent such as hydrazine, hydrazine dimethyl carbamide, acetone or methyl ethyl ketone is reacted at a temperature ranging from room temperature to 14 Torr C (preferably at about 50 ° C), thereby obtaining an ether compound 3 or an aldehyde 5 (Step a). The former is then subjected to mercaptomethylation, for example, in an inert solvent (preferably dioxane methane) of trioxane and HBr (preferably 62% aqueous HBr). (lower (preferred) treatment to obtain highly reactive, often very unstable, electrophilic material 4 (step b). Electrophilic feed 4 is suitable for alkoxy-acetic acid brewing 7 (Ru = lower alkyl) The enolate is alkylated to treat 7 of the lithium enolates prepared by treatment with a strong non-nucleophilic base such as lithium diisopropylguanidinium in a reagent such as tetrahydrofuran. The reactivity of the alcoholated electrophile, so in the presence of a cosolvent such as hexamethylenephosphonium dimethyl 3,4,5,6·tetrahydro-2(1Η)-pyrimidinone (DMPU) The reaction is preferably carried out to obtain ester 9 (step d). Alternatively, it may also be vnsmeier for caramification or via formazanization in the presence of titanium tetrachloride (for at between -78. Preferably, the aldehyde compound 5 (step c) and the enolate of the alkoxy-acetate (7) are obtained in the dioxane at a temperature between the mud back temperatures (for example, in---- 41 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585
四氫呋喃《/谷劑中的如二異丙基醯胺鋰之強的非親核性鹼 在-78 C下處理7所製得的烯醇化鋰較佳)在如四氫呋喃之溶 d中反應以約-78 C的溫度較佳,以得到成為非對映異構 物混合物足醛醇產物8。以在如三氟化硼之路易士酸或在如 三氣醋酸之非質子惰性酸存在下的三乙基甲矽烷在如三氟 醋魬本身或二氯甲烷之適合的溶劑中以介於〇。〇至6〇。〇之間 除去在8中的苄系羥基,以得到外消旋酯9(步驟f)。或者可 將链5與在如異丙醇、二氯甲乾〜或四氫吱喃或其混合物之溶 劑中的Wittig鹽(如氯化(乙氧基:乙氧羰基_甲基)_三苯基鎸 或溴化(甲氧基-甲氧羰基-甲基)_三苯基鱗)在如碳酸鉀或 1,8 一吖雙%[5.4.0]十一 _7_埽(DBU)之鹼的存在下反應, 以介於〇 c至落劑的回流溫度下較佳,以得到成為£及/或z 異構物的丙晞酸酯H)(步驟g)。在如甲醇、四氫呋喃、醋 I、一氣甲烷及其混合物之溶劑中使用在木炭上的纪作為 觸媒的丙烯酸酯丨〇的氫化作用(以在室溫及丨大氣壓的氫氣 壓下較佳)供給外消旋性酯9(步驟h)。可以使用預定的時間 進行其中以R3-R4與和其附著之苯環一起形成苯并呋喃部份 的化合物的氫化作用,以提供對應的笨并二氫呋喃類似 物。在其中以R3-R4與和其附著之苯環一起形成苯并嘍吩部 份的化合物中,以在如四氫呋喃/甲醇之溶劑混合物中的鎂 以介於室溫至溶劑的回流溫度進行雙鍵還原作用較佳。可 視需要根據標準步騾水解酯9及_1〇,例如以在如四氫呋喃/ 乙醇/水之極性溶劑混合物中的如LiOH或NaOH之鹼性氫氧 化物處理,生成羧酸1 1(步驟i)。 ____- 42 - 本纸張尺度適用中國國家標準(CNS> A4规格(210x 297公釐)It is preferred to treat the lithium enolate prepared by treating a strong non-nucleophilic base such as lithium diisopropylguanidinium at -78 C in a tetrahydrofuran/valid in a solution such as tetrahydrofuran. The temperature of -78 C is preferred to give the diastereomeric product a fulleraldehyde product 8 . Triethylmethane in the presence of a Lewis acid such as boron trifluoride or an aprotic acid such as tri-acetic acid in a suitable solvent such as trifluoroacetic acid itself or dichloromethane . 〇 to 6〇. The benzylic hydroxyl group in 8 is removed between the oximes to give the racemic ester 9 (step f). Or a Wittig salt (such as chlorinated (ethoxy: ethoxycarbonyl-methyl)-triphenyl) in a solvent such as isopropanol, dichloromethane or tetrahydrofuran or a mixture thereof. Base or brominated (methoxy-methoxycarbonyl-methyl)-triphenyl scales in, for example, potassium carbonate or 1,8 吖 %% [5.4.0] 十一_7_埽 (DBU) The reaction is carried out in the presence of a base, preferably at a reflux temperature of 〇c to the falling agent, to obtain a propionate H) which is a beta and/or z isomer (step g). The hydrogenation of acrylate oxime as a catalyst on charcoal (preferably at room temperature and hydrogen pressure at atmospheric pressure) is used in a solvent such as methanol, tetrahydrofuran, vinegar I, monomethane and mixtures thereof. Racemic ester 9 (step h). Hydrogenation of a compound in which R3-R4 forms a benzofuran moiety with a benzene ring attached thereto can be carried out for a predetermined period of time to provide a corresponding stupid dihydrofuran analog. In the compound in which R3-R4 forms a benzophenan moiety together with the benzene ring to which it is attached, the double bond is carried out at a reflux temperature from room temperature to the solvent in magnesium in a solvent mixture such as tetrahydrofuran/methanol. The reduction is preferred. The esters 9 and 〇 can be hydrolyzed according to standard procedures, for example, by treatment with an alkali hydroxide such as LiOH or NaOH in a polar solvent mixture such as tetrahydrofuran/ethanol/water to form the carboxylic acid 1 1 (step i) . ____- 42 - This paper size applies to Chinese national standards (CNS> A4 size (210x 297 mm)
.裝 訂Binding
線 1328585 A7 B7Line 1328585 A7 B7
1328585 A7 _________ B7____ 五、發明説明(40 ) 鈦的存在下的甲醯化作用,以在介於_ 78〇c至溶劑的回流溫 度下的二氯甲烷中較佳(步驟b)。接著可將醛3與在如異丙 醇、二氣甲烷或四氫呋喃或其混合物之溶劑中的Wittig鹽 (如氯化(乙氧基-乙氧羰基-甲基)_三苯基鱗或溴化(甲氧 基-曱氧幾基-曱基)-三笨基鱗)在如碳酸鉀或i,8•二吖雙環 [5.4.0] Η -7-烯(DBU)之鹼的存在下反應,以在介於〇°C 至溶劑的戶流溫度下較佳,以得到成為E及/或z異構物的丙 烯酸酯4(步驟c)。以在木炭上的^巴在如曱醇、乙醇或四氫呋 喃之溶劑中-使丙烯酸酯4以觸媒·氫化作用生成酚5(步驟d)。 在以R3及R4與和其附著之苯環一起形成苯并噻吩或苯并呋 喃部份的案例中,以兩步驟較佳:在第一個反應中,使用 在甲醇與四氫呋喃之混合物中的鎂以介於室溫至溶劑的回 流溫度還原丙烯酸酯的雙鍵。接著將如苄酯之保護基裂 解例如使用在如二氯甲烷之溶劑中的二甲硫及三氟化硼 一乙链在介於室溫至溶劑的回流溫度之間裂解以得到酚 系化合物5。接著使用在方程式丨中供濃縮酚丨或4-羥基-苯 链6與芳基十坐所說明的已知步驟,以濃縮那些自分系化合物 與方基3唑6得到醚化合物7(步驟e)。可視需要將酯7使用鹼 性水解作用的標準條件色化成酸8 (步驟。 本纸伕尺度適用中國M規格(2ι〇χ2=治-------- 1328585 A7 B71328585 A7 _________ B7____ V. INSTRUCTION DESCRIPTION (40) Metathylation in the presence of titanium is preferred in methylene chloride at a reflux temperature of from -78 ° C to the solvent (step b). The aldehyde 3 can then be combined with a Wittig salt (such as chlorinated (ethoxy-ethoxycarbonyl-methyl)-triphenyl scale or brominated in a solvent such as isopropanol, di-methane or tetrahydrofuran or a mixture thereof. (Methoxy-oxiranyl-fluorenyl)-trisyl scales are reacted in the presence of a base such as potassium carbonate or i.8.bi-bicyclo[5.4.0]indole-7-ene (DBU). Preferably, it is at a temperature of from 〇 ° C to the temperature of the solvent to obtain an acrylate 4 which is an E and/or z isomer (step c). The acrylate 4 is hydrogenated by a catalyst to produce phenol 5 in a solvent such as decyl alcohol, ethanol or tetrahydrofuran on charcoal (step d). In the case where R3 and R4 form a benzothiophene or a benzofuran moiety together with the benzene ring to which it is attached, it is preferably carried out in two steps: in the first reaction, magnesium in a mixture of methanol and tetrahydrofuran is used. The double bond of the acrylate is reduced at a temperature ranging from room temperature to the reflux temperature of the solvent. Next, the protecting group such as benzyl ester is cleaved, for example, using dimethyl sulfide and boron trifluoride-ethyl bromide in a solvent such as dichloromethane to cleave between room temperature and the reflux temperature of the solvent to obtain a phenolic compound 5 . The known procedure described in the equation 丨 for concentrating phenolphthalein or 4-hydroxy-benzene chain 6 with an aryl group is then used to concentrate those self-dividing compounds with the aryl 3 azole 6 to give the ether compound 7 (step e) . Ester 7 can be colored into acid 8 using standard conditions of alkaline hydrolysis as needed (step. This paper scale applies to China M specification (2ι〇χ2=治-------- 1328585 A7 B7)
13285851328585
α胺基gs 4之製備可藉由j)以在四氫吱喃之惰性溶劑中的 如二異丙基醯胺鋰之強的非親核性鹼處理,將保護之甘胺 酸酯(以N-(二笨基亞甲基)甘胺酸乙酯較佳)在_78它下(較 佳)轉變成對應的晞醇化物(以埽醇化鋰較佳);η)將因此形 成的缔醇化物與芊基漠U在方程式1中的化合物4)反應, 以-78 t至室溫之間較佳,以在增加如六甲基磷醯胺 (HMPA)或 1,3 - 一甲基 _3,4,5,6-四氫-2( 1H) - 口密咬酮(DMPU) 之親電子物的反應性之共溶劑-的存.在下較佳:iH)亞胺中間 物與酸(例如,稀釋的氯化氫水溶液)的水解作用(步驟a)。 或者可以醛2(方程式丨中的化合物5)製備α胺基酯4,其係藉 由1)與在如二氣甲烷或四氫呋喃之溶劑中適合的二氧磷甘 胺酸酯(例如,Ν-(芊氧羰基)_α_二氧磷甘胺酸三甲酯)在 如胡尼格氏(Huenig)鹼之鹼的存在下以介於室溫至溶劑的 回流下濃縮,以生成烯胺胺基甲酸酯;3 ;丨i)使用例如氫在木 炭上的鈀的存在下,將在如醋酸乙酯、四氫呋喃或甲醇之 溶劑中的烯胺胺基甲酸酯3以觸媒氫化及去保護(步驟b, c) °以i)使用製備性對掌性HPLC管柱之色層分離法分離成 對映體或ii)缔胺胺基甲酸g旨3在搞有如ι,2·雙[(2S,5S)-2 5_ 二乙基磷烷醯基]苯之對掌性配體之鍺觸媒存在下的如甲醇 之溶劑中以觸媒氫化[比較J. Am. Chem. Soc.(2000), 122(16),3830-3838] ’接著使用如以免觸媒輔助的氫解作 用之標準反應條件除去Z-保護基。接著以α胺基酯4與在如 甲苯之惰性溶劑中適合的酮及在回流溫度下反應,視需要 在如對-甲苯磺酸之觸媒的存在下,以轉化成烯胺5。在木 -46 本紙張尺度適用中酉國家標準(CNS) Α4规格(210X297公釐) 1328585 A7 B7 五、發明説明( 炭上的Pd存在下及約18(TC的溫度下使用2·苯醯基環己酮作 為在如茴香醚之惰性溶劑中的酮組份之案例中,接著以芳 構化形成烯胺(步驟d)。可視需要將烯胺酯外消旋性_ 5或 (S)-5使用鹼性水解作用的標準條件皂化成酸外消旋性_6或 (S)-6(步驟 e)eThe preparation of the α-amino group gs 4 can be carried out by treating the glycinate as a strong non-nucleophilic base such as lithium diisopropylguanidinium in an inert solvent of tetrahydrofuran. Preferably, N-(diphenylmethylene)glycolate is converted to a corresponding decanoate (preferably lithium decanoate) under _78; η) will form a The alcoholate is reacted with the sulfhydryl group U in the compound 4) of the formula 1, preferably between -78 t and room temperature, in order to increase, for example, hexamethylphosphoniumamine (HMPA) or 1,3-methyl-methyl _3,4,5,6-tetrahydro-2( 1H) - the co-solvent of the electrophile of the benzoic ketone (DMPU) - preferably the following: iH) imine intermediate and acid Hydrolysis (for example, dilute aqueous hydrogen chloride solution) (step a). Alternatively, the alpha amino ester 4 can be prepared from aldehyde 2 (compound 5 in the formula ,) by using 1) a diphosphoric acid glycinate suitable for use in a solvent such as di-methane or tetrahydrofuran (for example, hydrazine- (Mercaptooxycarbonyl)_α_trioxophosphoric acid trimethyl ester) is concentrated in the presence of a base such as Huenig's base at room temperature to reflux of the solvent to form an enamine amine group. Formate; 3; 丨i) Hydrogenation and deprotection of enamine urethane 3 in a solvent such as ethyl acetate, tetrahydrofuran or methanol using, for example, hydrogen in the presence of palladium on charcoal (Step b, c) ° by i) Separation into enantiomers by preparative chromatographic HPLC column chromatography or ii) hydrazinocarbamic acid g3 in the presence of ι,2·双[( 2S,5S)-2 5_Diethylphosphinyl]phenyl to a palmitic ligand in the presence of a catalyst such as methanol in a solvent such as methanol hydrogenated [Comparative J. Am. Chem. Soc. (2000) ), 122(16), 3830-3838] 'The Z-protecting group is then removed using standard reaction conditions such as catalyst-free hydrogenolysis. Next, the α-amino ester 4 is reacted with a suitable ketone in an inert solvent such as toluene and at a reflux temperature, if necessary, in the presence of a catalyst such as p-toluenesulfonic acid to be converted into the enamine 5. In wood-46 paper scale applicable Chinese national standard (CNS) Α4 specification (210X297 mm) 1328585 A7 B7 V. Description of invention (in the presence of Pd on carbon and about 18 (using benzoyl group at TC temperature) The cyclohexanone is used as a ketone component in an inert solvent such as anisole, followed by aromatization to form an enamine (step d). The enamino ester racemization _ 5 or (S)- can be optionally used. 5 saponification to acid racemic _6 or (S)-6 using standard conditions of alkaline hydrolysis (step e)e
1328585 A7 B71328585 A7 B7
1328585 A7 _____ B7 五、發明説45) — 可以根據在方程式4中描述的方法或以本技藝中已知的類 似万法製備式8的單對掌性α烷氧基苯基丙酸化合物。 將熟知的對掌性輔助劑2 [ ( s) _ 4 -芊基噚唑烷_ 2 _酮]與烷氧 基乙醯氣1在如四氫呋喃之惰性溶劑中的如正丁基鋰的存在 下以约-78 C的溫度濃縮,以產生組塊3(步騾a)。接著根據 又獻步驟[Tetrahedron Asymmetry( 1999),10, 1353- 1 367], 將後者與在二氣甲烷中的二丁基硼-三氟甲磺酸酯及如三乙 胺之二級胺反應,以產生對應-的烯醇化硼,接著將其在低 溫下與苯醛4(在方程式!中的化合物5 )反應,以生成化合物 (5)(步驟b)。在化合物5中,所有4種可能的立體異構物的其 中之極佔優勢(沒有嚴格的證明顯示的立體化學)。接著 以還原方式除去苄系羥基,如在方程式1中將化合物8轉化 成化合物9的說明,以產生倒數第二個中間物6(步驟c)。最 後以醇納在作為溶劑的對應醇中或在如四氫呋喃或二呤烷 之洛劑中以約〇t的溫度小心醇解(步驟d)或以稀釋的Na〇H 在四氫咬喃/水中以〇°C小心醇解(步驟e),可以獲得酯7或酸 化合物8 ’不以外消旋作用。以對掌性hplc或以1H-NMR 光1晋學在如1·(9-蒽基)_2,2,2-三氟基乙醇之對掌性溶劑 的存在下可以測定化合物7及8的旋光純度,並在所有 以實例說明的案例中發現彼具有高純度。 已知或可以在本技藝中已知的方法合成酚1及/或醛 6(方程式1)、酚1及/或保護之盼2及/或保護之醛3(方程 式2)及》号嗤2 (方程式1)。在方程式5_丨2中提供這些關鍵的 中間物可能的合成實例。 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(46 )1328585 A7 _____ B7 V. Inventive Statement 45) - A single pair of palmitic alpha alkoxyphenylpropionic acid compounds of formula 8 can be prepared according to the methods described in Equation 4 or analogously known in the art. The well-known pair of palmitic adjuvant 2 [( s) _ 4 -mercaptooxazolidine 2 - ketone] and alkoxy oxime 1 in the presence of, for example, n-butyllithium in an inert solvent such as tetrahydrofuran Concentrate at a temperature of about -78 C to produce chunk 3 (step a). The latter is then reacted with dibutyl boron-trifluoromethanesulfonate in di-methane and a secondary amine such as triethylamine according to the additional procedure [Tetrahedron Asymmetry (1999), 10, 1353-1 367] To produce the corresponding-enolated boron, which is then reacted with benzaldehyde 4 (Compound 5 in Equation!) at low temperature to give compound (5) (step b). Among the compounds 5, all of the four possible stereoisomers are extremely dominant (there is no strict proof of the stereochemistry shown). The benzylic hydroxyl group is then removed in a reduced manner, as illustrated by the conversion of compound 8 to compound 9 in Equation 1, to produce the penultimate intermediate 6 (step c). Finally, the alcohol is carefully decomposed in a corresponding alcohol as a solvent or in a reagent such as tetrahydrofuran or dioxane at a temperature of about 〇t (step d) or diluted Na〇H in tetrahydroanhydride/water. By careful alcoholysis (step e) at 〇 ° C, ester 7 or acid compound 8 ' can be obtained without racemization. The optical rotation of compounds 7 and 8 can be determined by the presence of palmar hplc or 1H-NMR light in the presence of a palmitic solvent such as 1·(9-fluorenyl)_2,2,2-trifluoroethanol. Purity, and found in all case examples to be of high purity. It is known or can synthesize phenol 1 and/or aldehyde 6 (Equation 1), phenol 1 and/or protected 2 and/or protected aldehyde 3 (Equation 2) and 嗤 2 in a method known in the art. (Equation 1). A possible synthesis example of these key intermediates is provided in Equation 5_丨2. This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1328585 A7 B7 V. Invention description (46)
已知 4-羥基苯并呋喃 5[ Synthetic Communications( 1986), 16( 13), 1635- 1640; Helvetica Chimica Acta( 1933), 16, 121-129]及4-羥基苯并嘍吩 8[Jpn. Kokai Tokkyo Koho(2001), 2〇01048876A2]。因此’可將在5_位置上攜有不同的取代基 R6的環己烷-1,3-二酮1與在甲醇中的溴基丙酮酸在如氫氧 化卸之驗的存在下以介於〇。〇至曱醇的回流溫度之間的溫度 反應’接著在約l〇〇t:下以氫氣酸處理,以得到呋喃-羧酸 3(步驟a)。在十二烯之氫接受劑及在碳上的鈀的存在下處理 在如十氫茶之惰性溶劑中的這些呋喃-羧酸3,在回流下較 佳,以提供羧基苯并呋喃4(步驟b),將其以脫羧基成為苯 并呋喃5,例如,在介於2〇〇。(:至24〇。(:之間的溫度下使用在4-Hydroxybenzofuran 5 [Synthetic Communications (1986), 16(13), 1635-1640; Helvetica Chimica Acta (1933), 16, 121-129] and 4-hydroxybenzophenone 8 [Jpn. Kokai Tokkyo Koho (2001), 2〇01048876A2]. Therefore, 'cyclohexane-1,3-dione 1 carrying a different substituent R6 at the 5_ position can be interposed with bromopyruvate in methanol in the presence of, for example, a hydroxide desorption test. Hey. The temperature reaction between the reflux temperature of hydrazine and decyl alcohol is then treated with hydrogen acid at about 1 Torr to obtain furan-carboxylic acid 3 (step a). These furan-carboxylic acid 3s are treated in an inert solvent such as decahydrocha in the presence of a hydrogen acceptor of dodecene and palladium on carbon, preferably under reflux to provide carboxybenzofuran 4 (step b), decarboxylation to benzofuran 5, for example, at 2 Torr. (: to 24 〇. (: used between temperatures
1328585 A7 B7 五、發明説明(47 )1328585 A7 B7 V. Description of invention (47)
喳啉中的銅粉(步驟c)。以在如四氫呔喃或1,2·二甲氧基乙 烷之溶劑中適合的乙烯基鋰-或乙烯基鎂-衍生物處理2-嘍 吩羧醛6,以在介於· 78至室溫之間的溫度較佳,接著當 場以醋酸酐處理,以產生具有不同的取代基R6之噻吩7(步 驟d) »以一氧化碳(以2〇至6〇巴的壓力較佳)’如醋酸鈀之鈀 觸媒,如三笨膦之膦在溶劑混令物中(其典型係包括醋酸 肝、二乙胺、甲笨或四氫P夫喃)處理p塞吩7,以在介於1 至1 60 C之間的溫度較佳,以在〜醋酸酯官能性的皂化作用之 後供給苯并-4吩8(步驟e)。 方程式6Copper powder in porphyrin (step c). Treating 2-nonylcarboxyaldehyde 6 with a vinyl lithium- or vinyl magnesium-derivative suitable in a solvent such as tetrahydrofuran or 1,2 dimethoxyethane, at a distance of from 78 to The temperature between room temperature is preferred, followed by treatment with acetic anhydride to produce thiophene 7 having a different substituent R6 (step d) » with carbon monoxide (preferably at a pressure of 2 to 6 bar), such as acetic acid Palladium-based palladium catalyst, such as trisphosphine phosphine, in a solvent blend (which typically includes acetic acid liver, diethylamine, methyl bromide or tetrahydropyrene) to treat p-septene 7 at The temperature between 1 and 60 C is preferably such that benzo-4 phen 8 is supplied after the saponification of the -acetate function (step e). Equation 6
-51 --51 -
13285851328585
可將視需要在位置5上以溴取代之2-羥基-3-甲氧基苯醛i 轉變成苯并[b]苯硫_7_酚6或5_溴基苯并[b]苯硫_7•酚6。 了 X 士貝似於在 j. Chem. Soc.,Perkin Trans. 1 1983( 12), 2973- 7中說明的方法進行該順序。關於以2_羥基_ %甲氧基 苯醛成為笨并[b]苯硫·7_酚之轉變作用:在如在水中的氫 氧化鉀之水性鹼的存在下或在如二異丙基乙胺之有機鹼的 存在下,以在如四氫呋喃之溶劑中的Ν,Ν-二甲基硫代胺甲 醞基氣處理,以在介於〇r至室^之間的溫度較佳,以產生 硫逐胺基甲酸酯2(步驟a);在介於2〇〇。(:至28〇。(:之間的溫度 下,以沒有溶劑或在如二苯醚之惰性溶劑中(較佳)的2的熱 重組作用生成S·芳基硫逐胺基甲酸酷3(步驟b);接著以如 氫氧化麵或鉀之驗在如醇之溶劑中的色化作用±成苯硫齡 4,以在介於1溫至溶劑的回流溫度之間的溫度較佳(步驟 ^,以在水或水醇混合物中的苯硫酚4與氯基醋酸鈉在如氫 氧匕鈉或鉀之鹼的存在下以介於室溫至溶劑的回流溫度之 間的溫度反應,接著產生苯并1>塞吩_羧酸5(步驟幻;脫羧基 作用例如,在頁銅存在下的喹啉中以介於2〇〇。匚至24〇ec 之間的溫度,#著甲醚機能的裂開作用,例如,以在醋酸 中的水性氫漠酸在回流下處理1著最後產生苯并[b]苯 硫-7-朌6(步驟e)。7_幾基苯并吱喃是已知及市售商品 时Chem.( 1987),卯),训]。在類似於上述的順序 中’以2_經基-3-甲氧基苯^可以製備5_漠基同系物,其 係以在如Ν,Ν-二甲基甲gs·脖 > 六巾丨丄,, ^ . 丞T 妝足'谷劑中的2-羥基-3-甲氧基苯 链1與氯基醋酸乙酿在如碳酸卸之驗的存在下以介於6代至 本紙張尺度適財_家標準(CNS) A4規格(21QX297;^-------________ 1328585 A7 B7Conversion of 2-hydroxy-3-methoxybenzaldehyde i substituted with bromine at position 5 to benzo[b]phenylsulfonyl-7-phenol 6 or 5-bromobenzo[b]benzenesulfide _7• Phenol 6. This sequence is carried out as described in J. Chem. Soc., Perkin Trans. 1 1983 (12), 2973-7. Regarding the conversion of 2-hydroxyl-% methoxybenzaldehyde to stupid [b] phenylsulfan-7-phenol: in the presence of an aqueous base such as potassium hydroxide in water or in the presence of, for example, diisopropyl In the presence of an amine organic base, it is treated with hydrazine, dimethyl-dimethyl thiocarbamidine gas in a solvent such as tetrahydrofuran, preferably at a temperature between 〇r and chamber to produce Sulfur urethane 2 (step a); between 2 Torr. (: to 28 〇. (: between the temperature, the thermal recombination with no solvent or in an inert solvent such as diphenyl ether (preferably) 2 to produce S · aryl thiocarbamic acid formic acid 3 ( Step b); followed by a coloration of, for example, a hydroxide or potassium in a solvent such as an alcohol; benzene sulphur age 4, preferably at a temperature between 1 temperature and the reflux temperature of the solvent (steps) ^, reacting thiophenol 4 in sodium or sodium chloroacetate in a water or hydroalcohol mixture at a temperature between room temperature and the reflux temperature of the solvent in the presence of a base such as sodium or potassium hydroxide, followed by Producing benzo-1>cepheno-carboxylic acid 5 (step phantom; decarboxylation effect, for example, in quinoline in the presence of copper in the form of a temperature between 2 〇〇. 匚 to 24 〇 ec, #着甲Functional cleavage, for example, treatment of aqueous hydrazine in acetic acid under reflux to produce benzo[b]phenylsulfan-7-朌6 (step e). 7-Mercaptobenzopyran Is known and commercially available when Chem. (1987), 卯), in the order similar to the above, '5-carbyl-3-methoxybenzene can be used to prepare 5-formyl homologues, Its system is like , Ν-dimethyl kegs · neck > six 丨丄 丨丄,, ^ . 丞T makeup foot 'glutamine 2-hydroxy-3-methoxybenzene chain 1 and chloroacetic acid ethyl The existence of the unloading test is based on the 6th generation to the paper scale. The standard (CNS) A4 specification (21QX297; ^-------________ 1328585 A7 B7
五、發明说明( !20。(:之間的溫度下反應,以產生笨并呋喃羧酸7(步驟f)。 接著以如上述的脫羧基作用及確定的醚解離開作用(以在室 溫下的吡啶鹽酸鹽較佳)生成5_溴基_7_羥基苯并呋喃8(步驟 g)。 方程式7V. Description of the invention (!20. (: reaction between temperatures to produce stupid and furancarboxylic acid 7 (step f). Next with decarboxylation as described above and defined ether solution leaving (at room temperature) The lower pyridine hydrochloride is preferred to give 5-bromo-7-hydroxybenzofuran 8 (step g).
卜羥莕1及具有5、6及7個環尺寸之2,3-環節型酚2係市售 商品或是已知的[參考 J. Am. C hem. Soc.(1988),110(19), 6471-6480; U.S.(2000) 6121397; PCT Int. Αρρ1·( 1999) WO99/10339]。可自 3-硝基-1·甲氧萘 3 [ivlonatsh.Hydroxaquinone 1 and 2,3-linked phenol 2 having 5, 6 and 7 ring sizes are commercially available or known [Ref. J. Am. C hem. Soc. (1988), 110 (19) ), 6471-6480; US (2000) 6121397; PCT Int. Αρρ1·(1999) WO99/10339]. Available from 3-nitro-1·methoxynaphthalene 3 [ivlonatsh.
Chem.(1992),123(6-7),637-645]以完整建立的步郵製備允 _- 53 - 本纸弦尺度適用中固國家標準(CNS) A4规格(210X297公爱) 1328585 A7 B7 50 五、發明説明( 許在最後階段合成改進作用的撝有官能度的中間物3_漠基_ i -經茶4 ’即以硝基官能性的還原作用,例如,在纪觸媒存 在下的氫化作用,接著以重氮化作用,反應及甲 醚官能的裂解作用,以得到3-漠基小羥茶4(步驟&,b c)。 已知2,3-環節型羧酸5,已知其之3_溴基同系物6,或可以經 建立之芳族核的溴化法製備[j. 0rg. Chem ( 1987),43(11夂 2167-70; Ger· Offen_(i977),DE 2633905](步驟d)。接著可 > 裝 將3 -漠基苯曱酸以已知的方法·後化成對應酚7,如以例如甲 硼烷的摧毁性環原成對應醇,以例如使用Swern條件(在二 鼠甲纟元中的早驢氣/二甲基亞_5風/三乙胺,-78eC至室溫)氧 化成對醛’接著以在醋酸中的過醋酸(4〇%)的Baeyer· Villiger氧化作用(步驟e,f,g)。 — 方程式8 '0 X)、Chem. (1992), 123 (6-7), 637-645] Prepared by the complete established step _- 53 - This paper string scale applies to the China National Standard (CNS) A4 specification (210X297 public) 1328585 A7 B7 50 V. INSTRUCTION DESCRIPTION (In the final stage, the synthetically improved intermediates of the functionally modified intermediates 3_Moji_i- via tea 4' are reduced by nitro-functionality, for example, in the presence of a catalyst Subsequent hydrogenation followed by diazotization, reaction and methyl ether functional cleavage to give 3-amino-based small hydroxy tea 4 (step & bc). 2,3-linked carboxylic acid 5 is known. It is known that its 3-bromo homologue 6, or can be prepared by bromination of an established aromatic nucleus [j. 0rg. Chem (1987), 43 (11夂2167-70; Ger· Offen_(i977) , DE 2633905] (step d). It is then possible to post-degrade 3-oxalylphthalic acid to the corresponding phenol 7 in a known manner, such as by using a destructive ring of, for example, borane to form the corresponding alcohol. For example, using Swern conditions (early helium/dimethyl _5 wind/triethylamine in two mouse mitochonds, -78eC to room temperature) is oxidized to p-aldehydes followed by peracetic acid in acetic acid (4 〇%) of Baeyer Vill Eriger oxidation (steps e, f, g). — Equation 8 '0 X),
訂 線Ordering
_ - 54 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585 A7 B7_ - 54 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7
已知以環節型六氫吨喃環為特徵之澳基甲氧基化合物 l[Can. j. chem.( 1982),60(16),2〇93·8]。以吡啶鹽酸鹽在 約2〇()t下的甲氧醚官能之裂解作用生成3_溴酚2(步騾a)。 以如下可以獲得異構物組塊:可將羧酸3[1; s (丨999), 溴化,以得到3-溴基衍生物4(步驟…,以類似於 在方程式7中將化合物6轉變成化合物7所說明的順序,可將 其轉變成朌5(步騾c,d,e)。 方程式9 - 厂》3 ^4Alkyl methoxylates characterized by a hexahydro oxane ring are known [Can. j. chem. (1982), 60(16), 2〇93·8]. The methoxy ether-functional cleavage of pyridine hydrochloride at about 2 Torr (t) yields 3-bromophenol 2 (step a). The isomer block can be obtained as follows: the carboxylic acid 3[1; s (丨999) can be brominated to give the 3-bromo derivative 4 (step ..., similar to the compound 6 in the equation 7) Converted to the order illustrated by compound 7, which can be converted to 朌5 (step c, d, e). Equation 9 - Plant" 3 ^4
可將視需要攜有保護性官能基之3_溴酚1轉化成攜有不同 的官能基R6之同系酚2 ,先將溴基化合物轉變成對應芳基鋰 衍生物(例如,使用在如四氫呋喃之溶劑中的烷基鋰試劑, 以在約-78。(:的溫度下較佳),並接著使用在本技藝中熟知 的方法,以各種親電子物中止後者(步驟a) ^關於酚 (R6=OH)的合成,以芳基鋰化合物與三曱基甲硼烷在介於_ 78eC至四氫咬喃的回流溫度之間的溫度下反應,接著以例 如N-甲基嗎啉小氧化物氧化,以在四氫呋喃的回流溫度下 較佳[比較Syn丨ett 1995(09),93 1-932]。接著可將具有 R6=OH的這些酚2以熟知的方法轉變成對應謎化合物。The 3-bromophenol 1 carrying a protective functional group may be converted into a homologous phenol 2 carrying a different functional group R6, and the bromine compound is first converted into a corresponding aryl lithium derivative (for example, used in, for example, tetrahydrofuran) The alkyllithium reagent in the solvent, preferably at a temperature of about -78. (and preferably), and then using various methods well known in the art, to neutralize the latter with various electrophiles (step a). Synthesis of R6=OH) by reacting an aryllithium compound with trimethylborane at a temperature between _78eC and the reflux temperature of tetrahydroanthracene, followed by small oxidation with, for example, N-methylmorpholine The oxidation of the material is preferably carried out at the reflux temperature of tetrahydrofuran [Compared to Syn丨ett 1995 (09), 93 1-932]. These phenols 2 having R6 = OH can then be converted into corresponding genomic compounds by well-known methods.
方程式1 οEquation 1 ο
裝 可將視需要攜有保護性官能基之酿1以已知的親電子性芳 族取代法進—步官能化成攜有額外取代基R2之齡2。在許多 衣Π中將开,成鄰· /對_取代產物及鄰_ /對-取代產物,其比 例係依據精確的反應條件而定。在這些案例中,可以最完 善的反應條件達成最高可能的單·鄰位產物;也可將產物混 Μ«要以熟知的方法(如㈣膠色層分離法)分離成純 異構物(步驟a)。τ以視需要揭有保護性官能基之齡!以已知 的甲醞化作用(如Vi丨smeier甲醯化作用)或以二氣曱基甲醚 在四氣化鈦存在下的甲醯化作用獲得4•甲醯基化合物3,以 在一氯甲烷及在介於-781至溶劑的回流溫度之間的溫度較 佳(步驟b) °接著可以再使用4·甲酷基化合物3作為已知的親 電子性芳族取代法的原料,以生成攜有額外R2取代基之化 訂The beverage 1 can be functionalized with a protective functional group as desired by a known electrophilic aromatic substitution method to form an age 2 carrying an additional substituent R2. It will be opened in many coats, and will be substituted with o-/p-substituted products and o-/p-substituted products, the ratio of which depends on the precise reaction conditions. In these cases, the highest possible single ortho-product can be achieved with the most complete reaction conditions; the product can also be separated into pure isomers by well-known methods (eg (4) gel layer separation). a). τ is the age of protective functional groups as needed! Obtaining 4*-mercapto-based compound 3 with known formazamylation (such as Vi丨smeier formazonization) or for the formazanization of di-p-methyl ether in the presence of titanium tetra-carbide The temperature between the methyl chloride and the reflux temperature between -781 and the solvent is preferred (step b). Then, the methyl mercapto compound 3 can be reused as a raw material for the known electrophilic aromatic substitution method. Generating a formulation with an additional R2 substituent
線 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) —--- 1328585 A7 B7 五、發明説明(53 ) 合物4(步驟c)。 方程式1 1Line The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) —--- 1328585 A7 B7 V. Inventive Note (53) Compound 4 (Step c). Equation 1 1
醛1係市售商品或是已知的。根據文獻步驟(Diels,0.; Riley,K.; Chem Ber( 1915), 48, 897),將彼與二酮基單肟 2 在強酸(典.型係HC1)的存在下及如AcOH之極性溶劑中濃 縮’以產生哼唑-N-氧化物3(步驟a)。在回流下以在二氣甲 烷中的POCI;接著處理,以提供對應的主要氣化物4 (Goto, Y.; Yamazaki, M.; Hamana, M.; Chem Pharm Bull (1971), 1 9,2050 ’步驟b)。或使用原來的樣子的這些中間物,根據 冗整建立的方法轉變成對應醇或活化醇,如甲磺醯酸酯或 ____- 57 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) ----- 1328585 A7 _______B7 五、發明説明(e ) x 54 甲笨磺醯酸酯,或轉變成溴化物或碘化物,或最後進一步 經由與NaCI的SN2反應完成,以得到經由腈5 (步驟c)、摧毁 f生水%·作用(步驟d)及达原作用(例如,與在四氫p夫喃中的甲 硼院)(步驟e)之組塊7。 如例如在Bioorg. Med. Chem. Lett.(2000),10( 1 7), 2041- 2044的說明,以對應芳基或雜芳基羧醯胺及匕3_二氯丙酮 製備具有r7=氫之4 -氯甲基-2 -芳基或2-雜芳基<»号峻較佳。 方程式丨2 •二-Aldehyde 1 is commercially available or known. According to the literature procedure (Diels, 0.; Riley, K.; Chem Ber (1915), 48, 897), the diketone monofluorene 2 is present in the presence of a strong acid (formulae HC1) and as in AcOH Concentrate in a polar solvent to produce carbazole-N-oxide 3 (step a). POCI in digas methane under reflux; followed by treatment to provide the corresponding primary gasification 4 (Goto, Y.; Yamazaki, M.; Hamana, M.; Chem Pharm Bull (1971), 1, 9,2050 'Step b). Or use the original look of these intermediates, according to the method established by redundancy, to convert to the corresponding alcohol or activated alcohol, such as methyl sulfonate or ____ - 57 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) ----- 1328585 A7 ____B7 V. Description of the invention (e) x 54 sulfonate, or converted to bromide or iodide, or finally further via SN2 reaction with NaCI to obtain Block 7 via nitrile 5 (step c), destruction of f-water % effect (step d), and kinetic action (eg, with boron boron in tetrahydropyrene) (step e). As described, for example, in Bioorg. Med. Chem. Lett. (2000), 10 (17), 2041- 2044, with corresponding aryl or heteroaryl carboxamide and 匕3_dichloroacetone having r7=hydrogen The 4-chloromethyl-2-aryl or 2-heteroaryl group is preferred. Equation 丨 2 • Two -
___- 58 - 本纸張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 1328585 A7 B7 五、發明説明(~" " ~ N- SS基甘胺酸酯1或是市售商品,或是已知的,或可以標 準的N-酷化作用製備。將]以在如THF之溶劑中的如 LiHMDS之強的非親核性鹼經雙重去質子化作用,典型係 在-78°C下,接著以晞丙溴處理,可輕易獲得單缔丙基化酯 2,以選擇性產生C-烷基化產物2(步驟a)。以標準的水解作 用產生中間酸3(步騾b),接著以完整建立的步驟(J Med Chem.(1996),39,3897)轉變成化合物4(步驟c)。使用三氣 醋酸及三氟醋酸酐作為試劑,·$環閉合成嘮唑產生關鍵性 中間物5 (步驟d) ’最後經由例如以在THF中的9- BBN之加氯 硼化作用及繼續以H2〇2和NaOH的氧化整理,以達成標的醇 6(步驟e)。 進行以下的試驗’以測定式I化合物的活性。 可在尼寇斯(Nichols)JS等人之"發展用於以過氧物酶體 增殖劑活化之受體T配體結合區之閃爍親近法 (Development of scintillation proximity assay f〇r peroxisome proliferator-activated receptor gamma ligand binding domain)",( 1998) Anal. Biochem. 257:1 12- 1 19 中 發現進行檢定之背景資料。 分別以人類脂肪·及老鼠肝脂肪cRNA的RT- PCR獲得人類 PPAR α及老鼠PPAR 7之全長cdNA殖株,選殖成質粒載體 及以成DNA序列證實。結構細菌與哺乳類表現載體,以產 生稠合成 PPARr(aa 174 至 476)及 PPARa(aa 167 至 469)之 配體結合區(LBD)的谷胱甘肽-s-轉移酶(GST)及Gal4 DN A結合區蛋白質。為了完成該目的,以PCR放大全長殖 ______- 59 -___ 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585 A7 B7 五、發明説明(56 ) 株之以選殖序列編碼之LBD部位,並接著副選殖成質粒載 體pGEX4T-2(Pharmacia)及pFA-CMV (Stratagene)。以 DNA 序列分析證實最後的殖株。 在大腸桿菌株BL21 (pLysS)細胞中以標準法(參考:由威 利(Wiley)出版社以歐蘇貝爾(Ausubel)等人編輯之Current___- 58 - This paper size is applicable to China National Standard (CNS) Α4 specification (210X297 mm) 1328585 A7 B7 V. Invention description (~"" ~ N- SS-glycolate 1 or commercially available product , or known, or can be prepared by standard N-cooling. Will be double deprotonated by a non-nucleophilic base such as LiHMDS in a solvent such as THF, typically at -78 Monoc-propylated ester 2 can be readily obtained by treatment with guanidinium bromide at ° C to selectively produce C-alkylated product 2 (step a). Intermediate acid 3 is produced by standard hydrolysis (step 骡b), then converted to compound 4 (step c) in a completely established procedure (J Med Chem. (1996), 39, 3897). Using tri-acetic acid and trifluoroacetic anhydride as reagents, the ring is closed to carbazole. A key intermediate 5 is produced (step d) 'finally via oxidative chlorination of, for example, 9-BBN in THF and continued oxidative finishing with H 2 〇 2 and NaOH to achieve the target alcohol 6 (step e). The following test was carried out to determine the activity of the compound of formula I. It can be developed in Nichols JS et al. Development of scintillation proximity assay f〇r peroxisome proliferator-activated receptor gamma ligand binding domain", (1998) Anal. Biochem. 257:1 12- 1 Background information for the assay was found in 19. The full-length cdNA strains of human PPAR α and mouse PPAR 7 were obtained by RT-PCR of human fat and mouse liver fat cRNA, respectively, and cloned into plasmid vector and confirmed by DNA sequence. Bacterial and mammalian expression vectors to produce glutathione-s-transferase (GST) and Gal4 DN A in the ligand-binding domain (LBD) of fused synthetic PPARr (aa 174 to 476) and PPARa (aa 167 to 469) Binding region protein. In order to accomplish this, PCR amplification of full-length ______- 59 -___ This paper scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7 V. Invention description (56) The LBD site encoded by the cloning sequence was ligated into plasmid vectors pGEX4T-2 (Pharmacia) and pFA-CMV (Stratagene), and the final strain was confirmed by DNA sequence analysis. Standard method in E. coli strain BL21 (pLysS) cells (Reference: Current edited by Ausubel et al. by Wiley Press et al.
Protocols in Molecular Biology)進行 GST-LBD融合蛋白質 之誘發、表現及純化。 放射配體結仝檢宕 _ 在TKE10·中(10毫克分子量Tris-HCl,pH8、50毫克分子量 KC1、2毫克分子量EDTA、0.1毫克/毫升之無BSA之脂肪酸 及10毫克分子量DTT)檢定PPARa受體結合。將每96井以 2.4微克當·量GST-PPARa - LBD融合蛋白質及放射配體(例 如 ’ 40000dpm 之 2(S)-(2-苯醯基-苯基胺基)-3-{4-[1,1-ditritio-2-(5-甲基-2-苯基-吟唑-4-基)-乙氧基]-苯基卜丙 酸)在100微升體積中以室溫培育2小時。根據製造商的建 議,使用以80微升SG25填充之Multiscreen平盤(Millipore) ,以固相分離作用自未結合之配體取出結合之配體。 在TKE50中(50毫克分子量Tris-HCl,pH8、50毫克分子量 KC1、2毫克分子量EDTA、0.1毫克/毫升之無BSA之脂肪酸 及10毫克分子量DTT)檢定??八尺7受體結合。將每96井以 140微克當量GST_PpaR r - LBD融合蛋白質與1〇微克SPA珠 以搖動結合成最終50微升的體積《將所得泥漿在室溫下培 育1小時及在13〇(^下經2分鐘離心》除去含有未結合之蛋白 質的上層清液,並將含有以受體塗佈的珠之半乾片溶解在 -60 - 本纸張尺度適用中國囷家榡準(CNS) A4規格(21〇 X 297公爱〉Protocols in Molecular Biology) Induction, expression and purification of GST-LBD fusion proteins. Radioligand binding assay _ PPARa was assayed in TKE10· (10 mg molecular weight Tris-HCl, pH 8, 50 mg molecular weight KC1, 2 mg molecular weight EDTA, 0.1 mg/ml BSA-free fatty acid and 10 mg molecular weight DTT) Body combination. Add 2.4 μg of GST-PPARa-LBD fusion protein and radioligand per 96 wells (eg '400-dpm of 2(S)-(2-phenylmercapto-phenylamino)-3-{4-[ 1,1-ditritio-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl-propionic acid) was incubated for 2 hours at room temperature in a volume of 100 μl . The bound ligand was removed from the unbound ligand by solid phase separation using a Multiscreen flat disk (Millipore) filled with 80 microliters of SG25 according to the manufacturer's recommendations. In TKE50 (50 mg molecular weight Tris-HCl, pH 8, 50 mg molecular weight KC1, 2 mg molecular weight EDTA, 0.1 mg/ml BSA-free fatty acid and 10 mg molecular weight DTT) assay? ? Eight-foot 7 receptor binding. Each 96 wells were combined with 140 μg of equivalent GST_PpaR r - LBD fusion protein and 1 μg of UV beads into a final volume of 50 μl. The resulting slurry was incubated at room temperature for 1 hour and at 13 〇 (^ Minute centrifugation removes the supernatant containing unbound protein and dissolves the semi-dry sheet containing the beads coated with the receptor at -60 - This paper scale applies to China National Standard (CNS) A4 specification (21 〇X 297 public 〉
訂Order
13285851328585
50微升TKE中。關於放射配體結合,例如,加入在咒微升 中的lOOOOdpm之2(S)-(2:苯醯基-笨基胺基卜弘卜七山 dur山ο·2·(5-甲基-2-苯基-呤唑-4-基)·乙氧基]_苯基}•丙 酸,將反應在室溫下培育卜】、時,並進行閃爍親近計數❶在 96井平盤中進行所有的結合檢定,並使用〇ptiputes (Packard) ’在Packard TopCount上測量結合之配體數。在 1〇·4克分子量未標記之化合物的存在下測定非特異性結 合。在從10·10克分子量至10--4^分子量之濃度範圍内以重 複3次完成劑量反應曲線。 蟲螢光素酶轉錄受體某因檢宕 以大頰幼鼠的腎細胞(ΒΗΚ21 ATCC CCL10)在37t的 95%02 : 5%C02大氣中於含有i〇〇/oFbs之DMEM介質中生 長。將細胞以1 05細胞/井之密度接種在6井平盤中,並接著 以或pFA-PPARr -LBD或pFA-PPARa -LBD表現質粒加上 pFR- luc受體質粒(Stratagene)及作為正規化控制品的以表 現質粒編碼之鹼性鱗酸酶的隱蔽形式(SEAP)經批組轉染。 根據建議的樣式’以Fugene 6試劑(Roche Molecular Biochemicals)完成轉染作用。在轉染之後6小時,以消化作 用收成細胞.,並以104細胞/井之密度接種在96井平盤中。 在以24小時允許細胞附著之後,取出介質,並以1 〇〇微升含 有試驗物質或控制配體的無介質之酚紅(最終〇· 1 % DMSO)置 換。在以物質培育細胞24小時之後,回收50微升上層清 液’並分析其 SEAP 活性(Roche Molecular Biochemicals)。 將上層清液其其餘部份棄置,以50微升PBS加入每一個井 -61 - 本纸張尺度適用中国固家標準(CNS) A4规格(210X 297公釐) 訂 線 132858550 microliters of TKE. Regarding radioligand binding, for example, adding 2OO(S)-(2: phenylhydrazine-stupylamine-based honghongqi seven mountains dur mountain ο·2·(5-methyl-) in the micro-liter 2-Phenyl-oxazol-4-yl)·ethoxy]-phenyl}•propionic acid, the reaction was incubated at room temperature, and the scintillation proximity count was performed. All were carried out in a 96 well plate. The binding assay was performed and the number of bound ligands was measured on a Packard TopCount using 〇ptiputes (Packard)'. Non-specific binding was determined in the presence of 1 〇4 g of molecularly unlabeled compound. Dosage response curve was repeated 3 times in the concentration range of 10-4^ molecular weight. The luciferase transcription receptor was detected in 95% of the kidney cells of the large cheek pups (ΒΗΚ21 ATCC CCL10) at 37t. 02: 5% C02 atmosphere was grown in DMEM medium containing i〇〇/oFbs. Cells were seeded at a density of 10 cells/well in a 6 well plate, followed by either pFA-PPARr-LBD or pFA-PPARa - LBD expression plasmid plus pFR-luc receptor plasmid (Stratagene) and a conserved shape of a basic luciferase encoding a plasmid as a normalization control (SEAP) was transfected by batch. Transfection was performed according to the proposed style 'Fugene 6 reagent (Roche Molecular Biochemicals). 6 hours after transfection, cells were harvested by digestion, and at a density of 104 cells/well Inoculated in a flat well of 96. After allowing the cells to adhere for 24 hours, the medium was removed and replaced with 1 〇〇 microliter of medium-free phenol red (final 〇·1% DMSO) containing the test substance or control ligand. After incubating the cells with the substance for 24 hours, 50 μl of the supernatant was recovered and analyzed for its SEAP activity (Roche Molecular Biochemicals). The remaining portion of the supernatant was discarded and 50 μl of PBS was added to each well-61 - this The paper scale applies to the China National Standard (CNS) A4 specification (210X 297 mm). Ordering 1328585
中,接孝以-份體積之蟲勞光素酶怔定光試劑㈤心 M〇lecu丨ar B丨0chemicals)容離細胞及啟動蟲勞光素酶反^ 在Packard T〇pCount中;則量SEAp及蟲勞光素酶兩者的發 光。將蟲螢光素酶活性以SEAP矜制。 ίAP仫制σο正規化,並將在試驗In the Packard T〇pCount, the amount of SEAP is taken in the Packard T〇pCount And the luminescence of both luciferase. The luciferase activity was determined by SEAP. ί 仫 正规 正规 regularization, and will be experimenting
物貝=下的轉錄活性以超越在沒有物質存在下培育的細 胞的倍數活性表示。使用XLfit程式㈤β Ltd. UK)計算 EC50值。 S 本發明的化合物就ppar α及〜PPARr展現(Μ毫微克分子 量至50微克分子量之IC5〇值, 笔广克刀子 A 1笔儆克分予量至1 〇微名八 子量較佳,特別是1_ 3500毫 克刀 ^ θ δ .. 見刀子量’以1-500毫微克分 i 子里更佳。化合物就ppar 兄刀 八κ α及pp AR r進— 克分子量至50微克分予量之Ic ’笔微 Μ八早…土 IC50值,-以1毫微克分予量至1〇 微克刀子讀佳,以⑽毫微克分. SOO臺檄右厶名县_ 里& 1主iff别疋1 -The transcriptional activity under the object = is expressed as a multiple activity exceeding the cells cultured in the absence of substance. The EC50 value was calculated using the XLfit program (5) β Ltd. UK). S The compound of the present invention exhibits an IC5 enthalpy value of ppar α and ~PPARr (milligram molecular weight to 50 microgram molecular weight, pen gram knife A 1 gram gram weight to 1 〇 micro name 八子量 is better, especially 1_ 3500 mg knife ^ θ δ .. See the knife amount 'is better than 1-500 ng. The compound is ppar brother knives κ α and pp AR r into - gram molecular weight to 50 micrograms of the amount of Ic 'Pen Μ eight early ... soil IC50 value, - 1 ng to the amount to 1 〇 micro knives read good, to (10) nanograms. SOO Taiwan 檄 right 厶 county _ 里 & 1 main iff 疋 1 -
PPARa IC5〇 實例1 117毫微莫耳/公升 實例2 II·7毫Μ莫耳/公升 實例7 Η4毫微莫耳/公升 實例11 38.2毫微箪茸/公升 實例48 n.d 實例83 109毫微莫耳/公升 實例106 259毫微莫耳/公升 若西格利 它容 無活性 L13 毫^ 1L70毫微莫耳/公# 21i«WiLPPARa IC5〇 Example 1 117 nanomole/liter example 2 II·7 milligrams m/liter example 7 Η4 nanomole/liter example 11 38.2 nano velvet/liter instance 48 nd instance 83 109 nanometer Ear / liter example 106 259 nanometers per liter if siglia it is inactive L13 milli ^ 1L70 nanometer / male # 21i«WiL
丄8 8毫微莫耳/公并 94毫微莫耳/公斗 公升21毫微68毫微莫耳/公4 1 _ 21毫微莫耳/公4 8毫微莫耳/公升 746毫微莫耳/公斗 464毫微莫耳/公升 188毫微莫耳/公升丄 8 8 nanomoles / male and 94 nanometers of m / liters of liters 21 nanometers 68 nanometers / male 4 1 _ 21 nanometers / male 4 8 nanomoles / liters 746 nanometers Mohr / Gongdou 464 nanometers per liter 188 nanometers per liter
訂 線 丄j厶03δ:)Booking line 丄j厶03δ:)
五、發明説明( -63 - 可以式!化合物及其醫藥上可接受之M類和g旨類作為藥劑 :用,例如,以經腸、非經腸或局部投藥之醫藥製品形 ;。可將?以例如經口服投m,例如以藥片塗佈之藥 片、糖衣藥丸、硬或軟白明膠膠囊、溶液、乳液或懸浮液 形式’以經直腸投藥,例如’栓劑形以非經腸投藥, 例如,以軟膏、乳膏或油形式。 以任何熟悉本技藝的人熟悉的方式可以達成醫藥製品的 製作用,其係以經說明之式.u匕合物及其醫藥上可接受之 ,適合的無毒性、惰性、與治療法相容的固態或液態 載體物質及若必要常用的醫藥佐劑一起完成藥用的投藥形 式。 / 適合的載體物質不僅是無機載體物質,並也是有機載體 物興。因此可以使用例如乳糖、玉米澱粉或其衍生物、滑 石粉、硬脂酸或其鹽類作為藥片、塗佈之藥片、糖衣藥^ 及硬白明膠膠囊。適合於軟白明膠膠囊之載體物質係例如 植物油、蠟、脂肪及半固態及液態多元醇(依據在軟白明膠 膠囊案例中所需要的無載體之活性成份的本性而定)。適合 於產製溶液及糖漿之載體材料係例如水、多元醇、蔗粹、 轉化糖及類似物。適合於注射溶液之載體材料係例如水、 醇、多7C醇、甘油及植物油。適合於栓劑之載體材料係例 如天然油或硬化油、蠟、脂肪及半固態及液態多元醇。適 合於局部製品之載體材料係甘油酯、半合成及合成甘= 酯 '氫化油、液態蠟、液態石蠟、液態脂肪醇、甾醇、ρ 乙二醇及纖維素衍生物。 水 本紙張尺度適用中國国家標準(CNS) A4規格(210X297公釐) 訂 線 1328585 A7 B7 五、發明説明(60 ) 考慮以常用的穩定劑、保存劑、濕潤劑及乳化劑、稠度 改良劑、氣咮改良劑、滲透壓不同的鹽類、緩衝物、溶解 劑、著色劑及遮蔽劑和抗氧化劑作為醫藥佐劑。 式1化合物的劑量可在依據欲控制的疾病、年齡及病患的 個別病況與投藥模式而定的寬廣限制内改變,並當然符合 在每一種特殊應用中的個別需求。就成人病患而言,考慮 約1毫克至約1 000毫克之曰劑量,尤其是約1毫克至約1 00毫 克。依據劑量而定,方便將日-楚|量以許多劑量單位投藥。 醫藥製品方便包括约0.5- 500毫克式I化合物,以0.5.-100 毫克較佳。 以下的實例具有更詳細例證本發明的效用。但不是企圖 以其以任何方式限制本發明的範圍。- 實例 縮寫. nBu2BOTf=二甲基二氟甲績酸侧,br=寬,DBAD=偶氛二 羧酸二第三丁酯’ DBU= 1,8-二吖雙環[5 4.〇] -j---7-埽, DEAD=偶氮二致故二乙酿’ DIAD=偶氮二幾酸二異丙酉旨, DMPU=1,3-二甲基-3,4,5,6-四氫-2(1H)嘧啶酮,叫_=當 量,HPLC=.高性能液相色層分離法,LDA=二異丙基酿胺 鋰’ P0C13=磷醯氯,quint.=五重,rt=室溫,sept=七重, sext.=六重,THF=四氫p夫喃。 實例1 al2-甲氣基- 3-{4-『2-(5-甲基-2-笨甚-坐某厂氧 基1-笨并|~blp塞吩-7-基丨-丙酸乙醋 ____-64 -___— 本紙張尺度適财目S家標WNS) A4規格(⑽X 297公釐)'' 1328585 A7 ______B7____ 五、發明説明(61 ) 將1.0毫升nBuLi(1.5克分子量,己烷)經由注射筒加入在 -5 °C下的3毫升絕對THF中的0.162公克(1.6毫莫耳)二異丙 胺之溶液中,以製備LDA。在冷卻至-78。之後,加入溶解 在1毫升絕對THF中的0.1 77公克甲氧基醋酸乙酯(1.50毫莫 耳),並在室溫下維持1 5分鐘,以確定完全去質子化。接著 加入溶解在5毫升絕對THF中的0.343公克4-[2-(7·溴甲基笨 并[bp塞吩-4-基氧)乙基]-5-甲基-2-苯基-呤唑(〇.80毫莫 耳),然後加入3毫升DMPU。在^乾冰溫度下搅拌1 5分鐘及在 〇 °C下攪拌30分鐘之後,將反應混合物倒在碎冰上.,以 AcOEt萃取兩次,以水清洗,經硫酸鈉乾燥及蒸發至乾 燥。在0 C下自己坑結晶之後,以閃蒸色層分離法(§ i 〇 2, 己烷/ AcOEt= 75/2 5)產生成為白色固體之0.206公克標題化 合物,熔點59-61°。 MS : 465.1 (M) +,348.0, 186.0。 NMR : (CDC13 ’ 1H,5,TMS)1.21 (t,J=7,3H),2.43 (s, 3H), 3.09 (t, J=6.5, 2H), 3.15-3.3 (m, 2H), 3.33 (s, 3H), 4.15 (m,lH), 4.17 (q, J=7, 2H), 4.40 (t, J=6.5, 1H), 6.74 (d, J=8, 1H), 7.12 (d, J=8.5, 1H), 7.32 (d, J=5.5, 1H), 7.42-7·50 (m, 4H), 8.01 (br d, J=8, 2H)。 ί>12-甲氣基-3-{4-|~2-(5-甲某-2-笨基-p号岭-4·某乙1 基卜本·并丨blp墓吟-7-基丨-丙-龄 將0.丨84公克2-甲氧基-3-{4-[2-(5-甲基-2-苯基-»号。坐-4- 基)-乙氧基]•苯并[b]p塞吩-7-基}-丙酸乙醋(〇·4〇毫莫耳)溶 解在1¾升THF/MeOH=l/l中,並以0.670毫升之3NNaOH處 ______- 65 - 本纸乐尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) 1328585 A7 B7 五、發明説明(62 ) 理。將反應混合物維持在室溫下隔夜,並接著以倒在碎冰 / HC丨上中止。以AcOEt萃取兩次’以水清洗,經硫酸納乾 燥及以蒸發溶劑留下粗產物,將其以自Ac0Et/己烷結晶的 方式純化,以產生成為白色固體之〇1 58公克標題化合物, 熔點 12 1- 122°。 ISP MS : (MNa)+ 460.3,(MH)+ 438.3。 IR (公分」):3078,2922, 2853,1737, 1653,1554,1462, 1 378,1341,1272,1185,1125, 1—064,1025, 719, 688。 NMR : (DMS0-d6,lH, δ , TMS)2.40 (s, 3H), 3.02 (t, J=6.5, 2H), 3.00-3.10 (m,1H),3.13 (dxd’ J=5, J=14.5,1H), 3-20 (s, 3H), 4.06 (m,lH), 4.34 (t, J=6.5, 2H), 6.89 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.39 (d, J=5.5, 1.H), 7.42-7.52 (m, 3H), 7.63 (d, J=5.5, 1H), 7.92 (br d, J=8, 2H), 12.8 (br s,1H)。 實例2 2-乙乳基- 3- {4-『2-(5-甲基-2·笨基-p号吨_4.基)-乙氣基ι_ 冬并Γ b 1 口基吩-7-基}-丙齡 以類似於實例1的方式製備標題化合物,但是在步驟a]中 使用乙氧基醋酸乙酯代替甲氧基衍生物,並獲得成為熔點 147- 148°之白色晶體。 ISP MS : (M+Na)+ 474.2,(M+H)+ 452.4。 NMR : (DMSO-d6,lH, δ, TMS) 0.99 (t, J=7, 3H), 2.39 (s, 3H), 3-02 (t, J=6.5, 2H), 3.00-3.10 (m,ih), 3.12 (dxd, J=5, J=14.5, 1H),3.22-3.32 (m,ih),3.48-3.58 (m,1H),4.12 (m.lH). 4.35 (t, J=6.5. 2H), 6.90 (d, J=8, 1H), 7.15 (d, J=8, _ - 66 -___ 本纸張尺度適用中國國家標準(CNS) A4規格(210 x297公釐)V. INSTRUCTIONS (-63 - The compound and its pharmaceutically acceptable M and g classes are used as medicaments: for example, in the form of a medicinal preparation for enteral, parenteral or topical administration; For example, by oral administration, for example, in the form of a tablet coated tablet, a dragee pill, a hard or soft white gelatin capsule, a solution, an emulsion or a suspension, a rectal administration, such as a 'suppository form, is administered parenterally, for example, In the form of an ointment, cream or oil. The manufacture of a pharmaceutical product can be achieved in a manner familiar to those skilled in the art, which is described as a formula and a pharmaceutically acceptable, suitable non-toxic Sexual, inert, therapeutically compatible solid or liquid carrier materials and, if necessary, pharmaceutical adjuvants, complete the pharmaceutical form of administration. / Suitable carrier materials are not only inorganic carrier materials, but also organic carriers. For example, lactose, corn starch or a derivative thereof, talc, stearic acid or a salt thereof can be used as a tablet, a coated tablet, a dragee, and a hard white gelatin capsule. Suitable for soft white gelatin. The carrier materials of the capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the unsupported active ingredient required in the case of soft white gelatin capsules). Suitable carrier materials for the production of solutions and syrups. For example, water, polyols, cane, invert sugar and the like. Carrier materials suitable for injectable solutions are, for example, water, alcohols, poly 7C alcohols, glycerol and vegetable oils. Carrier materials suitable for suppositories are, for example, natural or hardened oils. , waxes, fats and semi-solid and liquid polyols. Suitable carrier materials for topical products are glycerides, semi-synthetic and synthetic glycerols - hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, ρ ethylene glycols. And cellulose derivatives. Water-based paper scale applicable to China National Standard (CNS) A4 specification (210X297 mm) Ordering 1328585 A7 B7 V. Description of invention (60) Consider common stabilizers, preservatives, wetting agents and emulsification Agent, consistency improver, gas improver, salt with different osmotic pressure, buffer, solvent, colorant, masking agent and antioxidant as medicine The dosage of the compound of formula 1 can vary within the broad limits depending on the disease, age and individual condition of the patient to be controlled and the mode of administration, and of course meet the individual needs in each particular application. In particular, a dose of from about 1 mg to about 1 000 mg, especially from about 1 mg to about 100 mg, is considered. Depending on the dosage, it is convenient to administer the dose in many dosage units. - 500 mg of the compound of the formula I, preferably 0.5 to 100 mg. The following examples illustrate the utility of the invention in more detail, but are not intended to limit the scope of the invention in any way. - Example abbreviations. nBu2BOTf = dimethyl Acid difluoride, acid side, br = wide, DBAD = di-tertiary dicarboxylic acid di-t-butyl ester ' DBU = 1,8-di-bi-bicyclo[5 4.〇] -j---7-埽, DEAD = azo bis, so the second brewing 'DIAD = azobis acid diisopropyl hydrazine, DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone , _= equivalent, HPLC =. High performance liquid chromatography, LDA = lithium diisopropyl amide 'P0C13 = phosphonium chloride, quint. = five weight, rt = room temperature, sept = Seven weights, sext. = six weights, THF = tetrahydro puffan. Example 1 al2-methyl-yl- 3-{4-『2-(5-methyl-2- stupid--a certain plant oxy 1-stupid|~blp thiophene-7-yl fluorene-propionic acid Vinegar ____-64 -___- This paper size is suitable for the standard of the goods S standard WNS) A4 specifications ((10) X 297 mm) '' 1328585 A7 ______B7____ V. Description of the invention (61) 1.0 ml of nBuLi (1.5 g molecular weight, hexane LDA was prepared by adding a solution of 0.162 g (1.6 mmol) of diisopropylamine in 3 ml of absolute THF at -5 °C via a syringe. Cool to -78. Thereafter, 0.177 grams of methoxyethyl acetate (1.50 mmol) dissolved in 1 ml of absolute THF was added and maintained at room temperature for 15 minutes to confirm complete deprotonation. Next, 0.343 g of 4-[2-(7.bromomethyl benzo[[pitophen-4-yloxy)ethyl]-5-methyl-2-phenyl-indole dissolved in 5 ml of absolute THF was added. The azole (〇.80 mmol) was then added to 3 ml of DMPU. After stirring at dry ice temperature for 15 minutes and at 〇 ° C for 30 minutes, the reaction mixture was poured onto iced ice, extracted twice with AcOEt, washed with water, dried over sodium sulfate and evaporated to dryness. After crystallization of the pit at 0 C, 0.206 g of the title compound was obtained as a white solid, m.p.: 59-61. MS: 465.1 (M) +, 348.0, 186.0. NMR : (CDC13 ' 1H, 5, TMS) 1.21 (t, J = 7, 3H), 2.43 (s, 3H), 3.09 (t, J = 6.5, 2H), 3.15-3.3 (m, 2H), 3.33 (s, 3H), 4.15 (m, lH), 4.17 (q, J=7, 2H), 4.40 (t, J=6.5, 1H), 6.74 (d, J=8, 1H), 7.12 (d, J=8.5, 1H), 7.32 (d, J=5.5, 1H), 7.42-7·50 (m, 4H), 8.01 (br d, J=8, 2H). ί>12-甲气基-3-{4-|~2-(5-甲某-2-笨基-p号岭-4·一乙1基卜本·丨丨blp tomb-7-based丨-C-age will be 0. 丨 84 grams of 2-methoxy-3-{4-[2-(5-methyl-2-phenyl-». sit-4-yl)-ethoxy] • Benzo[b]p-cephen-7-yl}-propionic acid ethyl vinegar (〇·4〇 mmol) dissolved in 13⁄4 liters of THF/MeOH = l/l and at 0.670 ml of 3N NaOH ______ - 65 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of the invention (62). Maintain the reaction mixture at room temperature overnight, and then pour in The crushed ice/HC 中 was suspended. It was extracted twice with AcOEt, washed with water, dried over sodium sulfate and evaporated to give a crude product which was purified from crystals from EtOAc to hexane to afford white solid. 〇1 58 g of the title compound, m.p. 12 1- 122°. ISP MS : (MNa) + 460.3, (MH) + 438.3. IR (cm): 3078, 2922, 2853, 1737, 1653, 1554, 1462, 1 378, 1341, 1272, 1185, 1125, 1-064, 1025, 719, 688. NMR: (DMS0-d6, lH, δ, TMS) 2.40 (s, 3H), 3.02 (t, J = 6.5, 2H), 3.00-3.10 (m,1H), 3.13 (dxd' J=5, J=14.5,1H), 3-20 (s, 3H), 4.06 (m,lH), 4.34 (t, J=6.5 , 2H), 6.89 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.39 (d, J=5.5, 1.H), 7.42-7.52 (m, 3H), 7.63 ( d, J=5.5, 1H), 7.92 (br d, J=8, 2H), 12.8 (br s, 1H). Example 2 2-Ethyl-3 - {4-"2-(5-methyl) -2· Stupid-p ton _4. yl)-ethane group i 冬 冬 Γ 1 1 1 1 1 1 1 1 1 1 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题 标题Ethyl ethoxyacetate was used instead of the methoxy derivative, and white crystals having a melting point of 147-148° were obtained. ISP MS : (M+Na) + 474.2, (M+H) + 452.4. NMR : DMSO-d6, lH, δ, TMS) 0.99 (t, J=7, 3H), 2.39 (s, 3H), 3-02 (t, J=6.5, 2H), 3.00-3.10 (m, ih), 3.12 (dx, J=5, J=14.5, 1H), 3.22-3.32 (m, ih), 3.48-3.58 (m, 1H), 4.12 (m.lH). 4.35 (t, J=6.5. 2H) , 6.90 (d, J=8, 1H), 7.15 (d, J=8, _ - 66 -___ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm)
裝 訂Binding
線 1328585 63 五、發明説明( 1H), 7.39 (d, J=5 1Η^ η IH、7 9» …, 5_7·53 (m,3H),7.63 (d j=5 5 lH).7.9l(brd5J=8,2H)>12 7(br SjlH)〇 ,; 5.5, 實例3 11_[土丨2-(5-甲—4_::2-笨炙- *、7 … 以類似於實例!的方式製備標題化合物 使用丙氧基Μ乙醋代替 · 秦⑽。之灰白㈣體。生物,並獲得成為这點 · (Μ+Κ)+ Μ.2’ (Μ,)+ 488.2, (M+H)+ 466.3。 I ::基3、(苹棊-咩乙氣某1 -奉并fb]喵吩-7-某卜呙吃 以㈣於實例1的方式製備標題化合物,但是在步驟a]中 使用丁乳基醋酸乙酉旨代卷甲笛並/ 、代瞀甲虱基何生物,並獲得成為熔點 123°(dec.)之灰白色固體。 MS : (M-H). 478.3。 實例5 1:異丁氧某-3-{4二·2_笨某.啐岫_d早)乙氧 基卜苯并fbl 4吩-7-甚卜丙啦 以類似於實例丨的方式製備標題化合物,但是在步驟a]中 使用異丁氧基醋酸乙酿代替T氧基衍生物,並獲得成為熔 點I 02。( dec.)之白色固體。 MS : (M-H). 478.3。 1R (公分-1) : 2924, 2853’ 1 737,1 653’ 1 555,1461,1384, -67 - 1328585 A7 ______B7 五、發明説明(64 ) 1342. 1271, 1174, 1121, 1〇66, 1030, 718, 689 NMR : (CDC13, 1H, δ , TMS)0.78, 0.79(2xd, J=7, 2x3H), 1.75 (septett, J=7, 1H), 2.40 (s, 3H), 3.06 (t, J=6.5, 2H), 3.00-3.10 (m, 1H), 3.19 (dxd, J=8, J=14.5, 1H), 3.27 (m, 1H), 3.36 (dxd, J=4.5, J=i4.5, 1H), 4.24 (m,lH), 4.37 (t, J=6.5,2H), 6.74 (d’ J=8,1H), 7.15 (d, J=8,1H),7.32 (d, J=5.5,1H),7.38- 7.48 (m,3H),7.48 (d,J=5.5, 1H),7.98 (br d,J=8, 2H),9_5 (非常寬的-l 1H)。 實例ό - 己氧基二3- { 4-f 2-( 5-_甲某-2-苽某-噚唑-4-某)-乙氣某l-本并『big基吩_7·基}-丙齡 以類似於實例1的方式製備標題化合物,但是在步驟a]中 使用己氧基醋酸乙g旨代替甲氧基衍生物,並獲得成為炫點 79-82°之淡黃色固體。 [SP MS : (M+K)+ 546.1,(M+Na)+ 530.2,(M+H)+ 508.4。 實例7 糾4二丨2-(4-溴甲基萘-丨二^基)乙某%甲其-2•笨某-啐砷 將0.494公克5-甲基-4-[2-(萘-1-氧基)乙基]_2-苯基_4唑 (1.50¾莫耳)在氬氣下溶解在6毫升CH2Cu中,並冷卻至 0。。加入0:455毫升之62%水性HBr,接著加入58毫克三哼 烷(0.644毫莫耳,丨.29當量)。在2小時之後,加入額外 0‘45)耄升之62%水性HBr,並在嚴格的溫度控制下持續攪 拌總共:> 小時。接著將反應混合物以CHfh稀釋,以 NaHCO;飽和水落液清洗,將水層再以cH/丨2萃取—次將 ____- 68 - 本纸張尺度適用中國國家標準(CNS) A4规格(210X 297公釐)Line 1325885 63 V. Description of the invention (1H), 7.39 (d, J=5 1Η^ η IH, 7 9» ..., 5_7·53 (m, 3H), 7.63 (dj=5 5 lH).7.9l (brd5J =8,2H)>12 7(br SjlH)〇,; 5.5, Example 3 11_[丨丨2-(5-甲-4_::2-炙炙- *, 7 ... in a manner similar to the example! Prepare the title compound using propoxy acetoacetate instead of Qin (10). Gray (four) body. Creature, and get this point · (Μ+Κ)+ Μ.2' (Μ,)+ 488.2, (M+H) + 466.3. I:: base 3, (appendix-咩乙气一一-beng and fb] 喵-7-7- 呙 呙 呙 (4) The title compound was prepared in the manner of Example 1, but used in step a] The butyl acetoacetate is intended to be a volcanic ketone, and it is obtained as a grayish white solid having a melting point of 123° (dec.) MS: (MH). 478.3. Example 5 1: isobutoxy a -3-{4 bis 2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In the case of using isobutoxyacetic acid, the T-oxyl derivative was replaced with a white solid which became the melting point I 02 (dec.) MS : (MH) 478.3. 1R (cm-1): 2924, 2853' 1 737,1 653' 1 555,1461,1384, -67 - 1328585 A7 ______B7 V. Description of invention (64) 1342. 1271, 1174, 1121, 1〇 66, 1030, 718, 689 NMR: (CDC13, 1H, δ, TMS) 0.78, 0.79 (2xd, J=7, 2x3H), 1.75 (septett, J=7, 1H), 2.40 (s, 3H), 3.06 (t, J=6.5, 2H), 3.00-3.10 (m, 1H), 3.19 (dxd, J=8, J=14.5, 1H), 3.27 (m, 1H), 3.36 (dxd, J=4.5, J =i4.5, 1H), 4.24 (m,lH), 4.37 (t, J=6.5,2H), 6.74 (d' J=8,1H), 7.15 (d, J=8,1H), 7.32 ( d, J=5.5,1H), 7.38- 7.48 (m,3H), 7.48 (d, J=5.5, 1H), 7.98 (br d, J=8, 2H), 9_5 (very wide -l 1H) . Example ό - hexyloxydi- 3 - { 4-f 2-( 5--methyl-2-pyrene-carbazole-4-)-Ethyl-l-this and "big base _7· base The title compound was prepared in a similar manner to Example 1 except that in the step a], the methoxyacetic acid was used in place of the methoxy derivative, and a pale yellow solid which became a bright spot of 79 to 82 was obtained. [SP MS : (M+K) + 546.1, (M+Na) + 530.2, (M+H) + 508.4. Example 7 Correction 4 丨2丨2-(4-bromomethylnaphthalene-fluorenediyl) Ethylaminopheny-2•stupid-arsenic arsenic 0.494 g 5-methyl-4-[2-(naphthalene- 1-Oxo)ethyl]_2-phenyl-tetrazole (1.503⁄4 mol) was dissolved in 6 ml of CH2Cu under argon and cooled to zero. . 0: 455 ml of 62% aqueous HBr was added followed by 58 mg of trioxane (0.644 mmol, 丨.29 equivalent). After 2 hours, an additional 0 '45) soaring 62% aqueous HBr was added and the total stirring was continued under strict temperature control: > hours. The reaction mixture is then diluted with CHfh, washed with NaHCO; saturated aqueous solution, and the aqueous layer is further extracted with cH/丨2 - times ____- 68 - This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 MM)
裝 訂Binding
線 1328585 A7 !__ _____B7 ___ 五 '發明説明(65 ) 合併的有機相經硫酸鈉乾燥及蒸發至乾燥《這樣留下〇.7〇 公克粗標題化合物,以其原樣子供以下步驟使用。產物非 常不穩定,並不可以在Si02上以管柱色層分離法純化,其 也容易在TLC-板上分解。 曱氣基-[2-(5-甲某芡其-碟峽_4·基乙氧 基丄-笨-丨-基卜丙酸乙酯 將丨.0毫升nBuLi(1.5克分子量,己烷)經由注射筒加入在_ 5 °C下的3毫升絕對THF中的0. 02公克(1.6毫莫耳)二異丙胺 之溶液中,-以製備LD A。在冷卻至-78。之後,加入溶解在1 毫升絕對THF中的0.177公克甲氧基醋酸乙酯(1.50毫莫 耳)’並將混合物維持在室溫下丨5分鐘,以確定完全去質子 化。接著加入溶解在6毫升絕對THF中的0.38公克粗4-[2-(4-溴甲基茬-1-氧基)乙基]·5_甲基_2·苯基-π等唑(<〇9〇毫 莫耳’如上述製得的1毫莫耳量),然後加入3毫升dmpu。 在乾冰溫度下攪拌1 5分鐘及在〇 下攪拌3 〇分鐘之後,將反 應混合物倒在碎冰上’以^0£1萃取兩次,以水清洗,經 硫酸鈉乾燥及蒸發至乾燥》以兩次閃蒸色層分離法(Si〇2 , 己烷/八(:0£1=74/26,接著以76/24)產生成為無色油之〇145 公克標題化合物。 MS : 459.2 (M) + , 386.1, 342.1 〇 gJ2-甲乳基- 3-{4-f2-(5-甲基-2-笨基-某乙望. 基1·奈-1-基丨-雨S会 將0_丨37公克2·甲氧基-3-{4-[2-(5-甲基-2-苯基-呤唑_4_ 基)-乙氧基]-莕-丨-基}-丙酸乙酯(0.298毫莫耳)溶解在2毫 ___-69 -__ 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) --- 1328585 A7 B7 五、發明説明(66 ) 升THF/EtOH= 1/1中’並以〇 745毫升之2N NaOH處理。將 反應;昆合物維持在室溫下24小時,並接著以倒在碎冰/ HC1 上中止。以AcOEt萃取兩次,以水清洗,經硫酸鈉乾燥及 以蒸發溶劑留下粗產物’將其以自Ac0Et/己烷結晶兩次的 方式純化’以產生成為白色固體之〇 〇76公克標題化合物, 熔點 128- 130° » MS : (M-H). 430.5。 IR (公分.1) : 2924,2854,17^3, .1650,1 585, 1553,1460, 1381.丨 343, 1270,1249,1165,1112,1094,1026,766,714, 692。 , NMR : (DMSO-d6,lH, <5, TMS) 2.42 (s, 3H), 3.08 (t,J=6 2H)’ 3.17 (s,3H),3.19 (dxd,1H),3.36 (dxd,J=5’ J=i4.5, 1H),3.96 (m,1H),4.38 (t,J=6.5, 2H),6.94 (d, J=8,1H) 7.26 (d, J=8, 1H), 7.45- 7.55 (m, 4H), 7.57 (t, J=7, 1H) 7.92 (br d,J=8, 2H),8.01 (d,J=8 5, 1H),8 18 (d,J=8,⑴ 12.8 (br s,1H) » ’ 厂 實例8 2-乙乳基-3~{4-丨2-(5-—^^^笨基_;>号唑_4_某1广 茗-1 -基卜丙酸 以類似於實例7的方式製備標題化合物,但是在步驟…中 使用乙氧基醋酸乙酿代替甲氧基衍生物,並獲得成為 105- 108°之灰白色晶體。 · MS : ( M)+ 445.3 « 實例9 本纸乐尺度適用中國國家標準(CNS) A4規格 ^70 - 1328585Line 1328585 A7 !__ _____B7 ___ Five 'Inventive Notes (65) The combined organic phases were dried over sodium sulfate and evaporated to dryness to leave a crude title compound as the title compound. The product is very unstable and cannot be purified by column chromatography on SiO 2 , which is also easily decomposed on TLC-plates. Helium base-[2-(5-A 芡 芡 - 碟 _ 4 4 4 4 丄 笨 笨 笨 笨 笨 笨 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0. LD A was prepared via a syringe in a solution of 0.02 g (1.6 mmol) of diisopropylamine in 3 ml of absolute THF at _ 5 ° C. After cooling to -78. 0.177 grams of methoxyethyl acetate (1.50 mmol) in 1 mL absolute THF' and the mixture was maintained at room temperature for 5 minutes to confirm complete deprotonation. Then added to dissolve in 6 mL absolute THF 0.38 g of crude 4-[2-(4-bromomethylindol-1-oxy)ethyl]·5-methyl_2·phenyl-π-isoxazole (<〇9〇 millimoles] 1 mM of the above obtained, then add 3 ml of dmpu. Stir at dry ice temperature for 15 minutes and stir for 3 〇 minutes under the armpit, then pour the reaction mixture onto crushed ice 'extracted with ^0 £1 Two times, washed with water, dried over sodium sulfate and evaporated to dryness by two flash chromatographic separations (Si〇2, hexane/eight (: 0 £1 = 74/26, followed by 76/24) Produced 145 grams of title compound as a colorless oil MS : 459.2 (M) + , 386.1, 342.1 〇gJ2-methyllacyl- 3-{4-f2-(5-methyl-2-phenyl---------- Rain S will be 0_丨37 grams of 2·methoxy-3-{4-[2-(5-methyl-2-phenyl-carbazole-4-yl)-ethoxy]-荇-丨- Base}-ethyl propionate (0.298 mmol) dissolved in 2 ___-69 -__ This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) --- 1328585 A7 B7 V. Invention (66) THF/EtOH = 1/1 </ RTI> and treated with 〇 745 mL of 2N NaOH. The reaction was carried out; the compound was maintained at room temperature for 24 hours and then quenched on crushed ice/HC1. It was extracted twice with AcOEt, washed with water, dried over sodium sulfate and evaporated to dryness eluting eluting eluting eluting of of , melting point 128-130° » MS : (MH). 430.5. IR (cm.1) : 2924,2854,17^3, .1650,1 585, 1553,1460, 1381.丨343, 1270,1249,1165 , 1112, 1094, 1026, 766, 714, 692., NMR: (DMSO-d6, lH, <5, TMS) 2.42 (s, 3H), 3.08 (t, J = 6 2H) ' 3.17 (s,3H), 3.19 (dxd,1H), 3.36 (dxd, J=5' J=i4.5, 1H), 3.96 (m,1H), 4.38 (t, J=6.5, 2H), 6.94 (d, J=8,1H) 7.26 (d, J=8, 1H), 7.45- 7.55 (m, 4H), 7.57 (t, J=7, 1H) 7.92 (br d, J=8, 2H ), 8.01 (d, J=8 5, 1H), 8 18 (d, J=8, (1) 12.8 (br s, 1H) » ' Factory example 8 2-Ethyl-based-3~{4-丨2- (5-^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Ethylene is substituted for the methoxy derivative and is obtained as an off-white crystal of 105-108. · MS : ( M)+ 445.3 « Example 9 This paper music scale applies to China National Standard (CNS) A4 specification ^70 - 1328585
3-{4-f2-(5-甲"基-2-2-丙氳某丙酸 以類似於實例7的方式製備標題 使用丙氧基醋酸乙酯代替甲氧λ 103- 105°之白色晶體。 -某彳-Λ氩基卜笨-1-某1- 化合物,但是在步驟b]中 衍生物,並獲得成為熔點 MS : 459.2 (M) + , 415.2, 372.2, 342,1 〇 實例1 0 2· X·乳基-3- {_!-丨2- ( 笨某咩岫-4 ·基)·乙M某Ί _ 苫-1 -某卜丙酸 以類似於實例7的方式製備標題化合物’但是在步驟…中 使用丁氧基醋酸乙酯代替甲氧基衍生物,並獲得成為熔點 88-90°之白色晶體。 MS : (Μ-Η)· 472.2。 實例1 1 §l.(-g>4-苄基-K(2S,3R_hJ-捋某-2-甲氮某-3- 4-Γ2-(^-甲 基苯基-°号°皇4 -基)-基〗_笨并「blp盡吩-7_某}而醢其、 °号吐炫 將0.24.9公克(S)-4-爷基-3-曱氧基乙臨基。号吱燒-2- _ (1.00毫莫耳)在氬氣下溶解在2.5毫升絕對CH2C12中,並以 〇· 167毫升三乙胺(1.2當量)處理《在冷卻至-78。之後,緩慢 加入nBu2BOTf( 1.1毫升在CH2C12中的1克分子量溶液),並 允許在- 78。下進行50分鐘及在〇。下進行50分鐘的烯醇硼酸 鹽形成作用。在再冷卻之後,經由滴管加入在3.5毫升絕對 CH2C12中的0.363公克4-[2-(5-甲基-2-笨基号峻-4-基).乙 _________- 71 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公爱)3-{4-f2-(5-A"-2-ylpropanolpropionic acid was prepared in a similar manner to Example 7 using the ethyl propoxyacetate instead of methoxy λ 103-105° white. Crystal. - A certain 彳-Λ Λ 卜 笨 -1- 1- some 1-, but the derivative in step b], and obtained into the melting point MS: 459.2 (M) + , 415.2, 372.2, 342,1 〇 Example 1 0 2· X·乳基-3- {_!-丨2- ( stupid 咩岫-4 · group)· B M Ί _ 苫-1 - a certain propionic acid prepared in a similar manner to Example 7 Compound 'But in the step... ethyl butoxyacetate was used instead of the methoxy derivative, and white crystals having a melting point of 88-90 were obtained. MS : (Μ-Η)· 472.2. Example 1 1 §l. -g>4-Benzyl-K(2S,3R_hJ-捋某-2-甲氮)-3- 4-Γ2-(^-methylphenyl-°号°皇四-基)-基〗 And "blp dictates to ___} and 醢 、, ° 吐 炫 will 0.24.9 grams (S) -4- 基 -3- 曱 曱 乙 临 。 。 。 。 。 -2- 1.00 1.00 1.00 Mol) dissolved in 2.5 ml of absolute CH2C12 under argon and treated with 167 ml of triethylamine (1.2 eq.) "after cooling to -78. Thereafter, slowly add nBu2BOTf (1.1 Raise 1 gram of molecular weight solution in CH2C12) and allow 50 minutes of enol borate formation for 50 minutes at -78. After re-cooling, add 3.5 ml absolute via a dropper. 0.363 g in CH2C12 4-[2-(5-methyl-2-indolyl-4-yl). B_________- 71 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297) Public love)
袭 訂Attack
1328585 A7 ______B7 五、發明説明1 68^ ' ~~~ 氧基]-苯并[bp塞吩-7-羧醛(i.o毫莫耳),並將混合物在 -78°下維持30分鐘及在〇。下維持6〇分鐘。倒在碎冰上,以 AcOEt萃取兩/欠’以食鹽水及水清力,經㉟酸鎮乾燥及获 ,溶劑,然後以閃蒸色層分離法(矽膠,己烷/Ac〇Et=7/3’) 最後留下成為淡黃色泡沫之0.259公克標題化合物。根據 NMR,四個異構物的其中之—極佔優勢。根據Tetrahedr〇n Asyminetry 1999, 1353,暫時將組態以 2S,3R命名。 Μί5Ι-4-^.3-((2$)-2- Ψ Μ-Γ2-Γ5- ^ ^ - 7- ^ ^ - P号唑基)-乙氣基卜茉并fh14吟-7-某}丙醯某)啐唑烷-2-酮 將以上製備的(5)-4-芊基-3-((28,311)-3-羥基-2-曱氧基_ 3-{4-[2-(夂甲基-2-苯基_崎唑_4_基)_乙氧基]_苯并[1);|11塞 吩-7-基}丙醯基)噚唑烷-2-酮(0.255公克,0.42毫莫耳)溶 解在2.2毫升三氟醋酸中,在0。下以〇 663毫升三乙基甲矽烷 (10當量)處理及接著維持在室溫下3小時,當TLC顯示沒有 原料的出現時。將反應混合物倒在碎冰/Ac〇Et/NaHC〇3 上,將有機層以水及食鹽水清洗(水相之pH〜8),經硫酸鎂 乾燥及蒸發至乾燥。以閃蒸色層分離法(Si02,己烷 /AcOEt= 7/3)輸送成為無色泡沫之〇.196公克標題化合物。 MS : 596.4 (M) +,564.3, 348.2。 NMR : (CDC13, 1H, δ , TMS) 2.39 (s, 3H), 2.78 (dxd, J=9.5, J=13.5, 1H), 3.05 (t, J=6.5, 2H), 3.25-3.31 (m, 3H), 3.41 (s, 3H), 3.91 (t, J=8, 1H), 4.07 (m,lH), 4.37 (t, J=6.5, 2H), 4.42 (m, 1H), 5.42 (t, J=6.5, 1H), 6.75 (d, J=8, 1H), 7.17- -72 - 本纸張尺度適用中國國家標準(CMS) A4规格(210 X 297公釐) 1328585 A7 ___ B7 五、發明説明(6g ) 7.4 (m,7H), 7.40-7.46 (m,4H),7.98 (br d,J=8, 2H)。 丨2-Liz 甲棊-2二笨某 莘、-产. 至_^1-笨并fbl唣吩-7-某}-丙醋 將0.195公克以上製備的(S)_4-芊基-3_((2s) 2·曱氧基% > 4- [2-( 5 -曱基-2-苯基-»号唑-4 -基)-乙氧基]•苯并[b]噻吩_ 7·基}丙酿基)崎唑烷-2_酮(0.32毫莫耳)溶解在2 25毫升 .THF中,並以0.81毫升之IN Na〇H(2.5當量)處理。將反應 混合物維持在〇。下及進行水解—,接著以TLC。在丨小時之 後,將反應混合物以倒在碎冰/HC1上中止,以Ac〇Et萃取 兩’人’以水及食鹽水清洗,經破酸鎂乾燥及以蒸發溶劑留 下粗產物’將其以自AcOEt/己烷結晶兩次的方式純化,以 除去對掌性輔助劑。藉此獲得成為白色固體之〇.丨〇2公克標 題化合物,熔點118-120。。根據iH_NMR,在>95%的極過 量旋光性純三氟甲基蒽基乙醇的存在下鑑定過量的對映 異構物。根據對掌性HPLC (Chiralpak-AD),其共計 99.3% » MS : 436.3 (M-H)·,404.3 〇 NMR : (CDCI3, 1H, (5, TMS) 2.40 (s, 3H), 3.06 (t, J=6.5, 2H), 3.20 (dxd, J=7.5, J=14.5, 1H), 3.32 (s, 3H), 3.36 (dxd, 1H), 4.20 (m,lH), 4.36 (t, J=6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.32 (d,-J=5.5, 1H), 7.40-7.45 (m, 3H), 7.48 (d, J=5.5, 1H), 7.97 (br d,J=8, 2H), COOH非常寬。 實例1 2 (S)-2-乙氣某-3· {4-『2-(5-甲某-2-苳某-呤唑-4-基)-r, g _- 73 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 x 297公釐) 1328585 A7 B71328585 A7 ______B7 V. INSTRUCTION DESCRIPTION 1 68^ '~~~oxy]-benzo[bp-sept-7-carboxaldehyde (io millimolar), and the mixture is maintained at -78 ° for 30 minutes and in 〇 . Maintain for 6 minutes. Pour on crushed ice, extract two/under s with AcOEt to remove salt water and water, dilute with 35 acid acid and obtain solvent, then use flash chromatography to separate the layer (silicone, hexane/Ac〇Et=7 /3') Finally, 0.259 g of the title compound was added as a pale yellow foam. According to NMR, one of the four isomers is extremely dominant. According to Tetrahedr〇n Asyminetry 1999, 1353, the configuration is temporarily named 2S, 3R. Μί5Ι-4-^.3-((2$)-2- Ψ Μ-Γ2-Γ5- ^ ^ - 7- ^ ^ - P oxazolyl)-ethane carbazyl and fh14吟-7- (5)-4-mercapto-3-((28,311)-3-hydroxy-2-indolyl-3-{4-[2-()夂Methyl-2-phenyl _ _ _ _ 4 _ _ _ ethoxy] benzo [1); | 11 thiophene-7-yl} propyl hydrazino) oxazolidin-2-one (0.255 G, 0.42 mmol, dissolved in 2.2 ml of trifluoroacetic acid at 0. It was treated with 663 663 ml of triethylmethane (10 eq.) and then maintained at room temperature for 3 hrs, when TLC showed no material. The reaction mixture was poured onto crushed ice / EtOAc / EtOAc / EtOAc (EtOAc)EtOAc. The title compound was obtained as a colorless foam by flash chromatography (SiO 2 , hexanes / EtOAc / 7 / 3). MS: 596.4 (M) +, 564.3, 348.2. NMR : (CDC13, 1H, δ, TMS) 2.39 (s, 3H), 2.78 (dxd, J = 9.5, J = 13.5, 1H), 3.05 (t, J = 6.5, 2H), 3.25-3.31 (m, 3H), 3.41 (s, 3H), 3.91 (t, J=8, 1H), 4.07 (m, lH), 4.37 (t, J=6.5, 2H), 4.42 (m, 1H), 5.42 (t, J=6.5, 1H), 6.75 (d, J=8, 1H), 7.17- -72 - This paper scale applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1328585 A7 ___ B7 V. Invention Description (6g) 7.4 (m, 7H), 7.40-7.46 (m, 4H), 7.98 (br d, J = 8, 2H).丨2-Liz 甲棊-2二笨某莘,-production. To _^1-stupid and fbl唣--7-a}--propyl vinegar (0.1) prepared by 0.195 grams or more (S) _ 4-mercapto-3_ ( (2s) 2·曱oxy% > 4- [2-( 5 -Mercapto-2-phenyl-»-azol-4-yl)-ethoxy]•benzo[b]thiophene-7· The oxazolidine-2-one (0.32 mmol) was dissolved in 2 25 mL of THF and treated with 0.81 mL of IN Na〇H (2.5 eq.). The reaction mixture was maintained at hydrazine. Under and carry out hydrolysis - followed by TLC. After 丨 hours, the reaction mixture was quenched on crushed ice/HC1, and the two 'people' were extracted with Ac〇Et and washed with water and brine, dried over magnesium sulfate and evaporated to leave a crude product. Purification by crystallization from AcOEt/hexane twice to remove the antagonistic adjuvant. Thus, a white solid was obtained as a white solid title compound, m.p.: 118-120. . The excess of the enantiomer was identified according to iH_NMR in the presence of >95% of very excess optically active pure trifluoromethylmercaptoethanol. Based on palmar HPLC (Chiralpak-AD), which totals 99.3% » MS : 436.3 (MH)·, 404.3 NMR : (CDCI3, 1H, (5, TMS) 2.40 (s, 3H), 3.06 (t, J =6.5, 2H), 3.20 (dxd, J=7.5, J=14.5, 1H), 3.32 (s, 3H), 3.36 (dxd, 1H), 4.20 (m,lH), 4.36 (t, J=6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.32 (d, -J=5.5, 1H), 7.40-7.45 (m, 3H), 7.48 (d, J=5.5, 1H), 7.97 (br d, J=8, 2H), COOH is very wide. Example 1 2 (S)-2-E gas a-3· {4-『2-(5-甲某- 2-苳- oxazol-4-yl)-r, g _- 73 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1328585 A7 B7
五、發明説明( 某卜苯幷fblp暮吩-7-基}-丙龄 以類似於貫例1 1的方式製備標題化合物,但是在步驟a] 中使用(S)-4-芊基-3-乙氧基乙醯基π号唑烷_ 2_酮代替甲氧芙 衍生物,並獲得成為熔點1 33- 1 34。( dec.)之白色晶體。根據 對應甲链之對掌性HPLC ( Chiracel- ODH),過量的對映異 構物共計> 99%。化合物受少量對掌性輔助劑的化學污 染。 MS : (M-H)· 450.3。 二 NMR : (CDC13, 1H, (5, TMS) 1.09 (t, J=7, 3H), 2.40 (s 3H), 3.07 (t, J=6.5, 2H), 3.18 (dxd, J=4.5, J=14.5, iH) 3 . j - 3.3 9 ( m,2 H), 3.5 2 ( m,1 H),4.2 7 (m,1H), 4 3 7 (t J=6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=7.5, 1H), 7.32 (d J-5.5, 1H), 7.41-7.48 (m, 3H), 7.48 (d, J=5.5, 1H), 7.98 (br d, J=8, 2H),COOH非常寬。 實例1 3 (S)-2-甲乳基- 3-{4-|~2-(5-甲基- 2-¾:基-p咢 <-4_ 某)_乙氧 基卜备_1-基}-丙酸 以類似於實例1 1的方式製備標題化合物,但是在步驟a] 中使用4- [2:(5-甲基-2-苯基号唑·4-基)乙氧基]萘-丨_羧醛 代替4-[2-(5-甲基-2-笨基-呤唑-4-基)·乙氧基卜苯並[b]嘍 吩-7-羧醛’並獲得成為熔點1 32- 1 33。之白色晶體。根據 1 H· NMR,在> 95%的極過量旋光性純三氟甲基惠基乙醇的 存在下鑑定過量的對映異構物。根據對掌性Hplc (Chiralpak-AD),其共計99.4%。化合物受少量對掌性 ______- 74 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(71 ) 輔助劑的化學污染。 MS : (Μ-ΗΓ 430.4。 IR (公分―1) : 2926, 2854,1 773,1650,1 585,1552,1461, 138 1, 1 343, 1270,1249,1164,1110,1095,1026, 766, 714, 693 〇 NMR : (CDC13, 1H, δ , TMS) 2.42 (s, 3H), 3.12 (t, J=6, 2H). 3.24 (s, 3H), 3.26 (dxd, 1H), 3.62 (dxd, J=4, J=14.5, 、’· **—- 1H), 4.11 (m, 1H), 4.41 (t, J=6^5, 2H), 6.78 (d, J=7.5, 1H), 7.28 (d, J=8, 1H), 7.40- 7.50 (m, 4H), 7.55 (d, J=7, 1H), 7.92 (br d, J=7, 2H), 8.00 (d, J=8.5, 1H), 8.30 (d, J=8, 1H)。 實例1 4 _ (S)-2-乙氧基-3-{4-「2-(5-甲基-2-笨基号- 4_基乙最. 基卜茬-丨-某丨-丙醢 以類似於實例1 3的方式製備標題化合物,但是在步驟a] 中使用(S) - 4 -节基-3 -乙氧基乙殖基σ号吨燒· 2 - g同代替甲氧基 衍生物,並獲得成為熔點1 33- 1 34。( dec.)之白色晶體。根據 對掌性HPLC (Chiralpak-AD),過量的對映異構物共計 > 99%。化合物受少量對掌性輔助劑的化學冷染。 MS : 445.4 (M) +,401.3, 3 72.2, 342.3 實例1 5 al2-(二笨甲叉胺基)-3- {4-[2-(5-甲某-2^_基_ @ 啥 _4_ 基)_乙&基1-条- l-基} -丙酸乙i旨 將2.0毫升nBuLi( 1.5克分子量,己炫)經由針汽加入在1〇5. Description of the invention (a certain benzoquinone fblp porphin-7-yl}-propionate The title compound was prepared in a similar manner to Example 1 1 but using (S)-4-mercapto-3 in step a] - Ethoxyethyl π-oxazolidine _ 2 - ketone in place of the methoxy oxime derivative, and obtained as a white crystal having a melting point of 1 33 - 34. (dec.). Chiracel- ODH), total enantiomeric excess > 99%. The compound was chemically contaminated with a small amount of palmitic adjuvant. MS: (MH) · 450.3. DiNMR: (CDC13, 1H, (5, TMS ) 1.09 (t, J=7, 3H), 2.40 (s 3H), 3.07 (t, J=6.5, 2H), 3.18 (dxd, J=4.5, J=14.5, iH) 3 . j - 3.3 9 ( m,2 H), 3.5 2 ( m,1 H),4.2 7 (m,1H), 4 3 7 (t J=6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=7.5, 1H), 7.32 (d J-5.5, 1H), 7.41-7.48 (m, 3H), 7.48 (d, J=5.5, 1H), 7.98 (br d, J=8, 2H), COOH Very wide. Example 1 3 (S)-2-Methylsyl- 3-{4-|~2-(5-Methyl-2-3⁄4:yl-p咢<-4_ _)_ethoxy b The title compound was prepared in a similar manner to Example 1 1 but using 4-[2:(5-methyl-2) in step a]. -Phenyl azole·4-yl)ethoxy]naphthalene-indole-carboxaldehyde instead of 4-[2-(5-methyl-2-indolyl-oxazol-4-yl)·ethoxy bromide And [b] porphin-7-carboxaldehyde aldehyde and obtain white crystals having a melting point of 1 32-33. According to 1 H· NMR, a very excess optical rotation of pure trifluoromethyl mercaptoethanol at > 95% Excess enantiomers were identified in the presence of a total of 99.4% according to the palmitic Hplc (Chiralpak-AD). The compound was subjected to a small amount of palmarity ______- 74 - This paper scale applies to the Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) 1328585 A7 B7 V. INSTRUCTIONS (71) Chemical contamination of adjuvants MS: (Μ-ΗΓ 430.4. IR (cm-1): 2926, 2854,1 773,1650,1 585 , 1552, 1461, 138 1, 1 343, 1270, 1249, 1164, 1110, 1095, 1026, 766, 714, 693 NMR: (CDC13, 1H, δ, TMS) 2.42 (s, 3H), 3.12 (t , J=6, 2H). 3.24 (s, 3H), 3.26 (dxd, 1H), 3.62 (dxd, J=4, J=14.5, , '· **—-1H), 4.11 (m, 1H) , 4.41 (t, J=6^5, 2H), 6.78 (d, J=7.5, 1H), 7.28 (d, J=8, 1H), 7.40- 7.50 (m, 4H), 7.55 (d, J =7, 1H), 7.92 (br d, J=7, 2H), 8.00 (d, J=8.5, 1H ), 8.30 (d, J=8, 1H). Example 1 4 _ (S)-2-Ethoxy-3-{4-"2-(5-methyl-2-indolyl- 4-yl-ethyl. Kibbi-丨-丨--- The title compound was prepared in a similar manner to Example 13 except that in step a], (S)-4-(4-)-3-ethoxyethyl- s- The derivative was obtained as a white crystal having a melting point of 1 33 - 34. (dec.). According to the HPLC (Chiralpak-AD), the total amount of the enantiomer was > 99%. The compound was subjected to a small amount of palm. Chemical cold dyeing of sex adjuvants MS : 445.4 (M) +, 401.3, 3 72.2, 342.3 Example 1 5 al2-(二笨甲甲胺基)-3- {4-[2-(5-甲某- 2^_基_ @ 啥_4_ base)_B& base 1-strip-l-yl}-propionic acid y is intended to add 2.0 ml of nBuLi (1.5 g molecular weight, hex) via needle steam at 1 〇
__- 75 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1328585 A7 ____B7_ 五、發明説明(~~ --- °C下的6毫升絕對THF中的0.324公克(32毫莫耳)二異丙胺 之溶液中,以製備LDA。在冷卻至_ 78。之後,逐滴加入溶 解在2毫升絕對THF中的〇.802公克N_(二苯基亞甲基)甘胺酸 乙酯(3.0耄莫耳),並將混合物維持在該溫度下丨5分鐘,以 確定完全去質子化《接著加入溶解在12毫升絕對THF中的 0. 81公克粗4-[2-(4-溴甲基莕_〗·氧基)乙基卜5甲基_2_苯 基-β咢唆(<0.20宅莫耳,如上述[實例7a]製得的2.06毫莫耳 量),然後加入5毫升DMPU。在—乾冰溫度下攪拌3〇分鐘及在 0 C下攪拌90分鐘之後,將均勻的反應混合物倒在碎冰 /N^C丨上’以AcOEt萃取兩次,以nhj丨清洗至pH7,經硫 酸鈉乾燥及蒸發至乾燥《以閃蒸色層分離法(Si〇2,己燒 / Ac0Et= 8/2)產生成為無色黏性油狀之0.829公克標題化合 物。 MS : (M)+ 608.3 〇 bl2 -胺基- 3- {4-『2-(5-甲基-2-笨基-。等吟._4 -某乙氧某1_ 茗-丨-基丙酸乙酯 將以上製備的2-(二苯曱又胺基)-3- { 4- [ 2- ( 5-甲基-2-苯 基咢唑-4-基)-乙氧基]-莕-1-基卜丙酸乙酯溶解在2〇毫升 THF中,並在0°下以5毫升2Ν HC1處理。以TLC監控保護基 的裂解。在5小時之後,將反應混合物倒在碎冰/NaHC03 上’並以AcOEt萃取兩次,.以水清洗,經硫酸納乾燥及以 1. V.除去溶劑。以閃蒸色層分離法(Si02,AcOEt)產製成為 無色油之0.505公克標題化合物》 ISP MS : (M+Na)+ 467.3, (M+H)+ 445.4 » __- 76 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐) 1328585 A7 _ B7 五、發明説明(~ NMR : (CDC13, 1H, (5, TMS) 1.22 (t, J=7, 3H), 1.49 (br s, 2H), 2.43 (s, 3H), 3.05 (dxd, J=8.5, J=14, 1H), 3.13 (t, J=6.5, 2H), 3.58 (dxd, J=5, J=U, 1H), 3.83 (dxd, J=5, J=8.5, 1H), 4.14 (q, J=7, 2H), 4.42 (t, J=6.5, 2H), 6.79 (d, J=7.5. 1H). 7.23 (d. J=7.5, 1H), 7.40-7.50 (m, 4H), 7.54 (br t, J=7, 1H), 7.96- 8.02 (m, 3H), 8.30 (d, J=8.5, 1H) 〇 £1..2- ( 2-笨醯基苽某胺基)-3-丨4_丨2- ( 甲某-2·笨某-P号峻· 4_二基)-乙氧基卜备- l-基} -丙酸-乙酿 將0.345公克2 -胺基- 3-{ 4-[2-(5-甲基-2-苯基-呤唑- 4- 基)-乙氧基]-各-1-基}-丙酸乙醋溶解在6毫升菌香链中, 並連續以0.181公克(1.15當量)2-苯醯基環己酮及60毫克 Pd/C( 10。/。)處理’以及在Ar下加熱至1 80- 1 85。。在80分鐘 之後’加入額外60毫克新鮮觸媒及持續再加熱3.5小時。冷 卻至室溫,倒在碎冰上’以AcOEt萃取兩次,以水清洗, 經硫酸鈉乾燥’並以閃蒸色層分離法(Si〇2,7/3之己烷 /AcOEt)產製0.075公克低極性餾份之標題化合物及0.285公 .克中間物蹄胺’再進行一次剛如以上的處理。最後的純化 作用留下成為黃色黏性油狀之〇 22 1公克合併的2- (2-苯醯 基-苯基胺基)-3-{4-[2-(5-甲基-2-苯基-呤唑-4-基)-乙氧 基]-茶-丨-基}-丙酸乙酯收成物。 ISP MS : (M+Na)+ 647.2, (-M+H)+ 625.1 〇 NMR : (CDCI3, 1H, <5, TMS) 1.13 (t, J=7, 3H), 2.41 (s, 3H), 3.10 (t, J=6.5, 2H), 3.44 (dxd, J=8.5, J=14, 1H), 3.71 (dxd, J=5.5, J=14, 1H), 4.13 (q, J=7, 2H), 4.38 (t, J=6.5, _^77 - 本纸張尺度適財g S家標準(CNS) A4規格(21G X 297公爱) 1328585 A7 B7 五、發明説明(74 ) 2H), 4.52 (q, J=7, 1H), 6.52 (m, 2H), 6.76 (d, J=8, 1H), 7.23 (t, J = 7.5,1H),7.35-7.6 (m,12H), 7.97 (br d,J=7..5, 2H), 8.04 (d, J=8.5, 1H), 8.28 (d, J=8.5, 1H), 8.96 (d, J=7, 1H)。 d~|2-(2 -苯醯基-笨某胺基-甲基-2-笨某-p号吃-4 -基)-乙氧基-基丨-¾齡 將0.21 3公克(0.341毫莫耳)2-(2-苯醯基-苯基胺基)-3-{4-[2-(5-甲基-2-苯基号嗤-4-基'丄-乙氧基]-茶- l-基} -丙酸乙 酯溶解在1.6毫升THF/EtOH=l/l中,並以0.568毫升之3N NaOH(5當量)處理。將反應燒瓶在室溫下攪拌20小時。接 著將混合物倒在碎冰/ NH4C丨上,以AcOEt萃取兩次,以食 鹽水清洗,經硫酸鈉乾燥及蒸發至乾燥。自己烷/AcOEt以 兩次結晶產生成為黃色晶體之〇. 1 99公克標題產物,熔點 125°(dec.)。 ISP MS : (M+K)+ 635.1, (M+Na)+ 619.1, (M+H)+ 597.1 = IR (公分.1) : 3318,2925,2854, 1 734,1622,1 585,1514, 1460,1379,1336,1249,1157,1090,1047,1025,938,701, 643。 NMR : (DMSO-d6, 1H, δ, TMS) 2.40 (s, 3H), 3.03 (t, J=6, 2H), 3.41 (dxd, 1H), 3.70 (dxd, 1H), 4.29 (m, 1H), 4.31 (t, J=6, 2H), 6.37 (t, J=7.5, 1H), 6.46 (d, J=8.5, IH), 6.85 (d, J=8, 1H). 7.13 (t, J=7.5, 1H), 7.20 (d, J=7.5, 1H), 7.31 (d, J=8. 1H). 7.40- 7.60 (m, 10H), 7.91 (br d, J=8, 2H), 8.12 (t, J = 7.5, 2H), 8.87 (d, J=7, 1H),14 (非常寬的 s,1H)。 _- 78 -__ 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)__- 75 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 ____B7_ V. Invention description (~~ --- °C 0.324 g in 6 ml absolute THF (32 mmol) To the solution of diisopropylamine to prepare LDA. After cooling to _78, 〇.802 g of N_(diphenylmethylene)glycine ethyl ester dissolved in 2 ml of absolute THF was added dropwise. (3.0 Torr), and the mixture was maintained at this temperature for 5 minutes to determine complete deprotonation. Then, 0.81 g of crude 4-[2-(4-bromo) dissolved in 12 ml of absolute THF was added. Methyl hydrazine _ _ oxy) ethyl b 5 methyl 2 - phenyl - β oxime (< 0.20 house Moule, 2.06 millimolar amount as prepared in [Example 7a] above), and then added 5 ml of DMPU. After stirring at dry ice temperature for 3 minutes and stirring at 0 C for 90 minutes, the homogeneous reaction mixture was poured onto crushed ice/N^C丨, extracted twice with AcOEt, and washed with nhj丨 until pH7, dried over sodium sulfate and evaporated to dryness. <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Compound: MS: (M) + 608.3 〇bl2 -amino-3 - {4-"2-(5-methyl-2-phenyl-.equequence _._4 - ethoxylated 1_ 茗-丨-yl Ethyl propionate 2-(diphenylfluorenylamino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]- Ethyl 荇-1- kibpropanoate was dissolved in 2 mL of THF and treated with 5 mL of 2 Ν HCl at 0°. The cleavage of the protecting group was monitored by TLC. After 5 hours, the reaction mixture was poured on crushed ice. /NaHC03 on 'and extracted twice with AcOEt. Wash with water, dry with sodium sulfate and remove the solvent with 1. V. to yield 0.505 g of colorless oil by flash chromatography (Si02, AcOEt). Compound ISP MS : (M+Na)+ 467.3, (M+H)+ 445.4 » __- 76 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1328585 A7 _ B7 , invention description (~ NMR: (CDC13, 1H, (5, TMS) 1.22 (t, J=7, 3H), 1.49 (br s, 2H), 2.43 (s, 3H), 3.05 (dxd, J=8.5 , J=14, 1H), 3.13 (t, J=6.5, 2H), 3.58 (dxd, J=5, J=U, 1H), 3.83 (dxd, J=5, J=8.5, 1H), 4.14 (q, J=7, 2H), 4.42 (t, J=6.5, 2H), 6.79 (d, J=7.5. 1H). 7.23 (d. J=7.5, 1H), 7.40-7.50 (m, 4H), 7.54 (br t, J=7, 1H), 7.96- 8.02 (m, 3H), 8.30 ( d, J=8.5, 1H) 1£1..2- (2-cracked 苽 苽 胺 胺 丨 丨 丨 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Dibasic-ethoxylated-l-yl}-propionic acid-ethyl-branched 0.345 g 2-amino- 3-{4-[2-(5-methyl-2-phenyl-carbazole- 4-yl)-ethoxy]-yl-1-yl}-propionic acid ethyl acetate was dissolved in 6 ml of the scent chain and continuously fed with 0.181 g (1.15 equivalents) of 2-benzofluorenylcyclohexanone and 60 mg. Pd/C (10. /. ) Treatment 'and heating to 180 to 1 85 under Ar. . After 80 minutes, add an additional 60 mg of fresh catalyst and continue to reheat for 3.5 hours. Cool to room temperature, pour on crushed ice 'extract twice with AcOEt, wash with water, dry over sodium sulfate' and prepare by flash chromatography (Si〇2, 7/3 hexanes/AcOEt) The title compound of 0.075 g of the low polarity fraction and 0.285 g of the intermediate compound of the snail amine were subjected to the same treatment as above. The final purification leaves a yellow viscous oil-like 〇22 1 gram combined 2-(2-phenylhydrazino-phenylamino)-3-{4-[2-(5-methyl-2- A phenyl-oxazol-4-yl)-ethoxy]-tea-oxime-yl}-propionic acid ethyl ester product. ISP MS : (M+Na)+ 647.2, (-M+H)+ 625.1 NMR: (CDCI3, 1H, <5, TMS) 1.13 (t, J=7, 3H), 2.41 (s, 3H) , 3.10 (t, J=6.5, 2H), 3.44 (dxd, J=8.5, J=14, 1H), 3.71 (dxd, J=5.5, J=14, 1H), 4.13 (q, J=7, 2H), 4.38 (t, J=6.5, _^77 - This paper scale is suitable for the g standard (CNS) A4 specification (21G X 297 public) 1328585 A7 B7 V. Invention description (74) 2H), 4.52 (q, J=7, 1H), 6.52 (m, 2H), 6.76 (d, J=8, 1H), 7.23 (t, J = 7.5, 1H), 7.35-7.6 (m, 12H), 7.97 (br d, J=7..5, 2H), 8.04 (d, J=8.5, 1H), 8.28 (d, J=8.5, 1H), 8.96 (d, J=7, 1H). d~|2-(2-phenylindolyl-stupylamino-methyl-2-stupyl-p-substitudin-4-yl)-ethoxy-yl-indole-3⁄4 age will be 0.21 3 g (0.341 m Mo)) 2-(2-phenylhydrazino-phenylamino)-3-{4-[2-(5-methyl-2-phenylindole-4-yl'-ethoxy-) The tea-l-yl}-propionic acid ethyl ester was dissolved in 1.6 ml of THF/EtOH = 1 / 1 and treated with 0.568 ml of 3N NaOH (5 eq.). The reaction flask was stirred at room temperature for 20 hours. The mixture was poured onto crushed ice / NH4C, extracted twice with AcOEt, washed with brine, dried over sodium sulfate and evaporated to dryness. hexane/AcOEt was crystallized twice to yield yellow crystals. 1 99 g of title product , melting point 125° (dec.) ISP MS : (M+K)+ 635.1, (M+Na)+ 619.1, (M+H)+ 597.1 = IR (cm.1) : 3318,2925,2854, 1 734,1622,1 585,1514, 1460,1379,1336,1249,1157,1090,1047,1025,938,701, 643. NMR: (DMSO-d6, 1H, δ, TMS) 2.40 (s, 3H) , 3.03 (t, J=6, 2H), 3.41 (dxd, 1H), 3.70 (dxd, 1H), 4.29 (m, 1H), 4.31 (t, J=6, 2H), 6.37 (t, J= 7.5, 1H), 6.46 (d, J=8.5, IH), 6.85 (d, J=8, 1H). 7.13 (t, J=7.5 , 1H), 7.20 (d, J=7.5, 1H), 7.31 (d, J=8. 1H). 7.40- 7.60 (m, 10H), 7.91 (br d, J=8, 2H), 8.12 (t , J = 7.5, 2H), 8.87 (d, J=7, 1H), 14 (very wide s, 1H). _- 78 -__ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297) MM)
裝 訂Binding
線 1328585 A7 B7 五、發明説明(75 ) 實例16 M2- +喔盖二苯基胺某)^_{4-『2彳5_甲基-2·苽基-呤唑-4-棊)-匕氣盖1-笨并rb]d%、-7 -甚1-而醢 以類似於實例1 5的方式製備標題化合物,但是在步驟a] 中使用4-[2-(7-溴曱基苯并[b]嘍吩_4_氧基)乙基]_5甲基_ 2-苯基号唑代替4_[2_(4_溴曱基莕_1氧基)乙基卜5甲基_ 2-苯基-吟唑’並獲得成為熔點丨24_丨27。之黃色固體。 ISP MS : (M+K)+ 641.1,(M+N三)+ _625.1,(M+H)+ 603.0。 1R (公分.1) : 3303,2925,2854,1732, 1624,1574,1516, 1460, 1379, 1346, 1258, 1 179, 1095, 1047, 1027, 937, 701, 643 · NMR : (DMSO-d6, 1H, δ , TMS) 2.35 (s, 3H), 2.98 (t, J=6.5, 2H), 3.24 (dxd, J=7.5, J=14.5, 1H), 3.37 (dxd, J=4.5, J=14.5, 1H), 4.30 (t, J=6.5, 2H), 4.63 (m, 1H), 6.54 (t, J=7.5, 1H), 6.76 (d, J=8.5, 1H), 6.84 (d, J=8, 1H), 7.20 (d, 1=8, !H), 7.29 (d, J=8, 1H), 7.30- 7.40 (m, 2H), 7.45-7.60 (m. 9H). 7.90 (br d, J=6, 2H), 8.73 (d,J=7.5, 1H),13.5 (非 常寬的s,1H)。 實例1 7 gl4-丨2-(2.6-二甲基苽氪某)乙某〗-5_甲某-2-苽基-p号唑 將1.1公克2,6-二甲基酚、_ 2.0 1公克2- (5-甲基-2-苯基-°号 唑-4-基)乙醇及2_6公克三苯膦溶解在30毫升THF中,並在 0。下以1 6毫升DEAD(偶氮二羧酸二乙酯)處理。將混合物維 持在室溫下隔夜《加入水。以AcOEt萃取兩次’以食鹽水 __- 79 - 本紙乐尺度適用中國國家標準(CNS) A4規格(210X297公爱) 政 訂Line 1328085 A7 B7 V. Description of the invention (75) Example 16 M2- + 喔-capped diphenylamine )) ^_{4-『2彳5_methyl-2·indolyl-carbazole-4-oxime)- The helium cap 1 - stupid and rb]d%, -7 - even 1 and the title compound was prepared in a similar manner to Example 15 but using 4-[2-(7-bromoindole) in step a] Benzo[b] porphin-4-yloxy)ethyl]_5methyl-2-phenyloxazole instead of 4_[2_(4_bromoindolyl 荇 oxy)ethyl b 5 methyl _ 2 -Phenyl-carbazole' is obtained as the melting point 丨24_丨27. Yellow solid. ISP MS: (M+K)+ 641.1, (M+N3)+ _625.1, (M+H)+ 603.0. 1R (cm.1): 3303,2925,2854,1732,1624,1574,1516, 1460, 1379, 1346, 1258, 1 179, 1095, 1047, 1027, 937, 701, 643 · NMR : (DMSO-d6 , 1H, δ , TMS) 2.35 (s, 3H), 2.98 (t, J=6.5, 2H), 3.24 (dxd, J=7.5, J=14.5, 1H), 3.37 (dxd, J=4.5, J= 14.5, 1H), 4.30 (t, J=6.5, 2H), 4.63 (m, 1H), 6.54 (t, J=7.5, 1H), 6.76 (d, J=8.5, 1H), 6.84 (d, J =8, 1H), 7.20 (d, 1=8, !H), 7.29 (d, J=8, 1H), 7.30- 7.40 (m, 2H), 7.45-7.60 (m. 9H). 7.90 (br d, J=6, 2H), 8.73 (d, J=7.5, 1H), 13.5 (very wide s, 1H). Example 1 7 gl4-丨2-(2.6-dimethyl oxime) B. _-5_A-2-mercapto-p-oxazole 1.1 g of 2,6-dimethylphenol, _ 2.0 1 Glucose 2-(5-methyl-2-phenyl-°oxazol-4-yl)ethanol and 2-6 g of triphenylphosphine were dissolved in 30 ml of THF at 0. It was treated with 16 ml of DEAD (diethyl azodicarboxylate). The mixture was maintained at room temperature overnight and "water was added. Extracted twice with AcOEt's salt water __- 79 - This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 public)
線 1328585 Α7 Β7 五、發明説明(76 ) 清洗,經硫酸鈉乾燥’並以蒸發溶劑提供粗產物,將其以 色層分離法(Si〇2,醚/環己烷)純化,以產生成為淺黃色由 之0.89公克標題化合物。 MS : (M)+ 307.2。 NMR(DMSO-d6, 1H, TMS) 2.14 (s, 6H), 2.39 (s 3H) 2.93 (t, J=7, 2H), 3.99 (t, J=7, 2H), 6.87-7.02 (m> 3H)^ 7.45- 7.55 (m,3H), 7.90-7.97 (m, 2H)。 ’ 1)14-丨2-(4-溴甲基-2,6-二甲基笨氩某)匕其卜1甲甘2 一 基-啐唑- ^ ~~ 允許在醋酸(33%)中的0.86公克4-[2-(2.6-二甲基苯氧基) 乙基]-5-曱基-2-笨基号唑及在HBr中的0.19公克對甲链之 溶液在室溫下放置3天。將混合物倒在碎冰上及以二氣甲燒 萃取。將合併的有機層以碳酸氫鈉飽和水溶液萃取,以食 鹽水清洗’經硫酸鎂乾燥及蒸發。將獲得的粗產物以色層 分離法(SI〇2,鍵/環己燒)純化及自己·烷結晶,以產生成為 白色固體之0.50公克標題化合物。 MS : (Μ)+ 399」。 NMR(CDC13, 1H, δ, TMS) 2.20 (s, 6H), 2.39 (s, 3H), 2.98 (t, J-6.5, 2H), 4.04 (t, J=6.6, 2H), 4.41 (s, 2H), 7.02 (s, 2H), 7.4 卜 7.44 (m, 3H), 7.97-8.01 (m, 2H) 〇 c]3-{375-一..y 基- 4-·(~2-(5-.甲某-2-笨基号咬-4-茱)氣 基基丨-2-乙氧基丙酸 以類似於實例2的方式製備標題化合物,但是使用4_ [2_ (4-溴甲基- 2、6-二甲基笨氧基)乙基]·5_甲基·2·苯基号唑Line 1328085 Α7 Β7 V. Description of the invention (76) Washing, drying over sodium sulphate and providing the crude product as evaporating solvent, which is purified by chromatography (Si 2 , ether / cyclohexane) to yield Yellow by 0.89 g of the title compound. MS: (M) + 307.2. NMR (DMSO-d6, 1H, TMS) 2.14 (s, 6H), 2.39 (s 3H) 2.93 (t, J=7, 2H), 3.99 (t, J=7, 2H), 6.87-7.02 (m> 3H)^ 7.45- 7.55 (m, 3H), 7.90-7.97 (m, 2H). '1) 14-丨2-(4-bromomethyl-2,6-dimethyl argon argon) 匕 1 1 甲甘 2 基-carbazole - ^ ~~ Allowed in acetic acid (33%) 0.86 g of 4-[2-(2.6-dimethylphenoxy)ethyl]-5-mercapto-2-yl azole and 0.19 g of a p-chain in HBr were placed at room temperature 3 days. The mixture was poured onto crushed ice and extracted with a second gas. The combined organic layers were extracted with a saturated aqueous solution of sodium hydrogen sulfate and washed with brine. The obtained crude product was purified by chromatography (yield: EtOAc, hexanes) to afford crystals of hexanes as a white solid. MS : (Μ)+ 399”. NMR (CDC13, 1H, δ, TMS) 2.20 (s, 6H), 2.39 (s, 3H), 2.98 (t, J-6.5, 2H), 4.04 (t, J=6.6, 2H), 4.41 (s, 2H), 7.02 (s, 2H), 7.4 Bu 7.44 (m, 3H), 7.97-8.01 (m, 2H) 〇c]3-{375-一..y base - 4-·(~2-(5 -. A-2-phenyl group -4- 茱) gas-based hydrazine-2-ethoxypropionic acid The title compound was prepared in a similar manner to Example 2, but using 4_[2_(4-bromomethyl) - 2,6-dimethylphenyloxy)ethyl]·5-methyl·2·phenylazole
· OU 本纸張尺度適用中國國家標準(CNS) Α4規格(210X297公爱) 1328585 A7 B7 五、發明説明( 77 )· OU This paper scale applies to China National Standard (CNS) Α4 specification (210X297 public) 1328585 A7 B7 V. Invention description ( 77 )
代替4-[2-(7-溴甲基苯并[13]嘍吩_4_氧基)乙基]_5_甲基_2 冬基-〃亏峻作為原料,並獲仔成為淺黃色油之標題化合物。 ISP MS : (M+K)+ 462.2,(M+Na)+ 446.3,(M+H)+ 424.4。 NMR(CDC13, lH, δ , TMS) 1.16 (t, J=6.9, 3H), 2.18 (s, 6H) 2.39 (s,3H), 2.85 (dxd, J=14.1 7.8, 1H),2.95-3.03 (m,3H) 3.39-3.50 (m,1H),3.52-3.60 (m,iH), 3.99-4.04 (m,3H) 6.85 (s,2H),7.40-7.45 (m,3H),7.96-8.00 (m,2H)。 實例18 -- 1^氧棊-..3-{3-甲基-4-『之-(5-甲甚-2-苽某-咩地_4_某)·, 氧基1-笨某丨-丙酸 以類似於實例17的方式製備標題化合物,但是使用鄰甲 酚代替2,6·-二甲基酚作為原料,並獲得成為白色 題化合物。 ISN MS : (M-H)· 408.4。 麵 R(DMSO-d6, m,TMS): i.03 (t,〇, 3H),2 〇6 (s 3H),2·35 (s,3H),2.74 (dxd,J=12 8, ih),2 83 二, J=12.8, 1H), 2.92 (t, J=7, 2H), 3.22-3.39 (nij 1H)> 3 41. 3-56 (m, 1H), 3.87-3.95 (m, 1H), 4.17 (t, J=7> 2H)> J g4 ((j> J=8, 1H), 6.97 (s, 1H), 6.98 (d, J=7, 1H)> 7.45-7 55 (m, 3H),7.87-7.96 (m, 2H)。 (, 實例19 . 甲某 _2_ 乙氧卷1-苯某丨-丙酸 · 以類似於實例15的方式製備標題化合物,但是使用 ----- - 81 - 本紙張尺度適用巾S g家辟(⑽)A4^格(21〇^^-------- 1328585 A7 B7 五、發明説明(78 (4-溴甲基-2,6-二甲基笨氧基)乙基]_5_甲基-2-苯基_呤唑 (實例丨7b)代替4- [ 2- ( 7-溴甲基苯并[b]嘍吩-4-氧基)乙基]_ 5·甲基-2-苯基-σ号唑作為原料,以產生淺黃色晶體。 1SN MS : (Μ-Η)· 573.2。 NMR(DMSO-d6, 1H, TMS) : 2.02 (s, 6H), 2.35 (s, 3H), 2.88 (t, J=6.3, 2H), 2.94 (dxd, J=13.8 6.6, 1H), 3.07 (dxd, •1=13.8 5.1, 1H), 3.91 (t, J=6.3, 2H), 4.52 (dxd, J-7.2 7.2j 1H), 6.60 (t, 1=7.2, 1H), 6.81J: s,. 2H), 6.83 (d, J=9, 1H), 7.34- 7.58 (m, 10H), 7.89- 7.92 (m, 2H), 8.64 (d, J=7.8, 1H) 13 (非常寬的s,1H)。 ’ ’ 實例20 U 2 -本酿基-冬基胺某)-3-{3-甲某·:4-[~2-(5-甲基-2笨其 3吐-4-某)-乙氧基1-苽甚}-丙醢 以類似於實例1 5的方式製備標題化合物,但是使用4_ (4- >臭甲基-2-甲基苯氧基)乙基]-5-甲基_ 2·苯基号唑(以類 似於合成4-[2-(4-漠甲基-2,6_二甲基笨氧基)乙基、甲 基-2·苯基·哼唑(實例17)的方式製得的)代替4 [2 (7溴甲 基苯并[b]嘧吩-4-氧基)乙基]_5_甲基_2_苯基〃号唑作為原 料,以產生淺黃色晶體。 ’’ ISP MS : (M+K)+ 599.1, (M+Na)+ 583.1, (M+H)+ 561 3 (CDa3, m,TMS) : 2.n (s,3H)’ 2 34 (s,3H), 2.96 (t」= 6.3. 2H). 3.H (dxd. >13.8 6 9, 1H),3 22 (dxd,’ J=13.8 6.0’ 1H),4.13 (t,>6.3, 2H),4·36 (dxd,卜6 6, 1H)’ 6.61 (t, J=8, 1H), 6.71 (t, J=7.5, 2H), ?.〇6 (s> 1H)) 7.07 ___- 82 -Instead of 4-[2-(7-bromomethylbenzo[13] porphin-4-yloxy)ethyl]_5_methyl_2-m-yl-indole as a raw material, it was obtained as a pale yellow oil. The title compound. ISP MS: (M+K) + 462.2, (M+Na) + 446.3, (M+H) + 424.4. NMR (CDC13, lH, δ, TMS) 1.16 (t, J=6.9, 3H), 2.18 (s, 6H) 2.39 (s,3H), 2.85 (dxd, J=14.1 7.8, 1H), 2.95-3.03 ( m,3H) 3.39-3.50 (m,1H), 3.52-3.60 (m,iH), 3.99-4.04 (m,3H) 6.85 (s,2H), 7.40-7.45 (m,3H),7.96-8.00 ( m, 2H). Example 18 - 1^Oxygen-..3-{3-Methyl-4-"-(5-A very-2-苽-咩地_4_某)·, oxy 1-stup The title compound was prepared in the same manner as in Example 17 except that o-cresol was used instead of 2,6-dimethylphenol as a starting material, and a white compound was obtained. ISN MS : (M-H)· 408.4. Surface R (DMSO-d6, m, TMS): i.03 (t, 〇, 3H), 2 〇6 (s 3H), 2·35 (s, 3H), 2.74 (dxd, J=12 8, ih ), 2 83 2, J = 12.8, 1H), 2.92 (t, J=7, 2H), 3.22-3.39 (nij 1H)> 3 41. 3-56 (m, 1H), 3.87-3.95 (m , 1H), 4.17 (t, J=7>2H)> J g4 ((j> J=8, 1H), 6.97 (s, 1H), 6.98 (d, J=7, 1H)> 7.45- 7 55 (m, 3H), 7.87-7.96 (m, 2H). (Example 19: A _2_ ethoxy oxime 1-phenyl hydrazine-propionic acid) The title compound was prepared in a similar manner to Example 15 but Use ----- 81 - This paper scale applies towel S g Jia Pi ((10)) A4 ^ grid (21〇^^-------- 1328585 A7 B7 V, invention description (78 (4-bromo Methyl-2,6-dimethylphenyloxy)ethyl]_5-methyl-2-phenyl-oxazole (Example 丨7b) instead of 4-[2-(7-bromomethylbenzo[b] ] 喽 -4- -4-oxy)ethyl]_ 5·methyl-2-phenyl-σ azole as a starting material to produce pale yellow crystals. 1SN MS : (Μ-Η)· 573.2. NMR (DMSO- D6, 1H, TMS) : 2.02 (s, 6H), 2.35 (s, 3H), 2.88 (t, J=6.3, 2H), 2.94 (dxd, J=13.8 6.6, 1H), 3.07 (dxd, •1 =13.8 5.1, 1H), 3.91 (t, J=6.3, 2H), 4.52 (dxd, J-7.2 7.2j 1H), 6.60 (t, 1=7.2, 1H), 6.81J: s,. 2H), 6.83 (d, J=9, 1H), 7.34- 7.58 (m, 10H), 7.89- 7.92 (m, 2H) ), 8.64 (d, J=7.8, 1H) 13 (very wide s, 1H). ' ' Example 20 U 2 - broth base - winter base amine) -3-{3-甲某·: 4- [~2-(5-Methyl-2) 3 oxi-4-)-ethoxy 1-indole}-propanoid The title compound was prepared in a similar manner to Example 15 but using 4_ (4- >Smelly methyl-2-methylphenoxy)ethyl]-5-methyl-2-phenyl azole (similar to the synthesis of 4-[2-(4-molyl-2,6_) Dimethyl[2-bromomethylbenzo[b]thiophene-4-oxo prepared by the method of dimethyloxy)ethyl, methyl-2-phenyl]carbazole (Example 17) The ethyl]ethyl]_5_methyl-2-phenyl oxazole is used as a raw material to produce pale yellow crystals. '' ISP MS : (M+K)+ 599.1, (M+Na)+ 583.1, (M+H)+ 561 3 (CDa3, m,TMS) : 2.n (s,3H)' 2 34 (s , 3H), 2.96 (t" = 6.3. 2H). 3.H (dxd. >13.8 6 9, 1H), 3 22 (dxd, ' J=13.8 6.0' 1H), 4.13 (t, > 6.3 , 2H), 4·36 (dxd, Bu 6 6, 1H)' 6.61 (t, J=8, 1H), 6.71 (t, J=7.5, 2H), ?.〇6 (s> 1H)) 7.07 ___- 82 -
本纸張尺度適用中國國家標準(CNS) A4規格(210X297公I) 1328585 A7 •_ B7_ 五、發明説明(79 ) J=8.7, 1H), 7.34- 7.60 (m, 1〇Η), 7.93- 7.96 (m, 2H), 8.82 (b r d, J = 6,1 Η)。 實例2 1 al 4,S-二甲基」2- (4-三氣甲基笨某)〇号p坐3 _氧仆物 將17.4公克4-三氟曱基苯醛(丨00毫莫耳)溶解在5〇毫升 AcOH中’並以1當量二乙醯基單月亏(ι〇·ι公克)處理。將反 應燒瓶冷卻至0。’並將乾HC1蒸汽以起泡流經溶液3 〇分鐘 (輕微放熱)。在再1/4小時之後〜,加入15〇毫升Et〇Et,並以 過濾分離沉澱物。藉此獲得成為白色晶體之1 8 · 6公克標題 分子,熔點179- 81°。This paper scale applies to China National Standard (CNS) A4 specification (210X297 public I) 1328585 A7 •_ B7_ V. Invention description (79 ) J=8.7, 1H), 7.34- 7.60 (m, 1〇Η), 7.93- 7.96 (m, 2H), 8.82 (brd, J = 6,1 Η). Example 2 1 al 4,S-dimethyl"2-(4-trimethylmethyl) a nickname p sits 3 _ oxygen servant will 17.4 grams of 4-trifluorodecylbenzaldehyde (丨00 mmol) Dissolved in 5 ml of AcOH' and treated with 1 equivalent of diethyl hydrazide in a single month (ι〇·ι). The reaction flask was cooled to zero. ' And dry HC1 vapor is bubbled through the solution for 3 minutes (slightly exothermic). After a further 1/4 hour~, 15 ml of EtEEt was added and the precipitate was separated by filtration. Thus, 1 8 · 6 g of the title molecule which became a white crystal was obtained, and the melting point was 179 - 81 °.
El MS : (M)+ 257_1,(M-OH)+ 240。 bl 4-氣甲基-5 -曱基-2-(4-三最.甲基笨某寄唑 將1 8.5公克以上製備的4,5-二甲基-2· (4-三氟甲基苯基) 哼唑3氧化物(72毫莫耳)溶解在250毫升CH2C12中,並以 7.909毫升?〇(:13(86_4毫莫耳)處理。將反應混合物經隔夜回 流,並接著以小心倒在碎冰/3N NaOH上中止。將層分離, 另外以CH2C丨2萃取水相’並將合併的有機層經硫酸鎂乾 燥’在溶劑蒸發之後留下成為淺棕色晶體之1 9.78公克粗產 物,以其原樣子供以下步驟使用。 ISP MS : ( M+H)+ 276.2。 cU5·甲基-2-(4-三氟甲某笨基)呤唑-4-某1乙腈 將在144毫升DMSO中的19.57公克以上製備的4-氣甲基-5 -甲基· 2- ( 4-三氟甲基苯基)»号唑之溶液經由滴管加入溶解 在72毫升〇^5〇中的5.3 9公.克1^3(:叫丨10毫莫耳)中(輕微放 ________-83 -______ 本纸張尺度適用中國國家標準(CMS) A4規格(210 X 297公釐) 1328585 A7El MS : (M) + 257_1, (M-OH) + 240. Bl 4-Oxomethyl-5-mercapto-2-(4-trimethyl.methyl benzoxazole 4,5-dimethyl-2·(4-trifluoromethyl) prepared over 1 8.5 g Phenyl) oxazole 3 oxide (72 mmol) was dissolved in 250 ml of CH2C12 and treated with 7.909 ml of 〇 (: 13 (86 _ 4 mmol). The reaction mixture was refluxed overnight and then carefully poured The reaction was stopped on crushed ice / 3N NaOH. The layers were separated and the aqueous phase was extracted with CH.sub.2.sub.2 and the combined organic layers were dried over magnesium sulfate. After evaporation of solvent, 1 .78 g of crude product was obtained as light brown crystals. Use the following procedure as it is. ISP MS : ( M+H) + 276.2. cU5·methyl-2-(4-trifluoromethyl) oxazole-4-one acetonitrile will be in 144 ml of DMSO A solution of 4-methylmethyl-5-methyl-2-(4-trifluoromethylphenyl)»azole prepared above 19.57 g was added via a pipette to 5.3 9 dissolved in 72 ml of 〇^5〇. Gongke 1^3 (: 丨10 millimoles) (slightly placed ________-83 -______ This paper scale applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1328585 A7
熱)。接著將反應混合物在35t下維持】小時及在价 持1晚。接著將反應漏合物倒在碎冰/AeC)Et上,將有機層以 水及食鹽水清洗,經硫酸鎂乾燥及蒸發至乾燥。以閃蒗色 層分離法(Si〇2,己烷/Ac0Et= 8/2)輸送成為淺黃色晶體之 8.8 1公克標題化合物’这點85_ %。。heat). The reaction mixture was then maintained at 35 t for an hour and at a price of 1 night. The reaction mixture was then poured onto crushed ice/AeC) Et. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to dry. The 8.8 1 g of the title compound was transferred to a light yellow crystal by flash chromatography (Si 〇 2, hexane / Ac0Et = 8/2). .
El MS : (M)+ 266.1 〇 H f 甲基-2· (4·二氟甲基笨甚)g p全_ 4_某[酷醋 將8.69公克以上製備的[5_又基·2_(4•三氟甲基苯基)气 唑-4-基]乙腈(32.6毫莫耳)溶解在1〇〇毫升Εί〇Η/水叫〇 中,並以10當量NaOH片(13公克)處理。允許在85«c下進行 隔夜的水解作用。倒在碎冰/HC丨上,以八〇〇以萃取兩次, 以水清洗,經硫酸鎂乾燥,蒸發溶劑,接著自Ac〇Et/己堍 再結晶’以產生成為灰白色晶體之7 3 5公克標題酸。 El MS : (M)+ 285.1 〇 兰12-[5-甲基-2-(4-三氣甲甚苯某)》号崠-4-某1乙酵 將7.33公克以上製備的[5_甲基-2-(4_三氟甲基苯基)„号 唆-4-基]醋酸(25.7毫莫耳)溶解在12〇毫升絕對THF中,並 在0°C下以64毫升之1克分子量bh3 · THF(2.5當量)處理。 接著將反應混合物維持在室溫下隔夜。以MeOH及冰小心中 止,以AcOEt萃取兩次,以水及食鹽水清洗,經硫酸鎂乾 燥’並以蒸發溶劑留下粗產物,將其在MeOH中回流30分 鐘’產生定量自由醇。以閃蒸色層分離法(Si02,己烷 /AcOEt= 7/3)輸送最後成為灰白色晶體之6.38公克標題化合 物。 * 84 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)El MS : (M)+ 266.1 〇H f methyl-2· (4·difluoromethyl stupid) gp full _ 4_ a [cool vinegar will be prepared above 8.69 grams [5_又基·2_(4 • Trifluoromethylphenyl)-oxazol-4-yl]acetonitrile (32.6 mmol) was dissolved in 1 mL of water/water and treated with 10 equivalents of NaOH tablets (13 g). Allow overnight hydrolysis at 85«c. Pour on crushed ice/HC丨, extract twice with gossip, wash with water, dry over magnesium sulfate, evaporate solvent, then recrystallize from Ac〇Et/hexane to produce 7 3 5 as grayish white crystals. The gram title is sour. El MS : (M)+ 285.1 〇兰12-[5-methyl-2-(4-three gas benzophenanyl)" 崠-4- certain 1 yeast will be prepared for 7.33 grams or more [5_甲Base-2-(4-trifluoromethylphenyl) oxime-4-yl]acetic acid (25.7 mmol) dissolved in 12 mL of absolute THF and 1 g of 64 ml at 0 °C Molecular weight bh3 · THF (2.5 eq.). The reaction mixture was maintained at room temperature overnight, carefully quenched with MeOH and ice, extracted twice with AcOEt, washed with water and brine, dried over magnesium sulfate and evaporated The crude product was left to reflux in MeOH for 30 min to yield quantitative free alcohol. <RTI ID=0.0>>>> 84 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)
裝 訂Binding
線 1328585 A7 ________ B7 五、發明説明(81 ) 甲基-2-μ-三氟甲某苽其、喵岫-4·莘1乙氣基} 条-1 -讀 將2.00公克2-[5-甲基-2-(4-三氟甲基苯基”咢唑-4-基]乙 醇(7_37念莫耳)溶解在37毫升甲苯中,並在〇。〇下連續以 丨·27公克4·羥基莕· 1-羧醛(7.37毫莫耳)、1.93公克三苯膦 (7,37毫莫耳)及1.49公克(7.37毫莫耳)DIAD處理。接著移 開冷卻浴及持續攪拌2小時。接著將反應混合物在真空中蒸 發至乾燥β在醚中沸騰之後,·$閃蒸色層分離法(Si02,己 坑/ Ac〇Et=.75/25)輸送成為灰白色晶體之丨.28公克標題化合 物。Line 1325885 A7 ________ B7 V. Description of the invention (81) Methyl-2-μ-trifluoromethyl 苽 喵岫, 喵岫-4·莘1 ethane base} Article-1 - Read 2.00 gram 2-[5- Methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]ethanol (7_37 Nym) was dissolved in 37 ml of toluene and was continuously dried at 丨·27 g 4· Hydroxy hydrazine 1-carboxyaldehyde (7.37 mmol), 1.93 g triphenylphosphine (7,37 mmol) and 1.49 g (7.37 mmol) DIAD treatment. The cooling bath was then removed and stirring was continued for 2 hours. The reaction mixture was then evaporated in vacuo to dryness. After boiling in ether, </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Compound.
Sl^ii_5L^-3-「(2S.3RH荈某-2-甲氪某甲 氟甲基苯基)°咢唑-4-基1乙氣基}笨-1-某)丙sfe其1 g咢唑烷_ 將0.374公克(S)-4-芊基-3-甲氧基乙酿基》号嗓燒-2_嗣 (1.50¾莫耳)在氬氣下溶解在μ毫升絕對ch2ci2中,並以 0.2:)1毫升三乙胺(ι·2當量)處理。在冷卻至·78。之後,緩慢 加入nBu2BOTf(1.65毫升在CH2C12中的1克分子量溶液),並 允許在-78。下進行1 5分鐘及在〇。下進行50分鐘的烯醇硼酸 鹽形成作用。在再冷卻之後,將在12毫升絕對CH2Cl2中的 0.638公克4-{2-[5-甲基-2-(4-三氟甲基苯基)呤唑_4_基]乙 氧基}笨-卜致链(L 5毫莫耳)之溶液經由滴管加入,並將混 合物在-78。下維持30分鐘及在〇。下維持60分鐘。倒在碎冰 上,以AcOEt萃取兩次,以食鹽水及水清洗,經疏酸鎂乾 燥及蒸發溶劑,接著以閃蒸色層分離法(矽膠,己虎 _ - 85 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585 A7 B7 五、發明説明(82 ) / AcOEt= 1/ 1)最後留下成為白色泡沫之0.840公克標題化合 物。 ISP MS : (M+H)+ 675.1,(M+Na)+ 697。 hl(S)-4-芊篡- 3-US)-2-甲氳基- 3-(4- (2-Γ5-甲某- 2-(4-三 氣甲某装某)啐峽-4_基1乙氧基}笨-1•某)丙醯基1崎唑烷-2- §同 將0.837公克以上製備的(S)-4-芊基·3-[(23,311)-3-羥基-2-甲氧基-3-(4-{2-[5-甲基-2:1_4-三氟甲基苯基)咩唑-4-基] 乙氧基}莕-1 -基)丙醯基]崎唑烷-2-酮(1.23毫莫耳)溶解在 3.2毫升三氟醋酸中,在〇。下以0.977毫升三乙基甲矽烷(5當 量)處理及接著維持在室溫下1 6小時,當TLC顯示沒有原料 的出現時。接著將反應混合物倒在碎冰/ AcOEt/NaHC03 上’將有機層以水及食鹽水清洗(水相之pH〜8),經硫酸鎮 乾燥及蒸發至乾燥》以閃蒸色層分離法(Si〇2,己烷 /AcOEt= 7/3)輸送成為白色泡沫之0.702公克標題化合物。 ISP MS : (M+H)+ 659.1, (M+Na)+ 681.1 〇 il(S)-2-甲氧基- 3-(4-{2-[5-甲基- 2-(4-三悬.甲某苯某)咩 °生-4-基~|乙氧基}笨-1-基)丙酸 將0.698公.克以上製備的(S)-4-卞基- 3- [(S)-2-甲氧基- 3· (4-{2-[5 -甲基-2-(4 -三氟甲基笨基)。号唑·4_基]乙氧基)莕· 1 -基)丙醯基]呤唑烷· 2_酮(丨03毫莫耳)溶解在7 5毫升THF 中,並以2_57毫升之IN NaOH(2.5當量)處理。將反應混合 物維持在0。下及進行水解’接著以TLC。在1小時之後,將 反應混合物倒在碎冰上,並以謎萃取,以除去對掌性辅助 - -86 -_ 本纸張尺度適用中國國家標竿(CNS〉A4規格(210X297公爱) -Sl^ii_5L^-3-"(2S.3RH荈一-2-甲氪一甲fluoromethylphenyl) ° carbazole-4-yl 1 ethyl group} stupid-1-some) propyl sfe its 1 g Oxazolidine _ Dissolving 0.374 g of (S)-4-mercapto-3-methoxyethyl aryl group - 2 - 嗣 (1.503⁄4 mol) in argon under μl absolute ch2ci2, Treated with 0.2:) 1 ml of triethylamine (1.2% equivalent). After cooling to 78., nBu2BOTf (1.65 ml of a 1 gram molecular weight solution in CH2C12) was slowly added and allowed to proceed at -78. The enol borate formation was carried out for 15 minutes at 15 minutes and in 〇. After re-cooling, 0.638 g of 4-{2-[5-methyl-2-(4-) in 12 ml of absolute CH 2 Cl 2 was added. A solution of trifluoromethylphenyl)carbazole-4-yl]ethoxy}brown-branched chain (L 5 mmol) was added via a dropper and the mixture was maintained at -78 for 30 minutes and in hydrazine. Maintain for 60 minutes. Pour on crushed ice, extract twice with AcOEt, wash with salt water and water, dry with magnesium sulfate and evaporate the solvent, then flash-separate method (矽胶,己虎_ - 85 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297) 1328585 A7 B7 V. INSTRUCTIONS (82) / AcOEt = 1/ 1) Finally left 0.840 g of the title compound as a white foam. ISP MS : (M+H) + 675.1, (M+Na) + 697 HL(S)-4-芊篡- 3-US)-2-Methyl-yl- 3-(4-(2-Γ5-甲某- 2-(4-三气甲一装某)啐峡- 4_Base 1 Ethoxy} Stupid-1•A) Propionyl 1 Soxazolidine-2- § (S)-4-Mercapto-3-([23,311)-3- prepared with 0.837 g or more Hydroxy-2-methoxy-3-(4-{2-[5-methyl-2:1_4-trifluoromethylphenyl)oxazol-4-yl]ethoxy}indole-1 -yl) Propionyl] oxazolidin-2-one (1.23 mmol) was dissolved in 3.2 mL of trifluoroacetic acid and treated with 0.977 mL of triethylmethane (5 eq.) and then maintained at room temperature. 1 6 hours, when TLC showed no material appeared. Then the reaction mixture was poured on crushed ice / AcOEt / NaHC03 'The organic layer was washed with water and brine (pH ~ 8 of water phase), dried by sulfuric acid and Evaporation to dryness, 0.702 g of the title compound was obtained as a white foam by flash chromatography (Si.sub.2, hexane/AcOEt = 7/3). ISP MS : (M+H) + 659.1, (M+Na )+ 681.1 〇 il(S)-2-methoxy- 3-(4-{2-[5-methyl- 2-(4-three-suspension. A certain benzene) 咩 °-4-yl~|B (S)-4-mercapto-3-([S)-2-methoxy-3 (4-{2-[ 5-Methyl-2-(4-trifluoromethylphenyl). Isoazyl-4-yl]ethoxy)indole-1-yl)propanyl]oxazolidine-2-one (丨03 mmol) dissolved in 7 5 ml of THF with 2_57 mL of IN NaOH (2.5 equivalents) treatment. The reaction mixture was maintained at zero. Lower and proceed to hydrolysis' followed by TLC. After 1 hour, the reaction mixture was poured onto crushed ice and extracted with mystery to remove the palmar aid. -86 -_ This paper scale applies the Chinese national standard (CNS>A4 specification (210X297 public))
線 1328585 A7 __B7___ 五、發明説明(83 ) 劑》接著將水層以HC1酸化,以八⑴以萃取兩次,以水清 洗’經疏酸鎂乾燥及蒸發至乾燥β自Ac〇Et結晶,最後產 生成為白色晶體之0.356公克標題產物,炫點丨67_68。。 1SN-MS : 498.2 (M-H)+。 NMR : (CDC13, 1H, (5, TMS) 2.44 (s, 3H), 3.14 (t, S=6.5, 2H), 3.25 (s, 3H), 3.28 (dxd, J=9, J=14.5, 1H), 3.61 (dxd, J=14.5, J = 4,1H),4.11 (m,m),4.41 (t, J=6.5, 2H), 6.78 (d, J=8, 1H), 7.30 (d, J=8, lH),-7.49. (m, 1H), 7.55 (m, 1H), 7.68 (d, J=8.5, 2H), 8.02 (d, J=8.5, 1H), 8.09 (d, J=8.5, 2H), 8.2 8 (d, J=7, 1H),COOH非常寬。 實例22 乙 - 3- (4- { 2- f 5-甲 t 2- (4-三 1 甲某苽某)口咢唑-4-基1乙氣基丨萁-l-某)丙齡 以類似於實例2 1的方式製備成為熔點1 5 3 _ 5 5。之白色晶 體,但是在步驟g]中使.用(S)-4_苄基·3·乙氧基乙醯基呤唑 烷-2·酮代替曱氧基衍生物。 ISN-MS : 512.2 (Μ-Η)+。 NMR : (CDC13,1Η,<5,TMS)l.〇15 (t,J=7,3Η),2.45 (s, 3H), 3.14 (t, J-6.5, 2H), 3.2-3.3 (m, 2H), 3.44 (m, 1H), 3.63 (dxd, J=14.5, J=4, 1H), 4.17 (m, 1H), 4.42 (t, J=6.5, 2H). 6.79 (d, J=8, IH), 7,29 (d, J=8, 1H),7,48 (m,1H), 7.55 (m, 1H), 7.68 (d, J-8.5, 2H), 8.03 (d, J=8.5, 1H), 8.09 (d. J=8.5, 2H), 8.28 (d,J=8.5,1 H),COOH非常寬。 實例23 ____- 87 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585Line 1328085 A7 __B7___ V. Inventive Note (83) Agent" The aqueous layer is then acidified with HC1, extracted with eight (1) twice, washed with water, dried with magnesium silicate and evaporated to dry β from Ac〇Et crystal, finally Produced as a white crystal 0.356 g of the title product, dazzling 丨 67_68. . 1SN-MS: 498.2 (M-H)+. NMR : (CDC13, 1H, (5, TMS) 2.44 (s, 3H), 3.14 (t, S=6.5, 2H), 3.25 (s, 3H), 3.28 (dxd, J=9, J=14.5, 1H ), 3.61 (dxd, J=14.5, J = 4,1H), 4.11 (m,m), 4.41 (t, J=6.5, 2H), 6.78 (d, J=8, 1H), 7.30 (d, J=8, lH), -7.49. (m, 1H), 7.55 (m, 1H), 7.68 (d, J=8.5, 2H), 8.02 (d, J=8.5, 1H), 8.09 (d, J =8.5, 2H), 8.2 8 (d, J=7, 1H), COOH is very wide. Example 22 B - 3- (4- { 2- f 5-甲 t 2- (4-三一甲甲苽) Oral oxazol-4-yl 1 ethane group 丨萁-l-m) propylene was prepared in a similar manner to Example 2 1 as white crystals having a melting point of 1 5 3 _ 5 5 , but in step g] Replace the oxirane derivative with (S)-4-benzyl·3·ethoxyethyl oxazolidine-2·one. ISN-MS : 512.2 (Μ-Η)+. NMR : (CDC13, 1Η, <5, TMS) l.〇15 (t, J=7, 3Η), 2.45 (s, 3H), 3.14 (t, J-6.5, 2H), 3.2-3.3 (m, 2H), 3.44 (m, 1H), 3.63 (dxd, J=14.5, J=4, 1H), 4.17 (m, 1H), 4.42 (t, J=6.5, 2H). 6.79 (d, J=8, IH), 7,29 (d, J=8, 1H), 7,48 (m,1H), 7.55 (m, 1H), 7.68 (d, J-8.5, 2H), 8.03 (d, J=8.5, 1H) , 8.09 (d. J=8.5, 2H), 8.28 ( d, J=8.5, 1 H), COOH is very wide. Example 23 ____- 87 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585
基_·3·(4·{2-丨三氟甲甚茉某)咩砷· }笨并 f bl4 吩-7-芊丨 Θ $ 以類似於實例21的方式製備成為熔點173·75。之灰白色晶 體,但是在步驟f]中使用4·幾基苯并[b]B塞吩_7__[Ger 〇^η·( 1998) DE 19711617 Αι]代替 4 羥基茶·丨羧醛。 ISN-MS : 504.2 (M-H)、 NMR: (CDC13, 1H, 5, TMS) 2.43 (s, 3H), 3.08 (t, J=6.5, 2H), 3.21 (dxd, J=8, J=14.5, IH), 3.33 (s, 3H), 3.38 (dxd, J-14.5, J=4.5, lH),4.20(m, lH),4.38(t, 1=6.5, 2H), 6.74 (d. J=8, 1H), 7.15 (d, J=8.5, 1H), 7.33 (d, J=5.5, 1H), 7.47 (d, J=5.5, 1H), 7.68 (d, J=8, 2H), 8.08 (d, J=8 5 2H) COOH非常寬。 ’ 實例24 (sp-乙氧基(心三氣甲某号唑· 4-基1乙氣某丨苯并丨bl唭吩-7-某、而醢 以類似於實例22的方式製備成為熔點126·28。之白色晶 體,但是在步驟f]中使用4_羥基苯并[b]嘍吩_ 7·羧醛[ Offen.( 1998) DE 19711617 A1]代替4_羥基莕_丨-羧醛。 1SN-MS : 518.1 (Μ·Η)+。 NMR : (CDCI.3, 1Η, 6, TMS) 1.09 (t, J=7, 3H), 2.42 (s, 3H).3.07(t,J-6.5,2H),3-.20(dxd,J=8,J=14.5,lH)3 3- 3.4 (m, 2H), 3.51 (m, 1H), 4.27 (m, 1H), 4.38 (t, j=6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.33 (d, J=5, 1H), 7.48 (d, J=5, 1H), 7.68 (d, J=8.5, 2H), 8.08 (d, J=8.5, I_- 88 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 五、發明説明( 85 A7 B7 1H),COOH非常寬< 實例25 二4_-基)乙氧.某1竿- LS)-3^.4-f 2-(2j_^4^ · 1-基}-2-乙氧基雨齡 以類似於實例22的方式 -/日 衣饰成為熔點140-45。之白多闳 體,但是以4-笨基笨醛代 疋白色固 序。 瞀4-二氟甲基苯醛開始反應順 ISN-MS : 520.3 (M-H)+ 〇 .. 實例26 - (S)-3-M-f2-(2 -聯苯 基 1-基}-2-丙氣基丙齡 以類似於實例25的方式劁偌士 ·Α — l 々八表備成為熔點151-54。之白眘闭 體,但是在丁間醇醛偶厶+脾士 m 两σ步驟中使用(S)-4-苄基_3_丙最某 乙醯基哼唑烷-2-酮代替乙氧基類似物。 ISN-MS : 534.2 (M-H)+。 實例27 fbl4吩-7-基}-2-丙袁其而_ 以類似於貫例26的方式製備成為熔點丨47_ 5丨。之灰 b 八曰色固 體,但是在Mitsunobu反應中使用4-羥基苯并[b]嘍吩7 a 链[Ger. Offen.( 1998) DE 19711617 A1]代替 4-羥基茶」: 醛。 夂 1SN-MS : 540.2 (M-H)+。 實例28 89 - 本纸張尺度適用中國画家標準(CNS) A4規格(210 X 297公釐) 1328585Base _·3·(4·{2-丨Trifluoromethane) arsenic· } stupid f bl4 phen-7-芊丨 Θ $ Prepared in a manner similar to Example 21 to a melting point of 173·75. It is an off-white crystal, but in the step f], 4· benzyl benzo[b]B thiophene _7__[Ger 〇^η·(1998) DE 19711617 Αι] is used instead of 4 hydroxy tea·丨carboxyl aldehyde. ISN-MS: 504.2 (MH), NMR: (CDC13, 1H, 5, TMS) 2.43 (s, 3H), 3.08 (t, J=6.5, 2H), 3.21 (dxd, J=8, J=14.5, IH), 3.33 (s, 3H), 3.38 (dxd, J-14.5, J=4.5, lH), 4.20 (m, lH), 4.38 (t, 1=6.5, 2H), 6.74 (d. J=8 , 1H), 7.15 (d, J=8.5, 1H), 7.33 (d, J=5.5, 1H), 7.47 (d, J=5.5, 1H), 7.68 (d, J=8, 2H), 8.08 ( d, J=8 5 2H) COOH is very wide. Example 24 (sp-ethoxyl (heart trimethyl ketone) 4-yl 1 ethane benzophenone bl 唭-7-, while hydrazine was prepared in a similar manner to Example 22 as melting point 126 • White crystals of 28. However, in the step f], 4-hydroxybenzo[b] porphin-7 carboxaldehyde [Offen. (1998) DE 19711617 A1] was used instead of 4-hydroxyindole-indole-carboxaldehyde. 1SN-MS : 518.1 (Μ·Η)+. NMR : (CDCI.3, 1Η, 6, TMS) 1.09 (t, J=7, 3H), 2.42 (s, 3H).3.07(t,J-6.5 , 2H), 3-.20 (dxd, J=8, J=14.5, lH)3 3- 3.4 (m, 2H), 3.51 (m, 1H), 4.27 (m, 1H), 4.38 (t, j =6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.33 (d, J=5, 1H), 7.48 (d, J=5, 1H), 7.68 (d, J=8.5, 2H), 8.08 (d, J=8.5, I_- 88 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) V. Description of the invention ( 85 A7 B7 1H), COOH is very wide < Example 25 bis 4_-yl) ethoxy. Some 1 竿- LS)-3^.4-f 2-(2j_^4^ · 1-yl}-2-ethoxylated rain The age was similar to that of Example 22 -/Nikko became the melting point of 140-45. The white polysteroids, but the 4-styl aldehydes were substituted for white solids. 瞀4-Difluoromethylbenzaldehyde began to reverse Should be cis-ISN-MS: 520.3 (MH) + 〇.. Example 26 - (S)-3-M-f2-(2-diphenyl-1-yl}-2-propenyl propylene age similar to Example 25 The way gentleman · Α - l 々 表 表 备 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 151 _3_ propyl most acetamidooxazolidine-2-one in place of ethoxy analog. ISN-MS: 534.2 (MH)+. Example 27 fbl4 phen-7-yl}-2-propanyl _ The ash b ochre solid which became the melting point 丨47_5丨 was prepared in a manner similar to Example 26, but the 4-hydroxybenzo[b] porphin 7 a chain was used in the Mitsunobu reaction [Ger. Offen. (1998) DE 19711617 A1] Instead of 4-hydroxy tea": aldehyde. 夂1SN-MS: 540.2 (MH)+. Example 28 89 - This paper size applies to the Chinese Painter Standard (CNS) A4 specification (210 X 297 mm) 1328585
氧基1篇- i^L-3二{ 4-丨 2- (2-聯苯-4二_4^甲某咩唑-4·某、Λ 丄-基丨-2-曱氧基丙酸 以類似於實例26的方式製備成為溶點1 56- 59。之白色固 體,但是在丁間醇_合步驟中使用(S)_4H3.甲氧基 乙醯基哼唑烷-2-酮代替丙氧基衍生物。 ISP-MS : 508.4 (M+H)+ 〇 實例2 9 111:.3- { 4-丨2-(2-聯苯-4二^。号嗤-4-某)乙免甚作· 1^棊}-2-(2,2,2-三氟乙 以颌似杰貫例2 8的方式製備成為熔點199_ 2〇〇。之白色固 體,但是在丁間料偶合步驟中使用⑻-4-节基-3-[(2,2,2_ 二齓乙氧基)乙醯基]嘮唑烷_ 2_酮代替甲氧基衍生物。 ISN-MS : 574.0 (M-H)+。 實例30Oxy 1 - i^L-3 bis { 4-丨2-(2-biphenyl-4 bis-4^methyl carbazole-4·, Λ 丄-yl 丨-2-methoxypropionic acid A white solid which became a melting point of 1 56-59 was prepared in a similar manner to Example 26, but (S)_4H3. methoxyethinyloxazolidine-2-one was used instead of Oxygen derivative. ISP-MS : 508.4 (M+H)+ 〇Example 2 9 111:.3- { 4-丨2-(2-biphenyl-4di^.嗤-4-) B _^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Replace the methoxy derivative with (8)-4-benzyl-3-[(2,2,2-dioxaethoxy)ethinyl]oxazolidine-2-one. ISN-MS : 574.0 (MH)+ Example 30
Lg)-3-{4-[2-(2-聯苯-4二4_^甲基呤咄-4·甚)Λ氳某1苽并 [1)1喝吩-7 -基丨-2-乙氣某 以類似於實例27的方式製備成為熔點163 164。之白色固 體,但疋在丁間醇醛偶合步驟中使用(s)_4•苄基_ 3•乙氧基 乙醯基哼唑烷-2-酮代替丙氧基衍生物。 ISN-MS : 526_0 (M-H)+。 實例3 1 (5)-3-(4-{2-11-(4-異甲某呤唑-4-基 1 乙氣基} 苯幷f b丨嚯吩-Z-基)-2-甲氣甚壬矽 以類似於實例2 3的方式製備成為熔點95_ 97。之淺黃色晶 -90 - 本紙俵尺度適用中國國家標準(CNS) A4規格(210X29741) 1328585 A7 B7Lg)-3-{4-[2-(2-biphenyl-4di-4_^methyl呤咄-4·very)Λ氲一苽苽[1)1喝苯-7-yl丨-2- Ethylene was prepared in a manner similar to Example 27 to mp 163 164. The white solid is used, but in the butanol coupling step, (s) _4•benzyl-3 ethoxylated oxazolidin-2-one is used in place of the propoxy derivative. ISN-MS: 526_0 (M-H)+. Example 3 1 (5)-3-(4-{2-11-(4-isomethyl oxazol-4-yl 1 ethyl group} phenylhydrazine fb porphin-Z-yl)-2-methyl What is prepared in a manner similar to that of Example 23 to a melting point of 95_97. The pale yellow crystal-90 - paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X29741) 1328585 A7 B7
五、發明説明(87 ) 體,但是使用4·異丙基笨發 料。 . 代替4-三氟甲基笨發作為 原 1SN-MS : 478.2 (M-H)+ 〇 實例32 (S)-3-(4-{2-f2-(4-異丙產 笨并 fbl 口塞吩-7-基— 基口咢口全-4- 尾乙乳某)1¾ S会 以類似於實例3 1的方式製備占么p 灰備成為熔點181-182。之白备日 體,但是在丁間醇㈣合步驟,吏用(s)_4-字基 = 三氟乙氧基)乙酿基]十坐燒_2,代替甲氧基衍生物。’’2· ISP-MS : 548.2 (M+H)+ 〇 實例33 (S)-3-(4-(2-[2-(3,5-二甲 | , . - —-— Ψ Λ. .f 1 ^ ^ 蒸} %>并丨.b]·»塞吩-7_基)· 2- f—氢基丙g会 以類似於實例23的方式製備成為熔點丨84 185。之白色晶 月a,但疋以3,5 - —甲基笨醛開始整個反應順序。 ISN-MS : 464.2 (M-H)+ 〇 實例34 0_>(4-{2-『2-(3,5-二^^苯基卜5_甲其碟地 氧基丨笨并fbh塞吩-7-基)-2-甲g其品齡 以類似於實例23的方式製備成為熔點194·丨95。之白色晶 體,但是以3,5-二甲氧基苯醛代替4-三氟甲基苯醛開始整 個反應順序= 1SN- MS : 496.0 (Μ-Η)+。 實例35 ---1_91 - 本纸張尺度適用中國國家標準(CNS) Α4規格(210X 297公釐)5. Inventive Note (87) Body, but using 4·isopropyl stupid hair. Instead of 4-trifluoromethyl stupid as the original 1SN-MS: 478.2 (MH) + 〇 Example 32 (S)-3-(4-{2-f2-(4-isopropyl stupid and fbl mouth phenophene -7-based - base mouth 全口 全-4- tail 乙乳) 13⁄4 S will be prepared in a manner similar to the case of Example 31, which is a mp 181-182. The intermediate alcohol (four) combined step, using (s) _ 4-word base = trifluoroethoxy) ethyl thiol] ten sit burning _2, instead of the methoxy derivative. ''2· ISP-MS : 548.2 (M+H)+ 〇Example 33 (S)-3-(4-(2-[2-(3,5-Dimethyl | , . - --- Ψ Λ. .f 1 ^ ^ steamed}%> and 丨.b]·»sep-7-yl)·2-f-hydrogen propyl g was prepared in a similar manner to Example 23 as the melting point 丨84 185. Jingyue a, but 疋 starts the entire reaction sequence with 3,5-methyl aldehyde. ISN-MS: 464.2 (MH)+ 〇Example 34 0_>(4-{2-『2-(3,5-II ^^phenyl bromide 5- _ 其 地 地 丨 并 并 并 并 f f f f f f f f f f f f f f f f f f f f f f f f f f f f f f 194 194 194 However, the whole reaction sequence was started by replacing 3,5-dimethoxybenzaldehyde with 4-trifluoromethylbenzaldehyde = 1SN-MS : 496.0 (Μ-Η)+. Example 35 ---1_91 - Paper scale Applicable to China National Standard (CNS) Α4 specification (210X 297 mm)
裝 訂Binding
線 1328585 A7 B7 五、發明説明(88 ) ^^11^{2-[2-(3.5-二甲基苯甚>>_5_曱基0号唑-4-某1乙羊 基)-2-甲氣某丙龄 以類似於實例28的方式製備成為熔點丨97- 198。之白色晶 體’但是以3,5-二甲基笨醛代替4-苯基苯醛開始整個反應 順序。 1SN-MS : 458.3 (M-H)+。 實例3 6 ^111111_2-丨2-(3,5-二氯笨基-)_5-甲某呤唑-4_基1乙氪其} ^ΙΜζ^ι_-7-基)-3·與某-2-甲Μ其呙紿广酷Line 1325885 A7 B7 V. Description of the invention (88) ^^11^{2-[2-(3.5-Dimethylbenzene- gt;>_5_曱基0 azole-4-one 1 ethyl)- 2-Methane was prepared in a manner similar to Example 28 to a melting point 丨97-198. The white crystal's but the replacement of 4-phenylbenzaldehyde with 3,5-dimethylalbenal started the entire reaction sequence. 1SN-MS: 458.3 (M-H)+. Example 3 6 ^111111_2-丨2-(3,5-dichlorophenyl-)_5-methyl carbazole-4_yl 1 ethyl hydrazide} ^ΙΜζ^ι_-7-yl)-3· with a - 2-A Μ Μ 呙绐 呙绐 呙绐 呙绐
根據標準步驟’以在3毫升絕對THF中的0.171公克二異丙 胺(丨.69宅莫耳)及丨·〇2毫升之i 5克分子量nBuLi (己烷)在 -10 C下製備在THF中的LDA溶液。-在冷卻至- 78。之後,加 入落解在丨毫升THF中的〇 18丨公克曱氧基醋酸乙酯(ι·54毫 莫耳)’並持續攪拌1 5分鐘,以完成烯醇酸鹽形成作用。加 入落解在1.5毫升THF中的0.166公克4-{2-[2-(3,5 -二氣苯 基)-5-甲基》号峻-4-基]乙氧基}笨并塞吩-7•羧醛(〇 38毫 莫耳),並將混合物在該溫度下再維持3〇分鐘。倒在碎冰 /NHeCI上’以AcOEt萃取兩次’以水及食鹽水清洗,經硫 酸鎂乾燥及蒸發溶劑,然後以閃蒸色層分離法(Si〇2,己烷 ’ AcOEt=7/3)輸送成為同/逆-異.構物之〇. 1 74公克標題化合 物。如實例2 1 a] - f]的說明製備必要的醛(4_ { 2_ [ 2- ( 3,5-二 氣苯基)-5-甲基哼唑-4-基]乙氧基}苯并吩_7_羧链), 但是以3,5-二氯基苯醛代替4-三氟甲基苯醛開始整個反應 順序及4-經基笨并[b]-塞吩-7-羧醛[Ger. Offen.( 1998) DE ___- 92 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) B7 89 五、發明説明( 19711617 A1]代替4-¾基某-1·幾链用於]yjitsunobu反應》 ISP MS : 550.1 (M+H)+。· IL外消旋性_1-3-(4-{2-12-(3.5-二氟苯某)-5-甲某峄峙 基丄工氧基丨苯并丨bl嚜吩-7-某)-2-f氣某丙酸乙酯 將0.173公克以上製備的3-(4-{2-[2-(3,5-二氣苯基)-5-甲 基°号唑-4-基]乙氧基}笨并[b]喵吩_7_基)_3_羥基_2·甲氧基 丙乙酯(0.31毫莫耳)溶解在ίο毫升三氟醋酸中,在〇。下 以0.2 5 0毫升二乙基甲矽坑(5宽量)處理及接著維持在該溫 度下4小時當TLC顯示原料消失時。接著將反應混合物倒 在碎冰/AcOEt/NaHC〇3上(水層之pH〜7 5),將有機層以水 及食鹽水清洗(水相之pH〜8) ’經硫酸鎂乾燥及蒸發至乾 保。以閃蒸色層分離法(Si〇2,已烷/Ac〇Ei==85/15)供給成 為白色晶體之0· 143公克標題化合物,炫點1 〇〇_丨〇2。。 ISP MS : 535.3 (M+H)+。 £1_1^沩旋性卜3-(4-{2.-[?:-(3,5-二畲苯某)-5-甲某口等唑-4-基丄笨并丨bp塞吩-7-基y |高始 將0.丨42公克以上製備的[外消旋性]_3_(4· ( 2_ [2_(3,5-二 氯苯基)-5-甲基噚唑-4-基]乙氧基}苯并[b]噹吩_7_基)_2_ 甲氧基丙§父乙g旨(0.27毫莫耳)溶解在4毫升THF/EtOH=l/l 中,並以0:68毫升之IN NaOH(2.5當量)處理。將反應混合 物在室溫下攪拌及進行水解,接著以TLC。在2小時之後, 將反應混合物倒在碎冰/稀釋的HC丨上,並以Ac〇Et萃取兩 ’入。。鼾有機層以水及食鹽水清洗,經硫酸鎂乾燥及蒸發至 乾燥。自AcOEt/己烷結晶,最後產生成為白色晶體之〇丨〇7 -93 - 1328585 A7 B7 五、發明説明( 公克標題產物,溶點160- 6 1。。 ISN-MS : 504.1 (M-H)+ 〇' NMR : (CDCI3, 1H, δ, TMS)2.41 (s, 3H), 3.06 (t, J=6.5, 2H), 3.21 (dxd, J=8, J=14.5, 1H), 3.34 (s, 3H), 3.36 (m-, 1H), 4.20 (m,lH), 4.37 (t, J=6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.33 (d, J=5.5, 1H), 7.37 (s, 1H), 7.46 (d, J=5.5. m), 7.86 (d, J=1.5, 2H),COOH非常寬。 實例37 -- 111卜4旋性]-.3-(4-{2-『2-(_^二|1苽&)_5_甲某[>夸崦-4-某1 虱棊}麥幷f b~|嚷吩-7_基)· 2·甲$基丙酸 以類似於實例36的方式製備成為熔點14 1 _ 142。之白色晶 體,但疋以3,5-二氟苯醛代替3,5_二氣苯醛開始整個反應順 序。 ISP-MS : 474.3 (Μ+Η)、 實例3 8 ⑷^生Η-丁氧基笨某甲某 圭-4-基丄乙氧基}莕并1 以類似於實例37的方式製備成為炫 丨从為忍點95-96。之白色晶 乙酯作為丁Prepared in THF at -10 C according to the standard procedure '0.171 g of diisopropylamine (丨.69 house mole) and 2 ml of i 5 g molecular weight nBuLi (hexane) in 3 ml absolute THF. LDA solution. - Cool down to -78. Thereafter, 〇 18 丨 g of methoxyacetic acid ethyl ester (1·1 mmol) was added to THF in THF and stirring was continued for 15 minutes to complete the enolate formation. Add 0.166 g of 4-{2-[2-(3,5-di-phenylphenyl)-5-methyl"-thin-4-yl]ethoxy}in a 1.5 ml THF solution -7• Carboxaldehyde (〇38 mmol) and the mixture was maintained at this temperature for an additional 3 minutes. Pour on the crushed ice / NHeCI 'extracted with AcOEt twice' with water and brine, dried over magnesium sulfate and evaporated solvent, then flash chromatographic separation (Si 〇 2, hexane ' AcOEt = 7 / 3 Transfer to the same/reverse-isostructure. 1 74 g of the title compound. Preparation of the necessary aldehyde (4_{ 2 -[ 2 (5,5-diphenyl)-5-methyloxazol-4-yl]ethoxy}benzene as described in Example 2 1 a] - f] The -7-carboxyl chain, but the replacement of 4-trifluoromethylbenzaldehyde with 3,5-dichlorobenzaldehyde, the entire reaction sequence and the 4-pyrimido[b]-cephen-7-carboxaldehyde [Ger. Offen. ( 1998) DE ___- 92 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) B7 89 V. Invention description (19111617 A1) instead of 4-3⁄4 base-1 Several strands were used for the [yjitsunobu reaction] ISP MS: 550.1 (M+H)+. · IL racemate_1-3-(4-{2-12-(3.5-difluorobenzene)-5-A峄峙 丄 丄 丄 丄 丨 -7 丨 -7 -7 -7 -7-7-))-2-f gas ethyl propionate will be 0.173 grams above prepared 3-(4-{2-[2-(3, 5-diphenylphenyl)-5-methyl ° oxazol-4-yl]ethoxy} benzo[b] porphin _7_yl)_3_hydroxy_2·methoxypropanethyl ester (0.31 Millions were dissolved in ίο ml of trifluoroacetic acid and treated with 0.250 ml of diethylformanium (5 liters) under hydrazine and then maintained at this temperature for 4 hours when TLC showed disappearance of starting material. The reaction mixture is then poured onto crushed ice / AcOEt / NaHC 3 (pH of the aqueous layer ~ 7 5), the organic layer was washed with water and brine (pH of the aqueous phase ~ 8) ' dried over magnesium sulfate and evaporated to dry. Separation by flash chromatography (Si〇 2, hexane / Ac 〇 Ei == 85 / 15) supplied as a white crystal 0 · 143 g of the title compound, dazzle 1 〇〇 _ 丨〇 2. ISP MS: 535.3 (M+H) +. £1_1 ^ 沩 性 3- 3-(4-{2.-[?:-(3,5-diphenylene)-5-methyl oxazol-4-ylindole 丄 丨 bp sept-7- Base y | Gao Shi will be 0. 丨 42 grams above prepared [racemic] _3_(4·( 2_ [2_(3,5-dichlorophenyl)-5-methyloxazol-4-yl] Ethoxy}benzo[b] is dissolved in 4 ml of THF/EtOH=l/l and is 0:68 when phenanthyl-7-yl)_2-methoxypropane s-g-g (0.27 mmol) ML <RTI ID=0.0># </RTI> NaOH (2.5 eq.). The reaction mixture was stirred at room temperature and hydrolyzed, followed by TLC. After 2 hrs, the reaction mixture was poured on crushed ice/diluted HC hydr. The two layers were extracted. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to dryness. Crystallized from AcOEt/hexanes to give white crystals. 7 -93 - 1328585 A7 B7 V. invention is described in (g title product, melting point 160-61. . ISN-MS : 504.1 (MH) + 〇' NMR : (CDCI3, 1H, δ, TMS) 2.41 (s, 3H), 3.06 (t, J=6.5, 2H), 3.21 (dxd, J=8, J= 14.5, 1H), 3.34 (s, 3H), 3.36 (m-, 1H), 4.20 (m,lH), 4.37 (t, J=6.5, 2H), 6.74 (d, J=8, 1H), 7.15 (d, J=8, 1H), 7.33 (d, J=5.5, 1H), 7.37 (s, 1H), 7.46 (d, J=5.5. m), 7.86 (d, J=1.5, 2H), COOH is very wide. Example 37 - 111 卜4 旋旋]-.3-(4-{2-『2-(_^二|1苽&)_5_甲某[>夸崦-4-一一虱棊} The wheat bran fb~|嚷 -7-7-base)·2·-methylpropionic acid was prepared in a manner similar to Example 36 to a melting point of 14 1 _ 142. The white crystal, but 疋 replaced 3,5-difluorobenzaldehyde with 3,5-difluorobenzaldehyde to start the entire reaction sequence. ISP-MS: 474.3 (Μ+Η), Example 3 8 (4)^ 生Η-丁氧笨甲甲圭-4-基丄ethoxy}荇 and 1 prepared in a manner similar to Example 37 to become dazzling From the point of forbearance 95-96. White crystal ethyl ester
間醇醛反應之偶合夥伴 ISN-MS : 514.2 (M-H) + 實例39 L_外消旋性1-2-丁氫基-3-M £_基呤唑-4-某1乙氳某}茇并『V sa ’但疋使用丁氣基醋酸丁 g旨代替曱氧義_奶 42- 某茉基)-5- -94 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1328585Coupling partner for the aldol reaction ISN-MS: 514.2 (MH) + Example 39 L_racemic 1-2-butyryl-3-M £_ carbazole-4-one 1 氲 氲 茇And "V sa ', but use butyl acetonate to replace oxime _ milk 42- a certain glutenyl) -5 - 94 - This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) ) 1328585
以類似於實例38的方式製備 二氟苯醛開始整個反 κ為熔點161-162。之白色晶 fla ’但是以3,5 -二曱氣基笨駿代替3 $ 應順序。 ’ 1SN-MS : 538.2 (M-H)+。 實例40 [外旋性 1-2-丁乳基- 3- (4. (2 r 〇 / 〇 -j~^Uip,5-二甲某茇其、-s-甲 基H4-基1乙氧基丨苯基)丙酸 以類似於實例38的方式製備、成為燦點174_175〇之白色晶 體’但是以3,5-二甲基苯醛代扶7 ς 产— +处代曰3,5-二氟苯醛開始整個反應 順序。 ISN-MS : 506.2 (Μ-Η)+。 實例4 1 L1卜4綠性1,3-(4-{2-「2-(丄^^苯基)-5_甲其。号唑_4_甚1 -乙乳棊丨木幷丨b卜篆吩-7-某)-2-乙氧其拓給 以類似於貫例38的方式製備成為熔點148_丨5〇。之白色晶 體,但是使用乙氧基醋酸乙酯代替甲氧基醋酸乙酯作為丁 間醇醛反應之偶合夥伴。 ISN-MS : 486.2 (M-H)+ « 實例42 gj 2- ( 4-甲氧着_苯醯基胺甚)戍-4·烯酸乙酯 將在250毫升絕對THF中的11.7公克(4-甲氧基苯醯基胺基) 醋酸乙酯(49.6毫莫耳)之溶液冷卻至— 78。,並以2.1當量六 甲基二矽疊氮化鋰(1〇4毫升,1克分子量[己烷])處理。在 攪拌30分鐘之後,將丨丨當量純烯丙基溴(4.62毫升)經由注 -95 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公爱) 1328585 A7Preparation of difluorobenzaldehyde in a manner similar to Example 38 began with the entire reverse κ as melting point 161-162. The white crystal fla ’ is replaced by 3,5 - 2 曱 笨 笨 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 ' 1SN-MS : 538.2 (M-H)+. Example 40 [External 1-2-butyryl- 3- (4. (2 r 〇 / 〇-j~^Uip, 5-dimethyl oxime, -s-methyl H4-yl 1 ethoxy) Phenyl phenyl) propionic acid was prepared in a manner similar to that of Example 38 to give a white crystal of 174 _ 175 ', but 3,5-dimethylbenzaldehyde was used to produce — ς 3,5- Difluorophenylaldehyde starts the entire reaction sequence. ISN-MS: 506.2 (Μ-Η)+. Example 4 1 L1 Bu 4 green 1,3-(4-{2-"2-(丄^^phenyl)- 5_甲其。 。 _ _ _ _ _ _ _ _ _ _ 棊丨 - -7 - - - - - - - - -2- -2- -2- -2- -2- -2- -2- 148 148 148 148 148 148 148 148 148 148 148白色5〇. White crystal, but using ethoxyethyl acetate instead of methoxyethyl acetate as a coupling partner for the aldol reaction. ISN-MS : 486.2 (MH)+ « Example 42 gj 2- ( 4 -Methoxy-benzoylamine even 戍-4. enoate ethyl ester 11.7 g (4-methoxyphenylhydrazino) ethyl acetate (49.6 mmol) in 250 ml absolute THF The solution was cooled to -78. and treated with 2.1 equivalents of lithium hexamethyldifluoride (1. 4 mL, 1 g molecular weight [hexanes]). After that, the equivalent of allyl bromo bromide (4.62 ml) is applied via the -95 - paper scale to the Chinese National Standard (CNS) A4 specification (210X297 public) 1328585 A7
_____BT 五、發明説明(92 ) 射筒加入’並將反應混合物維持在_ 78。下丨5分鐘及〇。下3〇 刀在里。倒在碎冰上,以^(^以萃取兩次,以水清洗兩次, 怠瓴酸鈉乾燥及蒸發溶劑,然後以閃蒸色層分離法(Si02, 己故/AcOEt=85/15)供給除了成為黃色油之2 74公克二烷基 化產物之外’還供給成為灰白色固體之1〇 56公克標題化合 物’熔點76- 7 8。。 ISP-MS : 278.2 (M+H)+。 KLlii 4·甲氧茱苯醯某胺甚)成-j-峥酩 將10.56公克以上製備的2·(4_甲氧基苯醯基胺基)戊·4•烯 酸乙酿(38.1毫莫耳)溶解在12〇毫升THF/EtOH=l/l中,並 在0。下以3 8毫升之2N NaOH處理。將反應混合物维持在該 溫度下3小時。接著將其倒在碎冰/HCi上,以Ac〇Et萃取兩 次,以食鹽水清洗及經硫酸鈉乾燥。蒸發溶劑,然後在 -20°下自AeOEt結晶,以產生成為白色晶體之8.41公克標題 酸,熔點 121- 124。。 ISN-MS : 248.1 (M-H) + p丄N- ( 1 -乙醯基丁 - 3-焙甚)-4·甲氧某苽醯胺 將21.2毫升峨啶及15.95毫升Ac20(5當量)連續加入8.41公 克以上製備.的2-(4-曱氧基苯醯基胺基)戊-4-烯酸(3 3.7毫莫 耳)之溶液中。將反應混合物維持在9〇。下45分鐘。在冷卻 之後,加入15.8毫升水,並再將混合物維持在85。下3〇分 鐘’以確定芫成水解作用。接著將其倒在碎冰/ HCM上,以 AcOEt萃取兩次,以2N HC1及水清洗,並經硫酸鈉乾燥。 蒸發溶劑,然後以閃蒸色層分離法(Si〇2,己烷/ Ac〇Et=7/3) _________- 96 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 93 五、發明説明( 供給成為黃色固體之6.45公克標題化合物,熔點58_ 5 9。。 ISP- MS : 248.3 (M+ H)+ 〇 ' 幻.丙基-2-ί 4-甲氧其苽某us·甲I々a 將以上製備的N-( 1-乙醯基丁 _3_缔基)_4_甲氧基苯醯胺 (6_45公克,26.1毫莫耳)在43.9毫升三氟醋酸(22當量)與 2 1.75笔升三氟醋酸酐(6當量)之混合物中以4〇。攪拌7小時 及在室溫下攪拌1 6小時。倒在碎冰上,以EtOEt萃取兩次, 以Na2C〇3溶液清洗三次,經硫-與鈉乾燥及蒸發溶劑,然後 以閃洛色層分離法(Si〇2,己烷/ AcOEt=9/ 1)最後產製成為 無色油之4.5 1公克標題化合物。 EI-MS : 229.2 (M)+。 gj_3 -丨2-(4_甲氣基笨基)甲坐基·[丙-1·醇 將以上製備的4-烯丙基- 2-(4-曱氧基苯基)-5-甲基噚唑 (4.51公克,丨9.7毫莫耳)溶解在60毫升絕對THF中,並在〇。 下以100毫升9-BBN溶液(0.5克分子量己烷)處理。允許在室 溫下進行2小時加氫硼化作用。然後同時加入56毫升之3N NaOH及114.5毫升之3 0%Η2〇2,藉此使初溫度上升至45。。 在卜】、時之後’將不均勻的混合物以冰及水稀釋,以Ac〇Et 萃取兩次,.以水清洗及經硫酸鈉乾燥。蒸發溶劑,然後以 閃蒸色層分離法(Si02,己烷/AcOEt=l/3)產生成為無色油 之4.5 4公克標題化合物。_ E卜 MS : 247.1 (M)+。 NMR : (CDC13, 1H, δ, TMS) 1.89 (quint, J=5.5, 2H), 2.31 (s, 3H), 2.62 (t, J=6.5, 2H), 3.55 (br s, OH), 3.75 (t, J=5.5, _ - 97 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公爱) A7 B7_____BT V. INSTRUCTIONS (92) The cartridge is added' and the reaction mixture is maintained at _78. Kneeling for 5 minutes and squatting. The next 3 knives are in the middle. Pour on crushed ice, extract twice with ^(^, wash twice with water, dry with sodium citrate and evaporate the solvent, then flash-separate (Si02, ruin/AcOEt=85/15) Provided in addition to 2 74 g of the dialkylated product as a yellow oil, 1 〇56 g of the title compound 'melting point 76-78.'. ISP-MS: 278.2 (M+H)+. KLlii 4·Methoxy benzoquinone, an amine, even to -j-峥酩 2·(4-methoxyphenylhydrazino) pentanoic acid (38.1 mmol) prepared above 10.56 g ) Dissolved in 12 mL of THF/EtOH = 1/l and at 0. It was treated with 3 8 ml of 2N NaOH. The reaction mixture was maintained at this temperature for 3 hours. It was then poured onto crushed ice/HCi, extracted twice with Ac〇Et, washed with brine and dried over sodium sulfate. The solvent was evaporated, and then crystallized from AeOEt at -20 to yield 8.41 g of the title acid as white crystals, melting point 121-124. . ISN-MS : 248.1 (MH) + p丄N- ( 1 -ethenyl 3- 3-baked) -4 ·Methoxy amidoxime 21.2 ml of acridine and 15.95 ml of Ac20 (5 equivalents) were continuously added 8.41 g or more of a solution of 2-(4-decylphenylphenylamino)pent-4-enoic acid (3 3.7 mmol) prepared. The reaction mixture was maintained at 9 Torr. Next 45 minutes. After cooling, 15.8 ml of water was added and the mixture was maintained at 85. The next 3 minutes' is determined to determine the hydrolysis. It was then poured onto crushed ice/HCM, extracted twice with AcOEt, washed with 2N EtOAc and water and dried over sodium sulfate. Evaporate the solvent and then use flash chromatographic separation (Si〇2, hexane/Ac〇Et=7/3) _________- 96 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 93 V. INSTRUCTIONS (available as a yellow solid, 6.45 g of the title compound, melting point 58_ 5 9 .. ISP-MS: 248.3 (M+H)+ 〇' phantom propyl-2-ί 4-methoxy Its us us us us 将 将 将 将 us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us us A mixture of acetic acid (22 eq.) and 2 1.75 liters of trifluoroacetic anhydride (6 eq.) was stirred for 7 hours, stirred at room temperature for 16 hours, poured over crushed ice and extracted twice with EtOEt. It was washed three times with Na2C〇3 solution, dried with sulfur-sodium and evaporated, and then finally purified by flash chromatography (Si〇2, hexane/AcOEt=9/1) to be 4.5 1 g of colorless oil. Title compound: EI-MS: 229.2 (M) + gj_3 - 丨2-(4_甲气基基基)甲坐基·[丙-1·醇 The 4-allyl-2-(4) prepared above 4-decyloxyphenyl)-5-methylcarbazole (4.51 Gram, 丨 9.7 mM) dissolved in 60 ml of absolute THF and treated with 100 ml of 9-BBN solution (0.5 g of molecular weight hexane) in a solution of 100 ml of BBN. Allow for 2 hours of hydroboration at room temperature. Then add 56 ml of 3N NaOH and 114.5 ml of 30% Η2〇2, thereby raising the initial temperature to 45. After the time, the mixture is diluted with ice and water to Ac. The extract was extracted twice with EtOAc (EtOAc) EtOAc (EtOAc). _ E 卜 MS : 247.1 (M) + NMR : (CDC13, 1H, δ, TMS) 1.89 (quint, J=5.5, 2H), 2.31 (s, 3H), 2.62 (t, J=6.5, 2H) , 3.55 (br s, OH), 3.75 (t, J=5.5, _ - 97 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 public) A7 B7
五、發明説明(94 2H),3.85 (s,3H),6 94 Μ τ,。 ),以4 (d,J=7, 2Η),7 89 (d f] 4-{3-Γ2-Γ4-Ψ 氧其父盆、c ; ?㈣ ~ 1 丙氣某}笨 將1 ·〇0公克以上製備的3- [2-(4-甲氧基苯基)-5-甲基口号 基]丙_1·醇(4.G4毫莫耳)溶解在2!毫升甲苯中,並在 〇。下連續以〇,696公克4-經基m盤(4·04毫莫耳)、 1.061公克三苯膦(4.04毫莫耳)及〇 818公克(4 〇4毫莫 耳)DIAD^。接著移開冷卻免及持續攪拌3小時。倒在碎 冰上:心㈣萃取兩次,以3Νν&〇η及水清《先,經硫酸 .美乾燥及洛發♦劑,然後以閃蒸色層分離法(碎膠,己燒 /AcOEt 7/3)最後留下成為淡黃色膠之(〇84公克標題化合 物。 ISP-MS : 402.5 (M+H)+。 3夂棊·2·甲苹華·3·(4·丨3_「2_(4_甲氧某芡某υ·甲甚 丙氧某}莕-1-基)丙龄λ S5 根據標準步驟,以在4毫升絕對THF中的0.166公克二異丙 胺(。1.64毫莫耳)及〇·964毫升之i 5克分子量』心(己炫)在_ 10C下製備在THF中的lDA溶液。在冷卻至_78。之後,加 入冷解在1.3毫升THF中的0.1 77公克曱氧基醋酸乙酯(丨.49毫 莫耳),並持續攪拌1 5分鐘,以完成烯醇酸鹽形成作用。加 入落解在2毫升THF中的0_200公克以上製備的4_ {3_[2-(4-甲氧基苯基)-5-甲基哼唑-4-基]丙氧基}莕·丨_羧醛(〇·5〇毫 莫耳),並將混合物維持在該溫度下再3〇分鐘。倒在碎冰 /NHqCl上’以AcOEt萃取兩次’以水清洗,經硫酸鈉乾燥 _____- QS - 本紙張尺度適用中@國家標準(CNS) A4規格(210 X 297公釐)V. Description of the invention (94 2H), 3.85 (s, 3H), 6 94 Μ τ,. ), to 4 (d, J=7, 2Η), 7 89 (df) 4-{3-Γ2-Γ4-Ψ oxygen parent bowl, c; ?(4) ~ 1 propylene gas one} stupid will be 1 · 〇0 3-[2-(4-Methoxyphenyl)-5-methyl s-propyl]propan-1-ol (4.G4 mmol) prepared above gram was dissolved in 2! Next, continue to 〇, 696 grams 4- via base m disk (4·04 millimoles), 1.061 grams of triphenylphosphine (4.04 millimoles) and 〇818 grams (4 〇 4 millimoles) DIAD^. Remove the cooling and keep stirring for 3 hours. Pour on the crushed ice: extract the heart (4) twice, with 3Νν&〇η and water clear. First, dry with sulfuric acid, beauty and Luofa ♦, then with flashing color layer The separation method (fragmented, burned/AcOEt 7/3) was finally left as a pale yellow gum (〇84 g of the title compound. ISP-MS: 402.5 (M+H)+. 3夂棊·2·甲苹华·3·(4·丨3_“2_(4_methoxy) υ 甲 甲 甲 氧 荇 荇 基 基 基 基 基 基 基 基 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据Diisopropylamine (1.64 mmol) and 964·964 ml i 5 g molecular weight 』 heart (Hyun) Prepare lDA solution in THF at _ 10 C. Cooling _78. Thereafter, 0.177 g of ethyl decyloxyacetate (丨.49 mmol) in 1.3 ml of THF was added and stirring was continued for 15 minutes to complete the formation of the enolate. 4_{3_[2-(4-Methoxyphenyl)-5-methyloxazol-4-yl]propoxy} 荇·丨_carboxaldehyde prepared in 0 ml of THF in 2 ml of THF · 5 〇 millimolar, and maintain the mixture at this temperature for another 3 minutes. Pour on crushed ice / NHqCl 'extracted with AcOEt twice' with water, dried with sodium sulfate _____- QS - paper Scale applicable @国标准(CNS) A4 specification (210 X 297 mm)
k 訂k order
1328585 A7 B7 五、發明説明(95 及蒸發溶劑,然後以閃蒸色層分離法(Si〇2 ,己烷 /AcOEt= 1/1)輸送成為同/逆·異構物之0.228公克標題化合 物(無色膠)。 1SP-MS : 520.3 (M+H)+。 111丨外岣旋性1 - 2-甲患.基-3- (4- { 3-「2- (4-甲氧某笨基)-5-玉_基°号唑_4·基1丙氣基}笨_卜某)丙酸乙酯 將0.228公克以上製備的3-輕基-2-曱氧基_3-(4-{3-[2· (4-甲氧基苯基)-5-甲基噚唑-4-二基]丙氧基·基)丙酸乙 酉旨(0.44¾莫耳)溶解在2.3毫升三氟酷酸中,在〇。下以〇、697 笔升二乙基甲矽坑(1 〇當量)處理及接著維持在〇 0下4小時。 接著將反應混合物倒在碎冰/Ac〇Et/NaHC〇3±,將有機層 以水清洗兩次,經硫酸鈉乾燥及蒸發至乾燥。以閃蒸色層 分離法(Si〇2 ’己燒/Ac〇Et=7/3)產生成為無色油之〇·丨43公 克標題化合物。 1SP-MS : (M+H)+ 504.4。 Ιΐ ί外消旋性1.-2-甲氧基-3-(4- f 3-Γ2-Μ-甲氣某苽基甲 基°号哇-4-基1丙乳基丨笔-i·基)丙龄 將0_ 143公克以上製備的[外消旋性卜2_甲氧基_3 (4_ ( 3_ [2-(4-甲氧基苯基)-5-甲基哼唑·4·基]丙氧基}莕_1_基)丙 酸乙醋(0.28毫莫耳)溶解在ι·5毫升THF/EtOH=l/l中,並以 0.47毫升之3N NaOH(5當量.)處理《將反應混合物在室溫下 揽拌2小時’並接著倒在碎冰/稀釋的9〇上,並以Ac0Et萃 取兩次。將有機層以水清洗,經硫酸鈉乾燥及蒸發至乾 燥。自AcOEt/己坑結晶,最後供給成為白色晶體之〇 12〇公 L_______ - 9a . 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱) ----1328585 A7 B7 V. Description of the invention (95 and evaporating solvent, then 0.228 g of the title compound as a homo/reverse isomer by means of flash chromatography (Si〇2, hexane/AcOEt = 1/1) Colorless glue) 1SP-MS : 520.3 (M+H)+. 111丨 岣 性 1 - 2-甲甲. 基-3- (4- { 3-"2-(4-methoxy) )-5-玉_基°号号 _4·基1丙气基} 笨_卜) Ethyl propionate 3-light ketone-2-oxime _3-(4- prepared by 0.228 g or more {3-[2·(4-Methoxyphenyl)-5-methyloxazol-4-diyl]propoxy-yl)propionic acid ethyl hydrazide (0.443⁄4 mol) dissolved in 2.3 ml of trifluoro In the sour acid, it is treated with 697, 697 liters of diethyl guanidine pit (1 〇 equivalent) and then maintained at 〇0 for 4 hours. Then the reaction mixture is poured on crushed ice / Ac〇Et/NaHC 〇3±, the organic layer was washed twice with water, dried over sodium sulfate and evaporated to dryness to give a colorless oil by flash chromatography (Si〇2 'hexane/Ac〇Et=7/3). 〇·丨43 g of the title compound. 1SP-MS : (M+H)+ 504.4. Ιΐ ί racemic 1.-2-methoxy-3-(4- f 3-Γ2-Μ-甲气Base Base [# w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w w -Methoxyphenyl)-5-methylcarbazole·4·yl]propoxy}荇_1_yl)propionic acid ethyl acetate (0.28 mmol) dissolved in ι·5 ml THF/EtOH=l /l, and treated with 0.47 ml of 3N NaOH (5 eq.) "The reaction mixture was stirred at room temperature for 2 hours" and then poured onto crushed ice / diluted 9 Torr and extracted twice with AcOE. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness. Crystallized from AcOEt/hexane pit, and finally supplied as white crystals. 〇12〇 public L_______ - 9a. This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 public) ----
k 訂 1328585 A7 _______B7 ___ 五、發明説明(96 ) 克標題產物,熔點67-70°。 ISN-MS : (M+H)+ 474.1 〇 NMR : (CDCI3. 1H, (5, TMS)2.22 (s, 3H), 2.29 (quint, J=6.5,2H), 2.79 (t,J=6.5, 2H), 3.26 (s,3H), 3.28 (dxd, J=8.5. J=14.5, 1H), 3.63 (dxd, J=i4.5, J=4, 1H), 3.86 (s, 3H), 4.1-4.2 (m, 3H), 6.72 (d, J=8j 1H), 6.94 (d, J=9, 2H), 7.28 (d, J=8, 1H), 7.48 (m, 1H), 7.55 (m, 1H), 7.92 (d, •1=8.5, 2H),8.03 (d,J=8.5, 1H·)之 8.35 (d,J=8.5, 1H),COOH 非常寬。· 實例43 [外消旋性卜3 - (4 - { 3 -『2 - (4-氰y芊)-甲某崎p坐-4-基1丙 乳基}莕-1-基)-2-甲氧基丙醋 7 以類似於實例42的方式製備成為白色泡沫之化合物,但 是以4-氣基苯酸代替4-甲氧基笨醛開始反應順序。 ISN-MS : 478.2 (M-H)+ = 實例44 f外消旋性〗_2·甲氧棊-3二(4-(3-「s_甲A - 7“4·三顧.甲基笨 基)°号峻基〗丙氧基丨笨并丨hi 〇盡吟-7-某)丙酸 以類似於實例42的方式製備成為熔點丨丨5_丨丨6。之白色晶 體’但是以4-三氟甲基苯醛代替4_曱氧基苯醛開始反應順 序及以4-經基笨并[b]噹吩-7-羧醛[Ger. 〇ffen.( 1998) DE 19711617 A1]代替4-起基莕-丨_複链用於Mitsun〇bu反應(步 驟η)。 1SN-MS : 5 18.0 (Μ-Η)+。 ______- 100 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210X 297公釐) 1328585 A7 B7 五、發明説明(97 ) 實例45 |外消旋性】-2·乙氧基^基_2“4 r:蟲甲其父 基)哼唑-4-基1丙氧基_1苯并丨blP^__7_某)丙龄 以類似於實例44的方式製備成為熔點丨12_丨14。之白色晶 體,但是以乙氧基醋酸乙酯代替甲氧基醋酸乙酯作為偶合 夥伴用於丁間醇醛反應(步驟g))。 ISN-MS : 532.1 (M-H)+ 〇 實例46 - f外消旋性〗-3 - (4- { 3 - [ 2- (4-氣笨某%甲某g寄唑-4-某1丙 氳某丨笨· 1 -基)-2 -異丙氧某而給 以類似於實例43的方式製備成為熔點η7_ 1 58。之灰白色 晶體,但是以異丙氧基醋酸乙酯代替甲氧基醋酸乙酯用於 丁間醇醛反應(步驟g))。 ISN-MS : 506.2 (M-H)+ 〇 實例47 (S)-2-Jf氧基- 3-(4- { 三氩甲基笨某、垵4 _ 4-基1丙氧基丨萁-1-基)丙醢 ” 以類似於實例2 1的方式製備成為無色泡沫之化合物,但 是以3-[5-曱.基-2-( 4-三氟甲基苯基)噚唑-4_基]丙-丨_醇(以 類似於實例42a]-e]製得的)代替2· [5-甲基- 2-(4-三氟甲基 苯基广号唑-4-基]乙醇用於Mitsunobu反應(步驟f))。 iSN-MS : 512.3 (M-H)+。 實例48 f外消旋性卜3- ( 4_ {.3 J:2-丄氮茇葚I s·甲某呤唑· 4-某1而 _-101 -___ 本紙張尺度適用中国國家標準(CNS) A4規格(210X297公发) ' 1328585 A7 B7 五、發明説明(98 ) 1暴丨苯并『b〗·»宗吩·7_基)_2·甲患其壬給 以類似於實例43的方式製備成為熔點1〇5_ 1〇7。之白色晶 體’但是以4-羥基苯并[b]噻吩-7_羧醛[Ger 〇ffen( 1998) DE 19711617 A1]代替4-羥基莕·ι·羧醛用sMitsun〇bu反應 (步驟f))。 1SN-MS : 484.1 (M-H)+。 實例49 1_外消旋性卜2-乙氧茱甲g某茉某)_5_甲其 号唑-4-基1丙氧基}茬-1-某、而1 以類似於實例42的方式製備成為熔點M丨_ M2。之灰白色 晶體,但是以乙氧基醋酸乙酯代替甲氧基醋酸乙酯作為偶 合夥伴用於丁間醇醛反應。 ISN-MS : 488.2 (M-H)+。 實例5 0 [外沩旋性卜2_乙氧基·3·( 土昱而其黎某甲i °咢唑-4-基1丙氧基丨笨· 1-甚)丙敗 以類似於實例49的方式製備成為白色泡沫之化合物,但 是以4-異丙基苯醛代替4-曱氧基笨醛開始反應順序。 ISN-MS : 500.3 (M-H) + 實例5 1 f外岣旋性1-3-(4· { 3_[2-丄^苯基甲其碍唑_4·某]而 氧基丨莕-1 -基)-2-乙氣某而齡 以類似於實例49的方式製備成為熔點147_ 149。之灰白色 固體,但是以4-氣基苯醛代替4_甲氧基苯醛開始反應順 __- 102 -k Order 1328585 A7 _______B7 ___ V. Description of the invention (96) g title product, melting point 67-70 °. ISN-MS : (M+H)+ 474.1 NMR: (CDCI 3. 1H, (5, TMS) 2.22 (s, 3H), 2.29 (quint, J=6.5, 2H), 2.79 (t, J=6.5, 2H), 3.26 (s,3H), 3.28 (dxd, J=8.5. J=14.5, 1H), 3.63 (dxd, J=i4.5, J=4, 1H), 3.86 (s, 3H), 4.1 -4.2 (m, 3H), 6.72 (d, J=8j 1H), 6.94 (d, J=9, 2H), 7.28 (d, J=8, 1H), 7.48 (m, 1H), 7.55 (m , 1H), 7.92 (d, •1=8.5, 2H), 8.35 (d, J=8.5, 1H·) 8.35 (d, J=8.5, 1H), COOH is very broad. · Example 43 [racemic Sex Bu 3 - (4 - { 3 -『2 - (4-Cyanide y芊)-甲某崎p sit-4-yl 1 propanyl}}-1-yl)-2-methoxypropane vinegar 7 A compound which became a white foam was prepared in a similar manner to Example 42 except that 4-methoxyphenyl acid was used in place of 4-methoxy aldehyde to initiate the reaction sequence. ISN-MS: 478.2 (MH)+ = Example 44 f racemic 〗 〖_2 methoxy oxime-3 bis (4-(3-"s_A A - 7"4 · San Gu. Methyl stupid) ° No. 〖Jin 丨 丨 丨 丨 丨 丨 丨 丨 〇 吟 吟 吟7-m) propionic acid was prepared in a similar manner to Example 42 as a white crystal of melting point 丨丨5_丨丨6, but starting with 4-trifluoromethylbenzaldehyde instead of 4-methoxybenzaldehyde And 4-cyclopyridyl-丨- complex chain is used in the Mitsun〇bu reaction when 4-phenyl group and [b] phen-7-carboxaldehyde [Ger. 〇ffen. (1998) DE 19711617 A1] Step η). 1SN-MS : 5 18.0 (Μ-Η)+. ______- 100 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1328585 A7 B7 V. Invention Description (97) Example 45 | racemic] -2 · ethoxy group 2 "4 r: the parent family of worms] oxazol-4-yl 1 propoxy _1 benzopyrene blP^__7_ a) A white crystal having a melting point of 丨12_丨14 was prepared in a similar manner to Example 44, but ethyl ethoxyacetate was used in place of methoxyethyl acetate as a coupling partner for the aldol reaction (step g)) ISN-MS : 532.1 (MH)+ 〇 Example 46 - f racemic 〖-3 - (4- { 3 - [ 2- (4- gas stupid % A certain g azole -4- a 1 C The hydrazine η7_1 58 was prepared in a manner similar to that of Example 43. The crystal was off-white, but ethyl isopropylacetate was used in place of ethyl methoxyacetate for the aldol reaction (step g)). ISN-MS: 506.2 (MH) + 〇 Example 47 (S)-2-Jfoxy- 3-(4- { tri-argonmethyl phenyl, 垵4 -4-yl 1-propoxy fluorene-1- A compound which became a colorless foam was prepared in a similar manner to Example 21, but 3-[5-fluorenyl-2-(4-trifluoromethylphenyl)carbazole-4-yl] Propyl-co-alcohol (prepared in analogous to Examples 42a]-e) was substituted for 2·[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]ethanol Mitsunobu reaction (step f)). iSN-MS: 512.3 (MH) +. Example 48 f racemic bucker 3- ( 4_ {.3 J: 2-丄N-sodium I s-methyl carbazole · 4 - 1 and _-101 -___ This paper size applies to China National Standard (CNS) A4 specification (210X297 public) " 1328585 A7 B7 V. Invention description (98) 1 violent benzo" b〗 ·» 7_基)_2·A. The ruthenium was prepared in a manner similar to that of Example 43 as a white crystal of melting point 1〇5_1〇7. However, 4-hydroxybenzo[b]thiophene-7-carboxaldehyde [Ger 〇ffen (1998) DE 19711617 A1] Instead of 4-hydroxyindole·carboxaldehyde, sMitsun〇bu reaction (step f)) 1SN-MS: 484.1 (MH)+. Example 49 1_ Racemic Bu 2 - ethoxylated g茉5) _5_methyl oxazol-4-yl 1 propoxy} 茬-1-, and 1 was prepared in a similar manner to Example 42 as the melting point M 丨 M 2 . Ethyl acetate was used as a coupling partner for the aldol reaction with ethyl acetate. ISN-MS: 488.2 (MH)+. Example 5 0 [outer cyclonicity 2 ethoxy] 3 (earth昱 昱 其 其 i i i i i i i -4- -4- 基 基 基 丙 · · · 1- 1- 1- 1- 丙 丙 丙 以 以 以 以 以 以 以 以 以 以 以 以 以 以 以 以 以The reaction sequence was started instead of 4-decyloxy aldehyde. ISN-MS : 500.3 (MH) + Example 5 1 f external cyclonic 1-3-(4· { 3_[2-丄^phenylmethyl oxazole _ 4. 某 而 而 而 - - - ) -2- -2- 某 某 某 某 某 某 某 某 某 某 某 某 某 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 147 Methoxybenzaldehyde begins to react cis __- 102 -
本紙張尺度適用中国國家標準(CNS) A4规格(210X297公爱I 1328585 A7 B7. 五、發明説明(99 ) 序0 ISN-MS : 492.1 (M-H)+ 〇 實例52 }笨-1-基)-2-甲氣 「夕卜消旋性1-3-(4-{3-『2-丄£^ 否羞_苯基)-5二王基噚唑-4_某1 以類似於實例50的方式製備成為白色泡沫之化合物,p 是以甲氧基醋酸乙S旨代替乙氧基醋酸乙g旨作為偶合夥伴用 於丁間醇醛反應。 -- ISN-MS : 486.3 (M-H)+ 〇 實例53 生卜3-(4-{2二1_2-_〇^^基茉某)_%甲芊|?罢4 /| 莕并[bi^i^二二乙 i 某雨硓 以類似於實例40的方式製備成為熔點149_丨5〇。之白色晶 體,但是以乙氧基醋酸乙酯代替丁氧基醋酸丁酯作為偶合 夥伴用於丁間醇醛反應。 ISN-MS : 478.2 (M-H)、 實例54This paper scale applies to China National Standard (CNS) A4 specification (210X297 public I 1328585 A7 B7. V. Invention description (99) Preface 0 ISN-MS: 492.1 (MH) + 〇 Example 52 } stupid-1-base)- 2-Methane "Essence of 1-3-(4-{3-"2-丄£^ 羞 _ phenyl)-5 bis-carbazol-4_ a 1 similar to Example 50 The compound was prepared as a white foam, and p was replaced by ethoxyacetic acid ethyl acetate as the coupling partner for the aldol reaction. -- ISN-MS : 486.3 (MH) + 〇 Example 53 生卜3-(4-{2二1_2-_〇^^基茉)_%甲芊|?止4 /| 荇和[bi^i^二二乙i A certain rain 硓 is similar to the example 40 The method was prepared as a white crystal having a melting point of 149 Å 丨 5 ,, but using ethyl ethoxyacetate instead of butyl butyl ethoxide as a coupling partner for the aldol reaction. ISN-MS: 478.2 (MH), Example 54
LiLiUm卜3<4]2二基苽某卜5-甲其喵^ 11^1^基}芩幷丨一吩-7-基)-2_r. y芊系祐 以頡似於實例39的方式製備成為溶點1 58丨59。之白色晶 體,但是以乙氧基醋酸乙酯代替丁氧基醋酸丁酯作為偶合 夥伴用於丁間醇醛反應。 1SN-MS : 510.2 (M-H)+。 實例5 5 ____- 103 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585LiLiUm Bu 3<4]2 Diyl 苽 卜 5 - - - 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备Become a melting point 1 58丨59. The white crystals were replaced with ethyl ethoxyacetate in place of butoxybutyl butyl acetate as a coupling partner for the aldol reaction. 1SN-MS: 510.2 (M-H)+. Example 5 5 ____- 103 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1328585
100100
今。圭-4-某1丙氣某丨苽并「bloi:吩_ ·7 τ ^)丙齡 以類似於實例4 9的方式製備忐·ά h 爾成為熔點121-123。之灰白色 晶體,但是以4-羥基苯并[b]噻吩7获 J s H竣蛀[Ger. 〇ffen.( 1998) DE 1 97 1 1 6 1 7 A 1 ]代替4-羥基笨_】.,A糾 ' 1 ·枚路用於Mitsunobu反應 (步驟f))。 ISN-MS : 494.1 (M-H)+。 實例56 -- 甲氧基-3-i^u^^甲氳某策某 !i_啥-4-棊1丙氧基}苯并丨基)丙龄 以類似於實例55的方式製備成為熔點丨27_ ι29。之白色晶 體’但是以甲氧基醋酸乙酿代替乙氧基醋酸乙醋作為偶合 夥伴用於丁間醇醛反應。 13 ISN-MS : 480.2 (M-H)+。 實例5 7this.圭-4- some 1 propylene gas and "bloi: _ _ · 7 τ ^) C. age similar to the method of Example 49 to prepare 忐·ά h 尔 into the melting point 121-123. Gray-white crystal, but 4-Hydroxybenzo[b]thiophene 7 is obtained by J s H竣蛀 [Ger. 〇ffen. (1998) DE 1 97 1 1 6 1 7 A 1 ] instead of 4-hydroxy stupid _]. The road is used for the Mitsunobu reaction (step f)). ISN-MS: 494.1 (MH)+. Example 56 - methoxy-3-i^u^^甲氲一策!i_啥-4-棊1 propoxy}benzoxanyl) propylene was prepared in a similar manner to Example 55 as a white crystal of the melting point 丨27_ ι29, but was used as a coupling partner with methoxyacetic acid ethyl acetate instead of ethoxyacetic acid ethyl vinegar. Aldol reaction: 13 ISN-MS: 480.2 (MH)+. Example 5 7
Lfh.消旋性丄氧基-3-丨^_〇^2-(4•墓而甚茇甚甲某 口号。坐-4-基1丙氧基}苯并丨bl 4吩-7-甚〉兩齡 以類似於實例55的方式製備成為熔點9〇_93。之白色固 體,但是以4-異丙基苯醛代替4_甲氧基苯醛開始反應順 序。 ISN-MS : 506.2 (M-H)+ 〇 . 實例58 1_外消旋性卜3-(4-{3-[2-(1二異丙氳某苇其小5-甲甚。^^1 基1丙氣基丨笨并「bp塞吩-7-某)-2-甲a,其丙酸 -104 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 ____B7 五、發明説明(101) 以類似於實例57的方式製備成為熔點丨〇3·丨〇5。之白色晶 體,但是以甲氧基醋鉍乙酯代替乙氧基醋酸乙酯作為偶合 夥伴用於丁間醇醛反應。 α ISN-MS : 492.2 (Μ-Η)+ 〇 實例59 『外4旋性hKi-{3-丄g-丄苯某甲某g号唑^ 氧基}苯幷丨bl 4吩-7_基:)二基丙醢 以類似於實例5 7的方式製備〜成為熔點8 9 _ 9 5。之白色固 體’但是以.4_氯基苯K替4_異丙基苯链開始反應順序。 ISN-MS : 498.0 (M-H)+。 實例60 甲某 p寄岭·4_ &基} +并fblp篆吩-7·基)-2 -氧基而两六 以類似於實例59的方式製備成為炫.I 105- 107。之白色曰 體,但是以甲氧基醋酸乙酿代替乙氧基醋酸乙酉旨作為偶Γ 夥伴用於丁間醇醛反應》 ° ISN-MS : 484.1 (M-H)+ « 實例6 1 1消旋性卜2-乙氧茱曱又 °咢唑-4-基1丙氣基}茬-1-某 以類似於實例42的方式製備成為熔點丨4卜142。之灰白 晶體,但是以乙氧基醋酸乙酉旨代替甲氧基醋酸乙醋 合夥伴用於丁間醇醛反應。 θ ISN-MS : 488.2 (M-H)+ = 105 - 本紙張尺度適用中國國家標竿(CNS) A4規格(210 X 297公釐) 1328585Lfh. Racemic 丄oxy-3-丨^_〇^2-(4•Tomb and even 茇 某 slogan. Sit-4-yl 1 propoxy} benzopyrene bl 4 -7-7- 〉 Two-stage preparation of a white solid having a melting point of 9〇_93 was prepared in a similar manner to Example 55, but starting the reaction sequence with 4-isopropylbenzaldehyde instead of 4-methoxybenzaldehyde. ISN-MS : 506.2 (MH ) + 〇. Example 58 1_ Racemic Bu 3-(4-{3-[2-(1 diisopropyl 氲 苇 苇 小 小 小 小 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ "bp stopper-7-"-2-A, its propionic acid-104 This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 ____B7 V. Invention description (101) A white crystal having a melting point of 丨〇3·丨〇5 was prepared in a manner similar to Example 57 except that ethyl ethoxyacetate was used in place of ethoxyethyl acetate as a coupling partner for the aldol reaction. ISN-MS : 492.2 (Μ-Η)+ 〇Example 59 『External 4-spinning hKi-{3-丄g-丄Benzene A A certain g-azole oxime ^oxy}phenylhydrazine bl 4 -7-7 base: Diethyl propyl hydrazine was prepared in a manner similar to that of Example 57. ???~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The propyl benzene chain begins the reaction sequence. ISN-MS: 498.0 (MH)+. Example 60 A ke singling ·4_ & yl} + and fblp 篆 -7-7-yl)-2-oxy and two A white carcass was prepared in a manner similar to that of Example 59, but was replaced by methoxyacetic acid in the form of an acetoxyacetate as an oxime partner for the aldol reaction. ° ISN- MS: 484.1 (MH)+ « Example 6 1 1 racemic -2- ethoxy oxime and oxazol-4-yl 1 propyl group} 茬 -1- was prepared in a similar manner to Example 42丨 4 142. Gray crystal, but with ethoxyacetate instead of methoxyacetic acid acetate for the aldol reaction. θ ISN-MS : 488.2 (MH) + = 105 - the paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585
102 實例62 ^外β 氧基·3二^^_ί2_ί4·昱咼甚苽甚甲基 以類似於實例6丨的方式製備成為白色泡沫之化合物,但 是以4-異内基苯兹代替扣甲氧基苯醛開始反應順序。 ISN- MS : 500.3 (M-H)+。 實例63 ^外^旋^笨某、-5-甲某g号唑-4-某1丙 翌基}余..二11_基)-2 -乙氳甚而畤 以颂似於Λ例6 1的方式製備成為熔點μ、149。之灰白色 固,但疋以4-氣基苯醛代替4•甲氧基苯醛開始反應順 序。 ISN-MS : 492.1 (M-H)+ 〇 實例64 異而某笨 ^-5-甲基 以頒似於實例;)3的方式製備成為熔點128_ 129。之白色晶 體’但是以4-異丙基苯醛代替3,5·二甲基苯醛開始整個反 應順序。 ISN-MS : 492.1 (M-H)+ 〇 實例65 LS)-2-丁二3-」咏_礼基-3-(土異而某茇某ι <^_^妄 唑-4-基1乙氧基_!苯并 以類似於貫例3丨的方式製備成為熔點丨24·丨26。之白色晶 -106 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公爱) 1328585 A7 --- B7 五、發明説明( ") " '~ V 103 > 體,但是在丁間醇醛偶合步驟中使用以(S)-4-芊基_3-丁- 烯氧基乙醯基°号唑烷-2-酮代替(S)-4-苄基·3_甲氧基乙醯 基呤唑烷-2·酮。 ISN-MS : 518.1 (Μ-Η)+。 以如下製備必要的組塊(s)_ 4_芊基· 3_ 丁 _ 3烯氧基乙醯基 吟唑烷-2-酮: §1 T · 3二極氧某醋齡 將72丨宅克3-丁埽·ι_醇(1〇毫-荖耳)在〇。下加入在丨〇毫升絕 對THF中的480毫克NaH(在50%礦物油中,〜2〇毫莫耳)中, 並將混合物攪拌5分鐘。(放出H2) ^接著加入溶解在丨〇毫升 THF中的1.39公克溴基醋酸(1〇毫莫耳),並將混合物維持在 0°下再5分鐘及在室溫下2小時◊倒在碎冰/稀釋的HC丨上, 以AcOHt萃取兩次’以食鹽水清洗,經硫酸鈉乾燥及蒸發 溶劑’以供給1.65公克標題化合物,其受礦物油污染,但 是對以下步驟有足夠的純度。 丁 - 3-烯氧基乙醯甚g号唑烷-2-酮 將1·6公克以上製備的丁 ·3_烯氧基醋酸(9 9毫莫耳)以3 35 升-5,03公克草醯氣(4當量)及1滴絕對dmF處理。立即開 始放出氣體,並將反應混合物維持3小時。小心蒸發過量的 試劑及乾燥’以產生丨.3 5公克醯基氣,在以下步驟使用未 進一步純化之該產物》 _ 將1.77公克(S)-4 -节基-2-ρ号吃;1¾明毫莫耳)溶解在30 毫升絕對THF中,並冷卻至-78°。經由注射筒加入6.67毫升 之1 ·5克分子量nBuLi (己烷)(強烈放熱),以去質子NH。在 ____- 107 -_______ 本故張尺歧用巾國画家標準(CNS) A4規格(210X 297公釐)' ' 1328585 A7 B7 五、發明説明(104 1 〇分鐘《後,加入溶解在丨〇毫升THF中的以上製備的粗醯 基氣’並在- 78°C下持續攪拌3〇分鐘及在〇,c下攪拌3〇分 鐘。倒在碎冰/Nha上,以八⑴以萃取兩次,以水清洗, 經硫鉍鈉乾燥及蒸發溶劑,然後以閃蒸色層分離法(Si02, 己烷/ AcOEt= 7/3)供給成為無色黏性油狀之〇 69 1公克標題 化合物。 1SP-MS : 290.3 (M+H) +,307.4 (M+NH)+。 NMR · (CDClj, 1H, δ , TMS)2.46 (m, 2H), 2.81 (dxd, J=9.5} J-13.3, 1H)’ 3·34 (dxd,J=3, j=13 5, 1H), 3 66 (t,J=7,.2H), 4.20-4.34 (m, 2H), 4.62-4.76 (m, 3H), 5.09 (d, J=l〇.5, 1H), 5.15 (d, J-17, 1H), 5.86 (m, ih), 7.20-7.39 (m, 5H) 〇 實例66 L·外消旋性卜^丙某苽某卜5_甲甚 乳基}夺-1 -基)-氣甚而給 以類似於實例64的方式製備成為白色泡泳之化合物, 是以4-經基代替心經基苯并[小塞吩十祕用於 =。二反應'在丁間醇越偶合步驟中使用丙氧基醋酸乙 固曰代替乙氧基醋酸乙g旨。 1SN-MS : 5Q0.2 (M-H)+。 實例67 [外 >肖旋性1-2-乙fi芊Μ Ά η ,,田^计^ Τ~~ΓΤΤ -1~~~基座A)-5-甲甚 /類似於實例66的方式製備成為白色泡沐之化合物,但 疋在丁間醉醛偶合步驟中使用乙氧基醋酸乙酉旨代替丙氧基 本纸張尺度適用中國國- 1328585102 Example 62 ^Exo β oxy·3 2^^_ί2_ί4·昱咼 苽 苽 甲基 甲基 以 以 以 苽 苽 苽 苽 苽 以 以 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于The base of benzaldehyde starts the reaction sequence. ISN-MS: 500.3 (M-H)+. Example 63 ^External ^ 旋 ^ 某 、, -5 - A g gazole -4- a 1 propyl hydrazine}. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The manner of preparation became the melting point μ, 149. It is grayish white, but the reaction sequence begins with 4-methoxybenzaldehyde instead of 4-methoxybenzaldehyde. ISN-MS: 492.1 (M-H) + 〇 Example 64 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The white crystal was replaced by 4-isopropylbenzaldehyde instead of 3,5-dimethylbenzaldehyde. ISN-MS : 492.1 (MH)+ 〇Example 65 LS)-2-丁二3-"咏_礼基-3-(土异一一茇一ι <^_^ oxazol-4-yl 1 B The oxy-! benzo is prepared in a manner similar to the example 3丨 as the melting point 丨24·丨26. White crystal-106 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 public) 1328585 A7 - -- B7 V. Inventions ( ") " '~ V 103 > body, but in the aldol aldol unit coupling step with (S)-4-mercapto-3-but-enyloxyacetamidine Substituting oxazolidine-2-one for (S)-4-benzyl-3-methoxy-3-indenyl-2-oxazolone. ISN-MS: 518.1 (Μ-Η)+. The necessary block (s) _ 4_ thiol · 3 _ _ 3 alkenyloxy acetyl oxazolidin-2-one: § 1 T · 3 dipolar oxygen vinegar age will be 72 丨 克 3-丁ι·ι_alcohol (1〇mmol-荖耳) was added to 480 mg of NaH (in 50% mineral oil, ~2 〇 millimolar) in 丨〇ml absolute THF, and the mixture was stirred. 5 minutes (release H2) ^ then add 1.39 grams of bromoacetic acid (1 mM millimolar) dissolved in THF, and maintain the mixture at 0 ° for 5 minutes The mixture was shaken on crushed ice/diluted HC® at room temperature for 2 hours, extracted twice with AcOHt, washed with brine, dried over sodium sulfate and evaporated solvent to afford 1.65 g of title compound, which was obtained from mineral oil. Contamination, but sufficient purity for the following steps. Butyl-3-enoxyacetamidine g-oxazolidine-2-one will be 1·6 g or more of D-3·-enoxyacetic acid (9 9 mmol) Ear) Treated with 3 35 liters - 5,03 grams of grass cockroach (4 equivalents) and 1 drop of absolute dmF. Immediately begin to vent the gas and maintain the reaction mixture for 3 hours. Carefully evaporate excess reagent and dry to produce hydrazine. 3 5 g of hydrazine base gas, using the product without further purification in the following procedure _ 1.77 g (S)-4 - benzyl-2-p eat; 13⁄4 min mil) dissolved in 30 ml absolute THF And cooled to -78°. 6.67 ml of 1. 5 g of molecular weight nBuLi (hexane) (strong exotherm) was added via a syringe to deprotonate NH. In ____-107 -_______ The original Zhang Jianqi towel National Painter Standard (CNS) A4 specification (210X 297 mm) ' ' 1328585 A7 B7 V. Invention description (104 1 〇 minutes, after adding dissolved in 丨〇 The above prepared crude base gas in THF was continuously stirred at -78 ° C for 3 minutes and stirred at 〇, c for 3 minutes. Pour on crushed ice / Nha, extract with eight (1) twice It was washed with water, dried over sulphur sulphate and evaporated, and then purified by flash chromatography (SiO2, hexane / AcOEt = 7/3) to afford to afford the title compound as a colorless viscous oil. -MS : 290.3 (M+H) +, 307.4 (M+NH) + NMR · (CDClj, 1H, δ, TMS) 2.46 (m, 2H), 2.81 (dxd, J=9.5) J-13.3, 1H ) ' 3·34 (dxd, J=3, j=13 5, 1H), 3 66 (t, J=7, .2H), 4.20-4.34 (m, 2H), 4.62-4.76 (m, 3H) , 5.09 (d, J=l〇.5, 1H), 5.15 (d, J-17, 1H), 5.86 (m, ih), 7.20-7.39 (m, 5H) 〇Example 66 L·racemic Bu 丙 苽 苽 卜 5 _ _ 5 5 5 5 5 - 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚 甚[ The small secret of the cymbal is used for =. The second reaction 'in the more coupling step of the butanol, the ethyl ethoxyacetate is used instead of the ethoxyacetic acid. 1SN-MS: 5Q0.2 (M-H)+. Example 67 [External > 旋旋性1-2-乙fi芊Μ Ά η,,田^计^ Τ~~ΓΤΤ -1~~~ pedestal A)-5-A very/similar to the way of Example 66 Preparation of a compound that becomes a white foam, but the use of ethoxyacetate in the butyl aldehyde coupling step in place of the propoxy group is suitable for the Chinese scale - 1328585
醋酸乙酯。 1SN-MS : 486.3 (M-H)+。 實例68 ί 外消旋性 1 - 3 - (4 - ί ? - f 9 - r 7 c ~~~~1~氧某苽甚U 5-甲某崎唑- 基1乙氧某}苯并f bl 口窠哈-7_ tf、. ^ ~ 2-異丙氣某丙酸 以類似於實例3 9的方式製偌忐·Α p . 、我恂成為熔點148_ 15〇。之白色晶 體,但是在丁間酵醛偶入牛BS· A u 咚倘σ步驟中使用異丙氧基醋酸乙酯代 替丁氧基醋酸丁酯。如上诚w-iD ^ττ ν 珧以^r〇H、NaH及溴基醋酸,接 著以EtOH之酸催化酯化作用厶ώ 丁,μ " # u ϋ印用^成丁 · 3_晞氧基醋酸的方式 (參考實例6 5)合成前者試劑。 ISN-MS : 524.1 (M-H)+ = 實例69 (_g>3-(4- {2-f2-(3,5-二甲氧基甲某噚地-4•芊 1 广 氧基}冬并丨b~|pg吩-7-基)-2-異而氣某而_ 以類似於實例33的方式製備成為白色固體之化合物,但 是以3,5-二甲氧基苯醛代替3,5-二甲基苯醛開始整個反應順 序及在丁間醇越偶合步驟中使用以Μ)·4•苄基異丙氧基 乙酿基4哇烷-2-嗣代替(S)-4-节基_3-甲氧基乙醯基气1 坑-2_酮。未測定熔點,因為產物穸到微小的對掌性輔 助劑污染。 ISN-MS : 524.1 (M-H)+。-實例70 『外消旋性1 - 3 - (4 -丨3 -丨_2 - (4 -異丙基苯基)_ s _甲芊$岭_ 4 丙氣基丨笨并「bl嶁吩-7-某)-2-丙氣某而給Ethyl acetate. 1SN-MS: 486.3 (M-H)+. Example 68 ί Racemic 1 - 3 - (4 - ί - - f 9 - r 7 c ~~~~1~ Oxygen 苽 U U 5- 5- 5- 5- 5- 5- 5- 5- 5- - - - - - - - - - Bl 窠 窠 -7-7 tf, . ^ ~ 2-isopropyl gas a propionic acid in a manner similar to the example of 3 Α Α p. , I became the melting point of 148 _ 15 〇. The white crystal, but in Ding The meta-aldehyde enters the bovine BS·A u 咚 if the σ step uses ethyl isopropoxyacetate instead of butyl butoxyacetate. As above, w-iD ^ττ ν 珧 is ^r〇H, NaH and bromo Acetic acid, followed by acid catalyzed esterification with EtOH, μ "# u ϋ 用 用 成 成 3 3 3 3 ( ( ( ( ( ( ( ( ( ( ( ( I I I I I I I I I I I 4.1 4.1 4.1 4.1 4.1 4.1 4.1 4.1 4.1 (MH)+ = Example 69 (_g>3-(4-{2-f2-(3,5-dimethoxymethyl 噚 -4-4•芊1 聚oxy} winter 丨 丨 b~|pg phen -7-yl)-2-iso-gas _ a compound which became a white solid was prepared in a similar manner to Example 33, but 3,5-dimethylbenzaldehyde was replaced by 3,5-dimethoxybenzaldehyde. Start the entire reaction sequence and use the Μ)·4•benzylisopropoxyethyl 4 wowane-2-indole instead of the (S)-4-section in the interbutol coupling step. _3-methoxyethyl hydrazine gas 1 pit-2 ketone. The melting point was not determined because the product was contaminated with a slight contamination of the palm adjuvant. ISN-MS: 524.1 (MH)+.-Example 70 『racemic Sex 1 - 3 - (4 -丨3 -丨_2 - (4-isopropylphenyl)_ s _甲芊$岭_ 4 Propylene base 丨 并 and "bl嵝 -7-7"-2 - Propylene is given
__- 109 - 本紙張尺度適用中國國家標毕·(CNS) A4规格(210 X 297公爱) 1328585 A7 B7 五、發明説明(1〇6) 以類似於實例58的方式製備成為熔點72- 73。之白色晶 體,但是在丁間醇㈣合.步驟中使用丙氧基醋酸乙醋代替 甲氧基醋酸乙酯。 1SN-MS : 520_2 (M-H)+。 實例7 1__- 109 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public) 1328585 A7 B7 V. Description of invention (1〇6) Prepared as a melting point 72-73 in a manner similar to Example 58 . The white crystals were used, but in the step of the dibutyl alcohol (tetra), ethyl acetoxyacetate was used instead of methoxyethyl acetate. 1SN-MS : 520_2 (M-H)+. Example 7 1
LiLjl^#l·3パ4_{2q2-U^1^^氧某芡甚u5-甲某呤唑-棊1乙乳基}争-1-碁)·2·乙氧其巧觭 以類似於實例54的方式製備-券為熔點1 64_丨65。之白色晶 體,但是以4-羥基茶-1-羧駿代替4•幾基苯并[b]p塞吩_7_羧 链用於Mitsunobu反應。 1SN-MS : 504.2 (M-H)+。 實例72 L外靖旋性1 - 3_- ( 4- { 2_ [ 2-丄^^曱氣某茇甚甲其喵崦-ii基1乙孔基}萘-1-基)_2:丙氧其丙啭 以頒似於霄例7 1的方式製備成為熔點丨4〇_ 14丨。之白色晶 體,但是在丁間醇醛偶合步驟中使用丙氧基醋酸乙酯代替 乙氧基醋酸乙酯。 1SN-MS : 518.1 (M-H)+。 實例73 卜丄二甲氩某茇甚υ·甲某啐唑-氧基丨萘-1-暴)-2二氧某丙醢 以類似於實例68的方式製備成為熔點丨66_ 1 67。之白色晶 體,但是以4-羥基莕-1 -羧醛代替4_羥基笨并[b] b塞吩_ 7•羧 酸用於Mitsunobu反應。 ____ 110 - 本紙張尺度適用中圉@家標竿(CMS) A4規格(210X297公 1328585 A7 ______B7 五、發明説明(107) ISN-MS : 518.1 (M-H)+。 實例74 [外^旋性卜2-昇丙-氧棊·3·(4]2-丨2-f4-異丙某苽某)-5-甲 基哼唑-4-棊 以類似於實例73的方式製備成為白色泡沫之化合物,但 是以4-異丙基笨醛代替3,5_二甲氧基苯醛開始整個反應順 序。 ISN-MS : 500.2 (M-H)+ 〇 -- 實例75 - 將在190毫升THF中的3.50公克間-甲酚、9 87公克2_(5_甲 基-2-苯基-呤唑-4-基)乙醇及12 73公克三苯膦之溶液在 下以在7 5毫升T H F中的8 · 4 5公克偶氮二羧酸二乙酯(D E A D) 經20分鐘處理,並將棕色溶液在22艽下攪拌24小時。將溶 液蒸發,並將殘餘物分溶在CH2C12(3〇〇毫升)與〇 iN水性 NaOH(100毫升)之間。將有機層以水清洗兩次(2χι〇〇毫 升),乾燥及將有機溶劑蒸發,並將殘餘物在矽膠上經色層 分離(20: 1之正己烷/Ac0Et),以得到成為白色晶體之7 43 公克(7 8 %)標題化合物》 MS : (Μ+Η)+ 294.3。 NMR (CDC13, lH, TMS) : 7.97 (m, 2H), 7.45-7.35 (m, 3H). 7.14 (t, J=7.6, 1H), 6.77- 6.67 (m, 3H), 4.23 (t, 3=6 8 2H). 2·97 (t,J=6.8, 2H), 2.38 (s,3H),2.31 (s, 3H)。 »212二5.基-4-『2-(5-甲基-2-苯基-°号唑-4-某、-,.声|乎1_笨链 _____- 111 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585 A7 _________B7_____ 五、發明説明(1〇8) 將在30毫升CH2C12中的6.00公克5-甲基-2-苯基-4-(2-間-甲苯氧基乙基)噚唑及4.70公克二氯甲基甲醚之溶液在0°C 下以11.2毫升TiCl4經15分鐘處理,並在〇。下持績攪拌2.5小 時。將紅溶液在〇。下以6〇〇毫升之in水性HC1處理,將有機 層以0.1N水性NaOH清洗及以食鹽水清洗兩次。將有機層乾 燥’蒸發溶劑,並將殘餘物在矽膠上經色層分離(7: 1之正 己燒/AcOEt),以得到成為淡黃色固體之3.42公克(52%)標 題化合物。 -- MS : (M)+ 321,2 » IR(液體石蟻):1691s及 1679s(C=0) NMR (CDC13, 1H, δ, TMS) : 10.10 (s, 1H), 7.96 (m, 2H), 7.73 (d, J=8.6, 1H), 7.45-7.36 (m, -3H), 6.84 (dxd, J=8.6, 2.8, 1H), 6.73 (d, J=2.8, 1H), 4.32 (t, J=6.8, 2H), 3.00 (t, J=6.8, 2H),2.62 (s,3H),2.38 (s,3H)。 cl 2g二乙氧基- 3-{2-甲某- 4-「2-(5-甲某-2-茉某号唑- 4-基)-乙氧基1-苯基丨-丙橋酸L酷 將在30毫升i-PrOH中的1.50公克2-甲基-4-[2-(5-甲基-2-苯基-嘮唑-4-基)-乙氧基]·苯醛、3 〇〇公克wittig鹽[氣化 (乙乳基乙乳談基甲基)二苯鳞,Tetrahedron 50( 25),7543-56(1994)]及0.97公克碳酸鉀之懸浮液在22。(:下攪拌6天。加 入另一份1.50公克Wittig鹽及〇·48公克碳酸鉀,並在60。下 持續授拌隔夜’再加入另一份1.50公克Wittig鹽及0.48公克 碳酸鉀’並在60 °C下持續攪拌隔夜,在該時間之後完成轉 化作用。將混合物蒸發,並將殘餘物分溶在4〇毫升CH2Cl2 -112 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(109) 與40毫升飽和水性nh4C丨之間。將有機層以40毫升水清洗, 乾燥及蒸發。將殘餘物在s夕膠上經色層分離(8:1之正己烷 /AcOEt),以得到成為淡黃色固體之1 53公克(75%)標題化 合物。 MS : (M)+ 435.2 〇 1R(液體石蠟):1715s (C=0)。 NMR (CDC13, 1H, δ , TMS) : 8.05 (d, J=8.8, 1H), 7.97 (m, 2H). 7.45- 7.35 (m, 3H), 7.16 (s, 1H), 6.75 (dxd, J=8.8 2.4, 1H), 6.72 (d, J=2.4, 1H), 4.29 (q, J=6.8, 2H), 4.27 (t, J=6.8, 2H), 3.89 (q, J=6.8„ 2H), 2.98 (t, J=6.8, 2H), 2.3 8 (s, 3H), 2.35 (s, 3H), 1.35 (t, J=6.8, 3H), 1.28 (t, J=6.8 3H)。 ’ iLJZ-乙氧幕:3- {2-甲某- 4-f 甲甚笨茱-啐袖_4二 基)-乙乳基I -本基丨-丙缔酸 將〇·丨丨6公克LiOHxH20在22t下加入在10毫升THF、5毫 升MeOH及5毫升水中的〇·40公克2Z_乙氧基_3 {2•甲基· [2-(5-甲基-2-苯基-呤唑_4_基)-乙氧基卜苯基}_丙缔酸乙 Sa之冷液中,並持續揽拌2天。將黃色溶液蒸發,將殘餘物 溶解在20毫升水中,並使用約26毫升之1N水性HC丨將pH調 整至3。將懸浮液過濾,將殘餘物以水清洗及乾燥,以得到 成為白色固體之0.34公克(9—1%)標題化合物。 MS : (M+H)+ 408.3。 1R(液體石蠟):3100-2500m, br. (COOH),1 705s (C=0)。 ’R (CDC13, 1H,(5, TMS) : 1〇·5 (s,非常寬,1H),8 〇3 (d, -113 - 本紙張尺度適用中g国家標準(CNS) A视格(21GX297公釐) 1328585 A7 B7 五、發明説明(110) J=8.8. 1H), 7.98 (m, 2H), 7.47- 7.37 (m, 3H), 7.31 (s, 1H), 6.77 (dxd. J=8.8, 2.8, 1H), 6.73 (d, J=2.8, 1H), 4.27 (t, J = 6.8, 2H), 3.91 (q, )=1.2, 2H), 2.99 (t, J=6.8, 2H), 2.38 (s, 3H), 2.35 (s, 3H), 1.30 (t, J=7.2, 3H) « 實例76 Γ外消旋性卜2-乙氫某-3- {2-甲基-4-[2-(5-曱某-2-笨某-喵 唑-4-基)-乙氣基1-苽某}-丙醆 將在2毫升MeOH中的100毫2Z·乙氧基-3-{2-甲基-4-[2-(5-甲基-2-苯基-呤唑-4-基)-乙氧基]-苯基卜丙缔酸及 26毫克Pd/ C( 10%)之懸浮液在22 °C /1巴下經2天氩化。將懸 浮液過滤,將.過濾液蒸發及乾燥,以得到成為淡黃色固體 之89毫克(89%)標題化合物。 - MS : (M+H)+ 410.4 〇 1R (MIR) : 3100-2400m, br. (COOH), 1 725m (C=0) 〇 NMR (CDC13, 1H,<5, TMS) : 10.5 (s,非常寬,1H),7.96 (m, 2H), 7.45- 7.35 (m,3H),7.09 (d,J=8.4,1H),6.68 (s,br·, 1H), 6.66 (d, br. J=8.4, 1H), 4.19 (t, J=6.8, 2H), 3.96 (m, 1H), 3.50 (m, 1H), 3.27 (m, 1H), 3.07 (m, 1H), 2.95 (t, J=6.8, 2H),.2.87 (m, 1H), 2.36 (s, 3H),2.30 (s,3H),1.08 (t,J=7.2, 3H)。 實例77, 78 - al [外消旋性1-2-乙氣基-3-(2 -甲基-4-|~2-(5-甲基-2 -苯基-°号唑-4 -基)-乙氣某卜苽某丨-丙酸乙酯 將在8毫升MeOH、2毫升THF及0.5毫升AcOH中的400毫克 - -114" — 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)LiLjl^#l·3パ4_{2q2-U^1^^ Oxygen 芡 u u u5-A certain carbazole-棊1 ethyl lactyl} 碁-1-碁)·2· ethoxylate is similar to The preparation of Example 54 - the coupon was a melting point of 1 64 丨 65. The white crystal, but 4-hydroxycha-1-carboxylate was substituted for the 4·1 benzyl[b]p-septene-7-carboxyl chain for the Mitsunobu reaction. 1SN-MS: 504.2 (M-H)+. Example 72 L-exhibition 1 - 3_- (4- { 2_ [2-丄^^曱气茇茇甲甲喵崦喵崦-ii1一乙孔基}Naphthalene-1-yl)_2: Propoxyl Propionate was prepared as the melting point 丨4〇_ 14丨 in the same manner as in Example 71. It was white crystal, but ethyl propoxyacetate was used instead of ethyl ethoxyacetate in the aldol coupling step. 1SN-MS: 518.1 (M-H)+. Example 73 丄 丄 丄 丄 υ υ υ 甲 甲 甲 甲 甲 甲 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The white crystal, but 4-hydroxyindole-1 -carboxaldehyde was substituted for 4-hydroxyl bromide [b] b-cetin-7 carboxylic acid for the Mitsunobu reaction. ____ 110 - This paper size applies to the 圉@家标竿(CMS) A4 specification (210X297 公1328585 A7 ______B7 V. Invention description (107) ISN-MS : 518.1 (MH)+. Example 74 [External ^ 旋性卜 2 - propyl-oxo-3·(4]2-丨2-f4-isopropyl oxime)-5-methylcarbazole-4-oxime was prepared in a similar manner to Example 73 as a white foam compound. However, the entire reaction sequence was started by substituting 4-isopropylphenyl aldehyde for 3,5-dimethoxybenzaldehyde. ISN-MS: 500.2 (MH) + 〇-- Example 75 - 3.50 g in 190 ml of THF a solution of cresol, 9 87 g of 2-(5-methyl-2-phenyl-oxazol-4-yl)ethanol and 12 73 g of triphenylphosphine under the reaction of 8 · 4 5 g in 75 ml of THF Diethyl azodicarboxylate (DEAD) was treated for 20 minutes and the brown solution was stirred at 22 Torr for 24 hours. The solution was evaporated and the residue was partitioned between CH2C12 (3 mL) and EtOAc. Between NaOH (100 ml). The organic layer was washed twice with water (2 χ 〇〇 mL), dried and evaporated, and the residue was chromatographed on silica gel (20:1 n-hexane / Ac0Et ) to get 7 43 g (78%) of the title compound: MS: (Μ+Η)+ 294.3. NMR (CDC13, lH, TMS): 7.97 (m, 2H), 7.45-7.35 (m, 3H). 7.14 (t, J=7.6, 1H), 6.77- 6.67 (m, 3H), 4.23 (t, 3=6 8 2H). 2·97 (t, J=6.8, 2H), 2.38 (s, 3H) , 2.21 (s, 3H). »212 2. 5.-4-(2-(5-methyl-2-phenyl-° azole-4-some, -,. sound | 1_stupple chain _ ____- 111 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 _________B7_____ V. Description of invention (1〇8) 6.00g 5-methyl-2- to be in 30ml CH2C12 A solution of phenyl-4-(2-m-tolyloxyethyl)carbazole and 4.70 g of dichloromethyl methyl ether was treated at 11.2 ml of TiCl4 for 15 minutes at 0 ° C. Stir for 2.5 hours. Treat the red solution with 6 mL of water in HCl. The organic layer was washed with 0.1 N aqueous NaOH and washed twice with brine. The organic layer was dried to evaporate solvent and residue The material was chromatographed on silica gel (7:1 hexanes/EtOAc) to afford 3.42 g (52%) of the title compound as a pale yellow solid. -- MS : (M)+ 321,2 » IR (liquid stone ants): 1691s and 1679s (C=0) NMR (CDC13, 1H, δ, TMS) : 10.10 (s, 1H), 7.96 (m, 2H ), 7.73 (d, J=8.6, 1H), 7.45-7.36 (m, -3H), 6.84 (dxd, J=8.6, 2.8, 1H), 6.73 (d, J=2.8, 1H), 4.32 (t , J=6.8, 2H), 3.00 (t, J=6.8, 2H), 2.62 (s, 3H), 2.38 (s, 3H). Cl 2g diethoxy- 3-{2-甲某-4- "2-(5-methyl-2-pyranazole-4-yl)-ethoxy-1-phenylindole-propanol L cool will be 1.50 grams of 2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde in 30 ml of i-PrOH, 3 〇〇 克 wittig salt [gasification (ethyl lactyl ethyl) diphenyl scales, Tetrahedron 50 (25), 7543-56 (1994)] and 0.97 grams of potassium carbonate suspension at 22. (: Stir for 6 days. Add another 1.50 grams of Wittig salt and 48 kg of potassium carbonate, and continue mixing overnight at 60. Add another 1.50 grams of Wittig salt and 0.48 grams of potassium carbonate at 60 °. Stirring was continued overnight at C, after which time the conversion was completed. The mixture was evaporated and the residue was dissolved in 4 mL of CH2Cl2 - 112 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Inventive Note (109) Between 40 ml of saturated aqueous nh4C 。. The organic layer was washed with 40 ml of water, dried and evaporated. The residue was chromatographed on s. Hexane/AcOEt) to give a pale yellow solid 1 53 g (75%) of the title compound MS: (M) + 435.2 〇1R (liquid paraffin): 1715 s (c = 0) NMR (CDC13, 1H, δ, TMS): 8.05 (d, J = 8.8, (1), 7.97 (m, 2H) (q, J=6.8, 2H), 4.27 (t, J=6.8, 2H), 3.89 (q, J=6.8„ 2H), 2.98 (t, J=6.8, 2H), 2.3 8 (s, 3H) , 2.35 (s, 3H), 1.35 (t, J=6.8, 3H), 1.28 (t, J=6.8 3H). 'iLJZ-Ethoxy Screen: 3- {2-A - 4-f A茱-啐 sleeve_4 diyl)-ethyl lactyl I-benzin-propionic acid 〇·丨丨6 g LiOHxH20 was added to 〇·40 in 10 ml of THF, 5 ml of MeOH and 5 ml of water at 22 t.克 2Z_ethoxy _3 {2•methyl·[2-(5-methyl-2-phenyl-carbazole_4_yl)-ethoxyphenyl)}-propionic acid In the cold liquid, continue to stir for 2 days. The yellow solution was evaporated, the residue was dissolved in water (20 ml), and the pH was adjusted to 3 using about 26 ml of 1N aqueous HC. The suspension was filtered, and the residue was washed with water and dried to afford white crystals. MS: (M+H) + 408.3. 1R (liquid paraffin): 3100-2500m, br. (COOH), 1 705s (C=0). 'R (CDC13, 1H, (5, TMS): 1〇·5 (s, very wide, 1H), 8 〇 3 (d, -113 - This paper scale applies to the g national standard (CNS) A visual ( 21GX297 mm) 1328585 A7 B7 V. INSTRUCTIONS (110) J=8.8. 1H), 7.98 (m, 2H), 7.47- 7.37 (m, 3H), 7.31 (s, 1H), 6.77 (dxd. J= 8.8, 2.8, 1H), 6.73 (d, J=2.8, 1H), 4.27 (t, J = 6.8, 2H), 3.91 (q, )=1.2, 2H), 2.99 (t, J=6.8, 2H) , 2.38 (s, 3H), 2.35 (s, 3H), 1.30 (t, J=7.2, 3H) « Example 76 Γ Racemic Bud 2-Ethyl Hydrogen-3- {2-Methyl-4- [2-(5-曱--2-Butyl-oxazol-4-yl)-Ethylene-l-yl}-propanthene will be 100 mM 2 ethoxy-3- in 2 ml of MeOH {2-Methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl-propionic acid and 26 mg Pd/C (10% The suspension was argonized at 22 ° C / 1 bar for 2 days. The suspension was filtered, and the filtrate was evaporated and evaporated to crystals crystals - MS : (M+H)+ 410.4 〇1R (MIR) : 3100-2400m, br. (COOH), 1 725m (C=0) NMR (CDC13, 1H, <5, TMS) : 10.5 (s , very wide, 1H), 7.96 (m, 2H), 7.45- 7.35 (m, 3H), 7.09 (d, J=8.4, 1H), 6.68 (s, br·, 1H), 6.66 (d, br. J=8.4, 1H), 4.19 (t, J=6.8, 2H), 3.96 (m, 1H), 3.50 (m, 1H), 3.27 (m, 1H), 3.07 (m, 1H), 2.95 (t, J = 6.8, 2H), .2.87 (m, 1H), 2.36 (s, 3H), 2.30 (s, 3H), 1.08 (t, J = 7.2, 3H). Example 77, 78 - al [racemate 1-2-ethane-yl-3-(2-methyl-4-|~2-(5-methyl-2-phenyl-[[iota]-4]- Base) - Ethyl bromide - ethyl propionate will be 400 mg - -114 " in 8 ml of MeOH, 2 ml of THF and 0.5 ml of AcOH - This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210X297 mm)
裝 訂Binding
線 1328585 A7 B7 111 五、發明説明( 22-乙氧基-3-{2-甲基-4-[2-(5-甲基-2-苯基-哼唑-4-基)-乙氧基]-笨基卜丙缔酸乙酯及98毫克Pd/C( 10%)之懸浮液 在22°C /丨巴下經隔夜氫化。將懸浮液過濾,將過濾液蒸發 及乾燥’以得到成為無色油之38〇毫克(95%)標題化合物。 M H)·及KR)-乙黃疾-3-{2-甲基-4-f2-(5-甲某-2-苽篡-^吐-4 -基h乙氣某1 ·苽某丨_丙酸乙酯 在製備性管柱上((:1^31口3^八0,98:2之正己烷/£1〇11)解 離[外消旋性]-2-乙氧基-3-{2-二甲基-4-[2-(5-甲基-2-苯基-"号峻-4-基)-乙氧基]•苯基卜丙酸乙酯,以製備兩個標題化 合物’先溶離2(S)-對映異構物。 ?(3)-及2(丑)-乙氣某-3_^2_甲某-4_『2彳<;-甲基_2_苽某_;>寄 唑-4 -棊)-_乙氧基卜苽基丨-丙醢 _ 如貫例75d]的說明進行酯的水解作用,以得到具有 e_e_>99%的兩個標題化合物(chiralpakAD, 97:3之正己炫· / EtOΗ)。分光鏡數據與那些在實例76中說明的外消旋性化 合物的數據相同。以X-射線分析2(s)_酸,以建立絕對組 態。在22°c下自CHCIV正己烷生長晶體。 實例79 g_L;U2-(2,3-二甲基苯氧茱)甲其-2-笨某·啐砷 以類似於實例75a]的方式製備標題化合物,但是使用2 3_ 二甲基紛代替間-甲酴,以得到淡黃色固體(6 72公克’, 67%)。 MS : (M广 307.3。 NMR(CDC.3, 1H, TMS) : 7.97 (m> 2H), 7.45- 7.35 (m, ,115 - 本紙張尺度適用中圉國家標準(CNS) A4規格(210X297公if 1328585 A7 B7 五、發明説明(112) 3H), 7.02 (t, i=7.6, IH), 6.77-6.70 (m, 2H), 4.23 (t, J=6.8, 2H), 2.99 (t, J = 6.8, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 2.11 (s, 3H)。 bl 2,3-二曱基·4__丨2-(5-甲華-?·苽某-»等唑-4-基)-乙氳某1- 笨醛 以類似於實例75b]的方式製備標題化合物,但是使用4· [2-(2,3-二甲基苯氧基)乙基]· 5·甲基-2-苯基·哼唑作為原 料,以得到淡黃色固體(4 · 12公'克,7 1 % )。 MS : ( M)+ 335.1。 IR(液體石蠟):1689s (C=〇)。 NMR (CDCI3, (5, TMS) : 10.13 (s, 1H), 7.98 (m, 2H), 7.64 (d, J=8.4, 1H), 7.46-7.36 (m, 1H), 6.85 (d, J=8.4, 1H), 4.33 (t, J-6.4, 2H), 3.〇3 (t, J=6.4, 2H), 2.58 (s, 3H), 2.39 (s, 3H), 2.16 (s,3H) 〇 cl -」_2,3-二甲基唑_4 某、乙氫 基]-苯基丨- 2Z-乙氧某丙烯酸c酷 以類似於實例75c]的方式製備標題化 二甲基邻-(5-甲基-2-苯基.十“_基)_乙二使二作 為原料,以得到白色固體(50毫克,54%)。 MS ·· (M+H)+ 450.4 〇 1R(液體石蠟):1709s (C=0)。 NMR (CDCh, 1H, 6, TMS) : 7.97 (m, 2H), 7.81 (d, J=8.8, 1H), 7.45- 7.35 7.24(s, lH) 5 6.76 (d, J=8.8, 1H), 4-29 (q, J=7.2, 2H), 4.27 (t, J=6 2H)j 3 g4 j=6 -116 - 1328585 A7 B7 113 五、發明説明( 2H),3.00 (t,J-6.4, 2H),2.38 (s,3H),2 26 (s,3H),2 15 (s, 3H). L36(t, >7.2,3H),12Mu=6.8,2H)。 "-1…二甲幕二笨某-哼吔-4 ·某)·乙氫 基卜苯基} - 2Z-乙氧某而蟑酩 以頮似I實例75d]的方式製備標題化合物但是使用3· {—2.3- —甲基-4-[ 2-(5-甲基-2-笨基·噚唑_4•基)_乙氧基]· 笨基卜2Z-乙氧基丙缔酸乙酯作為原料,以得到白色固體 (0_32公克,86%)。 -、 MS : (M+H-)+ 422.3 » ' 1R(液體石蠟广 31〇0-2500m,br_ (C〇〇H),1698s (c=〇)。 NMR (CDC13, 1H,δ, TMS) : U_1〇 (s,非常寬,1H),7 98 (m. 2H), 7.80 (d, J=8.8, 1H), 7.46-.7.36 (m, 4H), 6.77 (d, J=8.8, 1H), 4.28 (t, J=6.4, 2H), 3.85 (q, 1=7.2, 2H), 3.02 (t, J-6.4, 2H), 2.39 (s, 3H), 2.27 (s, 3H), 2.15 (s, 3H), 1.26 (t, J=7.2, 3H)。 實例80 基)-乙乳基1-笨基丨-2-乙氧.甚丙酸 以類似於.實例76的方式製備標題化合物,但是使用3_ {2,3-二曱基-4-[2-(5-甲基-2-苯基·噚唑·4_基)·乙氧基]_ 令基}-2Z-乙氧基丙晞酸作·為原料,以得到白色固體(92毫 克,91%)。 MS : (Μ+Η)+ 424·4 » IR(液體石蠟):3 100-2500m,br. (COOH),1724s (0〇)》 -117 - 本紙張尺度適用中國国家橾準(CNS) A4規格(210X 297公爱) 1328585 114 發明説明( NMR (CDCI3, 1H, <5, IMS): (1_ 10 (s,非常寬,1H), 7.97 (m,2H),7.46- 7.36 (m,3H),6 9r _ J=8.4. 1H),4· 19 (t,J=6,4, 2H、 (d, J 8'4> 1H), 6.66 (d, 3.29 (m, 1H), 3.15 (dxd,J=l4 4 97 (m, 1H),3.49 (m,1H), 2.91 (dxd, J= 14.4, 8.8, 1H), 2 3 5 1H), 2,98 (t, J=6.4, 2H), (s, 3H),1.09 (“ J=6.8, 3H)。7 (S’ 3H),2.23 (S,3H),2·13 r實例8 1 al 4]2-(3,.5-二_1 基笔 以類似於實例75a]的方式製,7/ ~~縫.工坐 、I備標題化合物,彳曰是使 二甲基酚代替間-甲酚,以ρ , 彳一疋使用3,5· 乂钤到淡黃色油( 公克, 59%)。 二兄 MS : (M+H)+ 308.2 〇 NMR (CDCb, 1H, 5, TMS) : 7 ^ J 7-97 (m, 2H), 7.43- 7.33 (m, 3H), 6.59 (s, br., 1H), 6.53 (s br .〇Λ , br.s 2H), 4.20 (t j=6 4 2U) 2.96 (t,J=6.4,2H), 2.38 (s,3H)52.26 (Ss6H); ’ )’ bl 2,6-二甲基-4-f2-(5-甲莘-g· 二基)·乙氫某]· 笨醛 以類似於實例75b]的方式製備標題化合物但是使用扣 [2-(3,:)-二甲基苯氧基)乙基卜5.甲基_2•笨基-哼唑作為原 料,以得到成為淡黃色固體之丨:1的正異構物之混合物(83 毫克,78%)。將混合物在製備性HpLC上分離(Rp_i8, CH3CN/H2〇梯度),以得到成為白色固體之標題化合物(41 毫克,3 8 % )。 MS : (M),335.2。 ___ - 118 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X 297公釐〉 1328585 A7 B7 五、發明説明(115) IR(液體石蠟):1672。 NMR (CDC13, 1H, 6, TMS) : 10.46 (s, 1H), 1.9Ί (m, 2H), 7.46- 7.36 (m, 3H), 6.59 (s, 2H), 4.30 (t, J=6.4, 2H), 2.99 (t, J=6.4, 2H), 2.58 (s, 6H),2.38 (s, 3H)。 c| 3 - ! 2,6-二甲某-4- l~2-( 5-甲某-2-笟某岫-4 -某)-基卜苯基丨-2Z-乙氣某丙烯酸乙酯 將2.88公克Wittig鹽[氯化(乙氧基乙氧羰基甲基)三苯 鱗,Tetrahedron 50(25),7543--乏6( 1994)]及 15 毫升 THF的懸 浮液冷卻至-78°C,以6.7毫升LiN (TMS)2(在THF中的1克分 子量)處理,將黃色溶液經1小時溫熱至221及冷卻至-78 °C。將溶液以在15毫升THF中的1.40公克2,6-二甲基-4-[2-(5-甲基-2-苯基号唑-4-基)-乙氧基_]-苯醛之溶液處理,並 在70°下持續攪拌7天。將混合物再以1.44公克Wittig鹽及 3.35毫升LiN (TMS)2(在THF中的1克分子量)處理,並在70。 下持續攪拌6天。將反應混合物蒸發,並將殘餘物分溶在 CH/h與飽和水性NH4C1之間。將有機層以水清洗,乾燥及 蒸發。將殘餘物在矽膠上經色層分離(8: 1之正己境 / Ac0Et) ’以得到成為淡黃色油之〇 _55公克(29〇/〇)標題化合 物。 MS : (M)+ 449.2。 IR (純):1721s (C=0)。 _ NMR (CDCI3, !Η, δ, TMS) : 1.91 (m, 2H), 7.46-7.36 (m 3H), 7.03 (s, 1H), 6.60 (s, 2H), 4.30 (q, J=7.2, 2H), 4.23 (t J=6.4, 2H), 3.56 (q, J=7.2, 2H), 2.97 (t, 5=6.4, 2H), 2.37 (s, ____- 119 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 1328585 A7 B7 五、發明説明(116) 3H),2.22 (s,6H),1.35 (t,7.2, 3H),1.05 (t,J=7.2, 3H)。 dl..3- { 2,6-二 T 基-U2-〇 甲_^2-笨某-咩 ^ -基1-表基}-2Ζ-乙氣基两締酸 以類似於實例75d]的方式製備標題化合物,但是使用3· { 2,6-二甲基-4-[2-(5-甲基-2-苯基· „号唑·4·基卜乙氧基]_ 苯基} - 2Ζ-乙氧基丙埽酸乙酯作為原料,以得到白色固體 (1 5 5 毫克,4 1 %)。 MS : (Μ+Η)+ 422.3。 -- -%» · 1R(液體石壤):3100-2500m,br. (COOH), 1716s (C=0)。 NMR (CDCI3. 1H. δ, TMS) : 9.50 (s, br., 1H), 7.98 (m, 2H), 7.46- 7.36 (m, 3H), 7.15 (s, 1H), 6.61 (s, 2H), 4.23 〇, J=6.4, 2H), 3.54 (q, J=7.2, 2H), 2.98 (t, J=6.4, 2H), 2.38 (s, 3H), 2.21 (s, 6H), 1.10 (t, J=7.2, 3H) 〇 實例82 al [外消旋性]-3- { 2,6-二甲基-4- Γ2- ( 甲某-2-笨基^ 4 -基)-乙乳基1-表基丨-2-乙氣基丙齡甲西旨 將1¾克峨及17毫克鍈接著加入在1.5毫升甲醇中的3 { 2,6- 一甲基- 4- [2-(5-甲基-2-苯基-σ号吐基)-乙氧基]_ 苯基} - 2Ζ-乙氧基丙烯酸乙酯之溶液中,並持續攪拌3小 時。加入另一份67毫克鎂,並持續攪拌i .5小時。將懸浮液 過濾,將過濾液蒸發’並將殘餘物在製備性HPLC分離上 (RP-1 8,CH3CN/H2〇梯度)’以得到成為白色固體之2毫克 (7%)標題化合物》 NMR (CDC13, 1H, TMS) : 7.98 (m, 2H), 7.45-7.35 (m __- 120 - 本纸張尺度適用中國國家標準(CNS) A4规格(21〇x 297公釐)Line 1328085 A7 B7 111 V. Description of the invention (22-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy A suspension of ethyl streptoacetate and 98 mg of Pd/C (10%) was hydrogenated overnight at 22 ° C / 。 bar. The suspension was filtered, and the filtrate was evaporated and dried to give Become a colorless oil of 38 mg (95%) of the title compound. MH)· and KR)-E.glycosis-3-{2-methyl-4-f2-(5-甲某-2-苽篡-^吐-4 - 乙h乙乙一1 ·苽一丨_ethyl propionate on the preparative column ((: 1^31 mouth 3^8, 98:2 n-hexane / £1〇11) dissociation [ Racemic]-2-ethoxy-3-{2-dimethyl-4-[2-(5-methyl-2-phenyl-" 峻-4-yl)-ethoxy • Phenyl propyl propionate to prepare two of the title compounds 'dissolved 2(S)-enantiomers. ?(3)- and 2(ugly)-ethane--3_^2_A a -4_『2彳<;-methyl_2_苽__;> azole-4 -棊)--ethoxy bromide-propionium _ as described in Example 75d] hydrolysis of the ester The effect is to obtain two title compounds with e_e_>99% (chiralpakAD, 97:3 of the genus / EtOΗ). Spectroscopic data and The data for the racemic compounds described in Example 76 were identical. The 2(s)-acid was analyzed by X-ray to establish an absolute configuration. Crystals were grown from CHCIV n-hexane at 22 ° C. Example 79 g_L; U2-(2,3-Dimethylphenoxyhydrazide)methan-2-bromo-arsenic arsenic The title compound was prepared in a similar manner to Example 75a], but using 2 3 dimethyl phthalocyanine instead of m-methylhydrazine, To give a pale yellow solid (6 72 g, 67%). MS: (M, 307.3. NMR (CDC.3, 1H, TMS): 7.97 (m > 2H), 7.45 - 7.35 (m, , 115 - The paper size is applicable to the China National Standard (CNS) A4 specification (210X297 public if 1328585 A7 B7 5. Invention description (112) 3H), 7.02 (t, i=7.6, IH), 6.77-6.70 (m, 2H), 4.23 (t, J=6.8, 2H), 2.99 (t, J = 6.8, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 2.11 (s, 3H). bl 2,3-dimercapto · 4__丨2-(5-methyl--···苽-»-oxazol-4-yl)-acetamyl 1- aldehyde The title compound was prepared in a similar manner to Example 75b], but using 4· [ 2-(2,3-Dimethylphenoxy)ethyl]·5·methyl-2-phenyl·carbazole as a starting material to give a pale yellow solid (4 · 12 ng, 7%, 7 1 %) . MS: (M) + 335.1. IR (liquid paraffin): 1689s (C=〇). NMR (CDCI3, (5, TMS): 10.13 (s, 1H), 7.98 (m, 2H), 7.64 (d, J=8.4, 1H), 7.46-7.36 (m, 1H), 6.85 (d, J= 8.4, 1H), 4.33 (t, J-6.4, 2H), 3.〇3 (t, J=6.4, 2H), 2.58 (s, 3H), 2.39 (s, 3H), 2.16 (s, 3H) 〇cl -"_2,3-dimethylazole_4, Ethyl]-phenylindole-2Z-ethoxyl Acrylic acid c Cooling Prepare the titled dimethyl o--(in a similar manner to Example 75c) 5-Methyl-2-phenyl. Ten "_yl" - Ethylene as the starting material to give a white solid (50 mg, 54%). MS ·· (M+H)+ 450.4 〇1R (liquid paraffin) ): 1709s (C=0) NMR (CDCh, 1H, 6, TMS): 7.97 (m, 2H), 7.81 (d, J=8.8, 1H), 7.45- 7.35 7.24(s, lH) 5 6.76 ( d, J=8.8, 1H), 4-29 (q, J=7.2, 2H), 4.27 (t, J=6 2H)j 3 g4 j=6 -116 - 1328585 A7 B7 113 V. Description of invention (2H ), 3.00 (t, J-6.4, 2H), 2.38 (s, 3H), 2 26 (s, 3H), 2 15 (s, 3H). L36(t, >7.2, 3H), 12Mu=6.8 , 2H). "-1...Dim 2, 笨 某 哼吔 · · · · · · · · 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备 制备The title compound but uses 3· {—2.3- — Base 4-[2-(5-methyl-2-phenyl-2-carbazole-4-yl)-ethoxy]- phenyl 2Z-ethoxypropionate as raw material to obtain white Solid (0-32 g, 86%) -, MS: (M+H-)+ 422.3 » ' 1R (liquid paraffin wax 31 〇 0-2500 m, br_ (C〇〇H), 1698s (c=〇). NMR (CDC13, 1H, δ, TMS) : U_1〇(s, very wide, 1H), 7 98 (m. 2H), 7.80 (d, J=8.8, 1H), 7.46-.7.36 (m, 4H), 6.77 (d, J=8.8, 1H), 4.28 (t, J=6.4, 2H), 3.85 (q, 1=7.2, 2H), 3.02 (t, J-6.4, 2H), 2.39 (s, 3H) , 2.27 (s, 3H), 2.15 (s, 3H), 1.26 (t, J=7.2, 3H). Example 80: yl)-ethyllacyl 1-phenylidene-2-ethoxyl.propionic acid The title compound was prepared in a similar manner to that of Example 76, but using 3_{2,3-didecyl-4-[2 -(5-Methyl-2-phenyl-oxazole·4-yl)·ethoxy]- aryl}-2Z-ethoxypropionic acid was used as a starting material to give a white solid (92 mg, 91%). MS : (Μ+Η)+ 424·4 » IR (liquid paraffin): 3 100-2500m, br. (COOH), 1724s (0〇)》 -117 - This paper scale applies to China National Standard (CNS) A4 Specification (210X 297 public) 1328585 114 Description of the invention (NMR (CDCI3, 1H, <5, IMS): (1_ 10 (s, very wide, 1H), 7.97 (m, 2H), 7.46- 7.36 (m, 3H),6 9r _ J=8.4. 1H),4· 19 (t,J=6,4, 2H, (d, J 8'4> 1H), 6.66 (d, 3.29 (m, 1H), 3.15 (dxd, J=l4 4 97 (m, 1H), 3.49 (m, 1H), 2.91 (dxd, J= 14.4, 8.8, 1H), 2 3 5 1H), 2,98 (t, J=6.4, 2H), (s, 3H), 1.09 (" J=6.8, 3H). 7 (S' 3H), 2.23 (S, 3H), 2·13 r Example 8 1 al 4] 2-(3,.5 - 2_1 base pen is made in a manner similar to that of example 75a], 7/~~ slit. Work-sitting, I prepare the title compound, 彳曰 is to make dimethylphenol instead of m-cresol, use ρ, 彳3,5· 乂钤 to pale yellow oil (g, 59%). Second brother MS : (M+H)+ 308.2 NMR (CDCb, 1H, 5, TMS) : 7 ^ J 7-97 (m, 2H ), 7.43- 7.33 (m, 3H), 6.59 (s, br., 1H), 6.53 (s br .〇Λ , br.s 2H), 4.20 (tj=6 4 2U) 2.96 (t, J=6.4 ,2H), 2.38 (s,3H)52.26 (Ss6H) ; ' )' bl 2,6-Dimethyl-4-f2-(5-formamidine-g.diyl)·ethylhydrogen]· aldehyde The title compound was prepared in a similar manner to Example 75b]. [2-(3,:)-Dimethylphenoxy)ethyl b.methyl-2-phenyl-carbazole as a starting material to give a light yellow solid: a positive isomer of 1 Mixture (83 mg, 78%). The title compound (jjjjjjjjjjjjjjjjjjjj 335.2. ___ - 118 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7 V. Description of invention (115) IR (liquid paraffin): 1672. NMR (CDC13, 1H, 6, TMS): 10.46 (s, 1H), 1.9 Ί (m, 2H), 7.46- 7.36 (m, 3H), 6.59 (s, 2H), 4.30 (t, J=6.4, 2H), 2.99 (t, J=6.4, 2H), 2.58 (s, 6H), 2.38 (s, 3H). c| 3 - ! 2,6-dimethyl-4-l~2-(5-methyl-2-pyrene-4-a)-pybylhydrazine-2Z-ethane Cooling a suspension of 2.88 grams of Wittig salt [ethoxy(ethoxyethoxycarbonylmethyl)triphenyl scale, Tetrahedron 50 (25), 7543--6 (1994) and 15 ml of THF to -78 °C Treated with 6.7 ml of LiN (TMS) 2 (1 gram molecular weight in THF), the yellow solution was warmed to 221 over 1 hour and cooled to -78 °C. The solution was 1.40 grams of 2,6-dimethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy-]benzaldehyde in 15 ml of THF. The solution was treated and stirring was continued for 7 days at 70 °. The mixture was treated with 1.44 g of Wittig salt and 3.35 ml of LiN (TMS) 2 (1 g molecular weight in THF) at 70. Stirring was continued for 6 days. The reaction mixture was evaporated and the residue was partitioned between CH/H and sat. The organic layer was washed with water, dried and evaporated. The residue was chromatographed on silica gel (8:1 hexanes / EtOAc) to afford y. MS: (M) + 449.2. IR (pure): 1721 s (C = 0). _ NMR (CDCI3, !Η, δ, TMS): 1.91 (m, 2H), 7.46-7.36 (m 3H), 7.03 (s, 1H), 6.60 (s, 2H), 4.30 (q, J=7.2, 2H), 4.23 (t J=6.4, 2H), 3.56 (q, J=7.2, 2H), 2.97 (t, 5=6.4, 2H), 2.37 (s, ____- 119 - This paper scale applies to Chinese national standards (CNS) A4 size (210 x 297 mm) 1328585 A7 B7 V. Description of invention (116) 3H), 2.22 (s, 6H), 1.35 (t, 7.2, 3H), 1.05 (t, J = 7.2, 3H ). Dl..3- { 2,6-di-T-group-U2-〇甲_^2-笨某-咩^-yl 1 -epi}-2Ζ-ethane-based di-acid is similar to Example 75d] The title compound was prepared in the same manner, but using 3·{ 2,6-dimethyl-4-[2-(5-methyl-2-phenyl· oxazolyl-4-yloxy)-phenyl} - 2Ζ-ethoxypropionate as a starting material to give a white solid (1 5 5 mg, 41%) MS: (Μ+Η)+ 422.3. - -%» · 1R (liquid stone soil) ): 3100-2500m, br. (COOH), 1716s (C=0). NMR (CDCI3.1H. δ, TMS): 9.50 (s, br., 1H), 7.98 (m, 2H), 7.46- 7.36 (m, 3H), 7.15 (s, 1H), 6.61 (s, 2H), 4.23 〇, J=6.4, 2H), 3.54 (q, J=7.2, 2H), 2.98 (t, J=6.4, 2H ), 2.38 (s, 3H), 2.21 (s, 6H), 1.10 (t, J = 7.2, 3H) 〇 Example 82 al [racemic]-3-{ 2,6-dimethyl-4- Γ2-(A-2-pyryl^4-yl)-ethyllacyl-1-epi--2-ethylene-based acesulfame-methyl 13⁄4 gram and 17 mg hydrazine were added to 1.5 ml of methanol. 3 { 2,6-monomethyl- 4-[2-(5-methyl-2-phenyl-σ- oxime)-ethoxy]-phenyl}- 2Ζ-ethoxy acrylate In the solution, and continue to stir for 3 hours. Another 67 mg of magnesium was continuously stirred for 1.5 hours. The suspension was filtered, the filtrate was evaporated and the residue was purified on preparative HPLC (RP-1, CH3CN/H.sub.2 gradient). 2 mg (7%) of the title compound as a white solid. NMR (CDC13, 1H, TMS): 7.98 (m, 2H), 7.45-7.35 (m __- 120 - This paper scale applies to the Chinese National Standard (CNS) A4 Specifications (21〇x 297 mm)
1328585 五、發明説明( 3H), 6.57 (S) 2H), 4.20 (t, J=6 4 1H) 3 72 ( a r ’ 2H),3.92 (dxd,卜8.8, 4.8, 1H), 3.72 (s, 3H), 3.52 (τη, (m, 4H),2.38 (s, 3H),2.31 (s 6m . m> lH), 3.05-2.93 ’ H), 1.09 (t, 7 9 飞]4、 以類似於實例7寧方式製備標題化合物,是外 4旋性」-3-{2广二甲基='[2'(5-甲基-2-笨基_ 口号嗤冬 基)-乙氧基]-苯基}-2-乙氧基-丙& 白色固體(1.·4公克,72%)。〜酸甲^日作為原料,以得到 MS : (M+H)+ 424.3 » NMR(CDCl3,1H,5,TMS):7.97(m,2H),7 46_7 36 (m, 3H), 6·59 (s,2H),4.21 (t,J=6 4, 2H),3 % (m, ih),3 45 (m,1H)’ 3.18(m’ 1H)’ 3.10 (m,1H),3 〇5 2 94 (m,4H) 2.38 (s,3H),2.33 (s,6H),1.05 (t,J=7 2, 3H)。 ’ 實例83, 84 aj 4-丨2-(苯并呋喃4-氧基)ϋ [ _ %甲某-2-苽某啐砷 以類似於實例75a]的方式製備標題化合物,但是使用4· 羥基笨并呋喃[Synthetic Communications( 1986),16(13) 1635-1640; Helvetica Chimica Acta(1993),16,121-129]代 替間-甲酚,以得到白色固體(2.4 1公克,76% )。 MS : (M)+ 319.1。 - NMR (CDC13, 1H, δ, TMS) : 7.97 (m, 2H), 7.52 (d, J=2.4, 1H), 7.46-7.36 (m, 3H), 7.19 (t, J=8.0, 1H), 7.12 (d, J=8.0, 1H), 6.83 (d, J=2.4, 1H), 6.68 (d, J=8.0, 1H), 4.39 (t, ____- 121 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公爱)1328585 V. INSTRUCTIONS (3H), 6.57 (S) 2H), 4.20 (t, J=6 4 1H) 3 72 ( ar ' 2H), 3.92 (dxd, 8.8, 4.8, 1H), 3.72 (s, 3H), 3.52 (τη, (m, 4H), 2.38 (s, 3H), 2.31 (s 6m . m> lH), 3.05-2.93 'H), 1.09 (t, 7 9 fly)4, similar to Example 7 The title compound was prepared in the same manner as the title compound. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Phenyl}-2-ethoxy-propanium & white solid (1. 4 g, 72%). ~ Acidic as a starting material to give MS: (M+H) + 424.3 » NMR (CDCl3, 1H,5,TMS): 7.97 (m, 2H), 7 46_7 36 (m, 3H), 6·59 (s, 2H), 4.21 (t, J=6 4, 2H), 3 % (m, ih) ),3 45 (m,1H)' 3.18(m' 1H)' 3.10 (m,1H),3 〇5 2 94 (m,4H) 2.38 (s,3H),2.33 (s,6H),1.05 ( t, J=7 2, 3H). 'Example 83, 84 aj 4-丨2-(benzofuran 4-oxy)ϋ [ _ %甲甲-2-苽A certain arsenic is similar to Example 75a] The title compound was prepared in the manner but using 4 hydroxy cumene furan [Synthetic Communications (1986), 16 (13) 1635-1640; Helvetica Chimica Acta (1993) 16,121-129] Instead of m-cresol to give a white solid (2.41 g, 76%) MS: (M) + 319.1 - NMR (CDC13, 1H, δ, TMS): 7.97 (m, 2H ), 7.52 (d, J=2.4, 1H), 7.46-7.36 (m, 3H), 7.19 (t, J=8.0, 1H), 7.12 (d, J=8.0, 1H), 6.83 (d, J= 2.4, 1H), 6.68 (d, J=8.0, 1H), 4.39 (t, ____- 121 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 public)
裝 訂Binding
1328585 A7 B71328585 A7 B7
J=6.4, 2H),3.06 (t,J=6.4, 2H),2.40 (s,3H) kL._4二Ll-H 甲ϋ 琴基-口乙 g 其 以類似於實例75b]的方式製備標題化合物,但是使用4 [2-(苯并呋喃-4-氧基)乙基]_5_甲基-2•苯基—噚唑作 料,以得到白色固體(〇 · 82公克,3 3% )。 ..... MS : (M+H)+ 348.4。 IR (MIR) : 1680s (C=0)。 -- NMRCCDC.3. 1H, 5,TMS): Γ〇.21 (s, 1H),7.98(m 2H) 7.74(d,J^8.4, lH),7.67(d,J=2.〇5 1 H), 7.46- 7.3 8 (m, 3H) 6.89 (d,>2.0, 1H),6.81 (d,4, ih),4 49 〇, j=6 4, 2H),3.09 (t,J=6.4, 2H),2.41 (s,3Fl)。 c,l. „2,Z-^2E- 6 甲某-2-芡某-碟砵 j 芊、· s乳基.1 - +并p夫喃-7 -基丨·丙缔g# ,.喷 以類㈣實m5e]的方式製備標題化合物,但是使用心 [2-(5-甲基-2-*基-十坐-4_基卜乙氧基]-苯并吱喃_7致醛 作為原料,以得到成為白色固體之2Z異構物(〇64公克, 65〇/〇”在第二個餾份中獲得成為無色油之異構物(79毫 克,8%)。 2 Z -異搆物的數_ : MS : ( M+H). 462.3。 IR(液體石蠟):1713s 及1704s (C=〇)。 NMR (CDCI3, IH, (5, TMS) : 8.14 (d, J=8.4, IH), 7.98 (m, 2H), 7o6 (d, J=2, 1H), 7.52 (s, 1H), 7.46- 7.36 (m, 3H), 本纸張尺度適用中國國家標準(CMS) A4規格(2l〇x 29^公釐)----- 訂 線 Λ 1328585 A7 B7J = 6.4, 2H), 3.06 (t, J = 6.4, 2H), 2.40 (s, 3H) kL._4 bis Ll-H 甲 琴 琴 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Compound, but using 4 [2-(benzofuran-4-oxy)ethyl]-5-methyl-2-phenyl-oxazole as a white solid (yield: 82 g, 3 3%). ..... MS : (M+H)+ 348.4. IR (MIR): 1680s (C=0). -- NMRCCDC.3. 1H, 5, TMS): Γ〇.21 (s, 1H), 7.98 (m 2H) 7.74 (d, J^8.4, lH), 7.67 (d, J=2.〇5 1 H), 7.46- 7.3 8 (m, 3H) 6.89 (d, > 2.0, 1H), 6.81 (d, 4, ih), 4 49 〇, j=6 4, 2H), 3.09 (t, J= 6.4, 2H), 2.41 (s, 3Fl). c,l. „2,Z-^2E- 6 A certain -2-芡某-碟砵 j 芊,· s milk base.1 - + and pfu -7-7 - 丨 丨 · 丙 g g# ,. spray The title compound was prepared in the manner of (4) m5e], but using the [2-(5-methyl-2-*-yl-s-s--4-yl-ethoxy)-benzopyran- 7 aldehyde as the aldehyde The starting material was obtained as a 2Z isomer (yield: 64 g, 65 〇 / 〇) as a white solid to obtain an isomer (79 mg, 8%) as a colorless oil in the second fraction. Number of substances _ : MS : ( M+H). 462.3. IR (liquid paraffin): 1713s and 1704s (C=〇). NMR (CDCI3, IH, (5, TMS): 8.14 (d, J=8.4, IH), 7.98 (m, 2H), 7o6 (d, J=2, 1H), 7.52 (s, 1H), 7.46- 7.36 (m, 3H), the paper size applies to the Chinese National Standard (CMS) A4 specification (2l〇x 29^mm)----- Set the line Λ 1328585 A7 B7
6.84 (d, J=2, 1H), 6,2 (d,J=8.4>1H)>4 43 (t j=64 4-3. (q. J=7.2. 2H),4.03(q, j=7 2( 2H), 3.06 〇 ;=6 5 ::;;2·40- 139 (t> — 3H), ,3S (t;J=7;2; 2E-異構物的教攄: MS : (M+H)+ 462.3。 IR(純):1732s, br_ (C=0)。 NMR(CDC,3, 1H, ,,TMS) :^7.99 (m, 2H)j 7>49 (d J==2 1H), 7,6-7.36 (m, 3H), 7.07 (d, J=8> 1H)>6.82(;.j=; ΐΗ),6·63(υ—-8,iH),6.22(slH) 4 37 (tj=“ , 4.05 (…2’ 2H),4.00 (….2, 2H) ·;, ;:;·/·40 (S' 3H)*,43 ^ — 3H), 〇,6 ;t;J=:;;; 乙氧基… 4乳基1-本并p失喃-7-基丨-丙; 以類似於實例75d]的方式製備標題化合物,但是使用仏 及2E-乙氧基- 3-{4-[2-(5-甲基_2_笨基号唑基)_乙氧 基]-苯并吱喃-7-基}•丙埽酸乙f旨作為原料,以得二成為= 色固體之2ΖΓ異構物(0.53公克,94%)及成為白色固體之2E_ 異構物(40爱克,67%)。 2Z-異構物的數攄: . MS : ( Μ- H)· 432.4。 IR (液體石蠟):3 100-2500w,br. (CO〇H),1709s (C=0)。 NMR (CDC13, 1H,(5, TMS) : 10.5 (s,非常寬,1H),8.15 (d, _____- 123 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)6.84 (d, J=2, 1H), 6,2 (d, J=8.4>1H)>4 43 (tj=64 4-3. (q. J=7.2. 2H), 4.03 (q, j=7 2( 2H), 3.06 〇;=6 5 ::;;2·40- 139 (t> — 3H), , 3S (t; J=7; 2; 2E-isomer teaching: MS: (M+H)+ 462.3. IR (p.): 1732s, br. (c = 0). NMR (CDC, 3, 1H, ,, TMS): ^7.99 (m, 2H)j 7>49 (d J==2 1H), 7,6-7.36 (m, 3H), 7.07 (d, J=8>1H)>6.82(;.j=; ΐΗ),6·63(υ—-8,iH ), 6.22(slH) 4 37 (tj=“ , 4.05 (...2' 2H), 4.00 (....2, 2H) ·;, ;:;···40 (S' 3H)*,43 ^ — 3H ), 〇,6;t;J=:;;; ethoxy... 4 milyl 1-benz and pentyl-7-ylindole-propene; the title compound was prepared in a similar manner to Example 75d.仏 and 2E-ethoxy- 3-{4-[2-(5-methyl_2-phenylidazolyl)-ethoxy]-benzopyran-7-yl}•propionic acid f is used as a raw material to obtain 2 isomers (0.53 g, 94%) of the color solid and 2E_isomer (40 g, 67%) which becomes a white solid. Number of 2Z-isomers : . MS : ( Μ- H)· 432.4. IR (liquid paraffin): 3 100-2500w, br. (C O〇H), 1709s (C=0). NMR (CDC13, 1H, (5, TMS): 10.5 (s, very wide, 1H), 8.15 (d, _____- 123 - This paper scale applies to Chinese national standards (CNS) A4 size (210X 297 mm)
裝 訂Binding
1328585 A7 B7 五、發明説明(120 J = 8.8, IH), 7.99 (m, 2H), 7.68 (s, 1H), 7.55 (d, J = 2, 1H), 7.46-7.36 (m, 3H),6.83 (d, J=2,1H),6.74 (d,J=8,8, 1H), 4.45 (t, J=6.4, 2H), 4.05 (q, J=7.2, 2H), 3.09 (t, J=6.4, 2H), 2.41 (s,3H), 1.38 (t, J=7.2, 3H)。 2 E ·異構物的數掉: MS : ( M-H). 432.4。 IR (MIR) : 3 100-2500w,br. (COOH),1712m,br. (C=0)。 NMR (CDC13,1H,<5, TMS) :1—0 (s,非常寬,1H), 7.95 (m, 2H), 7.48 (d, J=2, 1H), 7.45-7.35 (m, 3H), 7.32 (d, J=8.4, 1H), 6.78 (d, J = 2, 1H), 6.58 (d, J=8.4, 1H), 6.38 (s, 1H), 4.28 (t. J=6.4, 2H), 4.04 (q, J=7.2, 2H), 3.02 (t, J=6.4, 2H), 2.39 (s, 3H), 1.45 (t, J=7.2, 3H) « . 實例85 f外消旋性卜2-乙氳基-3-丨4-丨2-( 5-甲基-2-苽某-崎唑- 4-基)-乙乳基1-笨并p夫喃-7-基丨-丙酸 將在1毫升MeOH及1毫升CH2C12中的50毫克2Z-乙氧基-3-{4-[2-(5-甲基-2-笨基号峻-4-基)-乙氧基]-苯并p夫喃- 7-基卜丙烯酸及12毫克Pd/ C(丨0%)之懸浮液在22 °C / 1巴下經1 小時氫化。將懸浮液過濾,將過濾液蒸發,並將殘餘物以 製備性HPLC純化(RP-丨8,CH3CN/H20梯度),以得到成為 白色固體之標題化合物(29毫克,57%)。 MS : (M-H)· 434.4。 1R (MIR) : 3100-2500w, br. (COOH), 1724s, br. (C=0) 〇 NMR (CDC13, 1H,(5, TMS) : 9.5 (s,非常寬,1H),7.98 (m _____- 124 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)1328585 A7 B7 V. INSTRUCTIONS (120 J = 8.8, IH), 7.99 (m, 2H), 7.68 (s, 1H), 7.55 (d, J = 2, 1H), 7.46-7.36 (m, 3H), 6.83 (d, J=2,1H), 6.74 (d, J=8,8, 1H), 4.45 (t, J=6.4, 2H), 4.05 (q, J=7.2, 2H), 3.09 (t, J = 6.4, 2H), 2.41 (s, 3H), 1.38 (t, J = 7.2, 3H). 2 E · Number of isomers: MS : (M-H). 432.4. IR (MIR): 3 100-2500w, br. (COOH), 1712m, br. (C=0). NMR (CDC13, 1H, <5, TMS): 0-1 (s, very broad, 1H), 7.95 (m, 2H), 7.48 (d, J=2, 1H), 7.45-7.35 (m, 3H) ), 7.32 (d, J=8.4, 1H), 6.78 (d, J = 2, 1H), 6.58 (d, J=8.4, 1H), 6.38 (s, 1H), 4.28 (t. J=6.4, 2H), 4.04 (q, J=7.2, 2H), 3.02 (t, J=6.4, 2H), 2.39 (s, 3H), 1.45 (t, J=7.2, 3H) « . Example 85 f racemic卜 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- - propionic acid will be 50 mg of 2Z-ethoxy-3-{4-[2-(5-methyl-2-indolyl)-4-ethoxy) in 1 ml of MeOH and 1 ml of CH2C12 A suspension of benzo[p-p-pyran--7-ylbu-acrylic acid and 12 mg of Pd/C (丨0%) was hydrogenated at 22 ° C / 1 bar over 1 hour. The suspension was filtered, EtOAc EtOAc m. MS: (M-H)· 434.4. 1R (MIR) : 3100-2500w, br. (COOH), 1724s, br. (C=0) 〇NMR (CDC13, 1H,(5, TMS) : 9.5 (s, very wide, 1H), 7.98 (m _____- 124 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)
% 訂% order
1328585 A7 r-----5!_— _ 五、發明説明(121) 2H), 7.53 (d, J=2.4, 1H), 7.46-7.36 (m, 3H), 7.06 (d, J=8, ^), 6.82 (d, J=2.4, 1H), 6.61 (d, J=8, 1H), 4.35 (t, J=6.4, 2H). 4.26 (m, IH), 3.57-3.41 (m, 3H), 3.19 (m, 1H), 3.〇6 (t, ·ί = 6·4· 2H)· 2.40 (s. 3H)· 1.08 (t. J=7.4, 3H)。 實例8 6 乙氧基-3-(4-「2-(5-甲某-2-苽某-哼唑-4-苹、 基1-2T3 -二钮.笨并p夫喃-7-某兩酸 將在2毫升MeOH及2毫升CH-2_C12.中的100毫克2Z-乙氧基-3'{心[2-(5、曱基-2-苯基-«号唑-4-基)-乙氧基]-苯并呋喃-7-基}-丙烯酸及25毫克Pd/C(10%)之懸浮液在22°C /1巴下 •毯隔夜氫化^將懸浮液過濾,並將過濾液再以25毫克新鮮 觸媒經隔夜氫化。將懸浮液過濾,將過濾液蒸發,並將殘 餘物以製備性HPLC純化(RP-18,CH3CN/H20梯度),以得 到成為淡黃色固體之標題化合物(56毫克,56%)。 MS : ( Μ- H)· 436.4。 (液體石蠟):3 1 00-2400w,br. (COOH),1715s,br. (〇 〇) Ο NMR (CDC13, 1Η,(5, TMS) : 9.5 (S,非常寬,1Η), 7.97 (m, 2H), 7.46- 7.35 (m, 3H), 6.90 (d, J=8.4, 1H), 6.34 (d, J=8.4, 1H), 4.56 (d, J=8.8, 2H), 4.23 (t, J=6.4, 2H), 4.15 (m, 1H), 3.53 (m, 2H), 3.15-3.05 (m, 3H), 2.96 (t, 6.4, 2H), 2.88 (m, 1H), 2.37 (s, 3H), 1.14 (t, J=7.2, 3H) « 實例87, 88 al 4-丨2-(装砰呋喃-7-氣基)乙某1-5-甲基-2-苽呤唑 _- 125 - 本紙張尺度適用中国圉家橾準(CNS) A4规格(210X297公釐) 1328585 A7 B7 122 五、發明説明( 以類似於實例75a]的方式製備標題化合物,但是使用7_ 羥基苯并呋喃[J. Med. Chem.( 1987),30( 1), 62-7]代替間-甲酚,以得到白色固體(2.54公克,80%)。 MS : (M)+ 319.1 〇 NMR (CDC13, 1H, δ, TMS) : 7.97 (m, 2H), 7.61 (d, J=2.0, 1H), 7.45-7.35 (m, 3H), 7.18 (d, J=7.8, 1H), 7.14 (d, J=7.8, 1H), 6.83 (d, J=7.8, 1H), 6.75 (d, J=2.0, 1H), 4.47 (t, J=6.4, 2H), 3.09 (t, J=6.4, 2H),」.40 (s,3H)。 bl 7 -『2-(5 -甲基-2-笨基-°号峻-4-某乙氣基l -笨并g夫喃- 4-羧醛 以類似於實例75b]的方式製備標題化合物,但是使用4_ [2-(苯并呋喃-7-氧基)乙基]-5-甲基-2-苯基-呤唑作為原 料。以自CHzCl2/正己烷之結晶作用代替色層分離法完成純 化作用,以得到白色固體(1 · 5 7公克,7 1 %) » MS : (M)+ 347.1 » IR(液體石蠟):1690s (C=0)。 NMR (CDCI3,1H,占,TMS) : 10.03 (s,IH),7.97 (m, 2H), 7.77 (d, J=2.0, 1H), 7.65 (d, J=8, 1H), 7.52 (d, J=2, 1H), 7.47-7.37 (m, 3H), 6.93 (d, J=8, 1H), 4.57 (t, J=6.4, 2H), 3.13 (t. J = 6.4, 2H), 2.42 (s,3H)。 ’ c] 2Z-及2E-乙巩基-3 - { 7-丄甲某-2·苯苓_p号唑_4p_ 乙氫基卜苯并呋喃-4-某丨-丙烯醅乙酉旨 以類似於實例75c]的方式製備標題化合物,但是使用7_ [2-(5-甲基冬苯基·以·4.基)_乙氧基]_苯料喃_4·料 本紙張尺度適用中國国家標準(CNS) Α4規格(210 X 297公釐) 訂 線 126 - 1328585 A7 B7 五、發明説明(123 作為原料,以得到成為白色固體之2Z異構物(〇 93公克, 80%)。在第二個餾份中獲得成為無色油之2E•異構物(85毫 克,7%)。 gZ-異搆物的數櫨: MS : (M+H)+ 462.3。 1R(液體石蠟):1715s及 1703s (C=〇)。 NMR (CDC13, lH, δ, TMS) : 7.99 (m, 3H), 7.65 (d, J=2.0, 1H), 7.45- 7.35 (m, 3H), 7.26 (s, l.H), 6.98 (d, J=2.0, 1H), 6.86 (d, J=7.2, 1H), 4.51 (t, J=6.4, 2H), 4.32 (q, J-7.2, 2H), 3.96 (q, J=7.2, 2H), 3.10 (t, J=6.4, 2H), 2.40 (s, 3H), 1.38 (t, J=7.2, 3H), 1.33 (t, J=7.2, 3H)。 2E-異構物的數墟: MS : (M)+ 461 _2。 IR (純):1730s (C=0) 〇 NMR (CDC13? 1H, (5, TMS) : 7.97 (m, 2H), 7.60 (d, J=2.0, 1H), 7.46- 7.35 (m, 3H), 6.97 (d, J=8, 1H), 6.76 (d, J=8, 1H), 6.70 (d, J=2.0, 1H), 6.23 (s, 1H), 4.45 (t, J=6.4, 2H), 4.02 (q, J—7.2, 2H), 3.98 (q, J=7.2, 2H), 3.09 (t, J=6.4, 2H), 2.40 (s, 3H), 1.44 (t, J=7.2, 3H), 0.95 (t, J=7.2, 3H)。 _2Z-及2E-乙乳基- 3- {7-「-2-(5 -甲某-2-苯基-°号°坐-4-某)· 乙氧基1-苯并p夫喃-4-基丨-丙稀酸 以類似於實例75d]的方式製備標題化合物,但是使用2Z-及2E-乙氧基-3-{7-[2-(5-甲基-2-苯基-»号唑-4-基)-乙氧 ___- 127 - 本纸張尺度適用中国国家標準(CNS> A4规格(210X297公爱) 1328585 A7 B71328585 A7 r-----5!__ _ V. Description of invention (121) 2H), 7.53 (d, J=2.4, 1H), 7.46-7.36 (m, 3H), 7.06 (d, J=8 , ^), 6.82 (d, J=2.4, 1H), 6.61 (d, J=8, 1H), 4.35 (t, J=6.4, 2H). 4.26 (m, IH), 3.57-3.41 (m, 3H), 3.19 (m, 1H), 3.〇6 (t, ·ί = 6·4· 2H)· 2.40 (s. 3H)· 1.08 (t. J=7.4, 3H). Example 8 6 Ethoxy-3-(4-"2-(5-methyl-2-pyrene-carbazole-4-pin, 1-2T3-two-button. Stupid and p-fu--7-some The two acids will be 100 mg of 2Z-ethoxy-3'{heart [2-(5, decyl-2-phenyl-«oxazol-4-yl) in 2 ml of MeOH and 2 ml of CH-2_C12. a suspension of -ethoxy]-benzofuran-7-yl}-acrylic acid and 25 mg of Pd/C (10%) at 22 ° C / 1 bar • blanket overnight hydrogenation ^ filter the suspension and filter The mixture was re-slued with 25 mg of fresh solvent over night. The suspension was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjj Compound (56 mg, 56%) MS: ( Μ-H)· 436.4 (liquid paraffin): 3 1 00-2400w, br. (COOH), 1715s, br. (〇〇) Ο NMR (CDC13, 1Η , (5, TMS) : 9.5 (S, very wide, 1Η), 7.97 (m, 2H), 7.46- 7.35 (m, 3H), 6.90 (d, J=8.4, 1H), 6.34 (d, J= 8.4, 1H), 4.56 (d, J=8.8, 2H), 4.23 (t, J=6.4, 2H), 4.15 (m, 1H), 3.53 (m, 2H), 3.15-3.05 (m, 3H), 2.96 (t, 6.4, 2H), 2.88 (m, 1H), 2.37 (s, 3H), 1.14 (t, J=7.2, 3H) « Example 87, 88 al 4 -丨2-(furfuran-7-gas-based) B-1-5-methyl-2-carbazole _- 125 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 B7 122 V. Description of the Invention (The title compound was prepared in a similar manner to Example 75a), but was replaced with 7-hydroxybenzofuran [J. Med. Chem. (1987), 30(1), 62-7]. M-cresol to give a white solid (2.54 g, 80%) MS: (M) + 319.1 NMR (CDC13, 1H, δ, TMS): 7.97 (m, 2H), 7.61 (d, J=2.0 , 1H), 7.45-7.35 (m, 3H), 7.18 (d, J=7.8, 1H), 7.14 (d, J=7.8, 1H), 6.83 (d, J=7.8, 1H), 6.75 (d, J=2.0, 1H), 4.47 (t, J=6.4, 2H), 3.09 (t, J=6.4, 2H), ".40 (s, 3H). Preparation of the title compound by bl 7 -"2-(5-methyl-2-phenyl-[N-methyl-2-phenyl]- ethoxy-4-yl-l-benzofuran- 4-carboxaldehyde in a similar manner to Example 75b] , but using 4_[2-(benzofuran-7-oxy)ethyl]-5-methyl-2-phenyl-oxazole as a starting material. Instead of chromatographic separation by crystallization from CHzCl2/n-hexane Purification was carried out to give a white solid (1·5 7 g, 71%) » MS : (M) + 347.1 » IR (liquid paraffin): 1690s (c=0). NMR (CDCI3, 1H, account, TMS ) : 10.03 (s, IH), 7.97 (m, 2H), 7.77 (d, J=2.0, 1H), 7.65 (d, J=8, 1H), 7.52 (d, J=2, 1H), 7.47 -7.37 (m, 3H), 6.93 (d, J=8, 1H), 4.57 (t, J=6.4, 2H), 3.13 (t. J = 6.4, 2H), 2.42 (s, 3H). ' c ] 2Z- and 2E-ethylglycol-3 - { 7-丄甲一-2·benzoquinone_p-azole _4p_ ethylhydro benzofuran-4- 丨-acryl hydrazine The title compound was prepared in the manner of 75c], but using 7_[2-(5-methyl-t-phenylphenyl-tetrayl)-ethoxy]-benzene-furan-4. CNS) Α4 size (210 X 297 mm) Setting line 126 - 1328585 A7 B7 V. It is indicated that (123 is used as a raw material to obtain a 2Z isomer which is a white solid (〇93 g, 80%). In the second fraction, 2E•isomer (85 mg, 7%) which is a colorless oil is obtained. The number of gZ-isomers: MS: (M+H) + 462.3. 1R (liquid paraffin): 1715s and 1703s (C=〇). NMR (CDC13, lH, δ, TMS): 7.99 (m, 3H), 7.65 (d, J=2.0, 1H), 7.45- 7.35 (m, 3H), 7.26 (s, lH), 6.98 (d, J=2.0, 1H), 6.86 (d, J=7.2, 1H ), 4.51 (t, J=6.4, 2H), 4.32 (q, J-7.2, 2H), 3.96 (q, J=7.2, 2H), 3.10 (t, J=6.4, 2H), 2.40 (s, 3H), 1.38 (t, J=7.2, 3H), 1.33 (t, J=7.2, 3H). The number of 2E-isomers: MS: (M) + 461 _2. IR (neat): 1730s (C=0) 〇NMR (CDC13? 1H, (5, TMS): 7.97 (m, 2H), 7.60 (d, J=2.0, 1H), 7.46- 7.35 (m, 3H) , 6.97 (d, J=8, 1H), 6.76 (d, J=8, 1H), 6.70 (d, J=2.0, 1H), 6.23 (s, 1H), 4.45 (t, J=6.4, 2H ), 4.02 (q, J-7.2, 2H), 3.98 (q, J=7.2, 2H), 3.09 (t, J=6.4, 2H), 2.40 (s, 3H), 1.44 (t, J=7.2, 3H), 0.95 (t, J=7.2, 3H). _2Z- and 2E-ethyl lactyl- 3- {7-"-2-(5-methyl-2-phenyl-°°°-4- a) ethoxy 1-benzocypan-4-ylindole-acrylic acid The title compound was prepared in a similar manner to the compound of Example 75d], but using 2Z- and 2E-ethoxy-3-{7- [2-(5-Methyl-2-phenyl-»-oxazol-4-yl)-ethoxy___- 127 - This paper scale applies to Chinese national standards (CNS> A4 specification (210X297 public) 1328585 A7 B7
五、發明説明(124 基]-苯并呋喃-4-基}-丙烯酸乙酯作為原料,以得到成為白 色固體之2Z-異構物(0.61公克’ 97%)及成為白色固體之2e_ 異構物(48毫克,72%)。 j Z -異檨物的數墟: MS : (M-Η)· 432_3。 (液體石蠟):3 100-2500W, br. (COOH),1708s (C=0)。 NMR (CDC13,1H,(5, TMS) : 11 (s,非常寬,ΐΗ),7·99 (m, 3H), 7.66 (d, J=2.0, 1H), 7.47- 7.37 (m, 4H), 6.97 (d, J=2.0, 1H), 6.88 (d, J=8.8, 1H), 4.52 (t, J=6.4, 2H), 3.99- (q, J=7.2, 2H), 3.12 (t, J=6.4, 2H), 2.42 (s, 3H), 1.24 (t, J=7.2, 3H)。 2E-異構物的數猇: _ MS : (M-H)· 432.3。 1R(液體石蠟):3 100-2500w,br. (COOH), 1710s (〇0)。 NMR (DMSO-d6, 1H, δ , TMS) : 13.0 (s, 1H), 7.95 (d, J=2.0, 1H), 7.91 (m, 2H), 7.55-7.45 (m, 3H), 7.01 (d, J=8, 1H), 6.96 (d, J = 2.0, 1H), 6.88 (d, J=8, 1H), 6.17 (s, 1H), 4.39 (t, J=6.4, 2H), 3.95 (q, J=7.2, 2H), 3.00 (t, J=6.4, 2H), 2_38 (s, 3H).,1.32 (t, J=7.2, 3H)。 實例89, 90 i外消旋性卜2-乙氳某-3-(-7-丨2-(5-甲基-2-笨某-呤唑_ 4-基)-乙适某1-苽并咭喃-4-基丨-丙酸及ί外_消旋性卜7 - Λ氮 基-3-(7-『2-(5-甲某-2-芨某-口号唑-4-基)乙-氣某1-7夂二翁 苯并咭喃-4-某卜丙酸 __- 128 - 本紙張尺度適用中國國家標準(CMS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(125) 將在2毫升MeOH及2毫升CH2C12中的100毫克2Z-乙氧基-3_{7-[2-(5-甲基-2-苯基」呤唑-4-基)-乙氧基]-苯并呋喃-4-基丙埽酸及25毫克Pd/C( 10%)之懸浮液在22 °C /1巴下 經隔夜氫化。將懸浮液過濾,將過濾液蒸發,並將混合物 以製備性HPLC分離(RP-18,CH3CN/H20梯度),以得到[外 消旋性J - 2-乙氧基-3- { 7- [2-( 5-曱基-2-苯基-°号唑-4-基)乙 氧基]-2,3-二氫苯并呋喃-4-基}-丙酸(12.5毫克,12%)。 以第二個餾份包括成為白色固_體之[外消旋性卜2-乙氧基- 3- {7-[2-(5-甲基-2-苯基-哼唑-4-基)-乙氧基]-苯并呋喃- 4- 基}-丙酸(50毫克,50%) » f外消旋性1-2- Λ氣基-3-(7-『2-(5-甲基-2-苯某-啐唑-4-基) 乙乳基1-2,3 -二亂冬并p矢喃-4-基丨-丙酸的數據 MS : (M+H)+ 438.4 〇 IR(液體石蠟):3100-2500w,br. (COOH),1 736s 及 1716s (C = Ο)。 NMR (CDCI3,1Η,5, TMS) : 10 (s,非常寬,1Η),7·97 (m, 2H), 7.46- 7.36 (m, 3H), 6.72 (d, J=8.4, 1H), 6.66 (d, J=8.4, 1H), 4.61 (t, J=8.8, 2H), 4.29 (t, J=6.4, 2H), 4.04 (m, 1H), 3.57 (m, 1H), 3.42 (m, 1H), 3.21 (m, 2H), 3.06-2.97 (m, 3H), 2.88 (m,1H),2.36 (s,3H),1.16 (t, J=7.2, 3H) » f夕卜-消旋性1-2-乙氣某-3- (7-丨2-( 5-甲某-2-芡某-呤唑- 4-棊h乙氧羞1 -笨并咭喃-4-甚卜丙酸的數攄 MS : ( M+ H)+ 436.4 ° IR(液體石蠟):3 100-2500w,br. (CO〇H),1 733s, br. (C = _____- 129 -___ 本紙張尺度適用中國國家標竿(CNS) A4規格(210 x 297公釐) 1328585 A7 B7 五、發明説明(126 0)。 NMR (CDC13,1H,5, TMS) : 10 (s,非常寬,1H), 7.97 (m, 2H), 7.61 (d, J=2.0, 1H), 7.46- 7.36 (m, 3H), 7.00 (d, J-8, 1H), 6.85 (d, J=2.0, 1H), 6.76 (d, J=8, 1H), 4.43 (t, J=6.4, 2H), 4.11 (m, 1H), 3.52 (m, 1H), 3.40- 3.27 (m, 2H), 3.13 (m, 1H), 3.08 (t, J=6.4, 2H), 2.40 (s, 3H), l.l〇 (t, J=7.2, 3H) 〇 ’ 實例91 -- g丄4-(2-(茆滿-4-氣某)乙基5_甲某-2_茇其-喵〇也 將4.00公克甲烷磺酸2-(5-甲基-2-苯基-哼唑_4_基)乙能 [PCT Int. Appl.(2000) W00008002](14.22 毫莫耳)、2.00 公 克4-茆滿醇(14.93毫莫耳)及487.6毫克四丁基硫酸氫銨溶解 在65毫升甲笨中,並加熱至8〇它^接著緩慢加入 ΚΟΗ(10·66^升之2克分子量在h20中的溶液,21.33毫莫 耳)’維持在75- 80 C的溫度。將所得混合物在下揽拌4 小時。加入3 5毫升水,將混合物在80°c下再攪拌5分鐘,並 接著除去水相。將20毫升水加入甲苯相中,將混合物在8〇 C下攪摔5分鐘’並除去水相。將水相以二氣甲燒萃取3 次。將合併.的有機相經MgS〇4乾燥及蒸發,以供給成為標 色固體之4_90公克(1〇〇%)4-[2-(茚滿-4-氧基)乙基]· 5_甲 基-2-苯基-°号。坐。 _ MS : 3 19.2 (M)+,186.2 (M-茚滿醇)+。 NMR : (CDC13, 1H, δ , TMS, 300MHz)2.05 (quint., J=7 5 2H), 2.36 (s, 3H), 2.83 (t, J=7.5, 2H), 2.90 (t, J=7.5, 2H) ____- 130 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 ___B7 五、發明説明(127) 2.98 (t. J=6.5, 2H), 4.25 (t, J=6.5, 2H), 6.66 (d, J=7.5, 1H), 6.82 (d, J=7.5, 1H), 7.08 (t, J=8, 1H), 7.25-7.45 (m, 3H), 7.97 ( br d, J= 8,2H)。 kl.2-丨2-(5-甲棊-2-苯棊唑-4·某)Λ荦其i忒湍·4_斿趑 將4.00公克4-[2-(茚滿-4-氧基)乙基]·5_甲基-2-苯基-吟 哇(12.52毫莫耳)及2.29毫升二氯甲基甲醚(25.〇5毫莫耳)溶 解在300毫升二氣甲烷中。將該溶液冷卻至〇〇c,並緩慢加 入在75毫升二氣甲烷中的5毫兮四氯化鈦(44 69毫莫耳)。 將所得暗色溶液在0 °C下授拌3 0分鐘,並接著在〇 下緩慢 加入200毫升之IN HC1。將混合物在〇°c下攪拌3〇分鐘,將 兩相分離,並將水相以二氣甲烷清洗3次。將合併的有機相 經MgS〇4乾燥及蒸發’以供給4 · 5公克米黃色固體β以閃蒸 色層分離法(矽膠,環己烷/醋酸乙酯=9/ 1 ,接著以環己境/ 醋酸乙醋=4/1)最後留下成為米黃色晶體之2 96公克 (68%)7-[2-(5-甲基-2-苯基号唑_4-基)乙氧基]茚滿·4-羧 酸。 MS : 347.3 (Μ) + , 187.2 » NMR : (CDC13, 1Η,5, TMS,300MHz)2.12 (quint., J=7.5 2H), 2.39 (s, 3H), 2.82 (t, J=7.5, 2H), 3.02 (t, J=6.5, 2H) 3.28 (t, J=7.5, 2H), 4.35 (t, J=6.5, 2H), 6.81 (d, J=8.4, 7.43 (m, 3H), 7.62 (d, J=8.-5, 1H), 7.96-7.99 (m 2H), 9.98 (s,1H)。 5 cl 2Z-乙乳基- 3-{7-【2-(5-甲基-2-笨某-芊)乙氧..羡·丄 印滿-4 -基丨-丙烯酸乙g旨 -131 - -本故張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) " ------ 1328585 A7 B7 五、發明説明(128 將1.39公克7-[2-(5-甲基-2-苯基-呤唑-4·基)乙氧基]茚 滿-4-羧醛(4.00毫莫耳)及1.89公克氣化(乙氧基乙氧羰基甲 基)二苯鱗[Tetrahedron 50(25),7543- 56( 1994)](4.40 毫莫 耳)在氬氣下溶解在9毫升二氣甲烷/2_丙醇(ι/丨,體積/體積) 中。將該洛液冷卻至-1(TC,並加入855毫克碳酸鉀(6.00毫 莫耳)。將所得懸浮液授拌隔夜及允許達到室溫。加入額外 1.89公克氣化(乙氧基乙氧羰基甲基)三苯鋳(4·4〇毫莫耳), 將溶液冷卻至-1 〇°C,並加入S5〜5毫克碳酸鉀(6.00毫莫耳)。 將所得懸浮液攪拌60小時及允許達到室溫。再加入丨89公 克氣化(乙氧基乙氧羰基甲基)三笨鱗(44〇毫莫耳),將溶液 冷卻至-10°(:,並加入855毫克碳酸鉀(6,〇〇毫莫耳)。將所得 懸浮液揽掉隔夜及允許達到室溫。將混合物過滤,以二氣 甲烷清洗及蒸發過濾物。將殘餘物溶解在二氯甲烷中及以 食鹽水清洗。經硫3¾鎂乾燥’並蒸發溶劑’然後以閃蒸色 層分離法(矽膠,環己烷,接著以環己烷/醋酸乙酯=95/5, 接著以環己烷/醋酸乙酯=4/ 1)最後留下成為米黃色晶體之 1.215公克(65.8%)22-乙氧基-3-{7-[2-(5-曱基-2-苯基_。号 唑-4-基)乙氧基]茚滿-4-基}-丙晞酸乙酯。 MS : 461.2 (M) + , 186.1 〇 NMR : (CDC13, 1H, <5, TMS, 300MHz)1.33 (t, J=6.6, 3H), 1.36 (t, J=6.6, 3H), 2.07 (quint., J=7.5, 2H), 2.38 (s, 3H) 2.86 (t, J=7.5, 2H), 2.99 (t, J=6.9, 4H), 3.93 (q, J=7.i5 2H), 4.28 (q, J=7.2, 2H), 4.29 (t, J~7Hz, 2H), 6.73 (d, J=8.7, 1H), 7.05 (s, 1H), 7.39-7.46 (m, 3H), 7.96-7.99 (m, 2H), L.______- 132 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(129 8.05 (d, J=8.7, 1H)。 红1丨外消旋性1-2-乙氣基-'3- { 7·「2-(5-甲某-2-笨基-噚唑-4-基)乙氣某1茹滿-4-基卜丙酸乙酯 將250毫克Pd/C在氬氣下加入溶解在1〇毫升四氫呋喃中的 850毫克2Z-乙氧基-3 - {7-[2-(5-曱基-2-苯基号唑-4-基)乙 氧基]茚滿-4-基}-丙烯酸乙酯(1.84毫莫耳)中。接著以Η2代 替大氣,並將懸浮液在室溫的Η2氣壓下快速攪拌4小時。經 代卡利特(dicalite)過濾,並以_蒸發溶劑留下成為棕色油之 850毫克(99.6%)[外消旋性]-2-乙氧基-3-{7-[2-(5-甲基-2-苯基-σ咢唑-4-基)乙氧基]茚滿-4-基}-丙酸乙酯。 MS : 464·4 (Μ+Η)+。 NMR : (CDC13, 1H, δ, TMS, 300MHz)1.14 (t, J=6.9, 3H), 1.21 (t, J=7.1, 3H), 2.04 (quint., J=7.5, 2H), 2.38 (s, 3H), 2.84 (t, J=7.5, 2H), 2.95 (m, 6H), 3.32 (m, 1H), 3.56 (m, 1H), 3.95 (t, J=6.8, 1H), 4.15 (q, J=7.1, 2H), 4.22 (t, J=6.4, 2H), 6.61 (d, J=8.3, 1H), 6.95 (d, J=8.2, 1H), 7.40-7.46 (m, 3H), 7.96- 7.99 (m,2H)。 g_l f外戏性〗-2-乙氣某-3- {7-『2-(5-甲甚-2-笨基-p号吃-4- 基)乙乳基1 滿-4 -基丨-丙酸 將[外消旋性]-2-乙氧基-3- { 7- [2-( 5-甲基-2-苯基-3号唑-4-基)乙氧基]菲滿-4-基卜丙酸乙酯(85〇毫克,1 83毫莫耳) 落解在丨0爱升二呤烷中,接著在室溫下緩慢加入5毫升水及 LiOH(4_58毫升在水中的ιΝ溶液,4 58毫莫耳)。將所得混 合物在室溫下攪拌隔夜,並接著倒在冰上,以Ηα( 1N)中 二 133 本纸張尺度適用中國國家標準(CNS) A4規格(210X29·^公爱 1 1328585 A7 ____ _B7 五、發明説明(130) 和成pH4及以AcOEt萃取3次。將合併的有機相以水清洗, 經硫酸鎂乾燥及蒸發,以得到無色固體,將其在濕 磨丨5分鐘,過濾及乾燥,以產生成為無色晶體之47〇毫克 (58.9%)[外消旋性]-2-乙氧基-3_{7-[2_(5_甲基_2_苯基·^ 咬-4 -基)乙氧基]茚滿-4 -基}-丙酸。 MS : 434.4 (M-H)· » NMR ·· (CDC13, 1H, δ, TMS, 30〇MHz)1.14 (t, J=7, 3H), 2.04 (quint., J=7.4, 2H), 2.38-^, 3H), 2.84 (t, J-7.5, 2H), 2.88- 2.90 (m, 3H), 2.93 (t, 1=6.3, 2H), 3.01 (dxd, 1=4.8^9, 1H), 3.37 (m, 1H), 3.55 (m, ,H), 4.01 (dxd, 1=4.8^8.1, 1H), 4.21 (t, J=6.3, 2H), 6.62 (d, J=8.l, 1H), 6.98 (d, J=8丄 1H),7.39-7.46 (m,3H),7.95_ 7 98 (m, 2H),c〇〇H非, 常寬。 實例92 a] 4-「2-(t 甲暴乙氩某N5.6.7J-四葡 笨-1 -斿醛5. Description of the invention (124-)-benzofuran-4-yl}-ethyl acrylate as a starting material to obtain a 2Z-isomer as a white solid (0.61 g '97%) and 2e_isomeric as a white solid (48 mg, 72%). j Z - Number of isoforms: MS: (M-Η)· 432_3 (liquid paraffin): 3 100-2500W, br. (COOH), 1708s (C=0 NMR (CDC13, 1H, (5, TMS): 11 (s, very wide, ΐΗ), 7·99 (m, 3H), 7.66 (d, J=2.0, 1H), 7.47- 7.37 (m, 4H), 6.97 (d, J=2.0, 1H), 6.88 (d, J=8.8, 1H), 4.52 (t, J=6.4, 2H), 3.99- (q, J=7.2, 2H), 3.12 ( t, J=6.4, 2H), 2.42 (s, 3H), 1.24 (t, J=7.2, 3H). Number of 2E-isomers: _ MS : (MH)· 432.3. 1R (liquid paraffin) :3 100-2500w,br. (COOH), 1710s (〇0). NMR (DMSO-d6, 1H, δ, TMS) : 13.0 (s, 1H), 7.95 (d, J=2.0, 1H), 7.91 (m, 2H), 7.55-7.45 (m, 3H), 7.01 (d, J=8, 1H), 6.96 (d, J = 2.0, 1H), 6.88 (d, J=8, 1H), 6.17 ( s, 1H), 4.39 (t, J=6.4, 2H), 3.95 (q, J=7.2, 2H), 3.00 (t, J=6.4, 2H), 2_38 (s, 3H)., 1.32 (t, J = 7.2, 3H). Example 89, 90 i racemic buns 2-acetamidine -3-(-7-丨2-(5-methyl-2- benzo-carbazole-4-yl)-ethyl benzoyl 1-indeno-pyran-4-yl hydrazine-propionic acid Racemic Bu 7 - Indolyl-3-(7-"2-(5-methyl-2-pyrene-o-oxazol-4-yl)---a certain 1-7夂di-benzopyran -4-A certain propionic acid __- 128 - This paper size applies to Chinese National Standard (CMS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (125) will be in 2 ml of MeOH and 2 ml of CH2C12 100 mg of 2Z-ethoxy-3_{7-[2-(5-methyl-2-phenyl"oxazol-4-yl)-ethoxy]-benzofuran-4-ylpropanoid A suspension of acid and 25 mg Pd/C (10%) was hydrogenated overnight at 22 °C / 1 bar. The suspension was filtered, the filtrate was evaporated, and the mixture was purified by preparative HPLC (EtOAc, EtOAc, EtOAc (EtOAc) 2-( 5-Mercapto-2-phenyl-°oxazol-4-yl)ethoxy]-2,3-dihydrobenzofuran-4-yl}-propionic acid (12.5 mg, 12%) . In the second fraction, it is included as a white solid [racemic 2-ethoxy-3-(7-[2-(5-methyl-2-phenyl-oxazol-4-yl) )-Ethoxy]-benzofuran-4-yl}-propionic acid (50 mg, 50%) » f racemic 1-2-fluorenyl-3-(7-『2-(5- Methyl-2-phenyl-oxazol-4-yl) Ethyl lactate 1-2,3 - 2 chaotic winter p-Pan-4-ylindole-propionic acid data MS: (M+H)+ 438.4 〇IR (liquid paraffin): 3100-2500w, br. (COOH), 1 736s and 1716s (C = Ο). NMR (CDCI3,1Η,5, TMS) : 10 (s, very wide, 1Η), 7· 97 (m, 2H), 7.46- 7.36 (m, 3H), 6.72 (d, J=8.4, 1H), 6.66 (d, J=8.4, 1H), 4.61 (t, J=8.8, 2H), 4.29 (t, J=6.4, 2H), 4.04 (m, 1H), 3.57 (m, 1H), 3.42 (m, 1H), 3.21 (m, 2H), 3.06-2.97 (m, 3H), 2.88 (m ,1H), 2.36 (s,3H), 1.16 (t, J=7.2, 3H) » f 卜卜-racemic 1-2-ethane -3- (7-丨2-( 5-A) -2- 芡 呤 - oxazole - 4- 棊 h ethoxy group 1 - 笨 咭 咭 甚 甚 甚 甚 甚 摅 MS : ( M + H) + 436.4 ° IR (liquid paraffin): 3 100- 2500w,br. (CO〇H),1 733s, br. (C = _____- 129 -___ This paper scale applies to China National Standard (CNS) A4 Specifications (210 x 297 mm) 1328585 A7 B7 V. Description of invention (126 0) NMR (CDC13, 1H, 5, TMS): 10 (s, very wide, 1H), 7.97 (m, 2H), 7.61 ( d, J=2.0, 1H), 7.46- 7.36 (m, 3H), 7.00 (d, J-8, 1H), 6.85 (d, J=2.0, 1H), 6.76 (d, J=8, 1H) , 4.43 (t, J=6.4, 2H), 4.11 (m, 1H), 3.52 (m, 1H), 3.40- 3.27 (m, 2H), 3.13 (m, 1H), 3.08 (t, J=6.4, 2H), 2.40 (s, 3H), ll〇(t, J=7.2, 3H) 〇' Example 91 -- g丄4-(2-(茆满-4-气某)ethyl 5_甲某- 2_茇其-喵〇 will also be 4.00 grams of 2-(5-methyl-2-phenyl-carbazole-4-yl) methanesulfonate [PCT Int. Appl. (2000) W00008002] (14.22 mil Mohr), 2.00 g of 4-indanol (14.93 mmol) and 487.6 mg of tetrabutylammonium hydrogen sulfate dissolved in 65 ml of stupid and heated to 8 〇 it then slowly added ΚΟΗ (10·66^ A solution of 2 grams of molecular weight in h20, 21.33 millimolar) was maintained at a temperature of 75-80 C. The resulting mixture was stirred for 4 hours. 35 ml of water was added, and the mixture was further stirred at 80 ° C for 5 minutes, and then the aqueous phase was removed. 20 ml of water was added to the toluene phase, and the mixture was stirred at 8 ° C for 5 minutes' and the aqueous phase was removed. The aqueous phase was extracted 3 times with two gas. The combined organic phase was dried and evaporated by MgS〇4 to supply 4 to 90 g (1%) of 4-[2-(indan-4-yloxy)ethyl]·5_A as a color solid. Base-2-phenyl-°. sit. _ MS : 3 19.2 (M)+, 186.2 (M-indanol)+. NMR : (CDC13, 1H, δ, TMS, 300MHz) 2.05 (quint., J=7 5 2H), 2.36 (s, 3H), 2.83 (t, J=7.5, 2H), 2.90 (t, J=7.5 , 2H) ____- 130 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 ___B7 V. Invention description (127) 2.98 (t. J=6.5, 2H), 4.25 ( t, J=6.5, 2H), 6.66 (d, J=7.5, 1H), 6.82 (d, J=7.5, 1H), 7.08 (t, J=8, 1H), 7.25-7.45 (m, 3H) , 7.97 ( br d, J= 8,2H). Kl.2-丨2-(5-formaldehyde-2-benzoxazole-4·m) Λ荦其忒湍i44_斿趑 4.00 g 4-[2-(indan-4-ol) Ethyl]·5-methyl-2-phenyl-anthracene (12.52 mmol) and 2.29 ml of dichloromethyl methyl ether (25. 5 mmol) were dissolved in 300 ml of di-methane. The solution was cooled to 〇〇c and 5 mmol of titanium tetrachloride (44 69 mmol) in 75 ml of di-methane was slowly added. The resulting dark solution was stirred at 0 °C for 30 minutes, and then 200 mL of IN HC1 was slowly added under the sputum. The mixture was stirred at 〇 °c for 3 , minutes, the two phases were separated, and the aqueous phase was washed 3 times with di-methane. The combined organic phases were dried and evaporated by MgS 4 to provide 4 · 5 g of a beige solid β as a flash chromatographic separation method (silicone, cyclohexane / ethyl acetate = 9 / 1 , followed by cyclohexane) / Acetate acetate = 4 / 1) Finally left as a beige crystal 2 96 grams (68%) 7-[2-(5-methyl-2-phenyloxazole-4-yl)ethoxy] Indane·4-carboxylic acid. MS : 347.3 (Μ) + , 187.2 » NMR : (CDC13, 1Η, 5, TMS, 300MHz) 2.12 (quint., J=7.5 2H), 2.39 (s, 3H), 2.82 (t, J=7.5, 2H ), 3.02 (t, J=6.5, 2H) 3.28 (t, J=7.5, 2H), 4.35 (t, J=6.5, 2H), 6.81 (d, J=8.4, 7.43 (m, 3H), 7.62 (d, J=8.-5, 1H), 7.96-7.99 (m 2H), 9.98 (s, 1H). 5 cl 2Z-ethyl lactyl- 3-{7-[2-(5-methyl- 2-笨某-芊)Ethoxy..羡·丄印满-4 -基丨-Acrylic acid g--131 - -The original Zhang scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) " ------ 1328585 A7 B7 V. Description of the invention (128 will 1.39 grams of 7-[2-(5-methyl-2-phenyl-indazol-4)yl)ethoxy] 4-Carboxaldehyde (4.00 mmol) and 1.89 g of gasified (ethoxyethoxycarbonylmethyl) diphenyl scale [Tetrahedron 50 (25), 7543-56 (1994)] (4.40 mmol) in argon Dissolve in 9 ml of di-methane methane / 2 -propanol (ι / 丨, volume / volume). Cool the solution to -1 (TC, and add 855 mg of potassium carbonate (6.00 mmol). The resulting suspension was stirred overnight and allowed to reach room temperature. An additional 1.89 g of gasification (ethoxyethoxycarbonyl) was added. Triphenyl hydrazine (4·4 〇 millimolar), the solution was cooled to -1 〇 ° C, and S5~5 mg potassium carbonate (6.00 mmol) was added. The resulting suspension was stirred for 60 hours and allowed to reach At room temperature, add 89 g of gasification (ethoxyethoxycarbonylmethyl) to three scales (44 〇 millimolar), and cool the solution to -10 ° (:, and add 855 mg of potassium carbonate (6, The resulting suspension was taken up overnight and allowed to reach room temperature. The mixture was filtered, washed with di-methane and evaporated. The residue was dissolved in dichloromethane and washed with brine. Sulfur 33⁄4 magnesium was dried 'and the solvent was evaporated' and then flash chromatographic separation (silica gel, cyclohexane followed by cyclohexane / ethyl acetate = 95/5, followed by cyclohexane / ethyl acetate = 4 / 1) Finally, 1.215 g (65.8%) of 22-ethoxy-3-{7-[2-(5-fluorenyl-2-phenyl-.oxazol-4-yl)-B was obtained as a beige crystal. Ethyloxy]indan-4-yl}-propionate ethyl ester MS: 461.2 (M) + , 186.1 NMR: (CDC13, 1H, <5, TMS, 300 MHz) 1.33 (t, J = 6.6, 3H), 1.36 (t, J=6.6, 3H), 2.07 (quint., J=7.5, 2H), 2.38 (s, 3H) 2.86 (t, J=7.5, 2H), 2.99 (t, J=6.9, 4H), 3.93 (q, J=7.i5 2H), 4.28 (q, J=7.2 , 2H), 4.29 (t, J~7Hz, 2H), 6.73 (d, J=8.7, 1H), 7.05 (s, 1H), 7.39-7.46 (m, 3H), 7.96-7.99 (m, 2H) , L.______- 132 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (129 8.05 (d, J=8.7, 1H). Red 1丨 racemic 1-2-ethane group-'3-{7·"2-(5-methyl-2-phenyl-oxazol-4-yl)ethane gas 1 - ethyl bromopropionate 250 mg of Pd/C was added under argon to 850 mg of 2Z-ethoxy-3 - {7-[2-(5-mercapto-2-) dissolved in 1 ml of tetrahydrofuran Phenyloxazol-4-yl)ethoxy]indol-4-yl}-ethyl acrylate (1.84 mmol). The atmosphere was replaced by Η2, and the suspension was rapidly dried at room temperature Η2 atmosphere. Stir for 4 hours, filter through dicalite, and evaporate the solvent to leave 850 mg (99.6%) as a brown oil [racemic]-2-ethoxy-3-{7-[ Ethyl 2-(5-methyl-2-phenyl-σoxazol-4-yl)ethoxy]indan-4-yl}-propanoate MS: 464·4 (Μ+Η)+. NMR : (CDC13, 1H, δ, TMS, 300MHz) 1.14 (t, J=6.9, 3H), 1.21 (t, J=7.1, 3H), 2.04 (quint., J=7.5, 2H), 2.38 (s , 3H), 2.84 (t, J=7.5, 2H), 2.95 (m, 6H), 3.32 (m, 1H), 3.56 (m, 1H), 3.95 (t, J=6.8, 1H), 4.15 (q , J=7.1, 2H), 4.22 (t, J=6.4, 2H), 6.61 (d, J=8.3, 1H), 6.95 (d, J=8.2, 1H), 7.40-7.46 (m, 3H), 7.96- 7.99 (m, 2H). g_l f external play〗 -2- -3- {7-『2-(5-甲其-2-基基-p号吃-4-yl)ethyl lactyl 1 full-4 -ylindole-propionic acid [racemic]-2 -ethoxy-3-{ 7- [2-( 5-methyl-2-phenyl-3-oxazol-4-yl)ethoxy]phenanthyl-4-ylpropanoate (85〇 Milligram, 1 83 mmol.) Dissolve in 丨0 liters of dioxane, then slowly add 5 ml of water and LiOH (4_58 ml of ι solution in water, 4 58 mmol) at room temperature. The mixture was stirred overnight at room temperature and then poured onto ice to obtain the Chinese National Standard (CNS) A4 specification in Ηα( 1N) 133 paper scales (210X29·^公爱1 1328585 A7 ____ _B7 V. Invention Description (130) and pH 4 and extraction with AcOEt 3 times. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give a colorless solid, which was then wet-purified for 5 min, filtered and dried to give 47〇mg (58.9%) [racemic]-2-ethoxy-3_{7-[2_(5_methyl_2_phenyl·^ bit-4-yl) ethoxylate as a colorless crystal Base] indole-4 -yl}-propionic acid. MS : 434.4 (MH)· » NMR ·· (CDC13, 1H, δ, TMS, 30〇MHz) 1.14 (t, J=7, 3H), 2.04 (quint., J=7.4, 2H), 2.38-^ , 3H), 2.84 (t, J-7.5, 2H), 2.88- 2.90 (m, 3H), 2.93 (t, 1=6.3, 2H), 3.01 (dxd, 1=4.8^9, 1H), 3.37 ( m, 1H), 3.55 (m, ,H), 4.01 (dxd, 1=4.8^8.1, 1H), 4.21 (t, J=6.3, 2H), 6.62 (d, J=8.l, 1H), 6.98 (d, J=8丄1H), 7.39-7.46 (m, 3H), 7.95_ 7 98 (m, 2H), c〇〇H non, always wide. Example 92 a] 4-"2-(t A violent argon argon N5.6.7J-four-bank stupid-1 - furfural
在類似於實例9U]及b]說明的步驟中,將5,6 7 8·四氫莕_ 卜醇與甲烷磺酸2-(5-甲基-2-苯基号唑_4_基)乙酯[pcTIn a procedure similar to that described in Examples 9U] and b], 5,6 7 8·tetrahydroindole-bupropanol and methanesulfonic acid 2-(5-methyl-2-phenyloxazole-4-yl) Ethyl ester [pcT
Int. Appl.(2000) W00008002]反應,以得到 5 曱基·2_苯基_ 4-[2-(5,6,7,8-四氫莕-1-氧基)乙基]。号唑。以二氯甲基甲醚 及四氣化鈦處理5-甲基-2-苯基_4-[2·(5,6,7,8-四氫莕-1-氧 基)乙基]噚唑,接著得到成為黃色固體之4 [2 (5•甲基_2_ 苯基·》咢唑-4-基)乙氧基]· 5,6 7 8·四氫茬卜羧醛。 MS : 361 ·2 (Μ) +,186.2。 ---—-134 - 本纸張尺度適用中國國家標準(CNS) Α4規格(210 X 297公爱) % 訂Int. Appl. (2000) W00008002] Reaction to give 5 mercapto-2-phenyl-2-[2-(5,6,7,8-tetrahydroindol-1-oxy)ethyl]. No. azole. Treatment of 5-methyl-2-phenyl_4-[2·(5,6,7,8-tetrahydroindol-1-oxy)ethyl]anthracene with dichloromethyl methyl ether and titanium tetra-titanate The azole is then obtained as a yellow solid 4 [2 (5•methyl-2-phenyl)-oxazol-4-yl)ethoxy] 5,6 7 8·tetrahydroindole. MS: 361 · 2 (Μ) +, 186.2. -----134 - This paper size applies to China National Standard (CNS) Α4 specifications (210 X 297 public) %
線 1328585 A7Line 1328585 A7
NMR : (CDC13, ιΗ ,0,丁MS, 300MHz) 1 76 “ (s,3H), 2.63 (br,2H . . 6 (br,4H),2.3ί 3.02 (t,J=6.5,2H) i , 4.32 (t, J=6.5, 2H), 6 Rn r a t ,3·17 (br,2H) °-80 (d, J=8.5, 1H), 7 4〇 7^ . 7·62(^8·5,1Η),7 95 _ · ·4 (m,3H) 某-2·, (S,1H) 某1-5.6,7,8 -四爵 14·,甘、 -丙烯酸乙酯 在類似於實例9 1 ci今nH t CJ說明的步驟中,將4_丨 基-呤唑-4-基)乙氧基 -曱基-2. 基乙氧羰基曱基)久处與虱化(乙 本鱗反應,以得到成為米黃色 2Z-乙氧基-3-{4-Γ2 r^ 只巴固體 l2-(5_f基_2•苯基·呤唑 5,6,7,8·四氫茶]-基卜丙埽酸乙醋。 乳基 MS : 476.2 (M+H)+。 NMR : (CDC13, 1H, TMS> 3〇〇MHz)1.27 (t> j=7 1? 3H 1.35 〇’ J=7.1,3H), h76 (br,4H),2 38 (s,3h),2 J=5.8, 2H)’ 2.75 (t,J=5.8, 2H),2 99 (t,J=6 4, 2h),3 ^ J=7.0, 2H), 4.28 (m, 4H), 6.71 (d, J=8.7, lH), 7.18 (s, iH 7.39- 7.46 (m, 3H), 7.90 (d, J=8.7, 1H), 7.96-7.99 (, 2H)。 c][外消旋性卜2-乙ϋ-3-Μ·「2·(5_甲基-2_笨某峄地j 基)乙氣基卜5,6,7,8-四‘奇笨-ΐ·某丨-丙酸 在類似於實例9 1 d]及e]說明的步驟中,將2Ζ-乙氧基_3_ {4·[2-(5-甲基-2-苯基-哼唑-4-基)乙氧基]_5,6,7,8_四氫 某-1 -基}-丙晞酸乙g旨氫化,以得到[外消旋性]-2-乙氧基· 3- {4-[2-(5-甲基-2-笨基-呤唑-4-基)乙氧基]-5,6,7,8-四氫 ___- 135 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)NMR: (CDC13, ιΗ, 0, D, MS, 300MHz) 1 76 "(s,3H), 2.63 (br,2H . . 6 (br,4H),2.3ί 3.02 (t,J=6.5,2H) i , 4.32 (t, J=6.5, 2H), 6 Rn rat , 3·17 (br, 2H) °-80 (d, J=8.5, 1H), 7 4〇7^ . 7·62(^8· 5,1Η),7 95 _ · ·4 (m,3H) Some-2·, (S,1H) Some 1-5.6,7,8 - four-story 14·, Gan,-Acrylic acid ethyl ester is similar to the example 9 1 ci present nH t CJ in the step described, 4_mercapto-oxazol-4-yl)ethoxy-indenyl-2.ylethoxycarbonyl fluorenyl) long-term and sputum The reaction is carried out to obtain beige 2Z-ethoxy-3-{4-Γ2 r^ only solid l2-(5_f-based 2•phenyl-carbazole 5,6,7,8·tetrahydro tea]- Ethyl propyl acetoacetate. Milk-based MS: 476.2 (M+H)+ NMR: (CDC13, 1H, TMS > 3〇〇MHz) 1.27 (t> j=7 1? 3H 1.35 〇' J=7.1,3H ), h76 (br,4H),2 38 (s,3h),2 J=5.8, 2H)' 2.75 (t,J=5.8, 2H), 2 99 (t,J=6 4, 2h),3 ^ J=7.0, 2H), 4.28 (m, 4H), 6.71 (d, J=8.7, lH), 7.18 (s, iH 7.39- 7.46 (m, 3H), 7.90 (d, J=8.7, 1H) , 7.96-7.99 (, 2H). c] [racemicity 2-2-ϋ-3-Μ·"2·(5_基-2_笨某峄地j基)乙气基卜 5,6,7,8-四'奇笨-ΐ·丨-propionic acid in a procedure similar to that described in Example 9 1 d] and e] , 2Ζ-ethoxy_3_ {4·[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]_5,6,7,8-tetrahydro-1 -yl}-propionic acid ethyl ethane is hydrogenated to give [racemic]-2-ethoxy-3-(4-[2-(5-methyl-2-phenyl-carbazole-4) -yl)ethoxy]-5,6,7,8-tetrahydro___- 135 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)
裝 ··· 訂Pack ··· order
線 1328585 A7 B7 五、發明説明(132) 茶-1 -基}-丙酸乙酯》接著將[外消旋性]-2-乙氧基-3- { 4-[2-(5-甲基-2-苯基号吐-4-基)乙氧基]-5,6,7,8-四氫苔-卜 基}-丙酸乙酯皂化成無色晶體之[外消旋性]-2-乙氧基-3-{4-[2-(5-甲基2-苯基-o号。圭-4-基)乙氧基]-5,6,7,8-四氫 茶- l-基}••丙酸。 MS : 450.4 (M+H)+。 NMR : (CDC13) 1H, δ , TMS, 300MHz)1.12 (t, J=6.9, 3H), 1.74 (br, 4H), 2.37 (s, 3H), 2.62 (br, 2H), 2.72 (br, 2H), 2.89 (dxd, J=14.4, 8.7, 1H), 2.98 (t, J=6, 2H), 3.05 (dxd, J=14.4, 4.2, 1H), 3.31 (quasi-quint, J~7, 1H), 3.52 (quasi-quint, J〜7,1H), 3.98 (dxd, J=8.7, 4.2,1H), 4.19 (t, J=6.3, 2H), 6.63 (d, J=8.1, 1H), 6.98 (d, J=8.4, 1H), 7.39-7.46 (m, 3H),7.96-7.99 (m,2H),COOH非常寬。 實例93 a] ( 3-(4·芊氧基笨并Γί>1»实吟-7_某)-2ΓΖ.Ε)-乙氳甚1¾蜂紿 乙酯 將0.53 7公克(2.00毫莫耳)4-芊氧基苯并[bp塞吩-7-羧醛 [Ger. Offen.( 1998) DE 19711617 A1]在氬氣下溶解在 15毫 升2-丙醇中.β在冷卻至-20C之後’加入0.944公克(2 20毫 莫耳)氣化(乙氧基乙氧羰基曱基)三苯鱗[Tetrahedr〇n 50( 25),7543-56( 1994)]及0·4丨5公克(3.00毫莫耳)無水碳酸 鉀。將所得懸浮液在冰浴中攪拌’並允許達到室溫及在室 溫下攪拌隔夜。如上述在-20°C下進行第二次加入等量的 Witting試劑及碳酸鉀。在過濾及溶劑蒸發之後,將殘餘物 -136 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公爱) ' -- 1328585 A7 B7 以閃,务色層;7離法(石夕勝從w之己坡/Et〇Ac)純 化瑕後田下成為漫黃色油之0.586公克(77%)( 3-(4-节氧 基苯并·7.基)_2(Z e)乙氧基丙缔酸乙醋。 MS: 382.2 (M) + ,29l2 i89i〇 NMR . (CDC13, 1H, TMSi 3〇〇MHz)1.36 (t, J=7, 3H), 140 〇’ 卜7’ 3H)’ 4·〇1 (q,J=7, 2H), 4.34 (q,J=7, 2H),Line 1328085 A7 B7 V. Description of the invention (132) Tea-1 -yl}-ethyl propionate followed by [racemic]-2-ethoxy-3-{4-[2-(5-A) Saponification of ethyl-2-phenyl oxime-4-yl)ethoxy]-5,6,7,8-tetrahydrosol-buki}-propionate into colorless crystals [racemic]- 2-Ethoxy-3-{4-[2-(5-methyl 2-phenyl-o. g--4-yl)ethoxy]-5,6,7,8-tetrahydro tea- L-based}••propionic acid. MS: 450.4 (M+H)+. NMR : (CDC13) 1H, δ , TMS, 300MHz) 1.12 (t, J=6.9, 3H), 1.74 (br, 4H), 2.37 (s, 3H), 2.62 (br, 2H), 2.72 (br, 2H) ), 2.89 (dxd, J=14.4, 8.7, 1H), 2.98 (t, J=6, 2H), 3.05 (dxd, J=14.4, 4.2, 1H), 3.31 (quasi-quint, J~7, 1H) ), 3.52 (quasi-quint, J~7,1H), 3.98 (dxd, J=8.7, 4.2,1H), 4.19 (t, J=6.3, 2H), 6.63 (d, J=8.1, 1H), 6.98 (d, J=8.4, 1H), 7.39-7.46 (m, 3H), 7.96-7.99 (m, 2H), COOH is very broad. Example 93 a] ( 3-(4·芊 笨 笨 Γ & & & 1 1 1 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Ε 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 4-decyloxybenzo[bp-sept-7-carboxaldehyde [Ger. Offen. (1998) DE 19711617 A1] dissolved in 15 ml of 2-propanol under argon. β after cooling to -20 C' Add 0.944 g (2 20 mmol) of gasified (ethoxyethoxycarbonyl fluorenyl) triphenyl scale [Tetrahedr〇n 50 (25), 7543-56 (1994)] and 0.44 丨 5 g (3.00) Millions of anhydrous potassium carbonate. The resulting suspension was stirred in an ice bath' and allowed to reach room temperature and stirred at room temperature overnight. A second addition of the Witting reagent and potassium carbonate was carried out a second time at -20 ° C as described above. After filtration and evaporation of the solvent, the residue -136 - the paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 public) ' -- 1328585 A7 B7 to flash, color layer; 7 away from the law (Shi Xisheng Purification of yttrium from the sloping/Et〇Ac) to 0.586 g (77%) of a diffuse yellow oil (3-(4-ethoxybenzobenzo-7.)_2(Z e) ethoxy propyl Acetate vinegar MS: 382.2 (M) + , 29l2 i89i NMR . (CDC13, 1H, TMSi 3〇〇MHz) 1.36 (t, J=7, 3H), 140 〇' Bu 7' 3H)' 4 ·〇1 (q, J=7, 2H), 4.34 (q, J=7, 2H),
)_26 (S. 2H)’ 6.88 (d,J=8, 1H),7.23 (s,1H),7.35- 7.45 (m, 4H), 7·)〇 (m,2H),7·59 (d,1H),8.19 (d,1=8, 1H)。 bl [.外—旋性氡某装〜并rbl4吩·7·某)·2_乙氩基 丙酸甲酯 將〇·383公克(1.00毫莫耳)(3-(4-芊氧基苯并[b]嘧吩-7-基)-2(Z’E)-乙氧基丙烯酸乙酯在氬氣下溶解在2〇毫升 THF/MeOH(l:l)中。加入〇 248公克(1〇2毫莫耳)鎂,並接 訂)_26 (S. 2H)' 6.88 (d, J=8, 1H), 7.23 (s, 1H), 7.35- 7.45 (m, 4H), 7·) 〇 (m, 2H), 7·59 (d , 1H), 8.19 (d, 1 = 8, 1H). Bl [.external-spinning 氡 some loading ~ and rbl4 phen·7·some) · 2_ethyl ethionyl propionate 〇·383 g (1.00 mmol) (3-(4-decyloxybenzene) And [b] thiophen-7-yl)-2(Z'E)-ethoxy acrylate was dissolved in 2 mL of THF/MeOH (1:1) under argon. Add 〇248 g (1) 〇 2 millimoles of magnesium, and ordered
著將反應混合物溫熱至5(rc。在3〇分鐘之後,將其冷卻至 至溫及在至溫下攪拌隔夜。在25<3(:下加入額外5毫升hci(在 水中的25%)之後’將反應混合物劇烈攪拌卜】、時,接著以 EtOAc萃取(二次);將有機相以食鹽水清洗,經MgS〇4乾 燥’過滤及蒸發《以閃蒸色層分離法(矽膠,從9:丨至4:〗之 己燒/EtOAc)純化黃色油,以供給成為黃色油之〇 366公克 (99%)[外消旋性]_3_(4·芊氧基苯并[b]喵吩-7·基)_2_乙氧 基丙酸甲酯。 _ MS : 370.1 (M) + , 3 1 1.2, 253.1 » NMR : (CDCI3, 1H, δ , TMS, 300MHz)1.13 (t, J=8, 3H), 3.23 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.70 (s, 3H), _____- 137 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 134 B7 五、發明説明(The reaction mixture was warmed to 5 (rc. After 3 min, it was cooled to warmness and stirred overnight at ambient temperature. Add 5 ml of hci (25% in water) at 25 <3 (:) Afterwards, the reaction mixture was vigorously stirred. Then, it was extracted with EtOAc (secondary); the organic phase was washed with brine, dried over MgS 4 and filtered and evaporated. 9: 丨 to 4: 〗 hexanes / EtOAc) Purified yellow oil to supply 366 g (99%) of yttrium as a yellow oil [racemic] _3_(4·芊 oxybenzo[b] porphin -7·yl)_2_ethoxypropionic acid methyl ester. _ MS : 370.1 (M) + , 3 1 1.2, 253.1 » NMR : (CDCI3, 1H, δ , TMS, 300MHz) 1.13 (t, J=8 , 3H), 3.23 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.70 (s, 3H), _____- 137 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 134 B7 V. Description of invention (
4.24 (m,1H),5.21 (s 2H、A ,2Η),6·78 (d,J = 9, 1H),7.13 (d,J=9, H),7 38- 7 48 (m,6H),W(d,>6,1H)。 c] L外消旋性1 -2 - λ氧其W/1,朴 _ 〖bh塞吩-7-某)兩醢 ϋι - ^4.68^(12.6^莫耳)[外消旋性]3(m基苯㈣ 古7 土)2乙氧基丙酸甲酯在氬氣及室溫下溶解在I” 升CH2C12巾逐滴加入23 9毫升二甲硫及^ 毫升三乳 朋乙謎纟室溫下攪拌5小〜時之後,將反應混合物以倒 在碎冰水上中止’接著以CHaCI〗萃取三次。將有機相以食 ^水清洗,經MgS〇4乾燥,㈣及蒸發,以供給(92公克 只色油以閃蒸色層分離法(石夕膠己烷、cH2Cl2及Me〇H) 屯化〃得到成為&黃色固體之3..5 1公克(99%)[外消旋 ]2乙氧基3 (4 -芊氧基苯并[b]B墓吩_7_基)丙酸甲酯。 MS _· 279.1 (M-Η).。 NMR : (CDC13, 1H, TMS, 300MHz)1.13 (t, J=7, 3H), 3.22 (m, 2H), 3.35 (m, iH), 3.61 (m, 1H), 3.71 (s, 3H), 4.24 (m, 1H), 5.32 (s, 1H), 6.66 (d, J=8, 1H), 7.07 (d, J=8, 1H), 7.35 (d, J=5, 1H), 7.48 (d, J=5, 1H) » d] 1~^消旋性卜3-(4-{_2-[2-(4-漸苽某)-5-甲某噚唑-4-甚1 氧基}笨并丨bh裳吩-7·某)· 2-乙氣某丙醴 在類似於實例1 7a]說明的步驟中,將[外消旋性]_ 2_乙氧 基-3- (4-羥基苯并[b]4吩-7-基)丙酸甲酯與2- [2-(4-氯笨 基)-5-甲基》号吐-4-基]乙醇(以類似於在實例2丨a)至2 1 e]說 明的順序’以4-氣基苯醛轉化成2-[ 2-(4-氣苯基)-5-甲基》等 _____- 138 - 本纸乐尺度適用中國國家標準(CNS)A4規格(210X297公釐) 1328585 A7 B7 五、發明説明( 135 峻-4-基]乙醇所製得的)在三苯膦及dead(偶氮二羧酸二乙 酯)的存在下反應,以產生[外消旋性]_ 3 _ ( 4_丨2_ [ 2· ( 4氯笨 基)〇-甲基p亏唑-4-基]乙氧基}苯并[b] β塞吩_7_基)·2_乙氧 基丙魬甲酯,將其以類似於實例9 1 e]說明的步驟進一步皂 化’以產生成為淺黃色固體之[外消旋性卜3_(4·{2_[2·(4_ 氣+ f )-5-曱基》号唑-4-基]乙氧基}苯并[b]噻吩· 7_基 乙氧基丙酸。 MS : 484,3 (M-H)·,438.3。-〜 NMR · (CDC13, 1H, δ , TMS, 300MHz)1.09 (t, J=7, 3H), 2.39 (s, 3H), 3.06 (t, J=6, 2H), 3.18 (m, 1H), 3.28-3.43 (m, 2H), 3.50- 3.63 (m, 1H), 4.20-4.29 (d, J=5, 1H), 4.35 (t, J = 6, 2H), 6.74 (d, J=8, 1H), 7.11-7.24 (m, 3H), 7.32 (d, J=6, 1H), 7.47 (d, J=6, 1H), 7.88 (d, J=9, 2H), COOH# f見0 實例94 I.外.乳1性卜2- 基-3·(4·{2]?-(4-氣茇甚甲篡喝 嗑_..4H乙氧基}差_并f bh裳吩-7-其、石始 在類似於實例17a]說明的步驟中,將[外消旋性卜2_乙氧 基-3-(4-羥基苯并[13]嘧吩-7-基)丙酸甲酯與2_[2_(4_氟笨 基)-5-甲基呤唑-4-基]乙醇[j_ Med. Chem ( 1998),41(⑼, 5037- 5054]在三苯膦及DEAD(偶氮二羧酸二乙酯)的存在下 反應,以產生[外消旋性]-3-(4-{2-[2·(4-氟苯基)·5·甲基 吟唑-4-基]乙氧基}苯幷[b]嘍吩_7-基)2乙氧基丙酸甲 酯,將其以類似於實例9丨e]說明的步騾進一步皂化,以產4.24 (m,1H), 5.21 (s 2H, A, 2Η), 6.78 (d, J = 9, 1H), 7.13 (d, J=9, H), 7 38- 7 48 (m, 6H ), W(d, >6, 1H). c] L racemate 1 -2 - λ oxygen, its W/1, Pak _ 〖bh thiophene-7-some) two 醢ϋι - ^4.68^(12.6^莫耳)[racemic]3( M-based benzene (tetra) ancient 7 soil) 2 ethoxypropionate methyl ester dissolved in argon and room temperature in I liter CH2C12 towel drop added 23 9 ml dimethyl sulfide and ^ ml three nipples puzzle 纟 room temperature After stirring for 5 hours, the reaction mixture was stopped by pouring on crushed ice water and then extracted three times with CHaCI. The organic phase was washed with water, dried with MgS 4, (iv) and evaporated to supply (92 g). The color oil was purified by flash chromatography (Shixi gum, cH2Cl2 and Me〇H) to give a <yellow solid of 3..5 1 g (99%) [racemic] 2 Methyl 3-(4-methoxybenzo[b]B-tomb-7-yl)propionic acid methyl ester. MS _· 279.1 (M-Η). NMR : (CDC13, 1H, TMS, 300MHz) 1.13 (t, J=7, 3H), 3.22 (m, 2H), 3.35 (m, iH), 3.61 (m, 1H), 3.71 (s, 3H), 4.24 (m, 1H), 5.32 (s, 1H ), 6.66 (d, J=8, 1H), 7.07 (d, J=8, 1H), 7.35 (d, J=5, 1H), 7.48 (d, J=5, 1H) » d] 1~ ^ Racemic Bu 3-(4-{_2-[2-(4- 苽 ))-5-methyl oxazole-4-even 1 oxy} stupid 丨bh吩-7·某)· 2-Ethene a certain propionate in a procedure similar to that described in Example 1 7a], [racemic] _ 2_ethoxy-3-(4-hydroxybenzo[b] 4 phen-7-yl)methyl propionate with 2-[2-(4-chlorophenyl)-5-methyl" ox-4-yl]ethanol (similar to in Example 2 丨a) to 2 1 e] Description of the sequence 'conversion of 4-vaporaldehyde to 2-[2-(4-phenylphenyl)-5-methyl", etc. _____- 138 - This paper scale applies to Chinese national standards ( CNS) A4 size (210X297 mm) 1328585 A7 B7 V. Description of the invention (135 gram-4-yl) ethanol prepared in the presence of triphenylphosphine and dead (diazo azodicarboxylate) To produce [racemate]_ 3 _ ( 4_丨2_ [ 2· ( 4 chlorophenyl) 〇-methyl phenyl oxazol-4-yl] ethoxy} benzo[b] β phenanthrene _7_基)·2_ethoxypropyl ketone methyl ester, which was further saponified in a procedure similar to that described in Example 9.1 e] to produce a racemic buckling 3_(4·{ 2_[2·(4_gas + f )-5-fluorenyl) oxazol-4-yl]ethoxy}benzo[b]thiophene-7-ylethoxypropionic acid. MS: 484, 3 (M-H)·, 438.3. -~ NMR · (CDC13, 1H, δ, TMS, 300MHz) 1.09 (t, J=7, 3H), 2.39 (s, 3H), 3.06 (t, J=6, 2H), 3.18 (m, 1H) , 3.28-3.43 (m, 2H), 3.50- 3.63 (m, 1H), 4.20-4.29 (d, J=5, 1H), 4.35 (t, J = 6, 2H), 6.74 (d, J=8 , 1H), 7.11-7.24 (m, 3H), 7.32 (d, J=6, 1H), 7.47 (d, J=6, 1H), 7.88 (d, J=9, 2H), COOH# f 0 Example 94 I. Outer. Milk 1 Sex 2-Base-3·(4·{2]?-(4-Air 茇 篡 篡 嗑 _..4H Ethoxy) Poor _ and f bh -7- its, stone starting in a procedure similar to that described in Example 17a], [racemic 2 - ethoxy-3-(4-hydroxybenzo[13] cumphin-7-yl) propyl Methyl ester with 2_[2_(4_fluorophenyl)-5-methyloxazol-4-yl]ethanol [j_ Med. Chem (1998), 41 ((9), 5037-5054] in triphenylphosphine and DEAD Reaction in the presence of (diethyl azodicarboxylate) to give [racemic]-3-(4-{2-[2·(4-fluorophenyl)·5·methylcarbazole- Methyl 4-ethyl]ethoxy}phenylhydrazine [b] porphin-7-yl) 2 ethoxypropionate, which was further saponified in a similar manner to that described in Example 9 丨e]
裝 訂Binding
線 1328585 A7 B7 五、發明説明(136) 生成為淺黃色固體之[外消旋性]-3-( 4- {2-[ 2-(4-氟苯基)-5-甲基呤唑-4-基]乙氧基丨苯并[b]"塞吩-7-基)-2-乙氧基丙 酸。 MS : 468.2 (M-H)', 422.2 〇 NMR : (CDCl3, 1H, 6, TMS, 300MHz)1.10 (t, J=7, 3H), 2.39 (s, 3H), 3.05 (t, J=6, 2H), 3.16-3.24 (m, 1H), 3.31-3.43 (m, 2H), 3.51-3.63 (m, 1H), 4.23-4.29 (m, 1H), 4.35 (t, J=6, 2H), 6.72 (d, J=8, 1 H),_7.05-7.16 (m, 3H), 7.32 (d, J=5, 1H),7.48 (d, J=5, 1H), 7.93-7.99 (m, 2H),COOH非常 寬。 實例95 ί外消旋性卜2-乙氧基-3-(4-( 2-丨2-(2-乙氣某-4-氣苽某)-5-甲基哼唑-4-基1乙氣某丨茉并『bl歧吩-7-某)丙醢 在類似於實例1 7a]說明的步驟中,將[外消旋性]_ 2-乙氧 基-3-( 4-羥基苯并[b]噻吩-7-基)丙酸甲酯與2-[ 2-(2-乙氧 基-4-氟苯基)-5-甲基B号唑-4-基]乙醇(i)以在N,N-二甲基 甲醯胺中的乙基碘及碳酸鉀處理4-氟基-2-羥基苯醛[J.Line 1328085 A7 B7 V. INSTRUCTION DESCRIPTION (136) [Racecyclic]-3-(4-{2-[2-(4-fluorophenyl)-5-methylcarbazole-) 4-yl]ethoxylated benzo[b]"cephen-7-yl)-2-ethoxypropionic acid. MS: 468.2 (MH)', 422.2 NMR: (CDCl3, 1H, 6, TMS, 300 MHz) 1.10 (t, J=7, 3H), 2.39 (s, 3H), 3.05 (t, J=6, 2H ), 3.16-3.24 (m, 1H), 3.31-3.43 (m, 2H), 3.51-3.63 (m, 1H), 4.23-4.29 (m, 1H), 4.35 (t, J=6, 2H), 6.72 (d, J=8, 1 H), _7.05-7.16 (m, 3H), 7.32 (d, J=5, 1H), 7.48 (d, J=5, 1H), 7.93-7.99 (m, 2H), COOH is very wide. Example 95 ί racemic 2-Ethoxy-3-(4-(2-丨2-(2-ethane)-4-methylindole-5-methylcarbazol-4-yl 1 Ethene and a certain amount of 丨 并 『 bl bl 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢 醢And [b]thiophene-7-yl)propionic acid methyl ester and 2-[2-(2-ethoxy-4-fluorophenyl)-5-methyl B-oxazol-4-yl]ethanol (i) Treatment of 4-fluoro-2-hydroxybenzaldehyde with ethyl iodide and potassium carbonate in N,N-dimethylformamide [J.
Chem. Soc.,Perkin Trans. 1( 1994),( 13),1823-3 1],以得到 2-乙氧基-4-氟基苯醛;ii)以類似於在實例21a]至21e]說明 的順序,以2-乙氧基-4-氟基苯醛轉化成2-[2-(2-乙氧基-4-氟笨基)-5-甲基哼唑-4-基]乙醇,以製得2-[2·(2-乙氧基_ 4-氟苯基)-5-甲基《号哇-4-基]乙醇)在三苯膦及DEAD(偶氮 二羧酸二乙酯)的存在下反應,以產生[外消旋性]_ 2-乙氧 基-3-(4- {2-[2-(2-乙氧基-4-氟苯基)-5-甲基哼唑-4-基]乙 ______- 140 -_______ 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) " ' 1371328585 A7 B7 五、發明説明( 氧幻苯并[叫吩_7_基)丙酸甲g§,將其以類似於實例叫 說明的步驟進-步Μ,以產生成為淺黃色固體之[外消旋 性]-2-乙氧基.3·(4_{2·[2.(2_乙氧基_4•氟苯基)_5甲基^ 。坐-4-基]乙氧基}苯并[b]嘍吩-7_基)丙酸。 MS : 512.2 (M-H)·,494.1,466.2。 NMR : (CDCI3, 1H, 5, TMS, 300MHz) : i.〇9 (t, j=7> 3H), 1-44 (t, J=7, 3H), 2.38 (s, 3H), 3.09 (t, J=6, 2H), 3.12-3.39 (m, 3H), 3.51-3.61 (m, 1H),'4.08 (q, J=6, 2H)> 4 25 (m 1H), 4.36 (t, J=6j 2H), 6.64-6.75 (m, 3H), 7.11 - 7.24 ( 1H), 7.29 (d, J=6Hz, 1H), 7.48 (d, J=6, 1H), 7.80 (dxd 1H), COOH非常寬。 實例96 QLM.旋性l-2-_^氧基-3-(4-{上丄2_(4_甲氪甚笨某)_5_?气 坐-4-基1乙氧某}苽# r hl〇塞吩-夂其、壬給 在類似於實例17a]說明的步驟中,將[外消旋性卜2乙氧 基-3-(4-羥基苯并[b]嘧吩·7_基)丙酸甲酯與2 [2 (4甲氧 基苯基)-5-甲基吟唑-4-基]乙醇[j Med Chem (丨998), 41(25),503 7- 50 54]在三苯膦及DEAD(偶氮二羧酸二乙酯) 的存在下反應,以產生[外消旋性]_2_乙氧基_3_(4_{2_[2、 (4-甲氧基苯基)-5-甲基》号唑-4-基]乙氧基}苯并[b]»塞吩_7、 基)丙酸甲酯,將其以類似於實例9 1 e]說明的步驟進一步皂 化,以產生成為無色非晶形固體之[外消旋性]· 2-乙氧基、 3-(4_ { 2·[2·(4-甲氧基苯基)-5-曱基哼唑-4-基]乙氧基}笨 幷[b]°塞喻-7·基)丙酸。 _- -___- 141 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 1328585 A7 B7 五、發明説明(138) MS : 480.3 (M-H).,434.3。 NMR : (CDClj, 1H, <5, TMS, 300MHz) : 1.09 (t, J=7, 3H), 2.38 (s, 3H), 3.05 (t, J=6, 2H), 3.13-3.60 (m, 4H), 3.85 (s, 3H), 4.25 (m, 1H), 4.33 (t, J=6, 2H), 6.71 (d, J=8, 1H), 6.93 (d, J=9, 2H), 7.13 (d, J=8, 1H), 7.31 (d, J=5, 1H), 7.64- 7.73 (m, 1H),7.91 (d, J= 9, 2H),COOH非常寬。 實例97 [外消旋性卜2-乙氧基-3·(4· (2二「2·(4_異丙氣某茇某甲 基呤唑·4_基1乙氣基丨笨# fbl4岭-7-某)丙酸 在類似於實例1 7a]說明的步驟中,將[外消旋性]_ 2_乙氧 基- 3-(4-羥基笨并[b]噻吩-7-基)丙酸曱酯與2-[2-(4-異丙 氧基苯基)-5-甲基。号唑-4-基]乙醇_[PCT Int. Appl.(2000), WOOOO8002 A 1 ]在三苯騰及DEAD(偶氮二幾酸二乙酯)的存 在下反應’以產生[外消旋性卜2_乙氧基_3_(4·{2_[2·(4•異 丙氧基苯基)-5-曱基呤唑-4-基]乙氧基}苯并[b]嘧吩-7-基) 丙酸甲酯’將其以類似於實例9 1 e]說明的步驟進一步皂 化,以產生成為淺黃色非晶形固體之[外消旋性卜2-乙氧 基-3_(4-{2-[2-(4-異丙氧基苯基)-5-甲基,号唑-4-基]乙氧 基} ^并[b]B塞吩-7-基)两酸。 MS : 508.3 (M-H)·,462.3。 NMR : (CDC13, 1H, 5, TMS, 300MHz)1.09 (t, J=6, 3H), 1.35 (d, 1=6, 6H), 2.37 (s, 3H), 3.04 (t, J=6, 2H), 3.12-3.40 (m, 3H), 3.52-3.61 (m, 1H), 4.22-4.29 (m, 1H), 4.35 (t, J = 6, 2H), 4.55-4.67 (m, 1H), 6.72 (d, J=7, 1H), 6.89 (d, __- 142 -___ 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 訂Chem. Soc., Perkin Trans. 1 (1994), (13), 1823-3 1] to give 2-ethoxy-4-fluorobenzaldehyde; ii) similar to in Examples 21a] to 21e] Illustrated sequence, converted to 2-[2-(2-ethoxy-4-fluorophenyl)-5-methyloxazol-4-yl]ethanol with 2-ethoxy-4-fluorobenzaldehyde To obtain 2-[2·(2-ethoxy-4-cyclophenyl)-5-methyl "Wow-4-yl]ethanol) in triphenylphosphine and DEAD (azodicarboxylic acid II) Reaction in the presence of ethyl ester) to give [racemic] 2-ethoxy-3-(4-{2-[2-(2-ethoxy-4-fluorophenyl)-5- Methylcarbazol-4-yl]B______- 140 -_______ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) " ' 1371328585 A7 B7 V. Invention Description ( Oxygen Benzene [ It is called _7_yl) propionic acid methyl g §, which is further stepped in a step similar to the example to give a [racemic]-2-ethoxy group. (4_{2·[2.(2_ethoxy-4-4 fluorophenyl)_5 methyl^. -4-yl]ethoxy}benzo[b]porphin-7-yl)propionic acid MS: 512.2 (MH)·, 494.1, 466.2. NMR: (CDCI3, 1H, 5, TMS, 300MHz): i.〇9 (t, j=7> 3H), 1-44 (t, J=7, 3H), 2.38 (s, 3H), 3.09 (t, J=6, 2H), 3.12-3.39 (m, 3H), 3.51-3.61 (m, 1H ), '4.08 (q, J=6, 2H)> 4 25 (m 1H), 4.36 (t, J=6j 2H), 6.64-6.75 (m, 3H), 7.11 - 7.24 ( 1H), 7.29 ( d, J=6Hz, 1H), 7.48 (d, J=6, 1H), 7.80 (dxd 1H), COOH is very broad. Example 96 QLM. Rotational l-2-_^oxy-3-(4- {上丄2_(4_甲氪很笨某)_5_?气坐-4-基1乙氧某}苽# r hl〇塞吩-夂,壬 given in the steps similar to the example 17a], [Racemic 2-Ethoxy-3-(4-hydroxybenzo[b]sulfonyl-7-yl)propanoic acid methyl ester with 2 [2 (4-methoxyphenyl)-5-A Ketrazole-4-yl]ethanol [j Med Chem (丨998), 41(25), 503 7- 50 54] reacts in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate), To produce [racemate]_2_ethoxy_3_(4_{2_[2, (4-methoxyphenyl)-5-methyl)oxazol-4-yl]ethoxy}benzene [b]»cetin-7, yl)methyl propionate, which was further saponified in a procedure similar to that described in Example 9 1 e] to give [racemic] to 2-color as a colorless amorphous solid. Oxyl, 3-(4_ { 2·[2·(4-methoxybenzene) ) -5 Yue Well-yl-4-yl] ethoxy} stupid Bing [b] ° -7 plug Yu-yl) propionic acid. _- -___- 141 - This paper size applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) 1328585 A7 B7 V. Description of invention (138) MS: 480.3 (M-H)., 434.3. NMR : (CDClj, 1H, <5, TMS, 300MHz) : 1.09 (t, J=7, 3H), 2.38 (s, 3H), 3.05 (t, J=6, 2H), 3.13-3.60 (m , 4H), 3.85 (s, 3H), 4.25 (m, 1H), 4.33 (t, J=6, 2H), 6.71 (d, J=8, 1H), 6.93 (d, J=9, 2H) , 7.13 (d, J=8, 1H), 7.31 (d, J=5, 1H), 7.64- 7.73 (m, 1H), 7.91 (d, J= 9, 2H), COOH is very wide. Example 97 [Racemic Bu-2-Ethoxy-3·(4·(2二"2·(4_isopropyl gas 茇 some methyl carbazole · 4 _ 1 ethane group 丨 stupid # fbl4岭-7-)propionic acid in a procedure similar to that described in Example 1 7a], [racemic] _ 2 ethoxy-3-(4-hydroxybenz[b]thiophen-7-yl ) decyl propionate and 2-[2-(4-isopropoxyphenyl)-5-methyl.oxazol-4-yl]ethanol_[PCT Int. Appl. (2000), WOOOO8002 A 1 ] Reacts in the presence of triphenylene and DEAD (diethyl azodicarboxylate) to produce [racemicity 2_ethoxy_3_(4·{2_[2·(4•isopropoxy) Phenylphenyl)-5-mercaptooxazol-4-yl]ethoxy}benzo[b]sulfon-7-yl)methyl propionate's steps as described in Example 9 1 e] Further saponification to produce [racemic 2-2-ethoxy-3_(4-{2-[2-(4-isopropoxyphenyl)-5-methyl) as a pale yellow amorphous solid, Isoazol-4-yl]ethoxy}^ and [b]B-secen-7-yl)dioic acid MS: 508.3 (MH)·, 462.3. NMR: (CDC13, 1H, 5, TMS, 300MHz) 1.09 (t, J=6, 3H), 1.35 (d, 1=6, 6H), 2.37 (s, 3H), 3.04 (t, J=6, 2H), 3.12-3.40 (m, 3H), 3.52 -3.61 (m, 1H), 4.2 2-4.29 (m, 1H), 4.35 (t, J = 6, 2H), 4.55-4.67 (m, 1H), 6.72 (d, J=7, 1H), 6.89 (d, __- 142 -___ The paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)
線 發明説明( J=8, 2H), 7.15 (d, J=8, 1H), 7.31 (d, J=5, 1H), 7.63-7.73 (m. 1H). 7,88 (d. J=8, 2Ηί,COOH非常寬。 實例98 a] h.·丨2- ( 5-甲基-2-苯基号H )-乙氧某卜芣并『卜1 ^ H斿醛 在類似於實例91a]及b]說明的步驟中,將苯并[b]噻吩·7_ 醇[J. Chem. Soc·,Perkin Trans. 1( 1983),(12),2973-7]與甲 燒續酸2-(5-甲基-2-苯基嗅-4-基)乙酯[pct int Appl.(2000) W00008002]反應,以產生4-[2-(苯幷[b]口塞 吩-7-氣基)乙基]-5 -甲基-2-苯基号峻。以二氯甲基甲謎及 四氣化鈦處理4-[2-(苯并[b]嘧吩-7-氧基)乙基]-5_曱基_2_ 苯基-哼唑,接著得到成為黃色固體之7_[2_(5甲基·2苯 基-Β号0坐-4-基)-乙氧基]-苯并[b]<»塞吩_4 -叛盤〇 NMR : (CDC13, 1H, 5, TMS, 300MHz)2.45 (s, 3H), 3.12 (t, J-6, 2H), 4.55 (t, J=6, 2H), 6.92 (d, J=8, 1H), 7.39-7.46 (m, 3H). 7.66 (d, J=5, 1H), 7.80 (d, J=8, 1H), 7.95-7.99 (m, 2H),8.35 (d, J=5,1H), 10.1 (s, 1H) 〇 bl(S)-2-甲—氧基-3- { 7-|~2-(5-甲棊」2-茉茱-噚口Φ - 4_其、_ 氧基1-苯并丨bl»»裳吟-4-某丨-丙醢 在類似於實例1 1 a]至1 1 c]說明的步驟中,將7_ [ 2_ ( 5-甲 基-2-苯基号唑-4-基)·乙氧基卜苯并[b]D塞吩-4•羧醛與 (S)-4-节基-3-曱氧基乙醯基呤唑烷-2·酮及nBu2B〇Tf反 應’以產生(S)-4-苄基-3-[(2S,3R)-3-羥基-2-甲氧基-3-{ 7-(2-(5-甲基-2-苯基号唑-4-基)·乙氧基]-苯并[閃嘍吩· -143 - 1328585 A7 B7 五、發明説明(140 4-基}丙醯基]°号唑烷-2-酮(根據NMR,四個異構物的其中 之一極佔優勢,根據Tetrahedron Asymmetry 1999,1353, 暫時將組態以2S,3R命名)。將(s)-4-苄基-3-[(2S,3R)-3-經 基-2-甲氧基- 3- {7-[2-(5-曱基-2-苯基号吃-4-基)-乙氧 基]-苯并[bp塞吩-4-基}丙睦基]号吐炫^2 -酮以在三氟醋酸 中的三乙基甲矽烷還原,接著得到(S)-4-苄基- 3-(2(S)-2-甲氧基-3- { 7-[2-(5-甲基-2-笨基-哼唑-4·基)-乙氧基]-苯 幷[b] 吩-4_基}丙81基)°号唆-疼_ 2_酮。接著將(S)-4·爷基-3-(2(8)-2-甲氧基-3-{7-[2-(5-甲基-2-苯基-呤唑-4-基)-乙氧基]-苯并[b]"塞吩-4-基}丙酿基)》号〇坐燒_2-綱以在THF 中的IN NaOH皂化’以產生成為無色固體之(s)-2-甲氧基-3-{7-[2-(5-甲基-2-苯基-»号唑-4-基)-乙氧基]-苯并[b]嘍 吩-4-基}-丙酸。 MS : 436.4 (M-Η)·。 NMR : (CDC13, 1H, δ , TMS, 300MHz)2.44 (s, 3H), 3.06 (t, J=6, 2H), 3.21-3.31 (m,4H), 3.40-3.46 (dxd, Ji = 4, j2=14, 1H), 4.04-4.08 (m, 1H), 4.38 (t, J=6, 2H), 6.73 (d, J=8, 1H), 7.17 (d, J=8, 1H), 7.40- 7.47 (m, 5H), 7.95-7.98 (m, 2H), COOH非常寬。 實例99 2Z-乙氧基-3-丨7-『2-(5-甲某-2-笨某-啐吨-4-基)乙氧基1茚 滿-4 -基}-丙少希酸 將2Z-乙氧基-3-{7-[2-(5-甲基-2 -苯基-呤唑_4·基)乙氧 基]茚滿-4-基}-丙埽酸乙酯(實例91c])(i5〇毫克,0.325毫 ____- 144 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1328585 A7 B7 五、發明説明(141) 莫耳)落解在丨·7毫升二吟烷中,接著在室溫下緩慢加入〇 9 毫升水及LiOH(0.812毫升在水中的1Ν溶液,0.813毫莫 耳)。將所得混合物在室溫下攪拌隔夜。接著倒在冰上,以 HCI(IN)中和成ρΗ4及以AcOEt萃取3次。將合併的有機相以 水清洗,經硫酸鎂乾燥及蒸發,以得到成為無色晶體之14〇 毫克(99·4%)2Ζ-乙氧基-3-{7-[2-(5-甲基-2-苯基-呤唑-4- 基)乙氧基]印滿-4 -基}-丙缔酸。 MS : 432.5 (M-Η).。 NMR : (CDC13, 1H, (5, TMS, 300MHz)1.32 (t, J=7.1, 3H), 2.08 (quint., J=7.5, 2H), 2.39 (s, 3H), 2.86 (t, J=7.5, 2H), 3.00 (m, 4H), 3.95 (q, J=7.1, 2H), 4.30 (t, J=6.5, 2H), 6.74 (d, J=8.7, 1H), 7.20 (s, 1H), 7.39- 7.46 (m, 3H), 7.96-7.99 (m, 2H),8.02 (d,J=8.7, 1H),COOH非常寬。 實例100 (_S)-2-甲氧某-3-{7_〖2-(5-甲基-2-笨某-啐咄-4-某)乙氩某1 菲滿-4-某:丨-而醋 在類似於實例1 1 a]至1 1 c]說明的步驟中,將7- [ 2- ( 5-甲 基-2-苯基-呤唑-4_基)乙氧基]茚滿-4_羧醛(實例9ib])與 (S)-4-笮基-3-甲氧基乙醯基。号唑烷-2-酮及nBu2BOTf反 應,以產生(S)-4-苄基-3-[(2S,3R)-3-羥基-2-甲氧基-3-{7-[2-(5-甲基-2-苯基唑-4-基)乙氧基]茚滿-4-基}丙醯 基]°号唑烷-2-酮(根據NMR,四個異構物的其中之一極佔 優勢;根據Tetrahedron Asymmetry 1999, 1 353,暫時將组 態以2S,3R命名)。將(S)-4-苄基- 3-[(2S,3R)-3 -羥基-2-甲 __- 145 -___ 本纸張尺度適用中园圉家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(142) 氧基- 3-{7-[2-(5-甲基-2-苯基号吐_4_基)乙氧基]茚滿- 4-基}丙醯基]咩唑烷-2·酮以在三氟醋酸中的三乙基甲矽烷還 原,接著得到(S)-4-芊基-3-(2(S)-2-甲氧基-3-{7-[2-(5-甲基-2-苯基-B号唑· 4-基)乙氧基]茚滿-4_基丨丙醯基)σ号唑 炫-2-酮。接著將 基-3-(2(S)-2-甲氧基-3-{7-[2- (5·甲基-2-苯基-哼唑-4-基)乙氧基]茚滿_4•基}丙醯基)吟 吐烷-2-酮以在THF中的IN NaOH皂化,在自AcOEt/己烷結 晶之後,產生成為無色固體之·(多)-2-曱氧基_3-{7-[2-(5-甲 基-2-笨基-巧唑-4-基)乙氧基]菲滿-4_基卜丙酸。根據對掌 性HPLC (Chiralpak-AD)鑑定過量的對映異構物係 97.7%。 MS : 420.4 (M-Η)· » NMR : (CDCl3, 1H, 6, TMS)2.05 (quint., J=7.5, 2H), 2.38 (s, 3H), 2.84 (t, J-7.5, 2H), 2.87-3.00 (m, 5H), 3.05 (dxd, J-14.4, 4.8, 1H), 3.35 (s, 3H), 3.95 (dxd, J=7.8, 4.8, 1H), 4.21 (t, J=6.3, 2H), 6.63 (d, J=8.4, 1H), 6.98 (d, J=8.4, 1H), 7.40-7.46 (m, 3H), 7.95- 7.99 (m,2H), COOH非常寬。 實例1 0 1 a 1_L外消旋性1 - 3 - ( 4 -經基茶-1 -基)-2 ·甲氧某丙酸甲酷 在類似於實例93a]說明的步驟中,將4-笮氧基莕-1 _幾駿 (以在N,N-二甲基甲醯胺中-的4-羥基莕-1·羧醛、芊基氣及 碳酸鉀在室溫下製得的)與溴化(甲氧基甲氧羰基甲基)三笨 鋳[Tetrahedron 53( 50),17097- 171 14( 1997)]反應,以產生 3-(4-苄氧基萘-卜基)-2(Z,E) -甲氧基丙烯酸甲酯。如實例 ___- 14R -____ 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) : ' 1328585 A7 B7 五、發明説明(143) 91d]的說明’以3·(4_苄氧基莕-丨·基)·2(ζ,ε)_甲氧基丙烯 酸甲醋的氫化作用產生淺玫瑰色油之[外消旋性]_3_(4_羥 基莕-1-基)-2-甲氧基丙酸甲酯。 MS : 259.1 (M-H)·,229.2。 NMR : (CDC13, 1H, δ, TMS, 300MHz) : 3.31-3.38 (m, 4H), 3.44-3.49 (q, J=5, 1H), 3.72 (s, 3H), 4.09-4.13 (dxd, J, = 5, J2=8, 1H), 5.63 (s, 1H), 6.71 (d, J=7, 1H), 7.18 (d, J=8, 1H), 7.47-7.58 (m, 2H), 8.00'-'8.03 (m, 1H), 8.23- 8.26 (m, 1H) 〇 5 i外岣旆性1 - 3 - ( 4 - { 2 -『2 - ( 2-乙氣某-4 -患,笨某)_ %甲某 °坐-4-基1乙氳某}萁-1-基)-2-甲氫某而酩 在類似於實例1 7a]說明的步驟中、將[外消旋性】_3_(4_羥 基莕-1-基)-2-曱氧基丙酸曱酯與2·[2_(2_乙氧基_4_氟苯 基)-5-甲基呤唑-4-基]乙醇(實例95)在三笨膦及DEAD(偶氮 二羧酸二乙酯)的存在下反應,以產生[外消旋性]_ 3_ (4_ {2-[2-(2-乙氧基-4-乳苯基)-5-甲基σ号唆_4-基]乙氧基}莕_ 1 -基)-2 -曱氧基丙酸甲g旨’將其以類似於實例91 e ]說明的 步驟進一步皂化,以產生成為無色固體'之[外消旋性]_ 3_ (4-{2-[2-(2-乙乳基-4-氣冬基)·5 -甲基》号〇坐_4_基]乙氧基} 莕-1-基)-2-曱氧基丙酸。 MS : 492.2 (M-Η)·。 — NMR : (CDC13, 1H, δ , TMS, 300MHz) : \ A2 (t J=7, 3H), 2.41 (s, 3H), 3.12 (t, J—6, 2H), 3.23-3.31 4H), 3.52- 3.58 (dxd,Ji = 4, J2=14,1H),4.04-4.11 (m, 3H), 4 37 (t, -147 - 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公爱) ~ ---Line invention description (J=8, 2H), 7.15 (d, J=8, 1H), 7.31 (d, J=5, 1H), 7.63-7.73 (m. 1H). 7,88 (d. J= 8, 2Ηί, COOH is very broad. Example 98 a] h.·丨2-(5-methyl-2-phenyl H)-ethoxy oxime and 卜 1 ^ H furfural in a similar example 91a In the steps described in b], benzo[b]thiophene-7-ol [J. Chem. Soc., Perkin Trans. 1 (1983), (12), 2973-7] and methylate 2- (5-methyl-2-phenyl ol-4-yl)ethyl ester [pct int Appl. (2000) W00008002] reaction to produce 4-[2-(benzoquinone [b] ketone-7-gas Ethyl]-5-methyl-2-phenyl no. Jun 4-[2-(benzo[b]sulfon-7-oxy) treated with dichloromethyl mystery and titanium tetrachloride Ethyl]-5-fluorenyl-2-phenylene-carbazole, followed by 7-[2_(5-methyl-2-phenyl-indole 0--4-yl)-ethoxy]-benzene as a yellow solid And [b]<»cetin _4 - 叛 〇 NMR : (CDC13, 1H, 5, TMS, 300MHz) 2.45 (s, 3H), 3.12 (t, J-6, 2H), 4.55 (t, J=6, 2H), 6.92 (d, J=8, 1H), 7.39-7.46 (m, 3H). 7.66 (d, J=5, 1H), 7.80 (d, J=8, 1H), 7.95 -7.99 (m, 2H), 8.35 (d, J=5,1H), 10.1 (s, 1H) 〇bl(S)-2-methyl-oxy-3- { 7- |~2-(5-甲棊)2-茉茱-噚口Φ - 4_其, _ oxy 1-benzopyrene bl»»Shanxi-4-some 丨-Bing in a similar example 1 1 In the step described by a] to 1 1 c], 7_[ 2 —( 5-methyl-2-phenyloxazol-4-yl)·ethoxy bromide[b]D-cephen-4-carboxylate The aldehyde reacts with (S)-4-pyryl-3-methoxyethoxyethyloxazolidine-2·one and nBu2B〇Tf to produce (S)-4-benzyl-3-[(2S,3R) )-3-hydroxy-2-methoxy-3-{ 7-(2-(5-methyl-2-phenyloxazol-4-yl)·ethoxy]-benzo[flash porphin -143 - 1328585 A7 B7 V. Description of the Invention (140 4-yl}propanyl]°oxazolidine-2-one (according to NMR, one of the four isomers is predominant, according to Tetrahedron Asymmetry 1999, 1353, temporarily configure the configuration to 2S, 3R). (s)-4-benzyl-3-[(2S,3R)-3-yl-2-yloxy-3-{7-[2-(5-mercapto-2-phenyl) -4-yl)-ethoxy]-benzo[bp-cet-4-yl}propanyl]- oxo-2-ketone is reduced with triethylmethane in trifluoroacetic acid, followed by S)-4-benzyl-3-(2(S)-2-methoxy-3-{ 7-[2-(5-methyl-2-indolyl-oxazol-4yl)-B Oxy]-benzoquinone [b] phen-4-yl}propanyl 81) ° 唆 - pain _ 2 ketone. Next, (S)-4·Germanyl-3-(2(8)-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl) )-ethoxy]-benzo[b]"cephen-4-yl}propyl aryl) 〇 烧 _2 - 纲 纲 _2 IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN s)-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-»-oxazol-4-yl)-ethoxy]-benzo[b] porphin- 4-yl}-propionic acid. MS: 436.4 (M-Η)·. NMR : (CDC13, 1H, δ, TMS, 300MHz) 2.44 (s, 3H), 3.06 (t, J=6, 2H), 3.21-3.31 (m, 4H), 3.40-3.46 (dxd, Ji = 4, J2=14, 1H), 4.04-4.08 (m, 1H), 4.38 (t, J=6, 2H), 6.73 (d, J=8, 1H), 7.17 (d, J=8, 1H), 7.40 - 7.47 (m, 5H), 7.95-7.98 (m, 2H), COOH is very wide. Example 99 2Z-Ethoxy-3-indolyl-7-"2-(5-methyl-2-pyano-indol-4-yl)ethoxy 1 indane-4-yl}-propanoic acid 2Z-ethoxy-3-{7-[2-(5-methyl-2-phenyl-indazole-4(yl)ethoxy]]indol-4-yl}-propionate ethyl ester (Example 91c)) (i5〇mg, 0.325m________ 144 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 B7 V. Invention description (141) Moer) In 7 ml of dioxane, 9 ml of water and LiOH (0.812 ml of a 1 Torr solution in water, 0.813 mmol) were slowly added at room temperature. The resulting mixture was stirred at room temperature overnight. It was then poured onto ice, neutralized with HCI (IN) to form ρΗ4 and extracted with AcOEt three times. The combined organic phases were washed with water, dried over magnesium sulfate and evaporated to give <RTI ID=0.0>> -2-Phenyl-oxazol-4-yl)ethoxy]imprint-4-yl}-propionic acid. MS: 432.5 (M-Η). NMR : (CDC13, 1H, (5, TMS, 300MHz) 1.32 (t, J=7.1, 3H), 2.08 (quint., J=7.5, 2H), 2.39 (s, 3H), 2.86 (t, J= 7.5, 2H), 3.00 (m, 4H), 3.95 (q, J=7.1, 2H), 4.30 (t, J=6.5, 2H), 6.74 (d, J=8.7, 1H), 7.20 (s, 1H) ), 7.39- 7.46 (m, 3H), 7.96-7.99 (m, 2H), 8.02 (d, J=8.7, 1H), COOH is very broad. Example 100 (_S)-2-methoxy--3- 7_〖2-(5-methyl-2-stupid-啐咄-4-) Ethyl argon 1 phenanthrene-4-some: 丨- and vinegar is similar to the example 1 1 a] to 1 1 c] In the illustrated step, 7-[2-(5-methyl-2-phenyl-indazol-4-yl)ethoxy]indano-4_carboxaldehyde (Example 9ib)) and (S)- 4-mercapto-3-methoxyethenyl. Isooxazol-2-one and nBu2BOTf are reacted to give (S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2 -Methoxy-3-{7-[2-(5-methyl-2-phenylazol-4-yl)ethoxy]indan-4-yl}propanyl]°oxazolidine-2 - Ketone (according to NMR, one of the four isomers is predominant; according to Tetrahedron Asymmetry 1999, 1 353, the configuration is temporarily named 2S, 3R). (S)-4-Benzyl-3- [(2S,3R)-3 -hydroxy-2-methyl__- 145 -___ This paper size is suitable for the garden (CNS) A4 size (210 X 297 mm) 1328585 A7 B7 V. Description of invention (142) Oxy- 3-{7-[2-(5-methyl-2-phenyl-form _4_yl) Ethoxy]indan-4-yl}propanyl]oxazolidine-2·one is reduced with triethylformamidine in trifluoroacetic acid, followed by (S)-4-mercapto-3-() 2(S)-2-methoxy-3-{7-[2-(5-methyl-2-phenyl-B-oxazol-4-yl)ethoxy]indan-4_yl-propyl Mercapto) σ oxo-2-one followed by benzyl-3-(2(S)-2-methoxy-3-{7-[2-(5.methyl-2-phenyl-oxime) Zin-4-yl)ethoxy]indan-4-yl}propan-2-one is saponified with IN NaOH in THF to give a colorless solid after crystallization from AcOEt/hexane. ·(poly)-2-indolyl_3-{7-[2-(5-methyl-2-indolyl-cinazole-4-yl)ethoxy]phenanthrene-4_gibr acid. The excess enantiomer was 97.7% identified by HPLC (Chiralpak-AD). MS : 420.4 (M-Η)· » NMR : (CDCl3, 1H, 6, TMS) 2.05 (quint., J=7.5, 2H), 2.38 (s, 3H), 2.84 (t, J-7.5, 2H) , 2.87-3.00 (m, 5H), 3.05 (dxd, J-14.4, 4.8, 1H), 3.35 (s, 3H), 3.95 (dxd, J=7.8, 4.8, 1H), 4.21 (t, J=6.3 , 2H), 6.63 (d, J=8.4, 1H), 6.98 (d, J=8.4, 1H), 7.40-7.46 (m, 3H), 7.95- 7.99 (m, 2H), COOH is very wide. Example 1 0 1 a 1_L racemic 1 - 3 - ( 4 -yl-based tea-1 -yl)-2 -methoxy-propionic acid A cool in a procedure similar to that described in Example 93a], 4-笮Oxyquinone-1 _Junjun (prepared from 4-hydroxyindole-1·carboxaldehyde, sulfhydryl gas and potassium carbonate in N,N-dimethylformamide at room temperature) and bromine (methoxy methoxycarbonylmethyl) triammonium [Tetrahedron 53 (50), 17097-171 14 (1997)] reaction to produce 3-(4-benzyloxynaphthalene-bu)-2 (Z , E) - Methyl methacrylate. For example ___- 14R -____ This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm): ' 1328585 A7 B7 V. Description of invention (143) 91d] '3' (4_benzyl Hydrogenation of methoxy hydrazine-hydrazinyl)·2(ζ,ε)_methoxy methacrylate to produce [racemic]_3_(4-hydroxyindol-1-yl)-2 in light rose oil Methyl methoxypropionate. MS: 259.1 (M-H)·, 229.2. NMR : (CDC13, 1H, δ, TMS, 300MHz) : 3.31-3.38 (m, 4H), 3.44-3.49 (q, J=5, 1H), 3.72 (s, 3H), 4.09-4.13 (dxd, J , = 5, J2=8, 1H), 5.63 (s, 1H), 6.71 (d, J=7, 1H), 7.18 (d, J=8, 1H), 7.47-7.58 (m, 2H), 8.00 '-'8.03 (m, 1H), 8.23- 8.26 (m, 1H) 〇5 i exogenous 1 - 3 - ( 4 - { 2 -『2 - ( 2- 乙某-4 - suffering, stupid a) _% A certain ° sitting -4- group 1 氲 氲 萁 萁 基 基 基 基 -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于_3_(4-Hydroxyindol-1-yl)-2-decyloxypropionate oxime ester and 2·[2_(2-ethoxy-4-cyclofluoro)-5-methyloxazol-4-yl Ethanol (Example 95) was reacted in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to give [racemic] _ 3_ (4_ {2-[2-(2-ethoxy) 4-merylphenyl)-5-methyl 唆 唆 _ 4-yl] ethoxy} 荇 1 -yl)-2 - methoxypropionic acid 甲 g 'will be similar to Example 91 e] The steps described are further saponified to produce [racemate]_3_(4-{2-[2-(2-ethyllacyl-4-oxadonyl)·5-methyl as a colorless solid 》号〇 _4_基]Ethoxy} 荇-1-yl)-2-methoxypropane acid. MS: 492.2 (M-Η)·. — NMR : (CDC13, 1H, δ , TMS, 300MHz) : \ A2 (t J=7, 3H), 2.41 (s, 3H), 3.12 (t, J-6, 2H), 3.23-3.31 4H), 3.52- 3.58 (dxd, Ji = 4, J2=14, 1H), 4.04-4.11 (m, 3H), 4 37 (t, -147 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 public ) ~ ---
線 1328585 A7Line 1328585 A7
訂Order
線 1328585 A7 B7 145 五、發明説明( 冬并『^)1嚷吩-4 -基丨-丙矯酸 在類似於實例9 1 c]說明的步騾中,以在2_丙醇中的氯化 (乙氧基乙氧凝基甲基)三苯鳞[Tetrahedron 50(25),7543. 56( 1994)]在碳酸鉀的存在下處理7_[2·(5_甲基·2-苯基号 0坐-4 -基)-乙氧基]-苯并[b] ν»塞吩· 4-幾駿(實例98a]),以產 、生2Z-乙氧基·3-{7·[2·(5_甲基__2_苯基-崎咬·4·基)·乙氧 基]-苯并[b]嘍吩-4-基}-丙缔酸乙酯。將22•乙氧基_3_{7_ [2-(5-甲基-2-苯基-哼唑-4 -基j -乙氧基卜苯并[b]IJ塞吩_4_ 基}-丙晞酸乙酯以類似於實例99說明的步驟進一步包化, 以產生成為热色固體之2Z-乙氧基- 3- {7-[2-(5-曱基-2-苯 基-号峻-4 -基)-乙氧基]-冬并[b]p基吩-4 -基}-丙缔酸。 MS : 448.2 (M-H)·,376.2。 NMR : (CDC13, 1H, <5, TMS, 300MHz)1.33 (t, J=6, 3H), 2.45 (s, 3H), 3.11 (t, J=5,2H), 3.99 (q, J=6, 2H), 4·5〇 (t, J-5, 2H),6.87 (d,J=7,1H),7.39- 7.46 (m,3H),7,49-7,57 (m, 2H), 7.64 (s, 1H), 7.97-8.00 (m, 2H), 8.24 (d, J=7, 1H),COOH非常寬。 ’ 實例104 f外消旋性卜2-乙氫基-3-{7-「2-(5-甲某-2-苽某-呤唑-4_ 基)-乙乳基1-表并丨{31。篆吩-4 -基丨-丙酸 將0_ 175公克(0.39毫莫耳)2Z-乙氧基-3- { 7-[2-(5-甲基-2-苯基-。号唑-4-基)-乙氧基]-苯并[b]4吩-4-基}-丙晞酸(實 例103)以在乙醇中的外消旋性Ru(〇Ac)2[3 5_xyl_ MeOBIPHEP]觸媒在60°C及60巴壓力下氫化,以得到成為 -149 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1328585 A7 B7 五、發明説明(~~) ~ ~ ' 淺灰色固體之0· 167公克[外消旋性]-2-乙氧基-3-{7-[2-(5-甲基-2-苯基-崎唑-4 -基)-乙氧基]-苯并[bp墓吩.4基丨丙 酸0 MS : 450.2 (M-H)·,404.0。 NMR : (CDC13, 1H, 5, TMS, 300MHz)1.06 (t, J=6j 3H) 2.44 (S, 3H), 3.07 (t, J=5, 2H), 3.22-3.31 (m, 2H), 3.4〇. 3.55 (m, 2H), 4.10-4.14 (m, 1H), 4.38 (t, J=5, 2H)5 6.72 (d J=7, 1H), 7.16 (d, J=7, 1H), *7_.40.-7.47 (m, 6H), 7.95.7.98 (m,2H) » - 實例105 a~LLj卜岣旋性Ί - 2- Π -甲基-3-氣某-3 -笨某-(Z)-而·蜂胺某i _ 3- {4-『2-(5-甲茱-2-苯基-哼唑-4 -某乙氣某ι_不并[bl 4 吩-7 -基}-丙醢乙 將0.334公克(0.75毫莫耳)[外消旋性卜2-胺基-3·{4·[2_ (5-甲基-2-苯基-呤唑-4-基)-乙氧基]-苯并[b]p塞吩·7_基}· 丙酸乙酯(以類似於實例15a])及15b]說明的順序,以4_[2_ (7-溴曱基笨并[b]嘍吩-4-氧基)乙基]-5-曱基-2-笨基-哼唑 [PCT Int. Appl.(200I) W001/79202]及 N-(二甲基亞甲基) 甘胺酸乙酯製得的)及0.161公克(0.97毫莫耳)苯醯基丙酮溶 解在25毫升甲苯中。接著加入0.2〗毫升(丨.5毫莫耳)三乙胺 及0.026公克(0.15毫莫耳)4-甲苯磺酸,並將反應混合物在 回流下加熱2小時。在減壓下除去溶劑之後,將殘餘物以水 /碳酸氫鈉溶液稀釋,並將反應混合物以二氯甲烷萃取。將 合併的有機相經MgS04乾燥及蒸發。以閃蒸色層分離法(矽 _______- 150 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公爱) 1328585 A7 B7 五、發明説明(Line 1328085 A7 B7 145 V. INSTRUCTION DESCRIPTION (Winter 『 ^ 嚷 -4 -4 - - - - - - - -4 -4 -4 -4 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在(Ethoxyethoxymethyl)triphenyl scale [Tetrahedron 50 (25), 7543. 56 (1994)] Treatment of 7_[2·(5-methyl·2-phenyl) in the presence of potassium carbonate No. 0 sitting -4 -yl)-ethoxy]-benzo[b] ν» septene · 4-single (example 98a)), to produce, produce 2Z-ethoxy-3-{7·[ 2·(5-Methyl__2_Phenyl-Sakiji·4·yl)·Ethoxy]-benzo[b]nonphen-4-yl}-propionate ethyl ester. 22•Ethoxy_3_{7_[2-(5-methyl-2-phenyl-oxazol-4-yl-j-ethoxybenzo[b]IJ-septene_4_yl}-- Ethyl citrate was further coated in a similar manner to that described in Example 99 to give 2Z-ethoxy-3-{7-[2-(5-mercapto-2-phenyl-jun) as a hot solid. -4 -yl)-ethoxy]-when-[b]p-phenylphen-4-yl}-propionic acid MS: 448.2 (MH)·, 376.2. NMR: (CDC13, 1H, <5, TMS, 300MHz) 1.33 (t, J=6, 3H), 2.45 (s, 3H), 3.11 (t, J=5, 2H), 3.99 (q, J=6, 2H), 4·5〇(t , J-5, 2H), 6.87 (d, J=7, 1H), 7.39- 7.46 (m, 3H), 7, 49-7, 57 (m, 2H), 7.64 (s, 1H), 7.97- 8.00 (m, 2H), 8.24 (d, J=7, 1H), COOH is very broad. 'Example 104 f racemic 2-2-hydrogen-3-{7-"2-(5-A -2-苽--carbazole-4_yl)-ethyl lactyl 1 - acetonyl hydrazide {31. porphin-4 - hydrazino-propionic acid will be 0_175 g (0.39 mmol) 2Z-ethoxy- 3-{ 7-[2-(5-methyl-2-phenyl-.oxazol-4-yl)-ethoxy]-benzo[b]4-phen-4-yl}-propionic acid ( Example 103) hydrogenation with a racemic Ru(〇Ac) 2 [3 5_xyl_ MeOBIPHEP] catalyst in ethanol at 60 ° C and a pressure of 60 bar To become -149 - This paper scale applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 B7 V. Invention description (~~) ~ ~ ' Light gray solid 0. 167 g [racemic] -2-ethoxy-3-{7-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[bp tomb.4 base 丨Acid 0 MS : 450.2 (MH)·, 404.0. NMR: (CDC13, 1H, 5, TMS, 300 MHz) 1.06 (t, J=6j 3H) 2.44 (S, 3H), 3.07 (t, J=5, 2H ), 3.22-3.31 (m, 2H), 3.4〇. 3.55 (m, 2H), 4.10-4.14 (m, 1H), 4.38 (t, J=5, 2H)5 6.72 (d J=7, 1H) , 7.16 (d, J=7, 1H), *7_.40.-7.47 (m, 6H), 7.95.7.98 (m, 2H) » - Example 105 a~LLj 岣 Ί Ί - 2- Π -Methyl -3- gas a-3 - stupid - (Z) - and · beeamine a i _ 3- {4-『2-(5-methyl 茱-2-phenyl-carbazole-4 - a certain ethane Ι_不和[bl 4 phen-7-yl}-propionyl b will be 0.334 g (0.75 mmol) [racemic 2-amino-3·{4·[2_ (5-methyl-) 2-Phenyl-oxazol-4-yl)-ethoxy]-benzo[b]p-sept.7-yl}·ethyl propionate (in a similar order to that described in Examples 15a) and 15b] To 4_[2_(7-bromoindolyl][b]nonphen-4-oxy)ethyl]-5-fluorenyl -2-Phenyl-carbazole [PCT Int. Appl. (200I) W001/79202] and N-(dimethylmethylene) ethyl glycinate) and 0.161 g (0.97 mmol) Benzoylacetone was dissolved in 25 ml of toluene. Next, 0.2 mL (0.55 mmol) of triethylamine and 0.026 g (0.15 mmol) of 4-toluenesulfonic acid were added, and the reaction mixture was heated under reflux for 2 hours. After removing the solvent under reduced pressure, the residue was diluted with water / sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and evaporated. Flash-separated layer separation method (矽 ____- 150 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1328585 A7 B7 V. Description of invention (
147 膠,溶離劑:己烷與醋酸乙酯的梯度)純化殘餘物,以得到 成為淺黃色油之0.3 8公克(8 5 % )[外消旋性]-2 - [ 1 -甲基· 3 氧基-3-苯基- (Z) -丙烯基胺基]-3-{4-[2-(5-甲基-2-笨基 喝唑-4-基)-乙氧基]-苯并[b]。塞吩-7-基}-丙酸乙酯。 MS : 595.1 (M+H)+ 〇 NMR : (CDC13, 1H, δ , TMS, 300MHz)1.26 (t, J=6, 3H) 1.64 (s, 3H), 2.39 (s, 3H), 3.03-3.08 (t, J=6, 2H), 3 17 3.25 (dxd, J,= 8, J2=13, 1H)/3.44-3.5 1 (dxd, J, = 5, J2=12 1H), 4.19-4.26 (q,J=6, 2H),4.34-4.39 (t,J=5, 2H),4 58_’ 4.66 (m,1H),6.70-6.73 (d,J=7,1H),7.12-7.14 (d,j=7 1H),7.26- 7.52 (m,9H),7.84-7.99 (m,4H),11.73-11,76 (d J=8, 1H) 〇 ’ bl [.外消旋性卜2-_f 1-甲基-3-氯某-3-苽某-(Z、·而 3-{4-【2-(5-甲基:2-笨基-哼唑-4-基)-乙最甚1-吩-7_基}•丙酸 將0.333公克(0.56毫莫耳)[外消旋性]_2_ [ 1-曱基·3_氧基_ 3·苯基-(Ζ) -丙晞基胺基]·3·{4·[2-(5-甲基-2-苯基-吟唑_ 4 -基)-乙氧基]-笨并[b]噻吩-7-基卜丙酸乙酯溶解在1:1之 THF/EtOH(10毫升)中,並以i.4毫升(1 4毫莫耳)氫氧化鈉 水溶液(1莫耳)處理,以及將反應混合物在室溫下攪拌卜】、 時。接著以IN氫氣酸酸化及以二氣甲烷萃取。將合併的有 機相經MgSCU乾燥及蒸發。以閃蒸色層分離法(矽膠,溶離 劑.二氣甲烷及甲醇的梯度)純化,以得到成為淺黃色非晶 形固體之0.218公克(69〇/〇)[外消旋性]甲基_3氧基-弘 ____- 151 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)147 Glue, Eluent: Gradient of hexanes and ethyl acetate) Purify the residue to give 0.38 g (85 %) as a light yellow oil [racemic]-2 - [ 1 -methyl·3 Oxy-3-phenyl-(Z)-propenylamino]-3-{4-[2-(5-methyl-2-indolyloxazol-4-yl)-ethoxy]-benzene And [b]. Ethyl-7-yl}-propionic acid ethyl ester. MS: 595.1 (M+H)+ NMR: (CDC13, 1H, δ, TMS, 300 MHz) 1.26 (t, J=6, 3H) 1.64 (s, 3H), 2.39 (s, 3H), 3.03-3.08 (t, J=6, 2H), 3 17 3.25 (dxd, J, = 8, J2=13, 1H)/3.44-3.5 1 (dxd, J, = 5, J2=12 1H), 4.19-4.26 ( q, J=6, 2H), 4.34-4.39 (t, J=5, 2H), 4 58_' 4.66 (m, 1H), 6.70-6.73 (d, J=7, 1H), 7.12-7.14 (d , j=7 1H), 7.26- 7.52 (m, 9H), 7.84-7.99 (m, 4H), 11.73-11, 76 (d J=8, 1H) 〇' bl [. racemicity 2- _f 1-methyl-3-chloro-3-oxo-(Z, · and 3-{4-[2-(5-methyl:2-styl-oxazol-4-yl)-B Very 1-phenyl-7-yl}•propionic acid will be 0.333 g (0.56 mmol) [racemate]_2_ [1-indolyl-3-oxy 3 phenyl-(Ζ)-propionium Amino group]·3·{4·[2-(5-methyl-2-phenyl-indazol-4-yl)-ethoxy]- benzo[b]thiophen-7-ylpropanoic acid The ethyl ester was dissolved in 1:1 THF / EtOH (10 mL) and was taken <RTI ID=0.0> Bu], then, acidified with IN hydrogen acid and extracted with di-methane. The combined organic phase The MgSCU was dried and evaporated, and purified by flash chromatography (methylene gel, elutant, gradient of methane and methanol) to afford 0.218 g (69 〇/〇) as a pale yellow amorphous solid. ]Methyl _3oxy-Hong ____- 151 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)
參 訂Participation
1328585 A7 B7 五、發明説明( 148 苯基- (Z) -丙烯基胺基]-3· {4-[2-(5-曱基-2-苯基-哼唑- 4-基)·乙乳基]-表并[b]B塞吩-7-基}-丙酸。 MS : 565.1 (M-H)·,521.2。 NMR : (CDCI3, 1H, (5, TMS, 300MHz)1.56 (s, 3H), 2.38 (s, 3H). 3.03-3.07 (t, J=6, 2H), 3.20-3.28 (m, 1H), 3.54-3.59 (m, 1H), 4.30-4.32 (t, J=6, 2H), 4.64 (m, 1H), 5.55 (s, 1H), 6.66-6.69 (d, J=7, 1H), 7.10-7.13 (d, J=7, 1H), 7.26-7.53 (m, 9H), 7.84- 7.98 (m,4H),11:85-. 1 1.88 (d, 8, 1H) » 實例106 - 谷l.„l-(4-三氟甲某笨基)丁燒-i,3_二_ 將3.94毫升(40毫莫耳)醋酸乙酯及接著以〇丨毫升乙醇加 入維持在氬氣下的20毫升THF中的U70公克(39毫莫耳)氫化 鈉之攪拌懸浮液中。接著在低於25«c下加入在2〇毫升THF 中的3.76公克(20毫莫耳)4-三氟甲基乙醯苯之溶液,最後加 入0.12公克(0.32宅莫耳)二苯幷_18•冠狀_6,並將反應混合 物在回流下加熱90分鐘。在冷卻至約〇χ:之後,將反應混合 物以20毫升硫酸(在水中的丨〇%溶液)酸化,並將反應產物以 醚萃取的方式分離。將合併的有機相經MgS〇4乾燥及蒸 發。最後將.形成的殘餘物以閃蒸色層分離法(矽膠,溶離 劑:己烷與醋酸乙酯的梯度)純化,以得到成為黃色晶體之 3.54公克(77%) 1-(4-三氟甲_基苯基)丁烷丨,3二酮。 MS : 230.1 (M),215.0, 173.0。 NMR : (CDC13, 1H, 5, TMS, 300MHz)2.24 (s, 3H), 6.20 (s, 1H), 7.69-7.72 (d, J=7, 2H), 7.96-7.99 (d, J=7, 2H), 15.991328585 A7 B7 V. INSTRUCTIONS (148 phenyl-(Z)-propenylamino]-3· {4-[2-(5-nonyl-2-phenyl-indazole-4-yl)·B乳基]-表[b]B-cephen-7-yl}-propionic acid MS: 565.1 (MH)·, 521.2. NMR: (CDCI3, 1H, (5, TMS, 300MHz) 1.56 (s, 3H ), 2.38 (s, 3H). 3.03-3.07 (t, J=6, 2H), 3.20-3.28 (m, 1H), 3.54-3.59 (m, 1H), 4.30-4.32 (t, J=6, 2H), 4.64 (m, 1H), 5.55 (s, 1H), 6.66-6.69 (d, J=7, 1H), 7.10-7.13 (d, J=7, 1H), 7.26-7.53 (m, 9H ), 7.84- 7.98 (m, 4H), 11:85-. 1 1.88 (d, 8, 1H) » Example 106 - 谷 l.„l-(4-Trifluoromethane) Butadiene-i, 3_二_ 3.94 ml (40 mmol) of ethyl acetate and then 〇丨ml of ethanol was added to a stirred suspension of U70 g (39 mmol) sodium hydride in 20 ml of THF maintained under argon. Then, a solution of 3.76 g (20 mmol) of 4-trifluoromethylacetamidine in 2 ml of THF was added below 25 «c, and finally 0.12 g (0.32 house mole) diphenyl hydrazine was added. _18 • Coronal _6, and the reaction mixture is heated under reflux for 90 minutes. After cooling to about 〇χ: The mixture was acidified with 20 ml of sulfuric acid (丨〇% solution in water) and the reaction product was separated by ether extraction. The combined organic phases were dried over MgSO 4 and evaporated. The residue formed was flashed. Chromatography (purine, eliminator: gradient of hexanes and ethyl acetate) was purified to give 3.54 g (77%) of 1-(4-trifluoromethylphenyl)butane as a yellow crystal. 3 diketone MS: 230.1 (M), 215.0, 173.0. NMR: (CDC13, 1H, 5, TMS, 300 MHz) 2.24 (s, 3H), 6.20 (s, 1H), 7.69-7.72 (d, J= 7, 2H), 7.96-7.99 (d, J=7, 2H), 15.99
% 訂% order
線 A7Line A7
(s, 1 Η) 〇(s, 1 Η) 〇
甲某茇某)- 旋性卜2 - Γ丨-甲其_ ^-^Α^Αΐι,3-{4-ί2-〇. y 1 ^ 一 tr i JTT . % 基-°咢唑-4 -某)-乙氣 吩-7 -某丨-- 在類似於實例丨05a]說明 ± -I f/l , 步驟中,將[外消旋性]-2-胺 基-3-{4-[2-(5-甲基-2-苯基-咩-^ 」 索必7 〒唑-4·基)-乙氧基]-苯并[b] ,, Τ本中的1-(4-三氟甲基苯基)丁 达_1,3-二酮在以催化量的對_ 本飧酸存在下及在回流下反 應,以產生[外消旋性]-2·[κ甲基-3氧基 苯基)-(Ζ)·㈣基胺基 Η.Μ·[2·(5·η_2.«.^坐4_ 基)-乙氧基]·苯并[b]4吩.7.基}_丙酸⑽,將其以類似 於實例丨㈣]說明的步驟進—步μ,以產生成為淺黃色固 體之[外消旋性]-2-Μ-甲基·3.氧基_3_(4_三氟甲基笨基)_ (Ζ)-丙締基胺基]-3_{4_[2-(5_甲基2苯基呤唑_4·基)·乙 氧基]-笨并[b]p塞吩-7-基}-丙酸。 MS : 635.1 (M+H) + , 591.1 〇 NMR : (CDC13, 1H, <5, TMS, 300MHz)1.59 (s, 3H), 2.39 (s, 3H), 3.04-3.09 (t, J=6, 2H), 3.23- 3.28 (m, 1H), 3.53.3.59 (m, 1H), 4.30-4.34 (t, J=6, 2H), 4.67 (m, 1H), 5.53 (s, 1H) 6.67-6.70 (d,J=7,1H),7.10-7.12 (d,J=7,1H), 7.29-7.31 (d, J=5,1H),7.40- 7.48 (m,4H),7.61-7.64 (d,J=7, 2H) 7.92-7.97 (m,4H),1 1.93- 1 1.96 (d,J=8, 1H),COOH 非常 見0 實例107 __- 153 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇X 297公釐) 1328585 A7 B7 150 五、發明説明( ~~~- 4 -某)-乙氳 基塞吩-7m_r3-语其3 —甘 丨J私~^· - 3 -本其-1 -三i甲甚-將0.41毫升(2.3毫莫耳)N_乙基二異丙胺在低於5<>c下加入 幻0念升中的〇·347公克(。.77毫莫耳)[外消旋性]-2- 胺基3-{4-[2-(5-甲基_2-苯基“号„坐_4_基)_乙氧基]_苯并 [b]喝吩_7-基}.丙酸乙醋及〇 322公克(ι 16毫莫耳)(E/z)_ 3溴基4’4,4-二氟基_丨_苯-多丁 ·2·締_ι·酮[pcT… appl(2_),W0__2A1]之溶液中,並將反應混合物在 至皿下攪拌1 8小時。接著以水稀釋及以醋酸乙酯萃取。將 。併的有機相.經MgS04乾燥及蒸冑。將形成的殘餘物以閃 洛色層分離法純化(矽膠,溶離劑:己烷與醋酸乙酯的梯 度),以產生成為淺黃色固體之〇 49公克(98%)[外消旋性]· 3-{4-[2-(5-甲基-2-苯基-哼唑_4_基)·乙氧基]苯并[b]噻 吩-7-基}-2-[3-氧基_3_苯基_丨_三氟甲基·(ζ)_丙缔基胺 基]-丙酸乙自旨。 MS : 649.2 (Μ+Η)+。 NMR : (CDClj, 1H, δ , TMS, 300MHz)1.15 (t, J=6, 3H), 2.38 (s, 3H), 3.03-3.07 (t, J=6, 2H), 3.27- 3.34 (m, 1H), 3.40-3.47 (m, 1H),4.10-4.17 (q,J = 6, 2H),4.37 (t,J=6’ 2H),4.70-4.73 (m,1H),6.22 (s,1H),6.71-6.74 (d,J=7’ 1H), 7.11-7.14 (d, J=7, 1H), 7.30-7.32 (d, J=5, 1H), 7.40- 7.49 (m, 7H), 7.87- 7.99 (m, 4H), 10.96- 10.99 (d, J=95 1H) » ’ ___- 154 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公爱) 1328585 A7 B7 發明説明(A certain )) - 旋性卜 2 - Γ丨-甲其_ ^-^Α^Αΐι,3-{4-ί2-〇. y 1 ^ a tr i JTT . % base-°carbazole-4 - a)-Ethylene phen-7-a certain 丨-- in a similar manner to the example 丨05a] to illustrate ± -I f / l, in the step, [racemic]-2-amino-3-{4-[ 2-(5-methyl-2-phenyl-indole-^) Sorb-7 oxazol-4-yl)-ethoxy]-benzo[b], 1-(4-tri) Fluoromethylphenyl) butyl 1,3-1,3-dione is reacted in the presence of a catalytic amount of p-nonanoic acid and under reflux to give [racemic]-2·[kappamethyl-3 Oxyphenyl)-(Ζ)·(tetra)ylamino Η.Μ·[2·(5·η_2.«.^坐4_yl)-ethoxy]·benzo[b]4 phen.7. }_propionic acid (10), which was subjected to a procedure similar to that described in Example 丨(4)] to give [cyclomic]-2-Μ-methyl·3.oxy_3_ as a pale yellow solid. (4_Trifluoromethylphenyl)_(Ζ)-propyl-denylamino]-3_{4_[2-(5-methyl 2phenyloxazol-4-yl)·ethoxy]-stupid And [b]p-cephen-7-yl}-propionic acid. MS : 635.1 (M+H) + , 591.1 NMR: (CDC13, 1H, <5, TMS, 300 MHz) 1.59 (s, 3H), 2.39 (s, 3H), 3.04-3.09 (t, J=6 , 2H), 3.23- 3.28 (m, 1H), 3.53.3.59 (m, 1H), 4.30-4.34 (t, J=6, 2H), 4.67 (m, 1H), 5.53 (s, 1H) 6.67- 6.70 (d, J=7,1H), 7.10-7.12 (d, J=7,1H), 7.29-7.31 (d, J=5,1H), 7.40- 7.48 (m,4H), 7.61-7.64 ( d, J=7, 2H) 7.92-7.97 (m, 4H), 1 1.93- 1 1.96 (d, J=8, 1H), COOH Very see 0 Example 107 __- 153 - This paper scale applies to Chinese national standards ( CNS) A4 specification (21〇X 297 mm) 1328585 A7 B7 150 V. Invention description (~~~- 4 - a) - Ethyl thiophene-7m_r3-language 3 - Ganzi J private ~^· - 3 - the original -1 - three i - even - 0.41 ml (2.3 m moles) of N_ethyl diisopropylamine at less than 5 <>c to add 347·347 g in the illusion. .77 mmoler) [racemic]-2-amino 3-{4-[2-(5-methyl_2-phenyl" No. _4_yl)-ethoxy]_ Benzo[b]bend _7-yl}. Propionic acid ethyl vinegar and 〇322 g (ι 16 mmol) (E/z) _ 3 bromo 4'4,4-difluoro 丨 苯 benzene -Dodd·2·Conclusion_ι·ketone [pcT... appl(2_),W In the solution of 0__2A1], the reaction mixture was stirred under a dish for 18 hours. It was then diluted with water and extracted with ethyl acetate. Will. The organic phase was dried over MgS04 and evaporated. The resulting residue was purified by flash chromatography (yield, eluting solvent: gradient of hexanes and ethyl acetate) to yield a yel of 49 g (98%) as a light yellow solid. 3-{4-[2-(5-Methyl-2-phenyl-carbazole-4-yl)-ethoxy]benzo[b]thiophen-7-yl}-2-[3-oxy _3_Phenyl-indole-trifluoromethyl·(ζ)_propyl-phenylamino]-propionic acid B. MS: 649.2 (Μ+Η)+. NMR : (CDClj, 1H, δ, TMS, 300MHz) 1.15 (t, J=6, 3H), 2.38 (s, 3H), 3.03-3.07 (t, J=6, 2H), 3.27- 3.34 (m, 1H), 3.40-3.47 (m, 1H), 4.10-4.17 (q, J = 6, 2H), 4.37 (t, J=6' 2H), 4.70-4.73 (m, 1H), 6.22 (s, 1H) ), 6.71-6.74 (d, J=7' 1H), 7.11-7.14 (d, J=7, 1H), 7.30-7.32 (d, J=5, 1H), 7.40- 7.49 (m, 7H), 7.87- 7.99 (m, 4H), 10.96- 10.99 (d, J=95 1H) » ' ___- 154 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 public) 1328585 A7 B7 Description of invention (
其 1 .基二·!ΐ 二基乙 I 蓋_L_^_并丨bl44-7-其丄-2 r ,—. - 3 - ^ ^ - 1 -;急甲基 _ G)-丙餘胺某卜呙齡 e 1甲4 在類似於實例1 〇5b]說明的半趣丄 J疋的步驟中,將[外消旋性]_3 {4_ [-(5-甲基:2·苯基、七4.基)乙氧基]·苯并⑽塞吩_7_ 土} 2 [3氧基-3-苯基·ι_三氟甲基⑺丙缔胺基]丙酸乙 ^化^為玫瑰色固體之[外消旋性]-3-Η-[2-(5-甲基-2- 枣基唑-4-基)-乙氧基]•笨并〜[b]B塞吩_7基} 2_[3_氧基. 3-苯基-1·三氟甲基_(Z)_丙埽基胺基]•丙酸。 MS : 619.0 (M-H)-,575.0。 NMR.(CDC13,1H,<5,TMS,300MHz)2.37(s,3H),3.02-3.06 (t, J=6, 2H), 3.39- 3.45 (m, 2Ji), 4.22-4.26 (t, J=6, 2H), 4.77-4.81 (m, 1H), 6.23 (s, 1H), 6.65-6.68 (d, J=7, 1H), 7.15-7.18 (d, J=7, 1H), 7.26- 7.28 (d, J=5, 1H), 7.38- 7.51 (m, 7H), 7.85- 7.95 (m, 4H), 11.01-11.04 (d, J=9, 1H), COOH非常寬。 實例108 3~|4-卞氧基-5,6,7,8-四盡.笨-1-勒盤 在類似於實例91b]說明的步驟中,將5-芊氧基-1,2,3,4-四 氫莕[J. Org. Chem.(2001),66(5),1775- 1780]以二氣甲基曱 醚及四氣化鈦處理,以得-到成為黃色固體之4-芊氧基-5,6,7,8-四氫莕-1-羧醛。 MS : 266_2 (M), 91.2。 NMR : (CDC13, 1H, δ , TMS, 300MHz) 1.78- 1.82 (m, 4H), -155 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公爱) 1328585 A7 _ B7______ 五、發明説明(152) 2.74-2.76 (m, 2H), 3.18-3.20 (m, 2H), 5.16 (s, 2H), 6.84- 6.87 (d, J=7, 1H), 7.34- 7.45 (m, 5H), 7.63-7.66 (d, J=7, 1H),10.12 (s, 1H)。 bl丨外消旋性卜2-乙氡基- 3-(4-與某-5,6.7 四氪萁-1-基! 丙醆乙醋 在類似於實例93 a]說明的步驟中,將4-苄氧基-5,6,7,8-四 氫茶-1-羧醛與氣化(乙氧基乙氧羰基甲基)三苯鱗 [Tetrahedron 50(25),7543-56—(J_994)]反應,以產生3-(4-芊 氧基-5,6,7,8-四氫莕-1-基)-2(Z,E) -乙氧基丙晞酸乙酯。如 實例91(1]的說明,以3-(4-苄氧基-5,6,7,8-四氫莕-1-基)_ 2(Z,E)-乙氧基丙晞酸乙酯的氫化作用產生淺黃色油之[外 消旋性]-2-乙氧基- 3- (4 -短基-5,6,7,8-四氫茶-1-基)丙酸乙 酯。 MS : 310.4 (M+NH4) + , 293.4 (M+H) + , 247.3, 201.2 » NMR : (CDC13, 1H, δ, TMS, 300MHz) 1.14-1.17 (t, J=7, 3H), 1.21-1.25 (t, J=7, 3H), 1.79- 1.80 (m, 4H), 2.64-2.79 (m. 4H). 2.92-2.94 (d, J=6, 2H), 3.29-3.36 (m, 1H), 3.53-3.61 (m, 1H), 3.94-3.97 (t, J=6, 1H), 4.14-4.20 (q, J=7, 2H), 4.58 (s, 1H), 6.55-6.57 (d, J=8, 1H), 6.90-6.92 (d, J=8, 1H)。 cl丨外消旋性1-2-乙氣基-3-丨4-丨2-(4-異丙基苽某)-5-氩基 °号唑-4-某甲氣基1-5,6,7,8 -四箭茬-l -基丨-丙酸乙酯 將0.037公克(1·54毫莫耳)氫化鈉以小份量在低於30°C及 在氬氣下加入在5.0毫升Ν,Ν-二甲基甲醯胺中的〇.30公克 ___ - 156 -____ 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1328585 A7 __— —__B7 五、發明説明( (1.03毫莫耳)[外消旋性]_2乙氧基·3 (4經基_ 5 6 7,8四氫 莕-卜基)丙酸乙酯之溶液中。在1〇分鐘之後加入〇 384公 克(丨.54笔莫耳)4·氯甲基- 2-(4-異丙基苯基)-5-甲基哼唑 (在類似於實例2 1 a]及2 1 b]說明的步驟中,以4_異丙基苯醛 及二乙醯基單肟,並接著以P〇Cl3處理製得的),並接著將 反應/½。物在至溫下授拌w小時。接著以水稀釋及以鍵萃 取。將合併的有機相經MgS〇4乾燥及蒸發。將形成的殘餘 物以閃崧色層分離法純化(矽膠〜,溶離劑:己烷與醋酸乙酯 的梯度)’以得到成為無色油之〇 3 5公克(67% )[外消旋性卜 2-乙氧基-3-{4-[2-(4-異丙基苯基)_5_氧基噚峻_4•基甲氧 基]-5,6,7,8-四氫莕-1_基}_丙酸乙酯。 MS : 506.5 (M+H) +,528.4 (M+Na)t。 NMR · (CDC13, 1H, δ, TMS, 300MHz) 1.14-1.1 7 (t, J=7 3H),1.20- 1.24 (t,J=7,3H),1.27- 1.28 (d,J=7, 6H),1.76 (m, 4H), 2.42 (s, 3H), 2.70-2.75 (m, 4H), 2.94-2.96 (m, 3H), 3.31-3.35 (m, 1H), 3.55- 3.59 (m, 1H), 3.96-3.99 (t| j=7, 1H), 4.14-4.19 (q, j=7, 2H), 4.97 (s, 2H), 6.74-6.76 (d, 3=S, 1H), 6.98-7.00 (d, J=8, 1H), 7.29-7.31 (d, J=8 2H),7.92-7'94 (d, J=8, 2H)。 ’ cn丨外消旋性卜2·乙氧異丙襄笨某i °号唑·4·基甲氧基】_5,6,7,8-四·奇1-某r而給 在類似於實例91e]說明的步驟中,將[外消旋性乙氧 基- 3-{4-[2-(4-異丙基苯基)_5·氧基。号吐-4_基甲氧基] 5,6’7,8-四氫莕-丨-基}-丙酸乙酯皂化成為無色固體之[外消 -157 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) ' ------- 1328585 A7 B7 五、發明説明(154 旋性]-2-乙氧基- 3-{ 4-[2-(4-異丙基笨基)·5-氧基呤唑_4- 基甲氧基]-5,6,7,8-四氫莕-丨_基}•丙酸。 MS : 476.2 (Μ-Η)、 NMR : (CDCI3, 1H, δ, TMS, 300MHz) I. I 1 - 1.1 5 (t, J=9, 3H), 1.26- 1.29 (d, J=8, 6H), 1.74- 1.76 (m, 4H), 2.43 (s, 3H), 2.65-2.97 (m, 6H), 3.07-3.12 (dxd,】丨=4, J2=13,ih) 3.29-3.35 (m, 1H), 3.50-3.56 (m, 1H), 3.98-4.03 (dxd, 1, = 4, J2=8, 1H), 4.97 (s, 2H), 6.75-6.78 (d, J=7, 1H), 7.〇l-7.〇4 (d, J-7, 1H), 7.28-7.31 (d, J=7,2H), 7.91-7.94 (d, j=7 2H), COOH非常寬。 ’ ’ 實例109 L外消旋性1二2-乙氧基-J^· ( 5_甲篡-2•苇其- 氧基)-5,6,7,8 -四Μ‘备-1-基卜而够 在類似於實例1 08c]說明的步驟中,以在Ν,Ν_二甲基甲酿 胺中的4-氯甲基-5-甲基· 2-苯基_ α号唑及氫化鈉處理[外消 旋性]-2-乙氧基-3-(4-羥基_5,6,7,8•四氫莕_丨基)丙酸乙 酯,以產生[外消.旋性]-2-乙氧基·3-[4-(5-甲基-2-苯基_哼 唑-4-基甲氧基)-5,6,7,8-四氩莕·卜基]-丙酸乙酯,將其^ 類似於實例91e]說明的步驟皂化成為無色固體之[外消旋 性]-2-乙氧基-3-[ 4-(5-甲基_2-苯基-呤唑_4·基甲氧基^ 5,6,7,8-四氫莕-1-基]-丙酸_。 ^ MS : 434.3 (M-Η)·。 NMR : (CDCI3, 1H, δ , TMS, 300MHz) 1.1 1 - 1. ι 5 (t J=? 3H),1.69- 1.82 (m, 4H),2.44 (s,3H),2.66-2.94 (m,5H)’ -158 - 1328585 A7 B7 155 五、發明説明( 3-07-3.12 (m, 1H), 3.29-3.37 (m 1H)j 3.5〇-3.57 (m, 1H), 4.00-4.03 (m,1H),4.99 (s,2H) 6 76 6 78 ㈧,卜8, ih), ^02-7.04 (d, J=8, 1H), 7.43-7.47 (m, 3H), 8.00-8.02 (m, 2H),COOH非常寬。 實例1 10 •乙氣 其、. 在類似=實例Ha]說明的步-聲中,將[外消旋性]·2乙氧 基3 (4-¾-基-5,6,7,8-四氫莕_丨_基)丙酸乙酯(實例⑺❿]) 與2-[2-(2-乙氧基-4-氟笨基)_5_甲基吟唑_4_基]乙醇(實例 95)在三苯膦及DEAD(偶氮二羧酸二乙酯)的存在下反應, 以產生[外消旋性]_2-乙氧基_3_(4_{2-[2_(2_乙氧基_4_氟 苯基)-5-曱基哼唑-4_基]乙氧基卜5 6,7 8·四氫莕卜基)丙 酸乙酯,將其以類似於實例9le]說明的步驟進一步皂化, 以產生成為典色固體之[外消旋性]_2_乙氧基·3·(4-{2-[2-(2-乙氧基-4-氟苯基)-5-曱基"号。坐-4-基]乙氧基}-5,6,7,8-四或奈-1-基)丙酸。 MS : 510.3 (M-H)_。 NMR : (CDCI3, 1H, 6 , TMS, 300MHz) 1.10-1.14 (t, J=7> 3H), 1.44-1.47 (t, J=7, 3H), 1.67- 1.82 (m, 4H), 2.36 (s, 3H), 2.63- 2.75 (m, 4H), 2,86- 2.92 (m, 1H), 2.97-3.00 (t, J=6, 2H), 3.06-3.10 (m, 1H), 3.30-3.36 (m, 1H), 3.47-3.55 (m, 1H), 3.97-4.00 (m, 1H), 4.07-4.13 (q, J=7, 2H), 4.18-4.21 (t, J=7, 2H), 6.62-6.64 (d, J=8, 1H), 6.67-6.72 (m, -159 本纸彔尺度適用中國固家標準(CNS) A4規格(210X297公釐) 装 訂 線 1328585 A7 B7 五、發明説明(156) 2H),6.97-6.99 (d,J=8,1H),7,80-7.84 (m,1H),COOH非常 寬。Its 1. base II·! ΐ diylethyl I cap _L_^_ and 丨bl44-7- 丄-2 r , —. - 3 - ^ ^ - 1 -; acute methyl _ G) - propyl A Bu 呙 e e 1 A 4 In a procedure similar to the semi-precise J 说明 described in Example 1 〇 5b], [racemic] _3 {4_ [-(5-methyl: 2 phenyl, VII 4) .) ethoxy] benzo (10) phenan _7_ _} 2 [3 oxy-3-phenyl·ι_trifluoromethyl (7) propylamino) propionic acid ethoxylated as a rose solid [Racecycline]-3-Η-[2-(5-Methyl-2-jujuazol-4-yl)-ethoxy]• Stupid~[b]B-Septene_7-base} 2_[3_oxy. 3-phenyl-1·trifluoromethyl_(Z)-propionylamino]•propionic acid. MS: 619.0 (M-H)-, 575.0. NMR. (CDC13, 1H, <5, TMS, 300 MHz) 2.37 (s, 3H), 3.02-3.06 (t, J = 6, 2H), 3.39 - 3.45 (m, 2Ji), 4.22-4.26 (t, J=6, 2H), 4.77-4.81 (m, 1H), 6.23 (s, 1H), 6.65-6.68 (d, J=7, 1H), 7.15-7.18 (d, J=7, 1H), 7.26 - 7.28 (d, J=5, 1H), 7.38- 7.51 (m, 7H), 7.85- 7.95 (m, 4H), 11.01-11.04 (d, J=9, 1H), COOH is very wide. Example 108 3~|4-decyloxy-5,6,7,8-tetra. Stupid-1-Lemoral Disk In a procedure similar to that described in Example 91b], 5-decyloxy-1,2, 3,4-tetrahydroanthracene [J. Org. Chem. (2001), 66(5), 1775-1780] is treated with di-n-methyl oxime ether and titanium tetra-titanate to obtain a yellow solid. -decyloxy-5,6,7,8-tetrahydroindole-1-carboxaldehyde. MS: 266_2 (M), 91.2. NMR : (CDC13, 1H, δ , TMS, 300MHz) 1.78- 1.82 (m, 4H), -155 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 public) 1328585 A7 _ B7______ V. Invention Description (152) 2.74-2.76 (m, 2H), 3.18-3.20 (m, 2H), 5.16 (s, 2H), 6.84- 6.87 (d, J=7, 1H), 7.34- 7.45 (m, 5H) , 7.63-7.66 (d, J=7, 1H), 10.12 (s, 1H). Bl丨 racemic 2-ethyl-2-yl- 3-(4- with a certain-5,6.7 tetradec-1-yl; propylacetate in a procedure similar to that described in Example 93 a], 4 -benzyloxy-5,6,7,8-tetrahydrocha-1-carboxyaldehyde and gasified (ethoxyethoxycarbonylmethyl)triphenyl scale [Tetrahedron 50 (25), 7543-56-(J_994 The reaction was carried out to give ethyl 3-(4-decyloxy-5,6,7,8-tetrahydroindol-1-yl)-2(Z,E)-ethoxypropionate. Description of 91(1), with 3-(4-benzyloxy-5,6,7,8-tetrahydroindol-1-yl)-2-(Z,E)-ethoxypropionate Hydrogenation produces [racemic]-2-ethoxy-3-(4-cyano-5,6,7,8-tetrahydrocha-1-yl)propanoic acid ethyl ester as a pale yellow oil. : 310.4 (M+NH4) + , 293.4 (M+H) + , 247.3, 201.2 » NMR : (CDC13, 1H, δ, TMS, 300MHz) 1.14-1.17 (t, J=7, 3H), 1.21-1.25 (t, J=7, 3H), 1.79- 1.80 (m, 4H), 2.64-2.79 (m. 4H). 2.92-2.94 (d, J=6, 2H), 3.29-3.36 (m, 1H), 3.53-3.61 (m, 1H), 3.94-3.97 (t, J=6, 1H), 4.14-4.20 (q, J=7, 2H), 4.58 (s, 1H), 6.55-6.57 (d, J= 8, 1H), 6.90-6.92 (d, J=8, 1H) cl丨 racemic 1-2-ethenyl-3-indole 4-indole 2-(4-isopropyl hydrazine a certain -5-argon-based oxazol-4-one methyl group 1-5,6,7,8-four arrow 茬-l-yl hydrazine-propionic acid ethyl ester will be 0.037 grams (1·54 millimolar Sodium hydride is added in small portions at less than 30 ° C and under argon in 5.0 ml of Ν, Ν-dimethylformamide. 公 30 kg ___ - 156 -____ This paper scale applies to Chinese national standards (CNS) Α4 size (210 X 297 mm) 1328585 A7 __- —__B7 V. Description of the invention ((1.03 mmol) [racemic] _2 ethoxy·3 (4 via _ 5 6 7, 8 tetrahydroindole-diyl) ethyl propionate solution. After 1 minute, 〇384 g (丨.54 mol) 4·chloromethyl-2-(4-isopropylphenyl) was added. 5-5-methylcarbazole (in a procedure similar to that described in Examples 2 1 a) and 2 1 b], 4- isopropyl benzaldehyde and diethyl hydrazino monohydrazine, and then treated with P 〇 Cl 3 Derived), and then the reaction / 1⁄2. The material was mixed for a while under the temperature. It is then diluted with water and extracted by key. The combined organic phases were dried over MgSO4 and evaporated. The residue thus formed was purified by flash chromatography (yield: lysing: gradient of hexanes and ethyl acetate) to afford to be a colorless oil of 3-5 g (67%) [racemic 2-Ethoxy-3-{4-[2-(4-isopropylphenyl)-5-oxyindole_4•ylmethoxy]-5,6,7,8-tetrahydroanthracene- 1_base}_ethyl propionate. MS: 506.5 (M+H) +, 528.4 (M+Na). NMR · (CDC13, 1H, δ, TMS, 300MHz) 1.14-1.1 7 (t, J=7 3H), 1.20- 1.24 (t, J=7,3H), 1.27- 1.28 (d, J=7, 6H ), 1.76 (m, 4H), 2.42 (s, 3H), 2.70-2.75 (m, 4H), 2.94-2.96 (m, 3H), 3.31-3.35 (m, 1H), 3.55- 3.59 (m, 1H) ), 3.96-3.99 (t| j=7, 1H), 4.14-4.19 (q, j=7, 2H), 4.97 (s, 2H), 6.74-6.76 (d, 3=S, 1H), 6.98- 7.00 (d, J=8, 1H), 7.29-7.31 (d, J=8 2H), 7.92-7'94 (d, J=8, 2H). ' cn 丨 丨 性 卜 · · · · · · i i i i i i i i i i i i i i i i i i i i i i i i i i 某 某 某 某 某 某 某 某 某 某91e] In the illustrated step, [racemic ethoxy-3-{4-[2-(4-isopropylphenyl)-5.oxy). Saponin-4_ylmethoxy]5,6'7,8-tetrahydroindole-indole-yl}-propionic acid ethyl ester saponified into a colorless solid [external-157 - This paper scale applies to Chinese national standards ( CNS) Α4 size (210 X 297 mm) ' ------- 1328585 A7 B7 V. Description of the invention (154 旋性)-2-ethoxy- 3-{ 4-[2-(4- Propyl strepto)·5-oxycarbazole_4-ylmethoxy]-5,6,7,8-tetrahydroindole-indole_yl}•propionic acid MS: 476.2 (Μ-Η), NMR : (CDCI3, 1H, δ, TMS, 300MHz) I. I 1 - 1.1 5 (t, J=9, 3H), 1.26- 1.29 (d, J=8, 6H), 1.74- 1.76 (m, 4H ), 2.43 (s, 3H), 2.65-2.97 (m, 6H), 3.07-3.12 (dxd, 丨=4, J2=13, ih) 3.29-3.35 (m, 1H), 3.50-3.56 (m, 1H), 3.98-4.03 (dxd, 1, = 4, J2=8, 1H), 4.97 (s, 2H), 6.75-6.78 (d, J=7, 1H), 7.〇l-7.〇4 (d, J-7, 1H), 7.28-7.31 (d, J=7, 2H), 7.91-7.94 (d, j=7 2H), COOH is very broad. ' ' Example 109 L racemic 1 II 2-Ethoxy-J^·(5_甲篡-2•苇--oxy)-5,6,7,8-tetrakis-preparation-1-kib is similar to Example 1 08c] In the illustrated step, 4-chloromethyl-5-methyl-2-phenyl-α in hydrazine, hydrazine-dimethyl ketoamine Treatment of [racemic]-2-ethoxy-3-(4-hydroxy-5,6,7,8•tetrahydroindole-yl)propionic acid ethyl ester with azole and sodium hydride to produce [examination .Cyclosyl]-2-ethoxy 3-(4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-5,6,7,8-tetrahydroanthracene Ethyl propionate, which was saponified to a colorless solid [r-[rho]]-2-ethoxy-3-[4-(5-methyl-2-) -Phenyl-carbazole_4·ylmethoxy^5,6,7,8-tetrahydroindol-1-yl]-propionic acid_. ^ MS : 434.3 (M-Η)·. NMR : (CDCI3 , 1H, δ , TMS, 300MHz) 1.1 1 - 1. ι 5 (t J=? 3H), 1.69- 1.82 (m, 4H), 2.44 (s, 3H), 2.66-2.94 (m, 5H)' - 158 - 1328585 A7 B7 155 V. INSTRUCTIONS (3-07-3.12 (m, 1H), 3.29-3.37 (m 1H)j 3.5〇-3.57 (m, 1H), 4.00-4.03 (m,1H), 4.99 (s, 2H) 6 76 6 78 (8), Bu 8, ih), ^02-7.04 (d, J=8, 1H), 7.43-7.47 (m, 3H), 8.00-8.02 (m, 2H), COOH Very wide. Example 1 10 • Ethene gas. In a step-sound similar to that described in Example Ha], [racemic]·2 ethoxy 3 (4-3⁄4-yl-5,6,7,8- Tetrahydroindole_丨_yl)ethyl propionate (example (7)❿]) and 2-[2-(2-ethoxy-4-fluorophenyl)_5-methylcarbazole-4-yl]ethanol (example) 95) reacting in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to produce [racemic] 2 -ethoxy _3_(4_{2-[2_(2_ ethoxy) Ethyl 4-(fluorophenyl)-5-mercaptoindazole-4-yl]ethoxy bromide 5 6,7 8 · tetrahydroindenyl) propionic acid ethyl ester, which is similar to Example 9le] The step is further saponified to give [racemic]_2_ethoxy·3·(4-{2-[2-(2-ethoxy-4-fluorophenyl)-5) as a typical solid. - thiol " No. -4-yl]ethoxy}-5,6,7,8-tetra or naphthyl-1-yl)propionic acid. MS: 510.3 (M-H)_. NMR : (CDCI3, 1H, 6 , TMS, 300MHz) 1.10-1.14 (t, J=7> 3H), 1.44-1.47 (t, J=7, 3H), 1.67-1.82 (m, 4H), 2.36 ( s, 3H), 2.63- 2.75 (m, 4H), 2,86- 2.92 (m, 1H), 2.97-3.00 (t, J=6, 2H), 3.06-3.10 (m, 1H), 3.30-3.36 (m, 1H), 3.47-3.55 (m, 1H), 3.97-4.00 (m, 1H), 4.07-4.13 (q, J=7, 2H), 4.18-4.21 (t, J=7, 2H), 6.62-6.64 (d, J=8, 1H), 6.67-6.72 (m, -159 This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) Gutter 1328585 A7 B7 V. Description of invention (156) 2H), 6.97-6.99 (d, J=8, 1H), 7, 80-7.84 (m, 1H), COOH is very broad.
實例I I I L-外岣踌性1-2-乙氧基愈.笨某·)-5-甲某1>号 噢-4-基1乙氧基卜5,6,7,8 -四新茬-丨-其)丙酸 在類似於實例1 7a]說明的步驟中,將[外消旋性]_ 2•乙氧 基- 3- (4-½基- 5,6,7,8-四風茶-i_基)丙酸乙醋(實例i〇8b]) 與2-[2-(4-氟私基)-5-曱基-二号咕-4-基]乙醇[j. Med Chem.( 1998),41(25),5037- 5054]在三苯膦及 DEAD(偶氮二 知·酸一乙酿)的存在下反應’以產生[外消旋性]-2 -乙氧基 3-(4-{2-[2-(4-氟苯基)-5-甲基》号。坐-4-基]乙氧基) 5,6,7,8-四氫莕-1-基)丙酸乙酯,將其以類似於實例9ie]說 明的步驟進一步皂化,以產生成為無色固體之[外消旋性] 2-乙氧基-3-(4-{2-[2-(4-氟笨基)-5-甲基号唑_4·基]乙氣 基丨-5,6,7,8-四鼠奈-1-基)丙酸。 MS : 466.2 (Μ-Η) —,422.3。 NMR : (CDC13, 1H, 5, TMS, 400MHz) l.i2 (t, J=7 2 3H) 1.74 (m, 4H), 2.37 (s, 3H), 2.62-2.92 (m, 5H), 2.97 (/ J=6.4,2H),. 3.09 (dxd,Ji = 4, J2= 14.4,1H)’ 3.3 i_ 3 35 ’ 1H),3.49- 3.53 (m,1H),3.98-4.01 (m,1H),418·4 23 阳, 2H),6.63'(d,J=8, 1H),6.98 (d,J=8, 1H),7 〇9 7 13 ⑺’ 2H),7.94-7.98 (m,2H),COOH非常寬。 (印, 實例1 12 i外M性卜2-乙氧基某笨某Example III L-external 1-2-ethoxy group. Stupid ·) -5-A 1] 噢-4-yl 1 ethoxy b 5,6,7,8 -tetraxin - 丨-其)propionic acid in a procedure similar to that described in Example 1 7a], [racemic] _ 2 ethoxy 3-(4-1⁄2 yl - 5, 6, 7, 8 - 4 Wind tea-i_base) propionic acid ethyl vinegar (example i〇8b)) with 2-[2-(4-fluoro-secretyl)-5-mercapto-dimethyl-4-yl]ethanol [j. Med Chem. (1998), 41(25), 5037-5054] reacts in the presence of triphenylphosphine and DEAD (azodi-acid-ethyl) to produce [racemic]-2-ethoxy 3-(4-{2-[2-(4-fluorophenyl)-5-methyl). sit-4-yl]ethoxy) 5,6,7,8-tetrahydroindole-1 -yl)ethyl propionate, which was further saponified in a procedure similar to that described in Example 9ie] to give [racemic] 2-ethoxy-3-(4-{2-[2 -(4-Fluorophenyl)-5-methyloxazole_4.yl]ethenyl-5,6,7,8-tetranorazin-1-yl)propanoic acid. MS: 466.2 (Μ-Η) —, 422.3. NMR : (CDC13, 1H, 5, TMS, 400MHz) l.i2 (t, J=7 2 3H) 1.74 (m, 4H), 2.37 (s, 3H), 2.62-2.92 (m, 5H), 2.97 ( / J=6.4,2H),. 3.09 (dxd,Ji = 4, J2= 14.4,1H)' 3.3 i_ 3 35 ' 1H), 3.49- 3.53 (m,1H), 3.98-4.01 (m,1H), 418·4 23 阳, 2H), 6.63'(d, J=8, 1H), 6.98 (d, J=8, 1H), 7 〇9 7 13 (7)' 2H), 7.94-7.98 (m, 2H) , COOH is very wide. (Print, example 1 12 i outside M-sex 2-ethoxy a stupid
_____- 160 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1328585 A7 ______B7 五、發明説明(~~) ' !g吐-4-某1丙氧基卜5.6,7,8-四备芄_丨_某)丙酸 在類似於實例1 7a]說明的步驟中,將[外消旋性]_ 2•乙氧 基- 3-(4-羥基- 5,6,7,8-四氫葚·丨-基)丙酸乙酯(實例1〇8b]) 與3-[2-(4-甲氧基私基)·5 -甲基η号吐_心基]丙醇(實例42e]) 在二苯膦及DEAD(偶氮二羧酸二乙酯)的存在下反應,以產 生[外消旋性]-2-乙氧基-3-( 4-{3-[ 2-(4-甲氧基苯基)-5_曱 基3唑-4-基]丙氧基卜5,6,7,8-四氫莕_1-基)丙酸乙酯,將 其以類似於實例9 1 e]說明的步-赞進一步皂化,以產生成為 供色固體之[外消旋性]-2-乙氧基_3_(4-{3-[2-(4-曱氧基苯 基)-5-甲基。号唑-4-基]丙氧基}· 5 6 7 8_四氫莕_丨_基)丙 酸。 MS : 492.2 (Μ-Η)·,448.3。 NMR : (CDC13,1H,5,TMS,400MHz) 1.11 (t,3H),1.74 (m,4H),2.13 (t,J=6.4,2H),2.24 (s,3H),2.66-2.93 (m, 7H), 3.08 (d, J=12.4, 1H), 3.32 (m, 1H), 3.55 (m, 1H), 3.84- 3.98 (m, 6H), 6.57 (d, J=8.4, 1H), 6.93 (d, J=8.8, 2H) 6.99 (d, J=8.4’ 1H), 7.90 (d, J=8.8, 2H), COOH非常寬。 實例1 1 3_____- 160 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 ______B7 V. Invention description (~~) ' !g 吐-4-一一丙氧卜5.6,7, 8-tetramine 芄 丨 某 某 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 丙 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 类似于 外 外 外 外 外 外 外 外 外 外 外 外 外 外 外 外,8-tetrahydroanthracene-fluorenyl-propionate ethyl ester (Example 1〇8b]) with 3-[2-(4-methoxyl)·5-methylηη吐_心基]丙Alcohol (Example 42e)) is reacted in the presence of diphenylphosphine and DEAD (diethyl azodicarboxylate) to give [racemic]-2-ethoxy-3-(4-{3- [2-(4-Methoxyphenyl)-5-mercapto-3-oxazol-4-yl]propoxybu 5,6,7,8-tetrahydroindole-1-yl)propionic acid ethyl ester, It is further saponified in a similar manner to that described in Example 9 1 e] to give [racemic]-2-ethoxy_3_(4-{3-[2-(4-) as a coloring solid.曱oxyphenyl)-5-methyl. oxazol-4-yl]propoxy}· 5 6 7 8_tetrahydroindole_丨_yl)propionic acid. MS: 492.2 (Μ-Η)·, 448.3. NMR : (CDC13, 1H, 5, TMS, 400MHz) 1.11 (t,3H), 1.74 (m,4H), 2.13 (t,J=6.4,2H), 2.24 (s,3H),2.66-2.93 (m , 7H), 3.08 (d, J = 12.4, 1H), 3.32 (m, 1H), 3.55 (m, 1H), 3.84- 3.98 (m, 6H), 6.57 (d, J=8.4, 1H), 6.93 (d, J=8.8, 2H) 6.99 (d, J=8.4' 1H), 7.90 (d, J=8.8, 2H), COOH is very wide. Example 1 1 3
Li卜纳旋性卜2-乙氧基- 3-(4-(2 -「5-甲某- 2-(4-三患甲其节 赢丄哇-4-基1乙氧基.} · 5,6,7,8二笨-丨·某、而齡 在類似於實例丨7a]說明的步驟中,將[外消旋性]_ 2_乙氧 基- 3-(4-¾基- 5,6,7,8-四氫茶-1-基)丙酸乙酯(實例i〇8b)) 與2-[5-曱基-2-(4-三氟甲基笨基)噚唑_4_基]乙醇(在類似 於實例2U]至21e]說明的順序中,以4_三氟甲基苯醛轉化 __- 161 - 本纸張尺度逋用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7Li 纳旋旋卜 2-ethoxy- 3-(4-(2 - "5-甲某- 2-(4-三病甲节节赢丄哇哇-4-yl 1 ethoxy.} 5,6,7,8 2 stupid-丨·, and in the steps similar to the example 丨7a], [racemic]_ 2_ethoxy-3-(4-3⁄4 base- 5,6,7,8-tetrahydrocha-1-yl)propionic acid ethyl ester (example i〇8b)) with 2-[5-mercapto-2-(4-trifluoromethylphenyl)carbazole _4_yl]ethanol (in a similar manner to Examples 2U) to 21e], converted with 4-trifluoromethylbenzaldehyde __- 161 - This paper scale uses Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 1328585 A7 B7
成2-[5-曱基-2-(4-三氟曱基苯基)》号唑_4-基]乙醇所製得的) 在三笨膦及DEAD(偶氮二敖酸二乙酯)的存在下反應,以產 生[外消旋性]-2-乙氧基-3- (4· { 2- [ 5-甲基·2· (4-三氟甲兵 笨基)呤唑-4-基]乙氧基}-5,6,7,8-四氫莕.1-基)丙酸乙酯: 將其以類似於實例9丨e]說明的步驟進一步息化,以產生成 為無色固體之[外消旋性]-2-乙氧基- 3-(4- {2-[5-甲基_2 (4-二氟甲基苯基)》咢唑-4-基]乙氧基}-5,6,7,8 -四氫萘·卜基) 丙酸。 -- 土 MS : 516.2 (M-H)*, 472.1 〇 NMR : (CDC13, 1H, TMS, 300MHz) I.13 (t, J=7.〇, 3H) 1.69-1.80 (m, 4H), 2.40 (s, 3H), 2.60-2.74 (m, 4H), 2.86-3.05 (m, 4H), 3.30- 3.35 (m, 1H), 3.il-3.57 (m, 1H), 3.97. 4.01 (m. 1H). 4.20 (t, J=6.4, 2H), 6.63 (d, J=8.4, 1H), 6.99 (d, J=8.4, 1H), 7.66 (d, J=8.2, 2H), 8.08 (d, J=8.1, 2H), COOH非常寬。 , , 實例丨14 al氣化(苄氧羰基曱氣某甲基)三苽辞 將一甲乳基醋阪甲自旨(1.094公克,8·ΐ5毫莫耳)及 LiOH(420毫克,10毫莫耳)在〇°c下溶解5毫升二呤烷及5毫 升水中’並將反應混合物在〇。(:下攪拌3〇分鐘及在室溫下揽 拌0.75小時。接著將其以tBuOMe稀釋及以i克分子 冰清洗。將水層&化成pH2及以AcOEt萃取三次,將合併的 有機相經NasSO4乾燥及蒸發,以得到成黃色油之二甲氧基 醋酸(600毫克)。將以類似製備作用獲得的二曱氧基醋酸 ------ 162 - 本紙張尺度適用中國国家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 ._______B7 五、發明説明(159) (8.86公克,73·8毫莫耳)在0°C下溶解在1〇〇毫升乙腈中,接 著加入芊醇(7.3¾升,70毫莫耳)、EDCI(15&克,8〇毫莫 耳)及DMAP( 855毫克,7毫莫耳),並將反應混合物維持在 室溫下1 8小時。接著將其以AcOEt稀釋,以水、1克分子量 HCI、食鹽水、NaaCOd 1 〇% )及再以食鹽水清洗,並將合併 的有機相經NadO4乾燥及蒸發,以得到二曱氧基醋酸苄酯 (10.4公克)。將乙醯氣(2毫升)及作為觸媒的碘(1〇〇毫克)加 入粗二甲氧基醋酸芊酯(4.86公_克)中,並將混合物在65充 下加熱4小時,在加入1 00毫升醚之後蒸發,以丨〇毫升 CHfl2稀釋,並加入在50毫升CH2C12中的三苯膦(25毫莫 耳,6.63公克)之溶液中,以及在室溫下攪拌24小時。以色 層分離法(矽膠’ 0.6公斤,以AcOE_t&l/l之AcOEt/乙醇溶 離)提供成為白色泡沫狀之氯化(芊氧羰基甲氧基甲基)三苯 鱗(6.87 公克。62°/。)。 MS : (M+H+)+ 442.3。 NMR (CDC13, 1H, 6 , TMS) 3.91 (s, 3H), 4.92-5.17 (d, 2H), 6.98 (dxd, 2H), 7.19-7.31 (m, 3H), 7.55-7.90 (m, 15H), 8.64 (br.d, 1H) » U 3-甲某-4-丨2-(5-甲某-2-苽某-哼唑-4-某)-乙氣某1-笨醛 將在400毫升甲笨/丨〇〇毫升水中的4-羥基-3-甲基苯醛(9公 克’.66.10毫莫耳)、甲烷績.酸2-(5-甲基-2-苯基·哼唑-4-基) 乙酯[PCT Int. Appl.(2000) W00008002](22.5公克,80毫莫 耳)' ΚΟΗ(80毫莫耳,4.48公克)及四丁基硫酸氫銨(2公克) 在80°C下加熱1 7小時。接著將反應混合物冷卻至0。(:,以水 ------163 -____ 本纸張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐) 1328585 A7 B7 160 五、發明説明( /冰及食鹽水清洗,將水層以tBuOMe萃取,將合併的有機 層經Na2S〇4乾燥及蒸發。將粗產物以色層分離法(Si〇2 : AcOEt/庚坡)純化,並自庚烷結晶產物,以產生成 為白色固體之丨5公克(72% )標題化合物。 MS : (M+H+)+ 322.3,(2M+H+)+ 643.2。 NMR (CDCl3, lH, 5, TMS) : 2.23 (s, 3H), 2.38 (s, 3H), 3.03 (t, 2H), 4.35 (t, 2H), 6.94 (dxd, 1H), 7.40-7.45 (m5 3H),7.66-7.68 (m,2H),7.96-.乙99.(m,2H), 9.83 (s, 1H)。 (:12(27£)-1_氧基-3-{3-甲某_442_(5-甲某-2-苽某-噚岫· 4..-羞)-乙氧基1 -茉甚)-1¾烯g*芏酯 將3-甲基·4-[ 2-(5-甲基-2-苯基-哼唑-4·基)-乙氧基]-苯 駐(540毫克’ 1.68毫莫耳)溶解2毫升ch2C12中及在0°C下冷 卻’加入氣化(苄氧羰基甲氧基甲基)三苯鱗(丨.04公克, 2.丨8毫莫耳)’接著加入丨,I,3,3_四甲基胍,並將反應混合物 在室溫下攪拌3天,加入更多該兩種燐鹽及鹼(各1當量)。 將反應混合物以AcOEt稀釋,以1克分子量HC1/冰及食鹽水 清洗,將水層以AcOEt萃取,將合併的有機相經Na2S04乾 燥及蒸發。將粗產物以色層分離法(Si〇2 ; AcOEt/庚烷)純 化’以留下成為黃色油之6〇5毫克(74% )標題化合物。 MS : (M+H+)+ 484.4 〇 NMR (DMSO-d6, 1H, <5, TMS) : 2.10 (s, 3H), 2.36 (s, 3H), 2.96 (t, 2H), 3.67 (s, 3H), 4.25 (t, 2H), 5.25 (s, 2H), 6.81 (s, 1H), 7.00 (dxd, 1H), 7.30- 7.63 (m, 10H), 7.90-7.92 (m, 2H)。 164 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) 訂 線 1328585 A7 B7 五、發明説明(161) 幻_.丄及消旋後1-2-甲氳某-3“3-甲基-4-『?-(5-甲某-2-苽某-°号°坐·4_棊)-乙氣某卜苽某丙酸 以10% Pd-C處理溶解在5毫升乙醇中的2(Ζ,Ε) -甲氧基-3-{3-甲基-4-[2-(5-甲基-2-苯基-°号唑-4-基)-乙氧基]-苯 基}-丙’蹄酸苄酯(6〇〇毫克,1 _24毫莫耳),並將反應混合物 在室溫的A氣壓下劇烈攪拌7小時。接著將其經由c鹽過 遽’蒸發,經色層分離(Si〇2 ; AcOEt)及結晶(AcOEt/庚 烷)’以產生成為白色固體之1-4__5毫克(3 0%)標題化合物。 MS : (Μ-Η.)· 394.2。 NMR (DMSO-d6, 1H, TMS) : 2.05 (s, 3H), 2.36 (s, 3H), 2.71-2.76(2xdxd, 2xlH), 2.92 (t, 2H), 3.20 (s, 3H), 3.81-3.85 (m, 1H), 4.16 (t, 2H), 6.84 (dxd, 1H), 6.95-6.97 (m, 2H), 7.48-7.50 (m, 3H), 7.90-7.92 (m, 2H), 12.80 (br.s, 1H)。 實例1 1 5 f外消旋性卜2-甲氧基-3-丨3-甲氫某-4-「2-( 5-甲某-2-苽某-吟唑-4 -基)-乙I[.基μ笨某卜丙醢 在類似於實例1 14b]、c]及d]說明的步驟中,將香草链與 甲烷磺酸2-(5-甲基-2-苯基-〇号唑-4-基)乙酯[PCT Int. Appl_(2000) W00008002]反應,以得到 3-甲氧基-4-[2-(5- 甲基-2 -苯基号〇坐_4 -基)-乙氧基]-苯兹。以氣化(辛氧叛基 甲氧基甲基)三苯鑄處理3-甲氧基-4-[2-(5-甲基-2-苯基-吟 唑-4-基)-乙氧基]•苯醛,接著得到2(Z,E)-甲氧基-3·{3-甲 氧基-4-[2-(5-甲基-2-苯基-呤唑-4-基)-乙氧基]-苯基}-丙 _- 165 -_____ 本紙伕尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 裝 訂Manufactured as 2-[5-fluorenyl-2-(4-trifluorodecylphenyl)" azole-4-yl]ethanol) in triphenylphosphine and DEAD (diethyl azodicarboxylate) Reaction in the presence of ) to give [racemic]-2-ethoxy-3-(4· {2-[ 5-methyl·2·(4-trifluoromethyl) carbazole-4 -Ethyl]ethoxy}-5,6,7,8-tetrahydroindole. 1-yl)propionic acid ethyl ester: it was further subjected to a procedure similar to that described in Example 9丨e] to give a colorless Solid [racemate]-2-ethoxy-3-(4-{2-[5-methyl_2(4-difluoromethylphenyl)"oxazol-4-yl]ethoxylate Base}-5,6,7,8-tetrahydronaphthalene·bupropion) Propionic acid. - Soil MS : 516.2 (MH)*, 472.1 NMR : (CDC13, 1H, TMS, 300MHz) I.13 (t, J=7.〇, 3H) 1.69-1.80 (m, 4H), 2.40 (s , 3,,,,, 4.20 (t, J=6.4, 2H), 6.63 (d, J=8.4, 1H), 6.99 (d, J=8.4, 1H), 7.66 (d, J=8.2, 2H), 8.08 (d, J =8.1, 2H), COOH is very wide. , , Example 丨14 al gasification (benzyloxycarbonyl oxime, a methyl group), three 苽 将 一 一 一 一 一 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Mohr) Dissolve 5 ml of dioxane and 5 ml of water at 〇 °c and place the reaction mixture in hydrazine. (: stirring for 3 minutes and stirring at room temperature for 0.75 hours. Then it was diluted with tBuOMe and washed with i mole of ice. The aqueous layer & was converted to pH 2 and extracted with AcOEt three times, the combined organic phase was NasSO4 is dried and evaporated to give a dimethoxyacetic acid (600 mg) as a yellow oil. The dimethoxy acetic acid obtained in a similar manner is used. 162 - This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 1328585 A7 ._______B7 V. Description of the invention (159) (8.86 g, 73·8 mmol) dissolved in 1 ml of acetonitrile at 0 ° C, followed by sterol (7.33⁄4 liters, 70 millimoles), EDCI (15 & gram, 8 mM molars) and DMAP (855 mg, 7 millimoles) and maintain the reaction mixture at room temperature for 18 hours. It is diluted with AcOEt, washed with water, 1 gram of molecular weight HCI, brine, NaaCOd 1 〇%) and then with brine, and the combined organic phases are dried over NadO4 and evaporated to give benzyl dimethoxyacetate ( 10.4 grams). Ethyl xenon (2 ml) and iodine (1 mg) as a catalyst were added to the crude dimethyl dimethoxyacetate (4.86 g-g), and the mixture was heated at 65 for 4 hours while being added. After evaporation of 100 ml of ether, it was diluted with EtOAc (m.sub.2) (CH.sub.2), and added to a solution of triphenylphosphine (25 mM, 6.63 g) in 50 ml of CH2C12 and stirred at room temperature for 24 hours. The chlorinated (芊 oxycarbonylmethoxymethyl) triphenyl scale (6.87 g. 62°) was obtained as a white foam by chromatography (chromium sulphate '0.6 kg, dissolved in AcOEt/amp; l/l of AcOEt/ethanol). /.). MS: (M+H+)+ 442.3. NMR (CDC13, 1H, 6 , TMS) 3.91 (s, 3H), 4.92-5.17 (d, 2H), 6.98 (dxd, 2H), 7.19-7.31 (m, 3H), 7.55-7.90 (m, 15H) , 8.64 (br.d, 1H) » U 3-甲某-4-丨2-(5-甲某-2-苽某-哼azole-4-某)-乙气一一笨醛 will be at 400 4-hydroxy-3-methylbenzaldehyde (9 g '.66.10 mmol), methane, acid 2-(5-methyl-2-phenyl-carbazole) -4-yl) Ethyl ester [PCT Int. Appl. (2000) W00008002] (22.5 g, 80 mmol) 'ΚΟΗ (80 mmol, 4.48 g) and tetrabutylammonium hydrogen sulfate (2 g) Heat at 80 ° C for 17 hours. The reaction mixture was then cooled to zero. (:, with water ------163 -____ This paper scale applies Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1328585 A7 B7 160 V. Invention description (/Ice and saline cleaning The aqueous layer was extracted with tBuOMe, and the combined organic layers were dried over Na 2 S 〇 4 and evaporated. The crude product was purified by chromatography (Si 〇 2 : AcOEt / hept) and crystallized from heptane to produce 5 克 (72%) of the title compound as a white solid. MS: (M+H+) + 322.3, (2M+H+) + 643.2. NMR (CDCl3, lH, 5, TMS): 2.23 (s, 3H), 2.38 (s, 3H), 3.03 (t, 2H), 4.35 (t, 2H), 6.94 (dxd, 1H), 7.40-7.45 (m5 3H), 7.66-7.68 (m, 2H), 7.96-. (m, 2H), 9.83 (s, 1H). (:12(27£)-1_oxy-3-{3-甲某_442_(5-甲某-2-苽某-噚岫· 4..-Shame)-Ethoxy-1-moxa-l-butene g* oxime ester 3-methyl-4-[2-(5-methyl-2-phenyl-indazole-4·yl) )-ethoxy]-benzene station (540 mg ' 1.68 mmol) dissolved in 2 ml of ch2C12 and cooled at 0 ° C 'added gasification (benzyloxycarbonyl methoxymethyl) triphenyl scale (丨. 04 grams, 2. 丨 8 millimoles) 'Next join 丨I,3,3_tetramethylguanidine, and the reaction mixture was stirred at room temperature for 3 days, more of the two sulfonium salts and bases (1 equivalent each) were added. The reaction mixture was diluted with AcOEt to a molecular weight of 1 gram. HC1 ice and brine were washed, the aqueous layer was extracted with AcOEt, and the combined organic phases were dried over Na 2 SO 4 and evaporated. The crude product was purified by chromatography (Si〇2; AcOEt/heptane) to leave 6 〇 5 mg (74%) of the title compound. MS: (M+H+) + 484.4 NMR (DMSO-d6, 1H, <5, TMS): 2.10 (s, 3H), 2.36 (s, 3H), 2.96 (t, 2H), 3.67 (s, 3H), 4.25 (t, 2H), 5.25 (s, 2H), 6.81 (s, 1H), 7.00 (dxd, 1H), 7.30- 7.63 (m , 10H), 7.90-7.92 (m, 2H). 164 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm). Ordering 1328585 A7 B7 V. Invention Description (161) Magic _.丄 and racemic 1-2-A 氲-3 "3-methyl-4-"? -(5-甲某-2-苽一-°号°坐·4_棊)--A certain gas, a certain dipropionic acid, treated with 10% Pd-C, dissolved in 5 ml of ethanol, 2 (Ζ, Ε) -Methoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-°oxazol-4-yl)-ethoxy]-phenyl}-propyl hoof Benzyl acetate (6 mg, 1 - 24 mmol) was stirred vigorously at room temperature under a pressure of 7 hr. This was then evaporated over EtOAc EtOAc (EtOAc) (EtOAc:EtOAc: MS : (Μ-Η.)· 394.2. NMR (DMSO-d6, 1H, TMS): 2.05 (s, 3H), 2.36 (s, 3H), 2.71-2.76 (2xdxd, 2xlH), 2.92 (t, 2H), 3.20 (s, 3H), 3.81- 3.85 (m, 1H), 4.16 (t, 2H), 6.84 (dxd, 1H), 6.95-6.97 (m, 2H), 7.48-7.50 (m, 3H), 7.90-7.92 (m, 2H), 12.80 ( Br.s, 1H). Example 1 1 5 f racemic 2-methoxy-3-oxime 3-methylhydro-4-"2-(5-methyl-2-pyrimidin-4-yl)-B I. The base of the vanillyl group and the methanesulfonic acid 2-(5-methyl-2-phenyl-indoleazole-- 4-yl)ethyl ester [PCT Int. Appl_(2000) W00008002] to give 3-methoxy-4-[2-(5-methyl-2-phenyl-phenylindole-4-yl)- Ethoxy]-benz. Treatment of 3-methoxy-4-[2-(5-methyl-2-phenyl-oxazole) with gasification (octyloxymethyloxymethyl)triphenyl 4-yl)-ethoxy]•benzaldehyde, followed by 2(Z,E)-methoxy-3·{3-methoxy-4-[2-(5-methyl-2-benzene) Base-carbazol-4-yl)-ethoxy]-phenyl}-propyl_- 165 -_____ This paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) Binding
線 1328585 A7 '____B7 五、發明説明(162) 烯酲+酯,將其氫化,以產生成為無色固體之[外消旋性卜 2-甲氧基- 3-{3 -甲氧基- 4-[2-(5 -甲基_2 -苯基·»号唑-4·基)- 乙氧基]-苯基}-丙酸。 MS : ( Μ-Η)· 410.4。 NMR (DMSO-d6, 1H, δ, TMS) : 2.36 (s, 3H), 2.76 (dxd, 1H), 2.86 (dxd, 1H), 2.91 (t, 2H), 3.21 (s, 3H), 3.71 (s, 3H), 3.84- 3.88 (m, 1H), 4.14 (t, 2H), 6.70 (dxd, 1H), 6.82 (d, 1H), 6.85 (d, 1H), 7.46-7^.52-(m, 3H), 7.89-7.92 (m, 2H),12.90-(br.s,1H)。 實例1 1 6线1328585 A7 '____B7 V. INSTRUCTION DESCRIPTION (162) Iridinium + ester, which is hydrogenated to give a colorless solid [racemic 2-methoxy-3-methoxy- 4- [2-(5-Methyl-2-phenyl]-oxazole-4-yl)-ethoxy]-phenyl}-propionic acid. MS : ( Μ-Η)· 410.4. NMR (DMSO-d6, 1H, δ, TMS): 2.36 (s, 3H), 2.76 (dxd, 1H), 2.86 (dxd, 1H), 2.91 (t, 2H), 3.21 (s, 3H), 3.71 ( s, 3H), 3.84- 3.88 (m, 1H), 4.14 (t, 2H), 6.70 (dxd, 1H), 6.82 (d, 1H), 6.85 (d, 1H), 7.46-7^.52-( m, 3H), 7.89-7.92 (m, 2H), 12.90-(br.s, 1H). Example 1 1 6
Ll i外消,旋,丨生ΐ - 2·乙氧暴-3_ (4- - 3-甲免&苯某)丙酸乙 IL . 在類似於實例93a]說明的步驟中,將4_爷氧基_ 3_甲氧基 苯越與氣化(乙氧基乙氧羰基甲基)三苯鍀[Tetrahedr〇n 50( 25),7543- 56( 1 994)]反應,以產生3_(4-辛氧基-3-甲氧 基笨基)-2( Z,E)-乙氧基丙稀酸乙酷。如實例9 1 d]的說明, 以3-(4-苄氧基-3-甲氧基苯基)-2(Z,E) -乙氧基丙烯酸乙酯 的氫化作用產生成為無色固體之[外消旋性]_ 2_乙氧基-3_ (4-羥基-3-甲氧基苯基)丙酸乙酯β MS : (Μ)+ 268.1。 NMR (DMSO-d6, 1H, δ, TMS) : l.〇3 (t, 3H), 1.12 (t, 3H), 2.80 (dxd, 2H), 3.30-3.40 (m, 1H), 3.42-3.52 (m, 1H), 3.73 (s, 3H), 4.01-4.09 (m, 3H), 6.57 (dxd, 1H), 6.65 (d, 1H), 6.77 (d,1H), 8.74 (br.s, 1H)。 __- 166 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585 A7 B7 五、發明説明(163) k!_L外消旋性]-2-乙氳某-3- (3-甲氳某-4-『2-(5-甲某-2-赛 基-ρ号唑-4 -基)-乙氣某茉甚卜丙酸乙酯 在類似於實例丨7a]說明的步驟中,將[外消旋性]-2-乙氧 基-3-( 4-羥基-3-甲氧基苯基)丙酸乙酯與2-(2-苯基-5-甲基 啰唑-4-基)乙醇在三苯膦及DBAD(偶氮二羧酸二特丁酯)的 存在下反應’以產生成為無色油之[外消旋性]-2 -乙氧基-3-{3-甲氧基-4-[2-(5-甲基-2-苯基-呤唑-4-基)-乙氧基]-苯基}-丙酸乙酯。 -二. MS : (M+H+)+ 454.3,(M+2H+)+ 455.2。 gl ί外消旋性1-2-乙氣某-3-U-甲氣某-4-「2-〔5-甲基-2-茇 基号唑_4_基)-乙氣某1-笨基丨-丙酸鋰 將[外消旋性]-2-乙氧基-3- {3-甲-氧基-4-[2-(5-甲基- 2-笨基号唑-4-基)-乙氧基]-苯基}-丙酸乙酯(306毫克,0.67 毫莫耳)溶解在3毫升二咩烷及2毫升水中,加入50毫克氫氧 化鋰,並將混合物在室溫下攪拌24小時。接著將反應混合 物以鋰鹽經色層分離(MCI-凝膠;CH3CN/H2〇),以產生成 為白色膠之125毫克(43%)標題化合物。 MS : (M-H)· 424.4。 NMR (DMSO-d6, 1H, 5, TMS) : 0.98 (t, 3H), 2.36 (s, 3H), 2.55 (dxd, 1H), 2.80 (dxd, 1H), 2.85 (t, 2H), 3.05-3.15 (m, 1H), 3.48 (dxd, 1H), 3.52--3.62 (m, 1H), 3.70 (s, 3H), 4.13 (t, 2H), 6.67 (dxd, 1H), 6.80- 6.83 (m, 2H), 7.47-7.51 (m, 3H), 7.92 (dxd,2H)。 實例1 1 7 _- 1β7 - 表紙張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1328585 A7 B7Ll i exogenous, spin, axillary ΐ - 2 · ethoxy storm - 3_ (4--3-methyl free & benzophenone) propionic acid BIL. In a procedure similar to that described in Example 93a], 4_ The reaction of methoxy_3_methoxybenzene with gasified (ethoxyethoxycarbonylmethyl)triphenylhydrazine [Tetrahedr〇n 50(25), 7543-56 (1 994)] to give 3_( 4-octyloxy-3-methoxyphenyl)-2(Z,E)-ethoxypropionic acid. As illustrated in Example 9 1 d], hydrogenation of ethyl 3-(4-benzyloxy-3-methoxyphenyl)-2(Z,E)-ethoxy acrylate yielded a colorless solid. Racemic] _ 2_ethoxy-3-(4-hydroxy-3-methoxyphenyl)propanoic acid ethyl ester β MS : (Μ) + 268.1. NMR (DMSO-d6, 1H, δ, TMS): l.〇3 (t, 3H), 1.12 (t, 3H), 2.80 (dxd, 2H), 3.30-3.40 (m, 1H), 3.42-3.52 ( m, 1H), 3.73 (s, 3H), 4.01-4.09 (m, 3H), 6.57 (dxd, 1H), 6.65 (d, 1H), 6.77 (d, 1H), 8.74 (br.s, 1H) . __- 166 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7 V. Invention description (163) k!_L racemicity]-2-Ethyl -3- ( 3-methyl hydrazine -4- "2-(5-methyl-2-pyridyl-p-azol-4-yl)-ethyl acesulfame ethyl ester in a similar example 丨7a] In the step, [racemic]-2-ethoxy-3-(4-hydroxy-3-methoxyphenyl)propanoic acid ethyl ester with 2-(2-phenyl-5-methylindole) Zyzol-4-yl)ethanol is reacted in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to produce [racemate]-2-ethoxy-3- as a colorless oil {3-Methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester. - II. MS : (M+H+)+ 454.3,(M+2H+)+ 455.2. gl ί racemic 1-2-ethane a certain -3-U-methyl -4-(2-[5-methyl-2) - mercapto azole _4_yl)-ethyl benzene 1-phenyl hydrazine-lithium propionate [racemic]-2-ethoxy-3-{3-methyl-oxy-4-[ 2-(5-Methyl-2-pyromyl-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (306 mg, 0.67 mmol) dissolved in 3 mL of dioxane and Add 2 mg to 2 ml of water Lithium oxide was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then chromatographed with a lithium salt (MCI-gel; CH.sub.3CN/H.sub.2) to give a white powder of 125 mg (43%). MS: (MH) · 424.4. NMR (DMSO-d6, 1H, 5, TMS): 0.98 (t, 3H), 2.36 (s, 3H), 2.55 (dxd, 1H), 2.80 (dxd, 1H) , 2.85 (t, 2H), 3.05-3.15 (m, 1H), 3.48 (dxd, 1H), 3.52--3.62 (m, 1H), 3.70 (s, 3H), 4.13 (t, 2H), 6.67 ( Dxd, 1H), 6.80- 6.83 (m, 2H), 7.47-7.51 (m, 3H), 7.92 (dxd, 2H). Example 1 1 7 _- 1β7 - Table paper scale applicable to China National Standard (CNS) A4 specification (210x 297 mm) 1328585 A7 B7
五、發明説明( f外也兹性〗-3 - 基)-乙氧基1-苽某丨-2-甲氣基丙酸 在類似於實例1 14b]、c]及d]說明的步驟中,將3 5二甲 基-4-羥基苯醛與甲烷磺酸2-(5-曱基-2-苯基-气嗤_4•基)乙 酯[PCT Int· Appl.(2000) W00008002]反應,以得到3 5·二 甲基-4-[2-(5-甲基-2-苯基-哼唑-4-基)-乙氧墓]-苯醛。以 氣化(芊氧羰基甲氧基甲基)三苯鱗處理3,5-二甲基_4_[2_ (5-甲基-2-冬基亏峻-4-基)-&氣基]-苯酸,接著得到3_ {3,5-二甲基-4-[2-(5-甲基-2-苯基-呤唑-4-基)_乙氧基]_ 苯基}-2(Ζ,Ε)·甲氧基丙烯酸苄酯,將其氫化,以產生成為 淺黃色油之[外消旋性]-3- { 3,5-二甲基-4- [2-(5-甲基_2·苯 基-哼唑-4 -基)-乙氧基]-苯基卜2-甲|基丙酸。 MS : (M-H)· 408.2。 NMR (DMSO-d6, 1H, 5, TMS) : 2.09 (s, 6H), 2.38 (s, 3H), 2.67-2.80(2xdxd, 2xlH), 2.91 (t, 2H), 3.20 (s, 3H), 3.84-3.90 (m, 1H), 3.95 (t, 2H), 6.82 (s, 2H), 7.45-7.55 (m, 3H), 7.92 (dxd, 2H), 12.8 (br.s,1H)。 實例1 1 8 al 2 -輕基-4-「2-(5-甲基-2-笨基-巧g全-4-基)-乙氧.某:卜笨越 將在20毫升THF中的2,4-二羥基苯醛(2公克,14.5毫莫耳) 之溶液冷卻至0°C。將三苯膦(9.7公克,37毫莫耳)、2-(2-苯基-5-甲基咩唑-4-基.)乙醇(2.84公克,14毫莫耳)及最後 在0.75小時期間以在20毫升THF中的偶氮二羧酸二第三丁酯 (8.5 2公克,3 7毫莫耳)之溶液加入該溶液中。將反應混合 ------ ifift - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱) 1328585 A7 ____ B7 五、發明説明(165) 物在室溫下授:拌隔夜,蒸發至乾燥,以色層分離法(Si〇2; AcOEt/庚烷)純化,並自AcOEt/醚/庚烷結晶產物,以產生 成為播色固體之2.2公克(46%)產物。 NMR (CDC13, 1H, 5, TMS) : 2.37 (s, 3H), 2.97 (t, 2H), 4·31 (t, 2H), 6.44 (d, 1H), 6.53 (dxd, 1H), 7.39-7.43 (m, 4H),7.95-7.99 (m,2H), 9.70 (s,1H),11.42 (s, 1H)。 2-( 4-甲氧基芊氳基)-4-「2-(5 -甲某-2-笨某-崎唑-4-基)-I氧基1 -苽醛 將在6毫升甲笨及5毫升水中的2-經基-4-[2-(5-甲基-2-苯 基-°号嗤-4-基)-乙氧基]•苯醛(54毫克,0.167毫莫耳)、4-甲氧基苄基氣(58毫克,0.368毫莫耳)、ΚΟΗ(56毫克,1毫 莫耳)及四丁基硫酸氫録( 5 〇毫克)之-混合物在8 〇 ec下加熱6 小時。接著將反應混合物冷卻至〇t,以水/冰及食鹽水清 洗’將水層以AcOEt萃取,將合併的有機層經Na2s〇4乾燥 及蒸發。將粗產物以色層分離法(Si〇2 ; AcOEt/庚烷)純 化’並自庚烷結晶產物,以產生成為白色固體之2 5毫克 (34%)產物。 MS : (M+H+)+ 444.4, (M+Na+)+ 466.3 = NMR (CDC13, 1H, δ , TMS) : 2.37 (s, 3H), 2.99 (t, 2H), 3.82 (s, 3H), 4.31 (t, 2H), 5.06 (s, 2H), 6.52 (d, 1H), 6.55 (dxd, 1H), 6.91 (d, 2H), 7:33 (d, 2H), 7.40-7.43 (m, 3H), 7.80 (d,1H), 7.98 (dxd, 2H),10_32 (s,iH)。 £]2(2,£)-甲氣基-3-{2-(4-甲氣基芊氧亭)-4『2_(5_甲基_ 夺基-坐-4-基)-乙氧基1-装基丨-丙餘酿y啼 ____- 169 - 本纸張尺度適用中國國家標準(CNS) A4规格(210 K 297公釐) 1328585 A7 __B7 五、發明説明(166) 將2-(4-甲氧基芊氧基)_4-[2-(5-甲基-2-苯基-σ号唑-4-基)-乙氧基]-苯醛(400毫克,0.90毫莫耳)溶解2毫升CH2C12 中及冷卻至〇°C ’加入氯化(苄氧羰基甲氧基甲基)三苯鱗(實 例114a] )(1.04公克,2.18毫莫耳),接著加入l,l,3,3-四甲基 胍(丨毫升’ 8毫莫耳),並將反應混合物在室溫下攪拌3天, 接著將其以AcOEt稀釋,以HC1( 1克分子量)/冰及食鹽水清 洗,將水層以AcOEt萃取》將合併的有機相經Na2S04乾燥 及蒸發。將粗產物以色層分-離法(Si02 ; AcOEt/庚烷)純 化,以留下-成為油之424毫克(純度50% )標題化合物。-MS : (M+H+)+ 606.0,(M+Na+)+ 628.1。 41 f外消旋性1-3-(2-鞀某-4-「2-(5-甲某-2-茉某-噚唑-4-基)-乙氧基1-笨基丨-2-甲氣某丙酸- 將2(Z,E) -甲氧基-3- {2-(4-甲氧基芊氧基)-4-[2-(5-甲 基-2-苯基-咩唑_4·基)_乙氧基]-苯基卜丙烯酸苄酯(360毫 克,0.6毫莫耳)溶解在5毫升AcOEt中,並將反應混合物在 1 0% Pd- C的存在下及在室溫的H2氣壓下劇烈攪拌1 8小時。 接著將其經由C鹽過濾,蒸發,經色層分離(MCI-凝膠, CH3CN,H20)及結晶(AcOEt/庚烷),以產生成為白色固體 之30毫克(1 3%)標題化合物。 MS : (M+H+)+ 398.3 ° NMR (DMSO-d6, 1H, 6, TMS) : 2.36 (s, 3H), 2.55 (dxd, 1H), 2.87-2.92 (m, 3H), 3.25 (s, 3H), 3.46 (m, 1H), 4.10 (t, 2H), 6.24-6.26 (m, 2H), 6.90 (d, 1H), 7.48-7.50 (m, 3H), 7·90·7_92 (m, 2H),12.80 (br.s, 2H)。 ____- 170 -__ 本紙張尺度適用中國國家標準(CNS> A4規格(210 x 297公釐) 1328585 A7 B7 五、發明説明( 167 實例I 1 9 ^(2,£)-._玄氧羰基胺某-3-{3-甲某-4-「2-(5-甲某-2-茉甚-4 -基)-乙氧甚卜笨基丨_丙锍龄甲酿 將N-(卞氧羰基)· α -二氧磷甘胺酸三曱酯(773毫克,2 33 笔莫耳)及接著將胡尼格氏鹼(〇5毫升)加入冷卻至之在2 毫升及1毫升THF中的3-甲基-4-[2-(5-甲基-2-苯基-5吐-4-基)-乙氧基卜苯醛(5〇〇毫克,156毫莫耳)(實例 1 14b))之溶液中’並將反應混免物在室溫下攪拌6小時。接 著將其以AcOEt稀釋,以HC1 1克分子量/冰及食鹽水清洗, 將水層以AcOEt萃取’將合併的有機相經1^幻3〇4乾燥及蒸 發。將粗產物以色層分離法(Si〇2 ; AcOEt/庚烷)純化及結 曰日(AcOEt/庚烷)’以留下成為白色固體之548毫克(67%)標 題化合物。 MS : (M+H+)+ 527.2 〇 NMR (DMSO-d6, 1H, (5, TMS) : 2.06 (s, 3H), 2.36 (s, 3H), 2.96 (t, 2H), 3.69 (s, 3H), 4.26 (t, 2H), 5.10 (s, 2H), 6.99 (d, 1H), 7.23-7.40 (m, 6H), 7.45- 7.55 (m, 5H), 7.90-7.92 (m, 2H),9.01 (br.s,1H)。 kl「外旋性1-2 -胺基-3- {3 -甲基- 4- f2-(5-甲基-2-笑基 ?坐-4-某)-乙氣基1-笨基丨-丙酸甲酷镑祐睡 將溶解在20毫升AcOEt中-的2(Z,E) -苄氧羰基胺基_3]3_ 甲基-4-[2-(5 -甲基-2-苯基咢唑-4-基)_乙氧基]-苯基卜丙 烯酸甲酯(552毫克,1.05毫莫耳)在Pd-C的存在下及在 室溫的Η?氣壓下劇烈攪拌1 6小時。接著將反應混合物經由c _____- 171 - 本虼張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)V. INSTRUCTIONS OF THE INVENTION (f-external) -3 -yl)-ethoxy 1-indole-2-carbopropionic acid in a procedure similar to that described in Examples 1 14b], c] and d] , 3 5 dimethyl-4-hydroxybenzaldehyde and 2-(5-fluorenyl-2-phenyl-azain-4-yl)ethyl methanesulfonate [PCT Int· Appl. (2000) W00008002] The reaction was carried out to obtain 3 5 · dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxytomb]-benzaldehyde. Treatment of 3,5-dimethyl-4_[2_(5-methyl-2-methylene-hydroxy-4-yl)-< gas base with gasification (芊 oxycarbonylmethoxymethyl)triphenyl scale ]-benzoic acid, followed by 3_{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}- 2 (Ζ,Ε)·benzyl methacrylate, which is hydrogenated to give [racemic]-3-{3,5-dimethyl-4-[2-(5) as a pale yellow oil. -Methyl-2.phenyl-indazol-4-yl)-ethoxy]-phenyl-2-methyl-propionic acid. MS: (M-H)· 408.2. NMR (DMSO-d6, 1H, 5, TMS): 2.09 (s, 6H), 2.38 (s, 3H), 2.67-2.80 (2xdxd, 2xlH), 2.91 (t, 2H), 3.20 (s, 3H), 3.84-3.90 (m, 1H), 3.95 (t, 2H), 6.82 (s, 2H), 7.45-7.55 (m, 3H), 7.92 (dxd, 2H), 12.8 (br.s, 1H). Example 1 1 8 al 2 -Lightyl-4-"2-(5-methyl-2-phenyl-co-g-all-4-yl)-ethoxy. Some: Bu will be in 20 ml of THF A solution of 2,4-dihydroxybenzaldehyde (2 g, 14.5 mmol) was cooled to 0 ° C. Triphenylphosphine (9.7 g, 37 mmol), 2-(2-phenyl-5-A) Ketrazole-4-yl.)ethanol (2.84 g, 14 mmol) and finally dibutyl azodicarboxylate (8.5 2 g, 3 7 m) in 20 ml of THF over a period of 0.75 h A solution of Mohr) is added to the solution. Mix the reaction ------ ifift - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 1328585 A7 ____ B7 V. Description of invention (165 The material is allowed to stand at room temperature: it is stirred overnight, evaporated to dryness, purified by chromatography (Si 〇 2; AcOEt / heptane), and the product is crystallized from AcOEt / ether / heptane to give a smear solid. 2.2 g (46%) product NMR (CDC13, 1H, 5, TMS): 2.37 (s, 3H), 2.97 (t, 2H), 4·31 (t, 2H), 6.44 (d, 1H), 6.53 (dxd, 1H), 7.39-7.43 (m, 4H), 7.95-7.99 (m, 2H), 9.70 (s, 1H), 11.42 (s, 1H). 2-(4-methoxyindenyl) -4-"2-( 5-A-A-2-Butm-S-oxazol-4-yl)-I-oxyl-furfural will be 2-amino-4-[2-(5-A) in 6 ml of acetaminophen and 5 ml of water Benzyl-2-phenyl-[嗤-4-yl)-ethoxy]benzaldehyde (54 mg, 0.167 mmol), 4-methoxybenzyl gas (58 mg, 0.368 mmol) The mixture of hydrazine (56 mg, 1 mmol) and tetrabutyl hydrogen sulphate (5 〇 mg) was heated at 8 〇ec for 6 hours. The reaction mixture was then cooled to 〇t with water/ice and salt. Water-washing' The aqueous layer was extracted with AcOEt, and the combined organic layers were dried and evaporated over Na.sub.2, and the crude product was purified by chromatography (Si.sub.2; AcOEt/heptane) and crystallized from heptane. To give a product of 25 mg (34%) as a white solid. MS: (M+H+) + 444.4, (M+Na+)+ 466.3 = NMR (CDC13, 1H, δ, TMS): 2.37 (s, 3H) , 2.99 (t, 2H), 3.82 (s, 3H), 4.31 (t, 2H), 5.06 (s, 2H), 6.52 (d, 1H), 6.55 (dxd, 1H), 6.91 (d, 2H), 7:33 (d, 2H), 7.40-7.43 (m, 3H), 7.80 (d, 1H), 7.98 (dxd, 2H), 10_32 (s, iH). £]2(2,£)-Methane-based-3-{2-(4-Methane-based oxime)-4『2_(5_Methyl_ 夺基-坐-4-yl)-Ethoxy Base 1 - Packing 丨 - 丙余 brewing y啼 ____ - 169 - This paper scale applies to China National Standard (CNS) A4 specification (210 K 297 mm) 1328585 A7 __B7 V. Invention Description (166) (4-methoxydecyloxy)_4-[2-(5-methyl-2-phenyl-σ-oxazol-4-yl)-ethoxy]-benzaldehyde (400 mg, 0.90 mmol) Dissolve 2 ml of CH2C12 and cool to 〇 °C 'Add chlorinated (benzyloxycarbonylmethoxymethyl) triphenyl scale (Example 114a)) (1.04 g, 2.18 mmol), then add l, l, 3,3-Tetramethylhydrazine (丨 ml '8 mmol), and the reaction mixture was stirred at room temperature for 3 days, then diluted with AcOEt, washed with HC1 (1 g molecular weight) / ice and brine The aqueous layer was extracted with AcOEt. The combined organic phases were dried over Na 2 SO 4 and evaporated. The crude product was purified by EtOAc (EtOAc) (EtOAc) elute -MS : (M+H+)+ 606.0, (M+Na+)+ 628.1. 41 f racemic 1-3-(2-鼗-4-(2-(5-methyl-2-methyl-oxazol-4-yl)-ethoxy 1-phenyl]-2 -Methane a propionic acid - 2(Z,E)-methoxy-3-{2-(4-methoxyindolyl)-4-[2-(5-methyl-2-phenyl) -carbazole _4·yl)-ethoxy]-phenyl benzyl acrylate (360 mg, 0.6 mmol) dissolved in 5 mL of AcOEt and the reaction mixture in the presence of 10% Pd-C And vigorously stirring for 18 hours at room temperature under H2 pressure. Then it was filtered through C salt, evaporated, chromatographed (MCI-gel, CH3CN, H20) and crystals (AcOEt/heptane) to give 30 mg (1 3%) of the title compound as a white solid. MS: (M+H+) + 398.3 ° NMR (DMSO-d6, 1H, 6, TMS): 2.36 (s, 3H), 2.55 (dxd, 1H), 2.87-2.92 (m, 3H), 3.25 (s, 3H), 3.46 (m, 1H), 4.10 (t, 2H), 6.24-6.26 (m, 2H), 6.90 (d, 1H), 7.48-7.50 ( m, 3H), 7·90·7_92 (m, 2H), 12.80 (br.s, 2H). ____- 170 -__ This paper scale applies to Chinese national standards (CNS> A4 size (210 x 297 mm) 1328585 A7 B7 V. INSTRUCTIONS (167 EXAMPLE I 1 9 ^(2, £)-._X-Oxocarbonylamine A-3-{3- -4-"2-(5-甲某-2-莫甚-4 -yl)-ethoxy oxabene 丨 锍 锍 锍 将 将 将 N N (卞 羰 carbonyl) · α - dioxophos Trimethyl sulphate (773 mg, 2 33 moles) and then added to the 3-methyl-4-[2] cooled to 2 mL and 1 mL of THF. -(5-Methyl-2-phenyl-5-prop-4-yl)-ethoxybenzaldehyde (5 mg, 156 mmol) (Example 1 14b)) The admixture was stirred at room temperature for 6 hours. It was then diluted with AcOEt, washed with HC1 1 g molecular weight/ice and brine, and the aqueous layer was extracted with AcOEt. The combined organic phases were dried over 1×3D4. And evaporation. The crude product was purified by chromatography (EtOAc: EtOAc (EtOAc): EtOAc (EtOAc) : (M+H+)+ 527.2 NMR (DMSO-d6, 1H, (5, TMS): 2.06 (s, 3H), 2.36 (s, 3H), 2.96 (t, 2H), 3.69 (s, 3H) , 4.26 (t, 2H), 5.10 (s, 2H), 6.99 (d, 1H), 7.23-7.40 (m, 6H), 7.45- 7.55 (m, 5H), 7.90-7.92 (m, 2H), 9.01 (br.s, 1H). Kl "external 1-2-amino-3-{3-methyl- 4-f2-(5-methyl-2- laughing group? sit-4-)-ethane group 1-stupyl group - Propionate A Kubo Pound will dissolve in 2 ml of AcOEt - 2 (Z, E) -benzyloxycarbonylamino 3 - 3] 3 - methyl-4-[2-(5 -methyl-2-benzene Ketrazole-4-yl)-ethoxy]-phenyl methacrylate (552 mg, 1.05 mmol) was vigorously stirred in the presence of Pd-C at room temperature under a pressure of 16 hours. The reaction mixture is then applied to the Chinese National Standard (CNS) A4 specification (210X 297 mm) via c _____- 171 - this scale.
裝 訂Binding
線 1328585 A7 -------B7 五、發明説明(168) 鹽過遽’蒸發’經色層分離(Si〇2 ; AC〇Et)及結晶產物(在 链中的HC1) ’以產生成為白色固體之174毫克(40〇/〇)標題化 合物。 MS : (m+H+)+ 395.4 » NMR (DMSO-d6, 1H, δ , TMS) : 2.07 (s, 3H), 2.37 (s, 3H), 2 93 (t, 2H), 2.95-3.06 (m, 2H), 3.67 (s, 3H), 4.18 (t, 2H), 6.89-6.99 (m, 3H), 7.47-7.52 (m, 3H), 7.90-7.92 (m, 2H), 8.45 (br.s, 3H)。 -- 卜消旋-性卜3-{3-甲基·4·「2“5_甲某_2_芡某-崎唑·4· 羞)-乙氧某卜苯基}-2-(1-甲基-3-氣某-3-苽某-m -丙烯胺 基)丙醢甲酯 將在茴香醚(20毫升)中的[外消旋性]_ 2_胺基· 3_ { 3·甲基_ 4- [2-(5-甲基-2-苯基-»号唑-4-基)-乙氧基]-苯基}_丙酸甲 酯[1.83公克’ 4.64毫莫耳,經由HC1鹽(二氣甲烷,水性碳 酸鈉)的萃取作用所獲得的]與苯醯基丙酮(7.52公克,46毫 莫耳)之混合物在1 90 °C下回流3天,蒸發,經色層分離 (Si〇2 ; AcOEt/庚烷)及結晶’以輸送白色粉末之840毫克 (33%)標題化合物。 MS : (M+H+)+ 539.3。 NMR (DMS0-d6, 1H, <5, TMS) : 1.88 (s, 3H), 2.03 (s, 3H), 2.33 (s, 3H), 2.93 (t, 2H),-2.95 (dxd, 1H), 3.02 (dxd, 1H), 3.67 (s, 3H), 4.17 (t, 2H), 4.63-4.69 (m, 1H), 5.76 (s, 1H), 6.87 (d, 1H), 6.97-6.99 (m, 2H), 7.40-7.49 (m, 6H), 7.82 (dxd,2H),7.91 (dxd,2H), 11.4 (s, 1H)。 __- 172 -_____ 本纸張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 1691328585 -173 - 發明説明( 甲某-2 4其-,叶4 基)丙酸,病轉η : ο μ -^-Ώ-^k. 在類似於實例觀]說明的步驟中,將[外消旋性卜 甲基-4-[2·^5-甲基_2·苯基、峻.4·基)·乙氧基卜笨基卜2- (1-甲基-3-氧基_3_苯基.(ζ)_丙缔胺基)丙酸甲醋琶化,以 產生W消旋性]-3-{3·甲基·4_[2·(5•甲基_2苯基号啥心 基)-乙氧基]-苯基}-2-(1-曱基二3·氧基_3苯基_(ζ)丙埽胺 基)丙酸(0.798公克’ Κ52毫莫耳),將其溶解在三乙胺 (2.28。毫莫耳)存在下的1〇毫升乙醇中。將反應混合物加熱 至60°C經70分鐘,冷卻至室溫,並經15分鐘加入在5毫升水 中的Ca (CH3CO〇)2(i32毫克,〇 84毫莫耳)之溶液中。將懸 浮液以50毫升水稀釋,冷卻及㈣1小時。以過遽分離^ 鹽,以50毫升水清洗及乾燥,以獲得灰白色固體(62〇毫 克,75%) 〇 MS : (M-H)_ 523.1。 NMR (DMSO-d6> 1H, 5 , TMS) : 1.65 (s, 3H), 2.01 (s, 3H), 2.33 (s, 3H), 2.68 (dxd, 1H), 2.89 (t, 2H), 3.12 (dxd, 1H), 3.95-4.02 (m, 1H), 4.14 (t, 2H), 5.15 (s, 1H), 6.81 (d, 1H), 6.97-6.99 (m, 2H), 7.37-7.49( 2m, 2x3H), 7.76 (dxd, 2H), 7.90 (dxd, 2H), 1 1.4 (d, 1H)。 實例120 al 4- y氧某芄并4 _ 將在N,N_二曱基甲醯胺(8毫升)中的4-羥基苯并呋喃(2.6 本纸張尺度適用中國國家標準(CNS) A4规格(2ι〇χ297公釐) 訂 線 1328585 A7 B7 五、發明説明(170) 公克’ 1 9.4毫莫耳)之溶液(關於4_經基苯并咬喃的製備作 用’參考.G. ICneen,P, J. Maddocks,Syn. Commun. 1986, 1 6,1 63 5- 1 640)在2C的氬氣下加入在n,N-二甲基甲醯胺(8 毫升)中的碳酸鉀(2.68公克’ 19.4毫莫耳)之懸浮液中。在2 °C下攪拌50分鐘之後,在2°C下經15分鐘加入苄基溴(3.3毫 升’ 19.4毫莫耳)。將懸浮液在2。(:下再攪拌30分鐘及在室 溫下再攪拌1.5小時。在加入冰水(20毫升)之後,將溶液以 二***萃取兩次。將合併的萃!物以食鹽水清洗三次及經 硫酸鈉乾燥。以蒸發溶劑得到黃色油,將其以管柱色層分 離法(矽膠,己烷)純化,以得到成為無色油之4.3公克(1 9.2 毫莫耳,99%)標題化合物。 MS : 224.1 (M) +,91.2。 一 NMR : (CDC13, 1H, 400MHz, (5 , TMS) 5.21 (s, 2H), 6.72 (d, J=8, 1H), 6.91 (d, J=2, 1H), 7.14-7.26 (m, 2H), 7.31-7.42 (m, 3H), 7.48 (d, J=8, 2H),7.54 (d, J=2,1H)。 bl 氣基笨并p夫喃-7-卷兹 將無水N,N-二甲基甲醯胺(12.1公克,166毫莫耳)在氬氣 下以攪拌及冷卻逐滴加入磷醯氣(1 1.4公克,75毫莫耳) 中,該加入速度使溫度不超過1 〇 °C。在1 〇 °c下3 0分鐘之 後,在30分鐘之内加入在N,N-二甲基甲醯胺(9毫升)中的4-芊氧基笨并呋喃(9.3公克,_41毫莫耳)之溶液。將反應混合 物在室溫下攪拌30分鐘及接著持續加熱至100。(:。在l〇〇°C 下10分鐘之後,將混合物在8 5 °C下加熱3小時,冷卻至10 。(:,以25%水性醋酸鈉以冷卻中和,並以二***萃取。將 _____- 174 -_____ 本紙張尺度適用中國國家標竿(CNS) A4規格(210X 297公釐)Line 1328085 A7 -------B7 V. Description of the invention (168) Salt 遽 'evaporation' by chromatographic separation (Si〇2; AC〇Et) and crystalline product (HC1 in the chain)' 174 mg (40 〇 / 〇) of the title compound as a white solid. MS : (m+H+)+ 395.4 » NMR (DMSO-d6, 1H, δ, TMS) : 2.07 (s, 3H), 2.37 (s, 3H), 2 93 (t, 2H), 2.95-3.06 (m , 2H), 3.67 (s, 3H), 4.18 (t, 2H), 6.89-6.99 (m, 3H), 7.47-7.52 (m, 3H), 7.90-7.92 (m, 2H), 8.45 (br.s , 3H). -- 卜消旋-性卜3-{3-Methyl·4·"2"5_甲某_2_芡某-Sakizol·4· Shame)-Ethoxyphene phenyl}-2-( 1-methyl-3-oxan-3-indole-m-propenylamino)propanoxime methyl ester in the anisole (20 ml) [racemic]_ 2_amino group · 3_ { 3 Methyl 4-[2-(5-methyl-2-phenyl-»oxazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester [1.83 g] 4.64 mmol a mixture of phenylhydrazinone (7.52 g, 46 mmol) obtained by extraction of HC1 salt (dioxethane, aqueous sodium carbonate) was refluxed at 1 90 ° C for 3 days, evaporated, and colored. The layers were separated (Si 〇 2 ; AcOEt / heptane) and crystallized to afford 840 mg (33%) of the title compound as white powder. MS: (M+H+)+ 539.3. NMR (DMS0-d6, 1H, <5, TMS): 1.88 (s, 3H), 2.03 (s, 3H), 2.33 (s, 3H), 2.93 (t, 2H), -2.95 (dxd, 1H) , 3.02 (dxd, 1H), 3.67 (s, 3H), 4.17 (t, 2H), 4.63-4.69 (m, 1H), 5.76 (s, 1H), 6.87 (d, 1H), 6.97-6.99 (m , 2H), 7.40-7.49 (m, 6H), 7.82 (dxd, 2H), 7.91 (dxd, 2H), 11.4 (s, 1H). __- 172 -_____ This paper size applies to Chinese National Standard (CNS) A4 specification (210x 297 mm) 1691328585 -173 - Description of invention (A-2-2 4, -4 base) propionic acid, disease conversion η: ο μ -^-Ώ-^k. In a procedure similar to that described in the example], [racemic methyl-4-[2·^5-methyl_2·phenyl, ..4·yl) Ethoxy phenyl bromide 2-(1-methyl-3-oxy_3_phenyl.(ζ)_propyl-propylamino)propionic acid methyl hydrazide to give W racemability] -3-{3·Methyl·4_[2·(5•methyl_2phenyl fluorenyl)-ethoxy]-phenyl}-2-(1-indolyl 2 oxy) 3-Phenyl-(indolyl)propanyl)propionic acid (0.798 g' Κ52 mmol) was dissolved in 1 mL of ethanol in the presence of triethylamine (2.28 mmol). The reaction mixture was heated to 60 ° C for 70 minutes, cooled to room temperature, and added to a solution of Ca(CH3CO?) 2 (i.sup.32 mg, 〇 84 mM) in 5 ml of water over 15 minutes. The suspension was diluted with 50 ml of water, cooled and (iv) 1 hour. The salt was separated by hydrazine, washed with 50 ml of water and dried to give an off-white solid (62 g, 75%) 〇 MS : (M-H) _ 523.1. NMR (DMSO-d6 > 1H, 5, TMS): 1.65 (s, 3H), 2.01 (s, 3H), 2.33 (s, 3H), 2.68 (dxd, 1H), 2.89 (t, 2H), 3.12 ( Dxd, 1H), 3.95-4.02 (m, 1H), 4.14 (t, 2H), 5.15 (s, 1H), 6.81 (d, 1H), 6.97-6.99 (m, 2H), 7.37-7.49 ( 2m, 2x3H), 7.76 (dxd, 2H), 7.90 (dxd, 2H), 1 1.4 (d, 1H). Example 120 al 4- y oxo and 4 _ 4-hydroxybenzofuran in N,N-dimercaptocaramine (8 ml) (2.6 paper scale applicable to Chinese National Standard (CNS) A4 Specification (2 〇χ 〇χ 297 mm) Setting line 1325885 A7 B7 V. Description of invention (170) Solution of gram '1 9.4 millimoles (for preparation of 4_ benzopyrene) Reference. G. ICneen, P, J. Maddocks, Syn. Commun. 1986, 1 6,1 63 5- 1 640) Potassium carbonate in n,N-dimethylformamide (8 ml) was added under argon at 2C (2.68) In the suspension of grams ' 19.4 millimoles'. After stirring at 2 ° C for 50 minutes, benzyl bromide (3.3 ml liter ' 19.4 mmol) was added over 15 minutes at 2 °C. Place the suspension at 2. (: stirring for another 30 minutes and stirring at room temperature for another 1.5 hours. After adding ice water (20 ml), the solution was extracted twice with diethyl ether. The combined extracts were washed three times with brine and sulfuric acid. The title compound was obtained as a colorless oil (yield: EtOAc, hexane). 224.1 (M) +, 91.2. NMR: (CDC13, 1H, 400MHz, (5, TMS) 5.21 (s, 2H), 6.72 (d, J=8, 1H), 6.91 (d, J=2, 1H ), 7.14-7.26 (m, 2H), 7.31-7.42 (m, 3H), 7.48 (d, J=8, 2H), 7.54 (d, J=2,1H). bl gas base stupid and puff -7-Rolled anhydrous N,N-dimethylformamide (12.1 g, 166 mmol) was added dropwise with stirring and cooling under argon (1 1.4 g, 75 mmol) In this case, the addition speed is such that the temperature does not exceed 1 〇 ° C. After 30 minutes at 1 〇 ° c, 4- in N,N-dimethylformamide (9 ml) is added within 30 minutes. a solution of decyloxyfuran (9.3 g, _41 mmol). Stir at room temperature for 30 minutes and then continue heating to 100. (: After 10 minutes at 10 ° C, the mixture was heated at 85 ° C for 3 hours and cooled to 10 ° (:, 25% aqueous) Sodium acetate is neutralized by cooling and extracted with diethyl ether. _____- 174 -_____ This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)
線 1328585 A7 B7 五、發明説明( 171 萃取物以飽和水性碳酸氫鈉及水清洗,並經硫酸納乾燥。 在減壓下除去溶劑,以得到棕色油,將其以管柱色層分離 法(ί夕膠’己燒/ AcOEt= 1 9/1)純化,以得到成為黃色油之 1.8公克(7毫莫耳,17%)標題化合物。 MS : 252.1 (M) +,91.1。 NMR : (CDC13, 1H, 400MHz, 5 , TMS) 5.30 (s, 2H), 6.85 (d, J=8, 1H), 6.97 (d, J=2, 1H), 7.36-7.48 (m, 5H), 7.69 (d, J=2, 1H), 7.75 (d, J=8, 1H),lO:24-(s,1H)。 吐( 4-苄氧基苯并吱喃-7-基)-2Z-乙氩I雨烯酸乙酷 將在THF( 40毫升)中的氯化(乙氧基乙氧羰基.曱基)三苯鳞 (2.04公克,4.8毫莫耳)及〇811(0.8公克,5.2毫莫耳)之懸浮 液在室溫的氬氣下措:拌10分鐘[關於氯化(乙氧基乙氧凝基 甲基)三苯鱗的製備作用,參考:Κ. K. Bach,H. R EI. Seedi, Η. Μ. Jensen, Η. Β. Nielsen, I. Thomson, Κ.. Β G Torssell,Tetrahedron 1994, 50, 7543-7556]。加入 4-爷氧基 苯并呋喃-7-羧盤(〇_8公克,3.2毫莫耳),並將混合物在回 流下加熱1 2小時。將溶劑在減壓下濃縮,將殘餘物以醋酸 乙酯處理’以Nh^C丨飽和水溶液清洗及以食鹽水清洗兩次。 將有機層經硫酸鈉乾燥’在減壓下除去溶劑,並將殘餘物 以管柱色層分離法(矽膠,己烷/Ac〇Et=9/l)純化,以得到 成為無色油之0.8公克(2·2毫莫耳,69%)標題化合物。 MS : 366.1 (Μ) +,275.1,173.0, 91.1。 NMR : (CDC13, 1H, 400ΜΗζ, δ , TMS) 1.3 7- 1.45 (m, 6H), 4.04 (q, J=8, 2H), 4.32 (q, J=8, 2H), 5.24 (s, 2H), 6.77 (d,Line 1328585 A7 B7 V. Description of the invention ( 171 The extract is washed with saturated aqueous sodium hydrogencarbonate and water, and dried over sodium sulfate. The solvent is removed under reduced pressure to give a brown oil, which is obtained by column chromatography. Purification to give the title compound as a yellow oil (1.8 g, 7 mmol, 17%). MS: 252.1 (M) +, 91.1. NMR: (CDC13 , 1H, 400MHz, 5 , TMS) 5.30 (s, 2H), 6.85 (d, J=8, 1H), 6.97 (d, J=2, 1H), 7.36-7.48 (m, 5H), 7.69 (d , J=2, 1H), 7.75 (d, J=8, 1H), lO:24-(s,1H). Spit (4-benzyloxybenzopyran-7-yl)-2Z-ethyl argon I uric acid acetyl chloride (ethoxy ethoxycarbonyl. fluorenyl) triphenyl scale (2.04 g, 4.8 mmol) and 〇811 (0.8 g, 5.2 mmol) in THF (40 ml) The suspension of the ear) was argon at room temperature: mixing for 10 minutes [for the preparation of chlorinated (ethoxyethoxymethyl) methyl triphenyl scales, reference: Κ. K. Bach, H. R EI. Seedi, Η. Μ. Jensen, Η. Β. Nielsen, I. Thomson, Κ.. Β G Torssell, Tetrahedron 1994, 50, 7543-7556]. Benzofuran-7-carboxylate (〇_8 g, 3.2 mmol), and the mixture was heated under reflux for 12 h. The solvent was concentrated under reduced pressure and the residue was treated with ethyl acetate. ^C丨Aqueous saturated aqueous solution and washed twice with brine. The organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane, hexane/Ac 〇Et = 9/l) Purification to give 0.8 g (2·2 mmol, 69%) of the title compound as a colorless oil. MS: 366.1 (Μ) +, 275.1, 173.0, 91.1. NMR : (CDC13, 1H, 400ΜΗζ , δ , TMS) 1.3 7- 1.45 (m, 6H), 4.04 (q, J=8, 2H), 4.32 (q, J=8, 2H), 5.24 (s, 2H), 6.77 (d,
訂Order
線 1328585 A7 _____B7 五、發明説明(172) J=9, 1H), 6.92 (d, J=2> 1H), 7.33-7.49 (m, 5H), 7.53 (s, 1H), 7.58 (d, J=2, 1H), 8.Ϊ5 (d, J=8, 1H)。 虹[外#旋性卜3- dy氧基苯幷呤喃-7·某u 2_ Λ敉其兩酷 曱酯 將鎂屑(0.5公克,20.6毫莫耳)在室溫下加入在甲醇(26毫 升)及THF(13毫升)中的3_(4·芊氧基苯并呋喃_7基)_2Ζ•乙 氧基丙烯酸乙酯(0.8公克,2.18毫莫耳)之攪拌溶液中。將 懸浮液溫熱至40°C ,直到開始巷出氫氣為止。接著以水浴 代替加熱浴加熱額外鎂屑(1公克,41 2毫莫耳)及將反應 混合物持續攪拌12小時。將懸浮液冷卻至〇艺,接著加入 25%水性氫氯酸’直到所有固體溶解為止。將混.合物以醋 酸乙酯萃取兩次,將合併的醋酸乙酯溶液以水清洗三次及 經硫酸鈉乾燥。將溶劑蒸發,以供給標題化合物(〇.77公 克,2」6毫莫耳,99%),在以下步驟中使用未進一步純化 的該化合物。 MS : 354.2 (M) +,237.2, 91_2。 NMR : (CDC13, 1H, 400MHz, 5 , TMS) M2 (t, J=7.2, 3H) 3.19-3.38 (m, 3H), 3.55-3.61 (m, 1H), 3.68 (s, 3H), 4.23 (dxd, J=8.8, J=6.4, 1H), 5.18 (s, 2H), 6.65 (d, 1H), 6.90 (d, J=2.4, 1H), 7.05 (d, J=8.8, 1H), 7.34-7 42 (m 3H) 7.47 (d, J=8, 2H), 7.55 (d, J=2.4, 1H)。 ’ ’ g」i外消旋性1·2-乙氧基-3-(4-癖基)丙醢甲 將二甲硫(4·4毫升’ 6G$莫耳)及三氟化硼二乙則鄉純 -176 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585Line 1328585 A7 _____B7 V. Description of invention (172) J=9, 1H), 6.92 (d, J=2> 1H), 7.33-7.49 (m, 5H), 7.53 (s, 1H), 7.58 (d, J =2, 1H), 8.Ϊ5 (d, J=8, 1H). Rainbow [External #旋性卜3- dy oxybenzoquinone-7·a u 2_ Λ敉 曱 两 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 In a stirred solution of ethyl 3-(4-decyloxybenzofuran-7-yl)-2-indole•ethoxy acrylate (0.8 g, 2.18 mmol) in THF and THF (13 mL). The suspension was warmed to 40 ° C until the start of hydrogen evolution. The additional magnesium dust (1 gram, 41 2 millimoles) was then heated in a water bath instead of the heating bath and the reaction mixture was continuously stirred for 12 hours. The suspension was cooled to the hydrazine and then 25% aqueous hydrochloric acid was added until all solids dissolved. The mixture was extracted twice with ethyl acetate, and the combined ethyl acetate solution was washed three times with water and dried over sodium sulfate. The solvent was evaporated to give the title compound (j.j. MS: 354.2 (M) +, 237.2, 91_2. NMR : (CDC13, 1H, 400MHz, 5 , TMS) M2 (t, J=7.2, 3H) 3.19-3.38 (m, 3H), 3.55-3.61 (m, 1H), 3.68 (s, 3H), 4.23 ( Dxd, J=8.8, J=6.4, 1H), 5.18 (s, 2H), 6.65 (d, 1H), 6.90 (d, J=2.4, 1H), 7.05 (d, J=8.8, 1H), 7.34 -7 42 (m 3H) 7.47 (d, J=8, 2H), 7.55 (d, J=2.4, 1H). ' 'g"i racemic 1·2-ethoxy-3-(4-indolyl)propanyl dimethyl sulfide (4·4 ml '6G$mol) and boron trifluoride diethyl乡纯纯-176 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1328585
173 度,3.3毫升,12毫莫耳)方急各丁上、> ,,,f ,,....,, ).虱虱下加入在二氣甲烷(25毫升) 中的[外消旋性-3 ( 4-;蚤其^•姓t 土, (丁虱基冬并呋喃-7-基)-2-乙氧基丙 酸甲酉旨(0.85公克,24臺墓Jt、士、L·、人,.· .莫耳)疋冰冷落液中。將混合物在 室溫下攪拌6小時,倒在冰水上及_ — 久以一虱甲故卒取三次。將 合併的萃取物以食鹽水清洗及締 疋久,. 工石4自又鈉乾燥。在減壓下除 去溶劑,以得到榇色油,將並其 ” 將具以管枉色層分離法(矽膠,己 烷/AcOEt=4/l)純化,以得刭成.# 乂付A成為淺頁色油之〇 45公克 7 玄莫耳’ 71 % )標題化合物。--MS : 263.0 (M-Η)·。 NMR · (CDC13, 1H, 400MHz, (5 , TMS) 1.13 (t, J=7.2, 3H) 3.19-3.41 (m,3H), 3.56- 3.65 in ’ ’ im, 1H), 3.67 (s, 3H), 4.22 (dxd, J=8, J=7.2, 1H), 5.04 (s, 1H), 6.54 (d, J=8.8, 1H), 6.83 (d, J=2.4, 1H), 6.99 (d, J=8:S, 1H), 7.56 (d J=2 4 1H)。 , , fl f外消綠性卜2-乙氧羞二笨某-呤岫·4_其 甲氧基)苯并Ρ夫喃-7-某1-兩破 將碳酸鉀(37毫克,300微莫耳,14當量)及碘化鉀(々毫 克,30微莫耳,0.1當量)加入在ΝΝ二甲基甲醯胺(〇5毫升) 中的[外消旋性]-2-乙氧基_3_(4_羥基苯并呋喃_7基)丙酸 甲酯(50¾克,189微莫耳)及4_氣甲基甲基_2苯基_β号唑 (39毫克,189微莫耳,!當量)之溶液中。將混合物在8〇r 下搖動12小時,過濾及在真空中蒸發過濾物,以得到[外消 旋性]-2-乙氧基-3-[4-(5-甲基_2_苯基〃号唑_4_基甲氧基) 苯并呋喃-7-基]-丙酸甲酯。將粗[外消旋性]_2乙氧基_> ____- 177 - 本纸張尺度適用中國國家標準(CNS) A4规格(210X 297公爱) 訂 線 1328585 五、發明説明(174 A7 B7173 degrees, 3.3 ml, 12 mmol), squash, gt;,,, f,,...,,,,,,,,,,,,,,,,,,,,,,, Spiral-3 (4-; 蚤其^•姓特土, (丁丁基冬和furan-7-yl)-2-ethoxypropionic acid formazan (0.85 grams, 24 tombs Jt, Shi, L· , person, . . . Moer) 疋 ice in the cold liquid. Stir the mixture at room temperature for 6 hours, pour on the ice water and _ - long after taking a scorpion to take three times. The combined extracts in saline After cleaning and aging for a long time, the work stone 4 is dried by sodium. The solvent is removed under reduced pressure to obtain a ochre oil, which will be separated by a tube layer (矽, hexane/AcOEt=4). /l) Purification, to obtain 刭成.# 乂付A becomes a light-page oil 〇45 g 7 Xuan Mo Er '71 %) Title compound.--MS : 263.0 (M-Η)·. NMR · (CDC13 , 1H, 400MHz, (5 , TMS) 1.13 (t, J=7.2, 3H) 3.19-3.41 (m,3H), 3.56- 3.65 in ' 'im, 1H), 3.67 (s, 3H), 4.22 (dxd , J=8, J=7.2, 1H), 5.04 (s, 1H), 6.54 (d, J=8.8, 1H), 6.83 (d, J=2.4, 1H), 6.99 (d, J=8:S , 1H), 7.56 (d J=2 4 1H). , Fl f 外消绿性卜2-Ethylene shy two stupid - 呤岫 · 4_ its methoxy) benzocypan -7 - a 1-two broken potassium carbonate (37 mg, 300 micromoles , 14 equivalents) and potassium iodide (mg mg, 30 micromoles, 0.1 equivalent) added to [racemic]-2-ethoxy_3_(4) in dimethyl dimethylformamide (〇5 ml) Methyl hydroxybenzofuran-7-propionate (503⁄4 g, 189 micromolar) and 4-methyl-3-methylphenyl-2-pyrazole (39 mg, 189 micromolar, ! equivalent) In the solution, the mixture was shaken at 8 Torr for 12 hours, filtered and the filtrate was evaporated in vacuo to give [racemic]-2-ethoxy-3-[4-(5-methyl) 2_Phenyl-indole _4_ylmethoxy)benzofuran-7-yl]-propionic acid methyl ester. Crude [racemic] _2 ethoxy _> ____- 177 - paper Zhang scale applies to China National Standard (CNS) A4 specification (210X 297 public). Ordering 1328585 V. Invention description (174 A7 B7
[4-(5-甲基-2-苯基-噚唑-4-基甲氧基)苯并呋喃_7_基]•丙 酸甲酿溶解在THF/乙醇/水的2: 1: 1混合物中。加入氣氧化 鋰(40毫克,945微莫耳,5當量).,並將溶液在室溫下搖動 1 2小時。以25%水性氫氯酸酸化,並在真空中蒸發落劑’ 接著經由製備性HPLC管柱純化’以得到成為白色固體之標 題化合物(28毫克,66微莫耳,35%)。 MS : 420.2 (M-Η)·,374.2, 249.1。 NMR : (DMSO-d6, 1H, 400MHz, 5 , TMS) l.〇〇 (t> J=? 2 3H). 2.46 (s, 3H), 3.09 (dxd, J=15.2, J=8, 1H), 3.19 (dxd J=15.2, j=6.4, 1H), 3.28-3.30 (m, 1H), 3.47-3.53 (m> ^ 4.13 (dxd, J=8.8, 1=5.6, 1H), 5.13 (s, 2H), 6.90 (d, j=8.〇 1H), 6.91 (d, J=2.4, 1H)} 7.12 (d, J-8.0, 1H), 7.52-7.54 (m, 3H), 7.90 (d> J=2.4, 1H), 7.94-7.97 (m, 2H), 12.69 (s 1H) 〇 ’ 實例1 2 1 乙氣基-3-「4-(5-甲基-2-4 哈-2-其口芸岫.d 羞^甲乳基并p去喃-7-基1-丙酸 在類似於實例120f]說明的步驟中,將2-乙氧基_3_(4_經 基笨并呋喃.-7-基)丙酸甲酯(實例I20e])與4-氯甲基·5_甲 基-2-嚙吩-2-基咩唑(在類似於實例2 1 a])及b]說明的步驟 中,以4吩·2-羧醛及二乙-醯基單肟,接著以p〇Ci3處理製 得的)在碳酸鉀及碘化鉀的存在下反應,以產生[外消旋 t生]-2-乙乳基- 3- [4-(5-甲基- 2-»塞吩-2-基°号°生-4-基甲氧基) 笨并呋喃-7-基]-丙酸曱酯,將其以類似於實例1 2〇f]說明的 _____- 178 - 本纸張尺度適用中國國家標準(CMS) A4規格(210X297公爱)[4-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)benzofuran_7-yl]•propionic acid A brewed in THF/ethanol/water 2: 1: 1 In the mixture. Lithium oxide (40 mg, 945 micromolar, 5 equivalents) was added and the solution was shaken at room temperature for 12 hours. The title compound (28 mg, 66 micromoles, 35%) was obtained as a white solid. MS: 420.2 (M-Η)·, 374.2, 249.1. NMR: (DMSO-d6, 1H, 400MHz, 5, TMS) l.〇〇(t> J=? 2 3H). 2.46 (s, 3H), 3.09 (dxd, J=15.2, J=8, 1H) , 3.19 (dxd J=15.2, j=6.4, 1H), 3.28-3.30 (m, 1H), 3.47-3.53 (m> ^ 4.13 (dxd, J=8.8, 1=5.6, 1H), 5.13 (s, 2H), 6.90 (d, j=8.〇1H), 6.91 (d, J=2.4, 1H)} 7.12 (d, J-8.0, 1H), 7.52-7.54 (m, 3H), 7.90 (d> J=2.4, 1H), 7.94-7.97 (m, 2H), 12.69 (s 1H) 〇' Example 1 2 1 Ethyl-3- "4-(5-methyl-2-4) Oral.d shy ^methyl keto and p denor-7-yl 1-propionic acid in a procedure similar to that described in Example 120f], 2-ethoxy _3_(4_ via phenyl). -7-yl)methyl propionate (Example I20e)) and 4-chloromethyl-5-methyl-2-heptan-2-ylcarbazole (similar to Example 2 1 a)) and b] a step of reacting with potassium phenoxide and potassium iodide in the presence of potassium bromide and potassium iodide to produce [racemic t] -2-ethyllactyl- 3- [4-(5-methyl-2-ene-2-phenoxy-2-yloxy)-4-phenyloxy-7-yl]-propionic acid An oxime ester, which is _____-178 as described in Example 1 2〇f] - This paper size applies to the Chinese National Standard (CMS) A4 specification (210X297 public)
裝 訂Binding
線 1328585 A7 B7Line 1328585 A7 B7
步驟進一步皂化,以產生成為白色固體之[外消旋性卜I乙 氧基-3· [4-(5-甲基-2-B塞吩·2_基咩唑_4基甲氧基)苯并 喃-7-基]-丙酸。 尺 MS : 426.2 (M-Η)', 380.2, 249.0 〇 NMR · (DMSO-d6, 1H, 400MHz, δ , TMS) 1.00 (t, j= 7 2 3H), 2.43 (s, 3H), 3.07 (dxd, J=15.2, J=8, 1H), 3.19 (dxd J=15.2, J=6.4, 1H), 3.28- 3.32 (m, 1H), 3.49-3.53 (m, i^) 4·12 (dxd, J=8, J=6.4, 1H),5.TQ (s,2H), 6.87 (d,J=8’,, 6.90 (d,J=2.4, 1H),7.12 (d,J=8, 1H),7.21 (t,J=4, 1H), 7.66 (d, J=4, 1H), 7.76 (d, J=4, 1H), 7.90 (d, J=2.4, 1H/ 12.70 (br.s, 1H)。 ’ ), 實例122 _ al 4-亂曱基-2-(4-乙基苯某甲基g号口去 在類似於實例21a]說明的步驟中,將4_乙基苯醛與二乙 睦單的在冰醋酸及無水氣化氲蒸氣的存在下反應,以產生 2-(4-乙基笨基)-4,5-二甲基呤唑3_氧化物,將其在類似於 實例2 1 b]說明的步驟中進一步以在二氣甲烷中的磷醯氯處 理,以產生成為無色晶體之4-氯甲基_2-(4-乙基苯基)-5-甲 基σ号嗅。 MS : 236.2 (Μ+Η) +,200.3, 129.0。 NMR : (CDC13, 1H, 400MHz, 5 , TMS) 1.26 (t, J=7.2, 3H), 2.42 (s, 3H), 2.69 (q, J=7.2, 2H), 4.55 (s, 2H), 7.27 (d, J=8, 2H),7.91 (d, J=8, 2H)。 y_L外消旋性J-2-乙氧茱-3-_{4-Γ2-ί4- Λ其y茸15-甲某崎 L------ 17Q , 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公爱)The step is further saponified to give a white solid [racemic I ethoxy-3·[4-(5-methyl-2-B-sept. 2-ylcarbazole-4-ylmethoxy)) Benzo-n--7-yl]-propionic acid. MS: 426.2 (M-Η)', 380.2, 249.0 NMR NMR (DMSO-d6, 1H, 400MHz, δ, TMS) 1.00 (t, j= 7 2 3H), 2.43 (s, 3H), 3.07 ( Dxd, J=15.2, J=8, 1H), 3.19 (dxd J=15.2, J=6.4, 1H), 3.28- 3.32 (m, 1H), 3.49-3.53 (m, i^) 4·12 (dxd , J=8, J=6.4, 1H), 5.TQ (s, 2H), 6.87 (d, J=8',, 6.90 (d, J=2.4, 1H), 7.12 (d, J=8, 1H), 7.21 (t, J=4, 1H), 7.66 (d, J=4, 1H), 7.76 (d, J=4, 1H), 7.90 (d, J=2.4, 1H/ 12.70 (br. s, 1H). ' ), Example 122 _ al 4- 曱 曱 -2- (4-ethyl benzene 甲基 甲基 g 去 去 去 在 在 在 类似于 类似于 类似于 4 4 4 4 4 The aldehyde is reacted with diethyl hydrazine in the presence of glacial acetic acid and anhydrous vaporized hydrazine vapor to produce 2-(4-ethyl phenyl)-4,5-dimethylcarbazole 3 _ oxide, In a step similar to that described in Example 2 1 b], further treatment with phosphonium chloride in di-methane to produce 4-chloromethyl-2-(4-ethylphenyl)-5- as a colorless crystal Methyl Sigma No. MS: 236.2 (Μ+Η) +, 200.3, 129.0. NMR: (CDC13, 1H, 400MHz, 5, TMS) 1.26 (t, J=7.2, 3H), 2.42 (s, 3H) , 2.69 ( q, J=7.2, 2H), 4.55 (s, 2H), 7.27 (d, J=8, 2H), 7.91 (d, J=8, 2H). y_L racemic J-2-ethoxy oxime -3-_{4-Γ2-ί4- Λ其 y rong 15-A akisaki L------ 17Q, this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public)
1328585 五、發明説明(176) —~~基甲乳基1¾•并咕喊-7-甚·}-丙齡 在類似於實例12〇f]說明的步驟中,將2_乙氧基_3_(4羥 基苯并呋喃-7-基)丙酸甲酯(實例12〇6])與4_氯甲基·2(4_ 乙基苯基)-5-甲基呤唑在碳酸鉀及碘化鉀的存在下反應, 以產生[外消旋性]_2_乙氧基-3_丨4_[2_(4乙基苯基)5•甲 基气唑-4-基甲氧基]苯并呋喃_ 7_基卜丙酸甲酯,將其以類 似於實例120£]說明的步驟進一步包化,以產生成為白色固 體之[外消旋性]_2-乙氧基士-叫2·…乙基苯基)·5甲基 17号唑-4-基甲氧基]苯并呋喃-7_基卜丙酸。 MS : 448.2 (Μ-Η)·,375.1,281.2 » NMR : (DMSO-d6, 1H, 400MHz, 5 , TMS) l.〇〇 (t, j=7.2} 3H), 1.21 (t, J=8, 3H), 2.45 (s, 3H)5- 267 (q, J=8j 2H), 3.06 (dxd, J=15.2, J=8, 1H), 3.19 (dxd, J=15.2, J=6.4, 1H), 3-28-3.32 (m, 1H), 3.49-3.53 (m, lH), 4.12 (dxd, J=8! J=6.4, 1H), 5.12 (s, 2H), 6.90 (d, J=8, 1H), 6.91 (d, J=2.4} 1H), 7.12 (d, J=8, 1H), 7.36 (t, J=8, 2H), 7.86 (d, J=8, 2H), 7.90 (d,J=2.4, 1H), 12.70 (br.s, 1H)。 ’ 實例123 ?·-(4-第三丁基苯某)·4-氪甲某-5-甲其喵a 在類似於實例21a]說明的步驟中,將4•第三丁基苯醛與 二乙醯單肟在冰醋酸及無水氣化氫蒸氣的存在下反應以 產生2-(4-第三丁基苯基)_4,5_二甲基呤唑3•氧化物,將其 在類似於實例21b]說明的步驟中進一步以在二氯甲烷中的 磷醯氯處理,以產生成為無色固體之2_(4第三丁基苯基)· -180 - 本纸乐尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1328585 A7 _ B7 五、發明説明(177 ) 4-氯甲基-5-甲基噚唑。 MS : 264.3 (M+H) + , 228.3, 187.2 〇 NMR : (CDC13, 1H, 400MHz, δ , TMS) 1.34 (s, 9H), 2.42 (s, 3H), 4.56 (s, 2H), 7.45 (d, J=8.8, 2H), 7.92 (d, J=8.8, 2H)。 . , bl『外消旋性1 - 3- { 4-「2- (4-第三丁基茉某κ S-甲基噚岫_ 4二 基甲氧基1笨并哇喃-7-某丨-2-乙氳某丙醢 在類似於實例120f]說明的步及中,將2-乙氧基-3-(4-¾ 基苯并呋喃-7-基)丙酸甲酯(實例120e])與2-(4-第三丁基苯 基)-4-氯甲基-5-甲基喝唑在碳酸鉀及碘化鉀的存在下反 應’以產生[外消旋性]-3-{4-[2-(4-第三丁基苯基)-5-甲基 号唑-4-基曱氧基]苯并吱喃·7·基}· 2-乙氧基丙酸甲酯,將 其以類似於實例120f]說明的步驟進一步皂化,以產生成為 白色固體之[外消旋性]-3-{4-[2-(4-第三丁基苯基)_5-甲基 崎嗅-4-基甲氧基]苯并咬喃-7-基}-2-乙氧基丙酸。 MS : 476.2 (M-H)', 430.3, 381.1. 281.2 « NMR : (DMSO-d6, 1H, 400MHz, 5 , TMS) 1.00 (t, 3=7.2, 3H), 1.31 (s, 9H), 2.45 (s, 3H), 3.07 (dxd, J=15.2, J=8, 1H), 3.19 (dxd, J=15.2, J=6.4, 1H), 3.26-3.32 (m, 1H), 3.48-3.55 (m, 1H), 4.12 (dxd, J=8, J=6.4, 1H), 5.12 (s, 2H), 6.89 (d, J=8, 1H), 6.90 (d, J=2.4, 1H), 7.11 (d, J=8, 1H), 7.54 (d, J=8, 2H), 7.88 (d, J=8, 2H), 7.90 (d, J=2.4, 1H), 12.70 (br.s, 1H)。 實例124 -181 - 本纸張尺度適用中國圉家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明( 178 ) 異丙氧_^^)-5-甲甚啐唑 在類似於實例21a]說明的步驟中,將4異丙氧基苯醛血 二乙醯㈣在冰醋酸及無錢化氫蒸氣的存在下反應,以 產生2-(4-異丙氧基苯基)_4,5_二甲基。咢唑%氧化物,將其 在類似於實例21b]說明的步驟中進一步以在二氯曱烷中的 噼醯氯處理,以產生成為無色液體之4_氯甲基_2_(4_異丙 氧基苯基)-5-甲基呤唑》 MS : 266.3 (M+H) +,224.2, 18-8.3。 NMR : (CD-C13, 1H, 400MHz, 5;TMS) 1.36 (d, J=7.2, 6H), 2.40 (s, 3H), 4.54 (s, 2H), 4.61 (sept., J=7.2, 1H), 6.92 (d, J=8, 2H), 7.91 (d, J=8,2H)。 kU外消旋性1-2-乙氧某二異兩爸其 羞巧峻·4·棊甲氧基1苯并夫喃-7•甚卜岛祐 在類似於實例1 20f]說明的步驟中,將2乙氧基_ 3_ (4_羥 基苯并呋喃-7-基)丙酸甲酯(實例12〇6])與4氯甲基_2_(4_ 異丙氧基苯基)-5-甲基噚唑在碳酸鉀及碘化鉀的存在下反 應,以產生[外消旋性]-2-乙氧基_3_{4_[2·(4•異丙氧基苯 基)-5 -甲基噚唑-4 -基甲氧基]苯并呋喃· 7 _基卜丙酸甲酯, 將其以類似於實例120f]說明的步驟進一步包化’以產生成 為白色固體之[外消旋性]-2-乙氧基-3- {4- [2-(4-異丙氧基 笨基)-5-甲基哼唑-4-基甲氧基]苯幷呋喃_7_基}•丙酸。土 MS : 478.2 (M-H)·,432.6, 375.2, 281.2。 NMR : (DMSO-d6, 1H, 400MHz, <5 , TMS) l.〇〇 (t, J=7.2, 3H), 1.29 (d, J=6.4, 6H), 2.43 (s, 3H), 3.07 (dxd, J=15.2, -182 - 本纸張尺度適用中國國家標準(CNS)A4規格(210X297公釐)1328585 V. INSTRUCTIONS (176) —~~ 甲甲乳基13⁄4•和咕叫-7-甚·}- 丙龄 In the steps similar to the example 12〇f], 2_ethoxy_3_ Methyl (4hydroxybenzofuran-7-yl)propanoate (Example 12〇6)) and 4-chloromethyl-2(4-ethylphenyl)-5-methylcarbazole in potassium carbonate and potassium iodide The reaction is carried out to give [racemate]_2_ethoxy-3_丨4_[2_(4ethylphenyl)5.methyloxazol-4-ylmethoxy]benzofuran_7 Methyl ketopropionate, which was further packaged in a similar manner to that described in Example 120 to give [racemic] 2 -ethoxy-- 2...ethylbenzene as a white solid. Base)·5 methyl 17 oxazol-4-ylmethoxy]benzofuran-7- kipropropionic acid. MS: 448.2 (Μ-Η)·, 375.1, 281.2 » NMR: (DMSO-d6, 1H, 400MHz, 5, TMS) l.〇〇(t, j=7.2} 3H), 1.21 (t, J=8 , 3H), 2.45 (s, 3H)5- 267 (q, J=8j 2H), 3.06 (dxd, J=15.2, J=8, 1H), 3.19 (dxd, J=15.2, J=6.4, 1H ), 3-28-3.32 (m, 1H), 3.49-3.53 (m, lH), 4.12 (dxd, J=8! J=6.4, 1H), 5.12 (s, 2H), 6.90 (d, J= 8, 1H), 6.91 (d, J=2.4} 1H), 7.12 (d, J=8, 1H), 7.36 (t, J=8, 2H), 7.86 (d, J=8, 2H), 7.90 (d, J = 2.4, 1H), 12.70 (br.s, 1H). 'Example 123 ?--(4-Tertibutylbenzene)·4-氪甲一-5-甲甲喵a In a procedure similar to that described in Example 21a], 4•t-butylbenzaldehyde was Diethyl hydrazine is reacted in the presence of glacial acetic acid and anhydrous hydrogenated hydrogen vapor to produce 2-(4-t-butylphenyl)-4,5-dimethylcarbazole 3•oxide, which is similar In the step illustrated in Example 21b], further treated with phosphonium chloride in dichloromethane to produce 2_(4th butylphenyl)-180 which is a colorless solid. The paper scale applies to the Chinese national standard ( CNS) A4 size (210X297 mm) 1328585 A7 _ B7 V. Description of invention (177) 4-Chloromethyl-5-methylcarbazole. MS : 264.3 (M+H) + , 228.3, 187.2 NMR: (CDC13, 1H, 400 MHz, δ, TMS) 1.34 (s, 9H), 2.42 (s, 3H), 4.56 (s, 2H), 7.45 ( d, J = 8.8, 2H), 7.92 (d, J = 8.8, 2H). . , bl 『racemic 1 - 3- { 4-"2-(4-t-butyl 某 κ κ S-methyl 噚岫 _ 4 diyl methoxy 1 stupid and wow -7 - some Methyl 2-ethoxy-3-(4-3⁄4-ylbenzofuran-7-yl)propanoate (Example 120e) in a step similar to that described in Example 120f] ]) reacting with 2-(4-t-butylphenyl)-4-chloromethyl-5-methyloxazole in the presence of potassium carbonate and potassium iodide to produce [racemic]-3-{ 4-[2-(4-Tertiary phenyl)-5-methyloxazol-4-yl decyloxy]benzopyran-7·yl} 2-ethoxypropionate methyl ester, It was further saponified in a procedure similar to that described in Example 120f] to give [racemic]-3-{4-[2-(4-t-butylphenyl)-5-methyl succin as a white solid. Ollenyl-4-ylmethoxy]benzoin-7-yl}-2-ethoxypropionic acid MS: 476.2 (MH)', 430.3, 381.1. 281.2 « NMR : (DMSO-d6, 1H, 400MHz, 5, TMS) 1.00 (t, 3=7.2, 3H), 1.31 (s, 9H), 2.45 (s, 3H), 3.07 (dxd, J=15.2, J=8, 1H), 3.19 (dxd, J=15.2, J=6.4, 1H), 3.26-3.32 (m, 1H), 3.48-3.55 (m, 1H), 4.12 (dxd, J=8, J=6.4, 1H), 5.12 (s, 2H) , 6.89 (d, J=8, 1H) , 6.90 (d, J=2.4, 1H), 7.11 (d, J=8, 1H), 7.54 (d, J=8, 2H), 7.88 (d, J=8, 2H), 7.90 (d, J =2.4, 1H), 12.70 (br.s, 1H). Example 124 -181 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention ( 178 Isopropoxy _^^)-5-methyl carbazole in the procedure similar to that described in Example 21a], the presence of 4 isopropyloxybenzaldehyde in the presence of glacial acetic acid and vaginal hydrogen vapor The next reaction is carried out to give 2-(4-isopropoxyphenyl)-4,5-dimethyl.oxazole % oxide, which is further in the step similar to that described in Example 21b] in dichloromethane Treatment with hydrazine chloride to give 4-chloromethyl-2-(4-isopropoxyphenyl)-5-methylcarbazole as a colorless liquid MS : 266.3 (M+H) +, 224.2, 18-8.3. NMR : (CD-C13, 1H, 400MHz, 5; TMS) 1.36 (d, J=7.2, 6H), 2.40 (s, 3H), 4.54 (s, 2H), 4.61 (sept., J=7.2, 1H ), 6.92 (d, J=8, 2H), 7.91 (d, J=8, 2H). kU racemic 1-2-ethoxy, two different, two dad, its shameful, sputum, methoxy, 1 benzofuran, -7, and sulphate, in a procedure similar to that described in Example 1 20f] , 2 ethoxy_ 3_(4-hydroxybenzofuran-7-yl)propanoic acid methyl ester (Example 12〇6)) and 4-chloromethyl_2_(4-isopropylisophenyl)-5- Methylcarbazole is reacted in the presence of potassium carbonate and potassium iodide to give [racemic]-2-ethoxy_3_{4_[2·(4•isopropoxyphenyl)-5-methyl Methyl oxazol-4-ylmethoxy]benzofuran. 7- propylpropanoate, which was further encapsulated in a procedure similar to that described in Example 120f] to give [racemic] as a white solid. -2-ethoxy-3-{4-[2-(4-isopropoxyphenyl)-5-methyloxazol-4-ylmethoxy]benzofuran-7-yl}•C acid. Soil MS : 478.2 (M-H)·, 432.6, 375.2, 281.2. NMR: (DMSO-d6, 1H, 400MHz, <5, TMS) l. 〇〇(t, J=7.2, 3H), 1.29 (d, J=6.4, 6H), 2.43 (s, 3H), 3.07 (dxd, J=15.2, -182 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)
訂Order
線 1328585 A7 B7 179 五、發明説明( J=8, 1H), 3.19 (dxd, J=15.2, J=6.4, 1H), 3.27- 3.33 (m, 1H), 3.48- 3.55 (m, 1H), 4.13 (dxd, J=8, J=6.4, 1H), 4.70 (sept., ^=6.4, 1H), 5.10 (s, 2H), 6.89 (d, J=8, 1H), 6.91 (d, J=2.4, 1H), 7.03 (d, J=8.8, 2H), 7.11 (d, J=8, 1H), 7.85 (d, J=8.8, 2H),7.90 (d,J=2.4, 1H), 12.70 (br.s, 1H)。 實例1 2 5 乙氧苯并咭喃_7_ 基)丙酸乙酯 -- 將在甲醇(17毫升)中的3_(4-苄氧基苯幷呋喃_7基)2Z_ 乙氧基丙埽酸乙酯(420毫克,1.15毫莫耳)(實例12〇c])之溶 液在室溫下經10%在木炭上的鈀(100毫克)以2〇小時氫化。 將觸媒過濾,在減壓下蒸發溶劑,並將殘餘物經色層分離 (石夕膠,己坡/AcOEtM/D,以得到成為無色液體之^毫克 (0.86毫莫耳,75%)標題化合物。 MS : 279.1 (M-H).,265_2, 217.1,141.0。 NMR: (CDC13, 1H, 400MHz, d , TMS) l.i6(t) J=7.2> 3H) 1-22 (t, J=7.2,3H), 2.87-2.97 (^2^,3.15(1, 2H/ 3.36-3.44 (m,1H),3.55- 3.62 (m,1H),4 〇8 〇 j=7 2’ ih)’ 4.15 (q,J=7.2,2H), 4.59 (t, δ, 2H), 4.64 (b,s> 1H; 6 (d, J=8, 1H), 6.84 (d,J=8, 1H)。 ’ LLLtLii旋性卜2-乙氧棊号唑·4_其 卜2,3 -二氫苯并咬喃-7-甚1二丙酸 在類似於實例120f]說明的步驟中,將[外消旋性]2乙故 基-3七-經基-2,3-二氫笨并吱喃.7·基)丙酸乙自旨與4_氣= 183 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐) 1328585 A7 B7 五、發明説明(18〇) 基-5-甲基-2-苯基-呤唑在碳酸鉀及碘化鉀的存在下反應, 以產生[外消旋性]-2-乙氧基· 3- [ 4- ( 5-曱基-2-苯基-呤唑-4-基甲氧基)-2,3-二氳苯并呋喃-7-基卜丙酸乙酯,將其以 類似於實例120f]說明的步驟進一步皂化,以產生成為白色 固體之[外消旋性]-2-乙氧基_3-[4-(5-甲基-2-苯基-噚唑-4-基甲氧基)-2,3-二氫苯并呋喃_7_基μ丙酸。 MS : 422.2 (M-Η)·,378.3, 251.1。 NMR : (DMSO-d6, 1H, 400ΜΉζ, <5 , TMS) 1.03 (t, J=7.2, 3H), 2.44 (s, 3H), 2.71 (dxd, J=15.2, J=8, 1H), 2.83 (dxd, J=15.2, J=6.4, 1H), 3.06 (t, J=8, 2H), 3.25-3.32 (m, 1H), 3.45-3.52 (m, 1H), 3.96 (dxd, J=8, J=6.4, 1H), 4.52 (t, J=8, 2H), 5.00 (s, 2H), 6.58 (d, J=8, 1Ή), 6.93 (d, J=8, 1H), 7.48-7.55 (m, 3H), 7.93-7.96 (m, 2H), 12.55 (br.s,1H) e 實例126 f外消旋性1-2-乙氧基-3-丨4-『2-(4-乙其芡其U5-甲甚咩 4-基甲氣基1-2,3 -二氢笨并咬喃-7-某丨-雨龄 在類似於實例120f]說明的步驟中,將[外消旋性]_ 2-乙氧 基-3-( 4-經基-2,3-二氫苯并咬喃-7-基)丙酸乙酯(實例丨25 a]) 與4-氯甲基-2-(4-乙基苯基)-5-曱基号。坐(實例i22a])在破 酸鉀及碘化鉀的存在下反應,以產生[外消旋性]_2·乙氧 基- 3-{4-[2-(4-乙基苯基)-5-甲基1»号岐-4-基甲氧基]-2,3- 二氫苯并咬喃-7-基}-丙酸乙酯,將其以類似於實例12〇f] 說明的步驟進一步皂化,以產生成為白色固體之[外消旋 性]-2-乙氧基-3-{4-[2-(4-乙基苯基)-5-甲基《•号唑·4-基甲 -184 - 本纸張尺度適用中國國家標準(CNS) Α4规格(210Χ 297公釐) 裝 訂Line 1328085 A7 B7 179 V. Description of invention (J=8, 1H), 3.19 (dxd, J=15.2, J=6.4, 1H), 3.27- 3.33 (m, 1H), 3.48- 3.55 (m, 1H), 4.13 (dxd, J=8, J=6.4, 1H), 4.70 (sept., ^=6.4, 1H), 5.10 (s, 2H), 6.89 (d, J=8, 1H), 6.91 (d, J =2.4, 1H), 7.03 (d, J=8.8, 2H), 7.11 (d, J=8, 1H), 7.85 (d, J=8.8, 2H), 7.90 (d, J=2.4, 1H), 12.70 (br.s, 1H). Example 1 2 5 ethoxybenzopyranyl-7-yl)ethyl propionate - 3-(4-benzyloxybenzofuran-7-yl)2Z-ethoxypropionic acid in methanol (17 ml) A solution of ethyl ester (420 mg, 1.15 mmol) (Example 12〇c)) was hydrogenated at room temperature with 10% palladium (100 mg) on charcoal over 2 hrs. The catalyst was filtered, and the solvent was evaporated under reduced pressure, and the residue was separated by chromatography (yield: EtOAc/EtOAc/EtOAc/EtOAc/EtOAc) MS: 279.1 (MH)., 265_2, 217.1, 141.0. NMR: (CDC13, 1H, 400 MHz, d, TMS) l.i6(t) J=7.2> 3H) 1-22 (t, J= 7.2,3H), 2.87-2.97 (^2^, 3.15(1, 2H/ 3.36-3.44 (m,1H), 3.55- 3.62 (m,1H),4 〇8 〇j=7 2' ih)' 4.15 (q, J = 7.2, 2H), 4.59 (t, δ, 2H), 4.64 (b, s >1H; 6 (d, J = 8, 1H), 6.84 (d, J = 8, 1H). LLLtLii 旋性卜 2-ethoxyoxindole·4_2,3-dihydrobenzobenzopyran-7-l-dipropionic acid will be [racemic] in a procedure similar to that described in Example 120f] Sexuality] 2 Ethyl-3-7-trans-based-2,3-dihydro benzopyran.7·yl)propionic acid B and 4_gas = 183 - This paper scale applies to Chinese National Standard (CNS) A4 size (21〇x 297 mm) 1328585 A7 B7 V. Description of the invention (18〇) Group 5-methyl-2-phenyl-oxazole is reacted in the presence of potassium carbonate and potassium iodide to produce [examination Rotyl]-2-ethoxy-3-(4-( 5-indolyl-2-phenyl-oxazol-4-yl) Ethyloxy-2,3-dioxabenzofuran-7-ylpropanoic acid ethyl ester, which was further saponified in a similar manner to that described in Example 120f] to give [racemic] as a white solid. 2-Ethoxy_3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2,3-dihydrobenzofuran-7-yl-propionic acid. MS: 422.2 (M-Η)·, 378.3, 251.1. NMR: (DMSO-d6, 1H, 400 ΜΉζ, <5, TMS) 1.03 (t, J=7.2, 3H), 2.44 (s, 3H), 2.71 (dxd, J=15.2, J=8, 1H), 2.83 (dxd, J=15.2, J=6.4, 1H), 3.06 (t, J=8, 2H), 3.25-3.32 (m, 1H), 3.45 -3.52 (m, 1H), 3.96 (dxd, J=8, J=6.4, 1H), 4.52 (t, J=8, 2H), 5.00 (s, 2H), 6.58 (d, J=8, 1Ή) ), 6.93 (d, J=8, 1H), 7.48-7.55 (m, 3H), 7.93-7.96 (m, 2H), 12.55 (br.s, 1H) e Example 126 f racemic 1-2 -Ethoxy-3-indole 4-"2-(4-ethyl acetonide U5-methyl fluorene 4-ylmethyl group 1-2,3 - dihydro cumin and -7-something - rain In a similar procedure to that described in Example 120f], [racemic] 2-ethoxy-3-(4-amino-2,3-dihydrobenzoin-7-yl)-propyl Ethyl acetate (example 丨25 a)) and 4-chloromethyl-2-(4-ethylphenyl)-5-fluorenyl number. Sit (example i22a)) in the presence of potassium bromate and potassium iodide to give [racemic] _2 ethoxy-3-{4-[4-(4-ethylphenyl)-5- Methyl 1» 岐-4-ylmethoxy]-2,3-dihydrobenzoin-7-yl}-propionic acid ethyl ester, which is further described in a procedure similar to that described in Example 12〇f] Saponification to give [racemic]-2-ethoxy-3-{4-[2-(4-ethylphenyl)-5-methyl"-oxazol-4-yl as a white solid A-184 - This paper size is applicable to China National Standard (CNS) Α4 specification (210Χ 297 mm) Binding
1328585 五、發明説明( 181 A7 B71328585 V. Description of the invention (181 A7 B7
氧基]-2,3 -一氫苯并吱喃_7_基丨·丙酸。 MS : 450.3 (M-H)·,406_2, 251.1。 NMR : (DMS〇_d6, 1H,4〇〇MHU,TMS) 1 〇3 〇, J=7 2 3H), 1.21 (t, J=8, 3H), 2.43 (s, 3H), 2.64-2.74 (m 3H) 2.83 (dxd, J=15.2, J=6.4, 1H), 3.06 (t, j=8, 2H)> 3 25 3 32 (% 1H),3·45-3.52 (m,1H),3.96 (dxd, J=8, J=6 4, 1H) 4.51 (t, J=8, 2H), 4.98 (s, 2H), 6.58 (d, J=8> lH), 6.92 J=8,lH),7.36(d, J=8,2H), 7.-,5(,, J=8, 2H), 12.6〇 (br; 1H)。 ' 5 實例127 f外魅性1 p坐_ 4_某 甲巩d3-二虱乙氫甚^ 在類似於實例l20f]說明的步驟中,將[外消旋性]_2乙氧 基-3-(4·㈣_2,3·:氫苯料喃_7基)丙酸㈣(實例叫) 與2-(4_弟二丁基$基)-4-氣甲基-5-甲基嘮唑(實例123a)) 在後酸钟及蛾化却的存在下反應,以產生[外消旋性]-3-匕[2-(4·第三丁基苯基卜5-甲基呤〜基甲氧基卜2,3_二 氫私并夫南7-基} - 2-乙氧基丙酸乙醋,將其以類似於實例 120f]說明的步驟進一步皂化,以產生成為白色固體之[外 消旋性]-3-{4-[2-(4-第三丁基苯基)·5_甲基吟唑·4基f氧 基]-2,3-二氫苯并呋喃_7_基_卜2乙氧基丙酸。 MS . 478.2 (M-H)·,434.4, 375.1,299.1,281.2, 251.1 » NMR ·· (DMSO-d6,lH, 40〇MHz,TMS) 1·〇3 (t, J=7·2, 3H),1.31 (s,9H),2.43 (s,3H),2.71 (dxd,J=15.2, J=8, lH), 本纸張尺《用t國固家標準(CNS) A4規格(210 x 29匕茇)Oxy]-2,3-monohydrobenzopyran_7_ylindole·propionic acid. MS: 450.3 (M-H)·, 406_2, 251.1. NMR : (DMS〇_d6, 1H, 4〇〇MHU, TMS) 1 〇3 〇, J=7 2 3H), 1.21 (t, J=8, 3H), 2.43 (s, 3H), 2.64-2.74 (m 3H) 2.83 (dxd, J=15.2, J=6.4, 1H), 3.06 (t, j=8, 2H)> 3 25 3 32 (% 1H), 3·45-3.52 (m, 1H) , 3.96 (dxd, J=8, J=6 4, 1H) 4.51 (t, J=8, 2H), 4.98 (s, 2H), 6.58 (d, J=8> lH), 6.92 J=8, lH), 7.36 (d, J=8, 2H), 7.-, 5(,, J=8, 2H), 12.6〇(br; 1H). ' 5 Example 127 f external charm 1 p sitting _ 4_ a 甲 巩 d3-二虱乙氢和^ In the procedure similar to the example l20f], [racemic] _2 ethoxy-3- (4·(4)_2,3·: Hydrogen benzene _7-based) Propionic acid (iv) (example) and 2-(4-dibutyl butyl)-methyl-3-methylcarbazole ( Example 123a)) Reacts in the presence of a post-acid clock and a moth, to give [racemic]-3-匕[2-(4·t-butylphenyl) 5-methylindole~yl Ethyl bromide 2,3-dihydron-benzoic acid 7-yl}-2-ethoxypropionic acid ethyl acetonate, which was further saponified in a procedure similar to that described in Example 120f] to give a white solid. Racemic]-3-{4-[2-(4-t-butylphenyl)·5-methylcarbazole·4ylfoxy]-2,3-dihydrobenzofuran_7_ _ _ 2 ethoxypropionic acid. MS . 478.2 (MH)·, 434.4, 375.1, 299.1, 281.2, 251.1 » NMR ·· (DMSO-d6, lH, 40〇MHz, TMS) 1·〇3 (t , J=7·2, 3H), 1.31 (s, 9H), 2.43 (s, 3H), 2.71 (dxd, J = 15.2, J=8, lH), the paper ruler (CNS) A4 size (210 x 29匕茇)
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線 1328585 A7 B7 五、發明説明(182) 2.S3 (dxd, J=15.2, J=6.4, 1H), 3.06 (t, J=g, 2H), 3.25-3.32 (m, 1H), 3.45-3.52 (m, 1H), 3.95 (dxd, J=8, J=6.4,1H) 4.51 (t, J=8, 2H), 4.99 (s, 2H), 6.58 (d, J=8, 1H), 6.92 (d, J=8, 1H), 7.54 (d, J=8, 2H), 7.87 (d, J=8, 2H), 12.60 (br.s, 1H)。 實例128 Γ外消'旋性〗-2-乙氫基-3-j[ 4- [2-(_4-異丙氳甚节|)_5•甲I 噚唑-4-某甲氳某1-2,3-二氫笨并吱.喃-7-某ί -呙齡 在類似於實例120f]說明的步驟中,將[外消旋性卜2_乙氧 基-3-(4-羥基-2,3-二氫苯并呋喃-7-基)丙酸乙酯(實例1253]) 與4-氯甲基-2-( 4-異丙乳基本基)-5-甲基》号峻(實例124a]) 在碳酸鉀及碘化鉀的存在下反應,以產生[外消旋性]_ 2乙 氧基- 3- {4-[2-(4-異丙氧基苯基)-5-甲基。号咕基甲氧 基]_2,3-二氫苯并咬喃-7-基}-丙酸乙醋,將其以類似於實 例120f]說明的步驟進一步皂化,以產生成為白色固體之 [外消旋性]-2-乙氧基-3-{4-[2-(4-異丙氧基苯基)_5•甲基 σ亏°坐-4-基甲氧基]-2,3 -二風革并咬哺-7-基}-丙酸。 MS : 480.3 (Μ-Η)’,436.7, 281.2, 251·1。 NMR : (DMSO-d6,1Η,400MHz,<5,TMS) 1·〇3 (t,J=7 2 3H), 1.29 (d, J=7.2, 6H), 2.41 (s, 3H), 2.71 (dxd, J=l5.2 J=8, 1H),2.83 (dxd, J=15.2, J=6.4, 1H), 3.06 (t,J=8, 2H) 3.25-3.32 (m, 1H), 3.45-3.52 (m, 1H), 3.96 (dxd, J=8 J=6.4, 1H), 4.51 (t, J=8, 2H), 4.70 (sept., J=7.2, 1H), 4 97 (s, 2H), 6.57 (d, J=8, 1H), 6.92 (d, J=8, 1H), 7.03 j~g-186 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) -----Line 1328085 A7 B7 V. Description of invention (182) 2.S3 (dxd, J=15.2, J=6.4, 1H), 3.06 (t, J=g, 2H), 3.25-3.32 (m, 1H), 3.45- 3.52 (m, 1H), 3.95 (dxd, J=8, J=6.4, 1H) 4.51 (t, J=8, 2H), 4.99 (s, 2H), 6.58 (d, J=8, 1H), 6.92 (d, J=8, 1H), 7.54 (d, J=8, 2H), 7.87 (d, J=8, 2H), 12.60 (br.s, 1H). Example 128 ΓExhaustive 'spinning〗 -2-Ethylhydro-3-j[ 4- [2-(_4-isopropyl 氲 节 ) ) ) ) ) ) ) ) ) ) ) ) ) ) 某 某 某 某 某 某 某 某 1- 1- 1- 1- 1- 1- 2,3-Dihydro benzopyrene. -7-7- ί - 呙 - in the procedure similar to that described in Example 120f], [racemic 2 - ethoxy-3-(4-hydroxy-) Ethyl 2,3-dihydrobenzofuran-7-yl)propionate (Example 1253)) with 4-chloromethyl-2-(4-isopropyllactyl)-5-methyl Example 124a]) Reaction in the presence of potassium carbonate and potassium iodide to give [racemic] _ 2 ethoxy-3-{4-[2-(4-isopropoxyphenyl)-5- base. No. decyl methoxy] 2,3-dihydrobenzopyran--7-yl}-propionic acid ethyl acetonate, which was further saponified in a procedure similar to that described in Example 120f] to give a white solid. Racemic]-2-ethoxy-3-{4-[2-(4-isopropoxyphenyl)_5•methyl σ ° °-4--4-methoxy]-2,3 - Two wind leather and bite 7-based}-propionic acid. MS: 480.3 (Μ-Η)', 436.7, 281.2, 251·1. NMR: (DMSO-d6, 1 Η, 400 MHz, <5, TMS) 1·〇3 (t, J=7 2 3H), 1.29 (d, J=7.2, 6H), 2.41 (s, 3H), 2.71 (dxd, J=l5.2 J=8, 1H), 2.83 (dxd, J=15.2, J=6.4, 1H), 3.06 (t, J=8, 2H) 3.25-3.32 (m, 1H), 3.45 -3.52 (m, 1H), 3.96 (dxd, J=8 J=6.4, 1H), 4.51 (t, J=8, 2H), 4.70 (sept., J=7.2, 1H), 4 97 (s, 2H), 6.57 (d, J=8, 1H), 6.92 (d, J=8, 1H), 7.03 j~g-186 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) -----
裝 訂Binding
線 1328585Line 1328585
五、發明説明(183 2H),7.84 (d,J=8, 2H),12.60 (br.s,1H)。 實例129 al 4-芊氫某-2_- f碁莕醛 將無水N,N-二甲基甲醯胺(34.2毫升,444毫莫耳)在氣氣 下以攪拌及冷卻逐滴加入磷醯氯(1 8.3毫升,200毫莫耳) 中,該加入速度使溫度不超過1 0 °C。在0。〇下3 0分鐘之後, 在30分鐘之内逐滴加入在N,N-二甲基甲醯胺(22毫升)中的 卜芊氧基-3-甲基苯(22公克,1丄1毫莫耳)之溶液(關於丨节 氧基-3-甲基苯的製備作用,參考:D. Bogdal·,J. Pielichowski, A. Boron, Syn. Commun. 1998,28, 3029-3039)。將反應混合物在室溫下攪拌30分鐘及接著持續加熱 至1 1 0 °C。在I 1 〇 C下10分鐘之後,將混合物維持在9 下 3 ·5小時’冷卻至10°C,以25%水性醋酸鈉經冷卻中和,並 以醋乙§旨卒取。將合併的有機層以飽和水性碳酸氮納及 食鹽水清洗,並經硫酸鈉乾燥。在減壓下除去溶劑,以得 到棕色油’將其以管柱色層分離法(矽膠,己烷 /AcOEt= 19Π)純化’以得到成為黃色固體之4.3公克(19毫 莫耳,17%)標題化合物。 MS : 226.1 (M) + , 91.2 » NMR : (CDCI3, 1H, 400MHz, (5 , TMS) 2.65 (s, 3H), 5.13 (s, 2H), 6.83 (d, J=1.6, 1H),-6.91 (dxd, J=8.8, J=1.6, 1H), 7.32- 7.44 (m,5H), 7.75 (d,J=8.8, 1H),10.12 (s, 1H)。 kl_3-(4-苄氧基-2-甲基笨某)_2Z-乙氫某丙烯酸乙酯 將氯化(乙氧基乙氧羰基甲基)三笨鳞(379公克,8.8毫莫 ------ 1»7 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x297公釐) 1328585 A7 B7 184 五、發明説明( 耳)及\酸_ .46公克,} 〇 6毫莫耳)在} 〇。〇的氯氣下加入 ,異丙S| ( 10毫升)中的4节氧基· 2 _甲基苯链⑺』公克,3 $ 毫莫耳)之/合液中[關於氣化(乙氧基乙氧談纟甲基)三苯鱗 的製備作用’參考:κ κ Β吨H rΗ ΜV. Description of the invention (183 2H), 7.84 (d, J=8, 2H), 12.60 (br.s, 1H). Example 129 al 4-Hydrazine Hydrogen-2_- f furfural Anhydrous N,N-dimethylformamide (34.2 ml, 444 mmol) was added dropwise with stirring and cooling under a gas atmosphere. In the case of (1 8.3 ml, 200 mmol), the addition speed is such that the temperature does not exceed 10 °C. At 0. After 30 minutes of squatting, dipoxy-3-methylbenzene (22 g, 1 丄 1 mM) in N,N-dimethylformamide (22 ml) was added dropwise over 30 minutes. Solvent (for the preparation of oxime oxy-3-methylbenzene, see: D. Bogdal, J. Pielichowski, A. Boron, Syn. Commun. 1998, 28, 3029-3039). The reaction mixture was stirred at room temperature for 30 minutes and then continuously heated to 110 °C. After 10 minutes at I 1 〇 C, the mixture was maintained at 9 for 3 · 5 hours' cooling to 10 ° C, neutralized with 25% aqueous sodium acetate, and taken with vinegar. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give a brown oil, which was purified by column chromatography (EtOAc, hexane/AcOEt = 19 </ RTI> </ RTI> </ RTI> to afford a 4.3 g (19 mM, 17%) as a yellow solid. Title compound. MS : 226.1 (M) + , 91.2 » NMR : (CDCI3, 1H, 400MHz, (5, TMS) 2.65 (s, 3H), 5.13 (s, 2H), 6.83 (d, J=1.6, 1H),- 6.91 (dxd, J=8.8, J=1.6, 1H), 7.32- 7.44 (m,5H), 7.75 (d,J=8.8, 1H), 10.12 (s, 1H). kl_3-(4-benzyloxy -2-methyl stupid) _2Z-ethyl hydrogen ethyl acrylate will chlorinate (ethoxyethoxycarbonylmethyl) three stupid scale (379 grams, 8.8 millimoles ------ 1»7 - this The paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x297 mm) 1328585 A7 B7 184 V. Invention description (ear) and \acid _ .46 g, } 〇 6 m Mo) in } 〇.〇 Addition under chlorine, 4 ethoxy· 2 _methyl phenyl chain (7) gram in isopropyl S| (10 ml), 3 Å mAh / in solution [on gasification (ethoxy ethoxylate) Discussion on the preparation of trimethylbenzene triphenyl scales. Reference: κ κ Β 吨 H rΗ Μ
Jensen, Η. B. Nielsen, I. Thomson, K. B. G. Torssell, Tetfahedton 1994’ 50’ 7543_7556]。將懸浮液加熱至⑼乞。 在1 = J時及20小時之後,再加入氣化(乙氧基乙氧叛基甲基) 一苯鱗(每’入3.79公克,88毫·-墓耳)及碳酸鉀(每次146公 克,10.6¾-莫耳)❶在36小時之後,將懸浮液過濾並在減 壓下络發過滤物。將殘餘物溶解在二氯甲燒中以飽和水 f氣化銨及冰水π洗,並經疏酸鈉乾燥。在減壓下除去溶 劑’並將殘餘物以管柱色層分離法(料,n虎)純 化’以得到成為黃色液體之G7公克(2」毫莫耳,58%)標題 化合物。 MS : 340.2 (M)' 249.2, 147山 91」。 NMR : (CDC13, 1H, 400MHz, 5 , TMS) 1.31 (t, J=7.2, 3H), 1-37 (t, J=7.2, 3H), 2.37 (s, 3H), 3.91 (q, J=7.2, 2H), 4.30 (q, J=7.2, 2H), 5.07 (s, 2H), 6.82-6.85 (m, 2H), 7.18 (s, 1H), 7.33-7.44 (m, 5H),8.08 (d, J=8.8, 1H)。 祿性卜2-乙氧(4_與某· 2·甲基苽1)而醋,酯 將在乙醇(50毫升)中的3·(4•苄氧基·2甲基苯基)_2Z乙 氧基丙烯酸乙酯(1公克,2 9毫莫耳)之溶液在室溫下經1〇% 在木炭上的鈀(250毫克)以2小時氫化。將觸媒過濾,在減 壓下洛發溶劑,以得到成為黃色液體之6〇〇毫克(2 4毫莫 ^紙張尺歧財@时職CNS) A4胁(210X29$爱) 1328585 A7 _'____B7 五、發明説明(185) 耳’ 81%)標題化合物,在以下階段中使用未進一步純化之 該化合物。 MS : 270·4 (M+NH4) +,253 (M) +,207.2, 165.3。 NMR : (CDC13, lH, 400MHz, <5 , TMS) 1.15 (t, J=7.2, 3H), 1.22 (t, J=7.2, 3H), 2.30 (s, 3H), 2.95 (d, J=7.2, 2H), 3.28-3.36 (m, 1H), 3.54-3.62 (m, 1H), 3.95 (t, J=7.2, 1H), 4.16 (^> J—7.2, 2H), 4.54 (s, 1H), 6.59 (dxd, J=8, J= 1 6 1H) 6.63 (d,J=1.6, 1H),7.04 (d. JU)。 dl f外消旋性卜2-乙氧基-3-「2-甲某-4-ί5· f某·2-节其-喵 唑-4-某甲氳某)笨基1-丙醢 在類似於實例1 20f]說明的步驟中,將[外消旋性]_ 2乙氧 基-3-(4-羥基-2-甲基苯基)丙酸乙醋與4_氣甲基·5甲基_2_ 笨基-°号唑在碳酸鉀及碘化鉀的存在下反應,以產生[外消 旋性]-2-乙氧基-3- [2-甲基- 4-(5-甲基-2-苯基·噚唑-4-基 甲乳基)私基]-丙酸乙自旨’將其以類似於實例12 〇 f]說明的 步驟進一步皂化,以產生成為淺黃色固體之[外消旋性]_ 2_ 乙氧基- 3- [2-甲基- 4- (5-曱基-2-苯基-D号唆·4_基甲氧基)苯 基]-丙酸。 MS : 394.2 (M-Η)', 348.5 〇 NMR · (CDCI3, 1H, 300MHz, 5 , TMS) 1.13 (t} J=7 2 3H), 2.34 (s, 3H), 2.44 (s, 3H), 2.93 (dxd, J=15.2, J=8, 1H), 3.11 (dxd, J=15.2, J=4, 1H), 3.30-3.36 (m, 1H), 3.50-3.57 (m, 1H), 4.01 (dxd, J=8, J=4, 1H), 4.97 (s, 2H), 6.79 (dxd, J=8, J=1.6, 1H), 6.83 (d, J=i.6, 1H), 7.13 (d, J=8, 1H), I_____ - 1ftQ - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公爱) 1328585 A7 B7 五 發明説明(186 7.43-7.46 (m, 3H), 8.00-8.03 (m, 2H) · 實例130 ·Jensen, Η. B. Nielsen, I. Thomson, K. B. G. Torssell, Tetfahedton 1994’ 50’ 7543_7556]. Heat the suspension to (9) 乞. At 1 = J and after 20 hours, add gasification (ethoxyethoxymethomethyl) benzene scale (each 3.79 grams, 88 milligrams - tomb) and potassium carbonate (146 grams each time) , 10.63⁄4-mole) After 36 hours, the suspension was filtered and the filtrate was decompressed under reduced pressure. The residue was dissolved in methylene chloride to be washed with saturated water f-vaporized ammonium and ice water, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (yield: EtOAc) to afford the title compound. MS: 340.2 (M)' 249.2, 147 Mountain 91". NMR : (CDC13, 1H, 400MHz, 5 , TMS) 1.31 (t, J=7.2, 3H), 1-37 (t, J=7.2, 3H), 2.37 (s, 3H), 3.91 (q, J= 7.2, 2H), 4.30 (q, J=7.2, 2H), 5.07 (s, 2H), 6.82-6.85 (m, 2H), 7.18 (s, 1H), 7.33-7.44 (m, 5H), 8.08 ( d, J=8.8, 1H). Lu 2 - ethoxy (4_ with a · 2 · methyl oxime 1) and vinegar, ester will be in ethanol (50 ml) of 3 · (4 • benzyloxy · 2 methyl phenyl) 2 Z A solution of ethyl oxyacrylate (1 g, 2 9 mmol) was hydrogenated at room temperature over 1% palladium on charcoal (250 mg) over 2 hours. The catalyst is filtered, and the solvent is released under reduced pressure to obtain 6 〇〇 mg which becomes a yellow liquid (2 4 mAh paper size 财 财@时职 CNS) A4 threat (210X29$爱) 1328585 A7 _'____B7 V. INSTRUCTIONS (185) Ear '81%) of the title compound, which was used in the next stage without further purification. MS: 270·4 (M+NH4) +, 253 (M) +, 207.2, 165.3. NMR: (CDC13, lH, 400MHz, <5, TMS) 1.15 (t, J=7.2, 3H), 1.22 (t, J=7.2, 3H), 2.30 (s, 3H), 2.95 (d, J= 7.2, 2H), 3.28-3.36 (m, 1H), 3.54-3.62 (m, 1H), 3.95 (t, J=7.2, 1H), 4.16 (^> J-7.2, 2H), 4.54 (s, 1H), 6.59 (dxd, J=8, J= 1 6 1H) 6.63 (d, J=1.6, 1H), 7.04 (d. JU). Dl f racemate b 2-ethoxy-3-"2-甲某-4-ί5· f某·2-section-oxazole-4-some hyperthyroidism) stupid base 1-propanoid Similar to the procedure illustrated in Example 1 20f], [racemic] 2 ethoxy-3-(4-hydroxy-2-methylphenyl)propanoic acid ethyl acetonate and 4 qi methyl group 5 Methyl-2_ phenyl-pyrazole is reacted in the presence of potassium carbonate and potassium iodide to give [racemic]-2-ethoxy-3-[2-methyl-4-(5-methyl) -2-Phenyl-oxazol-4-ylmethylidyl)-propionic acid]-propionic acid B was further saponified by a procedure similar to that described in Example 12 〇f] to give a pale yellow solid [ Racemic] _ 2_ethoxy-3-(2-methyl-4-(5-fluorenyl-2-phenyl-D-indole-4-ylmethoxy)phenyl]-propionic acid. MS : 394.2 (M-Η)', 348.5 〇 NMR · (CDCI3, 1H, 300MHz, 5 , TMS) 1.13 (t} J=7 2 3H), 2.34 (s, 3H), 2.44 (s, 3H), 2.93 (dxd, J=15.2, J=8, 1H), 3.11 (dxd, J=15.2, J=4, 1H), 3.30-3.36 (m, 1H), 3.50-3.57 (m, 1H), 4.01 ( Dxd, J=8, J=4, 1H), 4.97 (s, 2H), 6.79 (dxd, J=8, J=1.6, 1H), 6.83 (d, J=i.6, 1H), 7.13 ( d, J=8, 1H), I_____ - 1ftQ - the paper scale With China National Standard (CNS) A4 size (210X 297 Kimiyoshi) 1328585 A7 B7 invention described five (186 7.43-7.46 (m, 3H), 8.00-8.03 (m, 2H) · 130 · Example
Lil:消旋性卜2-乙氧基-3_「2_甲某-4-(5-甲某·2· •其 竺唑-4-基甲氧基)苽某卜高齡 在類似於實例120f]說明的步驟中,將[外消旋性]_2_乙氧 基- 3-(4-羥基-2-曱基苯基)丙酸乙酯(實例129c))與4•氯甲 基-5-甲基-2〃塞吩-2-基噚唑在碳酸鉀及碘化鉀的存在下反 應,以產生[外消旋性]-2-乙氧多-3-[2-曱基-4-(5-甲基-2-噻吩-2-基呤唑-4-基甲氧基)苯基]-丙酸乙酯,將其以類似 於實例1 20f]說明的步驟進一步皂化,以產生成為淺黃色固 體之[外消旋性]-2-乙氧基_3_[2_曱基·4_(5_甲基_2•嘍吩_ 2-基呤唑-4-基甲氧基)苯基卜丙酸。 MS : 400.3 (M+H)·,354.1,281.2。 NMR : (CDC13, 1H, 300MHz, 5 , TMS) 1.13 (t, J=7.2j 3H) 2.34 (s, 3H), 2.41 (s, 3H), 2.93 (dxd, J=15.2, J=g.8j 1H) 3.12 (dxd, J=15.2, J=4, 1H),3.30-3.38 (m,1H), 3.49.3 57 (m, 1H), 4.01 (dxd, J=8, J=4.8, 1H), 4.94 (s, 2H) 6 78 (dxd, J=8, J=1.6, 1H), 6.82 (d, lH)) 7.08-7.14 (m 2H), 7.40 (dxd, J-4.8, J=〇.8, lH), 7.64 (dxd, J=4 0 J=〇 / 1H) 。 , 5 實例131 . 乙基茉甚 將[外消旋性]-2-乙氧 i外消旋性1-2-乙氣U- {4_「2^4 4 -基甲氧基1-2-甲基笨某}_兩畴 在類似於實例12〇f]說明的步驟中 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公 1328585 A7 _____ —______B7 五、發明説明(187) 基〇·(4·趣基·2_甲基苯基)丙酸乙酯(實例129c])與4-氯甲 基乙基苯基)-5-曱ί哼唑(實例122a])在碳酸鉀及碘 化钟的存在下反應’以產生[外消旋性]-2-乙氧基-3- {4- [2-(4-乙基苯基)_5_甲基„号唑_4_基甲氧基]_2_曱基苯基卜 丙酸乙酯,將其以類似於實例120f]說明的步驟進一步皂 化,以產生成為淺黃色固體之[外消旋性]·2·乙氧基_3_丨4_ [2-(4-乙基苯基)_5_曱基噚唑_4基甲氧基]·2甲基苯基卜 丙酸。 .. MS : 422.2 (Μ-Η)',376.3。 NMR : (CDC13, 1H, 300MHz, 5 , TMS) 1.12 (t, 1=7.2, 3H), 1.26 (t, J=8, 3H), 2.33 (s, 3H), 2.42 (s, 3H), 2.69 (q, j=8> 2H), 2.93 (dxd, J=15.2, J=8.8, 1H), 3.11 (dxd, J=15.2, J=4} 1H), 3.30-3.35 (m, 1H), 3.49-3.57 (m, 1H), 4.00 (dxd, J=8, J=4, 1H), 4.95 (s, 2H), 6.79 (dxd, J=8, J=1.6, 1H), 6.82 (d^ J=1.6, 1H), 7.12 (d, J=8, 1H), 7.27 (d, J=8, 2H), 7.92 (d J=8, 2H)。 ’ 實例132 生卜3- M-「2-(4- m三丁某苽基)·5·甲篡碟拣 ΐ.乳基1-2-甲基笨基丨-2-乙氳某丙酸 在類似於實例12〇f]說明的步驟中,將[外消旋性]_2乙氧 基-3-(4-羥基-2-甲基苯基)-丙酸乙酯(實例129(;])與2__(4_第 二丁基苯基)-4-氯甲基-5-甲基哼唑(實例123a])在碳酸鉀及 琪化鉀的存在下反應’以產生[外消旋性]_3_{4_[2(4_第 三丁基苯基)-5-甲基呤唑-4-基甲氧基]-2-甲基苯基卜2•乙Lil: racemic Bu 2-ethoxy-3_"2_甲-4-(5-甲某·2··· oxazol-4-ylmethoxy) 苽 高 高 高 在 在 类似于 类似于 类似于 类似于In the indicated procedure, [racemic]_2_ethoxy-3-(4-hydroxy-2-mercaptophenyl)propanoic acid ethyl ester (Example 129c)) and 4•chloromethyl-5 -Methyl-2-decenophen-2-ylcarbazole is reacted in the presence of potassium carbonate and potassium iodide to give [racemic]-2-ethoxyxo-3-[2-indolyl-4-( Ethyl 5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy)phenyl]-propanoate, which was further saponified in a procedure similar to that described in Example 1 20f] to give a shallow [Racecycling]-2-ethoxyl_3_[2_indolyl-4_(5-methyl-2•喽 _-2-yloxazol-4-ylmethoxy)phenyl Propionate MS: 400.3 (M+H)·, 354.1, 281.2. NMR: (CDC13, 1H, 300MHz, 5, TMS) 1.13 (t, J=7.2j 3H) 2.34 (s, 3H), 2.41 ( s, 3H), 2.93 (dxd, J=15.2, J=g.8j 1H) 3.12 (dxd, J=15.2, J=4, 1H), 3.30-3.38 (m,1H), 3.49.3 57 (m , 1H), 4.01 (dxd, J=8, J=4.8, 1H), 4.94 (s, 2H) 6 78 (dxd, J=8, J=1.6, 1H), 6.82 (d, lH)) 7.08- 7.14 (m 2H), 7.40 (dxd, J-4.8, J=〇.8, lH), 7.64 (dxd, J=4 0 J=〇/ 1H) . , 5 Example 131 . Ethyl oxalate will be [racemic]-2-ethoxyl i Racemic 1-2-E gas U- {4_"2^4 4 -ylmethoxy 1-2-methyl phenyl]_ two domains in a similar manner to the steps described in Example 12〇f] The scale applies to the Chinese National Standard (CNS) A4 specification (210X297 public 1328585 A7 _____ —______B7 V. Invention description (187) 〇·(4·趣基·2_methylphenyl)propionate ethyl ester (example 129c) Reaction with 4-chloromethylethylphenyl)-5-indoleazole (Example 122a)) in the presence of potassium carbonate and an iodide clock to yield [racemic]-2-ethoxy- 3-{4-[2-(4-Ethylphenyl)_5-methyl oxime _4_ylmethoxy]_2-decylphenylpropionic acid ethyl ester, similar to the example 120f The procedure described is further saponified to give [racemic]·2·ethoxy-3_丨4_[2-(4-ethylphenyl)-5-indenylcarbazole as a pale yellow solid. Methoxy] 2 methyl phenylpropionic acid. .. MS : 422.2 (Μ-Η)', 376.3. NMR : (CDC13, 1H, 300MHz, 5 , TMS) 1.12 (t, 1=7.2, 3H), 1.26 (t, J=8, 3H), 2.33 (s, 3H), 2.42 (s, 3H), 2.69 (q, j=8> 2H), 2.93 (dxd, J=15.2, J=8.8, 1H), 3.11 (dxd, J=15.2, J=4} 1H), 3.30-3.35 (m, 1H), 3.49 -3.57 (m, 1H), 4.00 (dxd, J=8, J=4, 1H), 4.95 (s, 2H), 6.79 (dxd, J=8, J=1.6, 1H), 6.82 (d^ J =1.6, 1H), 7.12 (d, J=8, 1H), 7.27 (d, J=8, 2H), 7.92 (d J=8, 2H). 'Example 132 生卜3- M-"2-(4- m三丁某苽基)·5·甲篡碟ΐ. Milk-based 1-2-methyl stupidin-2-ethyl hydrazine propionic acid [Racemic]_2ethoxy-3-(4-hydroxy-2-methylphenyl)-propionic acid ethyl ester (Example 129 (;) in a procedure similar to that described in Example 12]. Reaction with 2__(4_2t-butylphenyl)-4-chloromethyl-5-methylcarbazole (Example 123a)) in the presence of potassium carbonate and potassium hydride to produce [racemic ]_3_{4_[2(4_T-butylphenyl)-5-methyloxazol-4-ylmethoxy]-2-methylphenyl b 2•B
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線 -191 -Line -191 -
1328585 A7 ___ B7 五、發明説明(188) 氧基丙酸乙酯,將其以類似於實例l2〇f]說明的步驟進一步 皂化’以產生成為淺黃色固體之[外消旋性]·3_{4_[2_(4· 第三丁基苯基)-5•曱基嘮唑-4-基甲氧基]-2-甲基苯基卜2-乙氧基丙酸。 MS : 450.3 (Μ-Η)*,422.2, 404.3。 NMR : (CDC13, 1H, 300MHz, ό , TMS) 1.12 (t, J=7.2, 3H), 1.35 (s, 9H), 2.34 (s, 3H), 2.43 (s, 3H), 2.93 (dxd, J=15.2, J=8.8, 1H), 3.13 (dxd, J=15.2^ J=4.8, 1H), 3.26-3.38 (m, 1H),3.48-3.58 (m,ih),4.00 (dxd, J=8, J=4, 1H),4.96 (s, 2H), 6.79 (dxd, J=8, J=1.6, 1H), 6.82 (d5 J=1.6, 1H), 7.12 (d, J=8, 1H), 7.45 (d, J=8, 2H), 7.93 (d, J=8, 2H) « 實例133 _1328585 A7 ___ B7 V. INSTRUCTION DESCRIPTION (188) Ethyl oxypropionate, which is further saponified in a procedure similar to that described in Example l2〇f] to produce [racemic]·3_{ as a pale yellow solid 4_[2_(4·t-Butylphenyl)-5•mercaptoindazole-4-ylmethoxy]-2-methylphenyl- 2-ethoxypropionic acid. MS: 450.3 (Μ-Η)*, 422.2, 404.3. NMR : (CDC13, 1H, 300MHz, ό, TMS) 1.12 (t, J=7.2, 3H), 1.35 (s, 9H), 2.34 (s, 3H), 2.43 (s, 3H), 2.93 (dxd, J =15.2, J=8.8, 1H), 3.13 (dxd, J=15.2^ J=4.8, 1H), 3.26-3.38 (m, 1H), 3.48-3.58 (m,ih), 4.00 (dxd, J=8 , J=4, 1H), 4.96 (s, 2H), 6.79 (dxd, J=8, J=1.6, 1H), 6.82 (d5 J=1.6, 1H), 7.12 (d, J=8, 1H) , 7.45 (d, J=8, 2H), 7.93 (d, J=8, 2H) « Example 133 _
Lj卜消旋性l-2- Γϋ-3- Μ-Γ2-Μ-異丙氳某笨某U-甲篡 :f_吃-4·基甲氧某1-2-甲某笨基卜丙酸 在類似於實例120f]說明的步驟中,將[外消旋性卜2_乙氧 基-3-(4-羥基-2-甲基苯基)丙酸乙酯(實例129£;])與4_氯甲 基-2-(4-異丙氧基苯基)_5_甲基哼唑(實例1243])在碳酸鉀 及碘化鉀的存在下反應,以產生[外消旋性]_2_乙氧基_3_ {4-[2-(4-異丙氧基苯基)_5_曱基呤唑_4_基甲氧基]_2甲基 苯基}-丙酸乙酯,將其以類似於實例12〇f]說明的步驟進一 步惠化,以產生成為淺黃色固體之[外消旋性]·2_乙氧基_ 3- {4-[2-(4-異丙氧基苯基)_5•甲基哼唑_4_基甲氧基]_2_曱 基苯基丨-丙酸。 MS : .452.3 (Μ-Η)_, 406.3, 281.2 » _____ - 192 - 本紙張X·度適財g @家標準(CNS) Α4規格(21Gχ 297公爱) --- 1328585 A7 B7 五、發明説明(189) NMR: (CDCI3, 1H, 300MHz,5, TMS) 1.12 (t, J=7.2, 3H), 1.36 (d, J=7.2, 6H), 2.37 (s, 3H), 2.41 (s, 3H), 2.92 (dxd, J=15.2, J=8.8, 1H), 3.12 (dxd, J=i5.2, J=4.8, 1H), 3.26- 3.36 (m, 1H), 3.48-3.58 (m, 1H), 4.〇l (dxd> J=8? J=4, 1H), 4.61 (sept., J=7.2, 1H), 4.94 (s, 2H), 6.79 (dxd, J=8, 1H), 6.83 (d, J=i.6j 1H), 6.92 (d} J=8, 1H), 7.12 (d, J=8, 2H),7.93 (d, J=8, 2H)。 實例134 (8)-2-丁-3-締氧_^_3_{3,5_二甲基二1^2_(5_甲某-2_笨甚-g号唑-4-基)-乙氧某1_茇某丨-丙龄 在類似於實例113]至11〇]說明的步驟中,將3,5_二甲基_ 4-[2-(5-甲基-2-笨基-呤唑_4·基)·乙氧基]•苯醛(實例Π7) 與(5)-4-卞基-3-(2-丁_3-烯氧基乙醯基)1»号唑烷_2_酮(關於 (S)-4-节基-3-(2- 丁 - 3-烯氧基乙醯基)呤唑烷-2_酮的製備 作用’參考:Μ. T. Crimmins, A. L. Choy,J. Am. Chem. Soc. 1999,121,5653-5660)及 nBu2BOTf 反應,以產生(s)-4-苄基- 3-((2S,3R)-2- 丁- 3-埽氧基-3-{3,5-二甲基-4-[2- (5-甲基· 2-苯基号唑-4-基)-乙氧基]-苯基卜3_羥基丙醯基) 哼唑烷-2-酮(根據NMR,四個異構物的其中之一極佔優 勢;根據 D_ Haigh,H. C. Birrell,B. C· C. Cantello, D. S.LjBu racemic l-2- Γϋ-3- Μ-Γ2-Μ-isopropyl 氲 Some stupid U-甲篡:f_吃-4·基甲氧一1-2-甲某笨基卜Acid in a similar procedure to that described in Example 120f], [Racemic 2-Ethoxy-3-(4-hydroxy-2-methylphenyl)propanoic acid ethyl ester (Example 129 £;]) Reaction with 4-chloromethyl-2-(4-isopropoxyphenyl)-5-methylcarbazole (Example 1243) in the presence of potassium carbonate and potassium iodide to give [racemic]_2_ Ethoxy_3_ {4-[2-(4-isopropoxyphenyl)_5-mercaptocarbazole-4-yloxy]_2-methylphenyl}-propionic acid ethyl ester Steps similar to those described in Example 12〇f] were further optimized to give [racemic]·2_ethoxy_3-{4-[2-(4-isopropoxybenzene) as a pale yellow solid. Base)_5•methylcarbazole_4_ylmethoxy]_2_mercaptophenylphosphonium-propionic acid. MS : .452.3 (Μ-Η)_, 406.3, 281.2 » _____ - 192 - This paper X·度适财g @家标准(CNS) Α4Specifications (21Gχ 297 公爱) --- 1328585 A7 B7 V. Invention Description (189) NMR: (CDCI3, 1H, 300MHz, 5, TMS) 1.12 (t, J=7.2, 3H), 1.36 (d, J=7.2, 6H), 2.37 (s, 3H), 2.41 (s, 3H), 2.92 (dxd, J=15.2, J=8.8, 1H), 3.12 (dxd, J=i5.2, J=4.8, 1H), 3.26- 3.36 (m, 1H), 3.48-3.58 (m, 1H), 4.〇l (dxd> J=8? J=4, 1H), 4.61 (sept., J=7.2, 1H), 4.94 (s, 2H), 6.79 (dxd, J=8, 1H) , 6.83 (d, J=i.6j 1H), 6.92 (d} J=8, 1H), 7.12 (d, J=8, 2H), 7.93 (d, J=8, 2H). Example 134 (8)-2-but-3-oxo_^_3_{3,5-dimethyldi 1^2_(5_甲某-2_笨甚-g-azole-4-yl)-B Oxygen 1_茇一丨-Cailing in a procedure similar to that described in Examples 113] to 11〇], 3,5-dimethyl-4-(2-(5-methyl-2-phenyl)- Carbazole _4·yl)·ethoxy]benzaldehyde (Example Π7) and (5)-4-mercapto-3-(2-butyl-3-isopropoxyacetinyl)1»oxazolidine _2 ketone (for the preparation of (S)-4-pyryl-3-(2-but-3-enyloxyethyl) oxazolidine-2-one] Reference: Μ. T. Crimmins, AL Choy, J. Am. Chem. Soc. 1999, 121, 5653-5660) and nBu2BOTf reaction to produce (s)-4-benzyl-3-((2S,3R)-2-butyl-3-pyrene Oxy-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-phenyl b- 3 hydroxypropionate Oxazolidine-2-one (according to NMR, one of the four isomers is predominant; according to D_ Haigh, HC Birrell, B. C. C. Cantello, DS
Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron Asymmetry 1999,10,1353-1 367,暫時將组態以2S,3R命名)。以在三氟醋酸中的三乙 基甲矽烷還原(S)-4-芊基- 3-(( 2S,3R)-2- 丁 - 3-烯氧基-3- ____ 1Q^ - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron Asymmetry 1999, 10, 1353-1 367, temporarily named 2S, 3R). Reduction of (S)-4-mercapto-3-(( 2S,3R)-2-but-3-enyloxy-3- ____ 1Q^ - this paper scale with triethylformane in trifluoroacetic acid Applicable to China National Standard (CNS) A4 specification (210X297 mm)
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線 1328585Line 1328585
五、發明説明(190) { 3,5-二甲基- 4-[2-(5-甲基-2-苯基-σ号唑-4-基)-乙氧基卜 苯基} - 3-羥基丙醯基)噚唑烷-2-酮’以得到(S)- 4-笮基'3-((2S)-丁-3-晞氧基-3-{ 3,5-二甲基-4· [2-(5-甲基-2-苯基-呤唑-4-基)-乙氧基]-苯基}丙醯基)噚唑烷-2-酮。接著將 (S)-4-苄基- 3-((2S,3R)-2- 丁 -3-烯氧基-3- {3,5-二甲基 _4_ [2-(5-甲基-2-苯基-呤唑-4-基)-乙氧基]-苯基}-3-羥基丙 醯基广号唑烷-2-酮以在THF中的1克分子量NaOH皂化,以產 生成為無色固體之(S)-2-丁 締氧基- 3-{3,5 -二肀基 [2-(5-甲基-2-苯基-呤唑-4-基)-乙氧基]-苯基卜丙酸°-MS : 438.3 (M-Η).,394.2, 293.2, 263.1,219.4。 NMR : (DMSO-d6, 1Η,400MHz,(5,TMS) 2.10 (s,6Η),2.18 (q,J=7.2, 2H),2.38 (s,3H),2.67-2,77 (m,1H),2.81 (dxd, J=15.2, J=5.6,1H),2.91 (t,J=7.2, 2H),3.23-3.32 (m,2H), 3.51-3.57 (m,1H),3.90-3.98 (m,3H),4.94 (dxd,J=8·8, J=0.8, 1H),5.00 (dxd,J=16.8,J=0.8,1H),5.63-5.74 (m, 1H), 6.85 (s, 2H), 7.45-7.52 (m, 3H), 7.92 (dxd, J=8, J=〇·8» 2H), 12.65 (br.s, 1H)。 實例135 —甲某- 4·Ι~2-(5-甲基-2-尽基-,嗅-4 -甚乙乳~ 基〗篆基丨·2Ζ-乙氳基丙嫌酸 在類似於實例12〇f]說明的步驟中,將3- {3,5-二甲基-4-[2-(5 -甲基-2-苯基-p号唑_4·基)-乙氧基]-苯基}_2Z-乙氧基 丙烯故乙酉旨{在類似於實例1 14c]說明的步驟中,以3,5-二甲 基-4-[2-(5-甲基_2-苯基·。号唑-4-基)·乙氧基]_苯醛(實例 _________- 1Q4 -_____ 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)V. DESCRIPTION OF THE INVENTION (190) { 3,5-Dimethyl- 4-[2-(5-methyl-2-phenyl-σ-oxazol-4-yl)-ethoxyphenyl]} 3 -hydroxypropionyl)oxazolidin-2-one' to give (S)-4-indolyl'3-((2S)-but-3-oxooxy-3-{3,5-dimethyl -4· [2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}propenyl)oxazolidin-2-one. Next, (S)-4-benzyl-3-((2S,3R)-2-but-3-enyloxy-3-{3,5-dimethyl-4_[2-(5-methyl) -2-Phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-hydroxypropanylpolyoxazolidin-2-one is saponified with 1 gram molecular weight NaOH in THF to produce (S)-2-butoxy- 3-{3,5-dimercapto[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxylate as a colorless solid ]-Phenylpropionic acid °-MS: 438.3 (M-Η)., 394.2, 293.2, 263.1, 219.4. NMR: (DMSO-d6, 1 Η, 400 MHz, (5, TMS) 2.10 (s, 6 Η), 2.18 (q, J=7.2, 2H), 2.38 (s, 3H), 2.67-2, 77 (m, 1H), 2.81 (dxd, J = 15.2, J = 5.6, 1H), 2.91 (t, J = 7.2, 2H), 3.23-3.32 (m, 2H), 3.51-3.57 (m, 1H), 3.90-3.98 (m, 3H), 4.94 (dxd, J=8·8, J=0.8, 1H), 5.00 (dxd, J = 16.8, J = 0.8, 1H), 5.63-5.74 (m, 1H), 6.85 (s, 2H), 7.45-7.52 (m, 3H), 7.92 (dxd, J=8, J=〇 · 8» 2H), 12.65 (br.s, 1H). Example 135 - A certain - 4 · Ι ~ 2-(5-methyl-2-endyl-, scent-4 - very condensed ~ base 篆丨 Ζ Ζ Ζ 氲 氲 氲 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在5-methyl-2-phenyl-p-azole _4. yl)-ethoxy]-phenyl}_2Z-ethoxy propylene (in a similar manner to Example 1 14c), 3,5-Dimethyl-4-[2-(5-methyl_2-phenyl.carbazole-4-yl)·ethoxy]benzaldehyde (example _________- 1Q4 -_____) Zhang scale applies to China National Standard (CNS) A4 specification (210X 297 mm)
装 订Binding
1328585 A7 B7 五、發明説明(191 ) 11 *7)及氯化(乙氧基乙氧羰基甲基)三苯鎢(K. K. Bach,H. R. ΗΙ-Seedi, Η. M. Jensen, Η. Β. Nielsen, I. Thomson, K. B. G. Torssell,Tetrahedron 1994,50, 7543-7556)製得的化成 為無色晶體之3- {3,5-二甲基-4-[2-(5-甲基-2-苯基-哼唑_ 4 -基)-乙氧基]-苯基}·2Ζ-乙氧基丙烯酸。 MS : 420.3 (Μ-Η)·,348.3, 281.2, 255.2, 235.2。 NMR : (CDC13,1H,400MHz,<5,TMS) 1.38 (t,J=7.2, 3H), 2.23 (s, 6H), 2.40 (s, 3H), 3:01 (t, 5=1.2, 2H), 3.98 (q, 3=1.2, 2H),-4.09 (t, J-7.2, 2H), 7.02 (s, 1H), 7.41-7.46 (m, 5H), 7.99 (dxd,J=8, J=0.8, 2H)。 實例1 3 6 [外消旋性1-3- {4-『2-( 4-氪苯某甲基呤唑-4-其甲$早1 笨并咭喃-7-基卜2-乙氣某丙酸 在類似於實例2丨f]說明的步驟中,將[外消旋性卜2-乙氧 基-3- (4-羥基苯并呋喃· 7-基)丙酸甲酯(實例120e])與[2- (4-氣甲基)-5-曱基呤唑-4-基]曱醇(R. C. Self, W. E. Barber,J. P. Machin, J. M. Osbond, C. E. Smithen, B. P. Tong, J. C. Wickens, D. P. Bloxham, D. Bradshaw, C. H. Cashin, B. B. Dodge, E. J. Lewis, D. Westmacott,J. Med. Chem. 1991,34, 772-777)在三苯膦及偶氮二羧酸二乙酯的存在下反應,以 產生[外消旋性]-3- {4-[ 2-(4-氣苯基)-5-甲基呤唑_4_基甲 氧基]苯并呋喃-7-基}-2-乙氧基丙酸甲酯,將其以類似於 實例丨20f]說明的步驟進一步皂化,以產生成為無色固體之 [外消旋性]-3-{4-[2-(4-氯苯基)-5-甲基咩唑-4-基甲氧基] __- 1PR -_____ 本紙張尺度適用中國國家標準(CNS) A4规格(210X297公爱) '1328585 A7 B7 V. INSTRUCTIONS (191) 11 *7) and chlorinated (ethoxyethoxycarbonylmethyl)triphenyl tungsten (KK Bach, HR ΗΙ-Seedi, Η. M. Jensen, Η. Β. Nielsen , I. Thomson, KBG Torssell, Tetrahedron 1994, 50, 7543-7556) 3-{3,5-Dimethyl-4-[2-(5-methyl-2-benzene) Base-carbazole-4-yl)-ethoxy]-phenyl}·2Ζ-ethoxy acrylic acid. MS: 420.3 (Μ-Η)·, 348.3, 281.2, 255.2, 235.2. NMR: (CDC13, 1H, 400MHz, <5, TMS) 1.38 (t, J = 7.2, 3H), 2.23 (s, 6H), 2.40 (s, 3H), 3:01 (t, 5 = 1.2, 2H), 3.98 (q, 3=1.2, 2H), -4.99 (t, J-7.2, 2H), 7.02 (s, 1H), 7.41-7.46 (m, 5H), 7.99 (dxd, J=8, J = 0.8, 2H). Example 1 3 6 [Racemic 1-3- {4-『2-(4-氪Benzylmethylcarbazole-4-A$$1 1 stupid and 咭-7-kib 2-ethane a propionic acid in a procedure similar to that described in Example 2, f], [Racemic 2-ethyl-3-ethoxy-3-(4-hydroxybenzofuran-7-yl)propanoate (Example 120e) ]) with [2- (4-methylmethyl)-5-mercaptoindazole-4-yl] sterol (RC Self, WE Barber, JP Machin, JM Osbond, CE Smithen, BP Tong, JC Wickens, DP Bloxham, D. Bradshaw, CH Cashin, BB Dodge, EJ Lewis, D. Westmacott, J. Med. Chem. 1991, 34, 772-777) Reaction in the presence of triphenylphosphine and diethyl azodicarboxylate To produce [racemate]-3-{4-[2-(4-phenylphenyl)-5-methylcarbazole-4-yloxy]benzofuran-7-yl}-2 Methyl ethoxypropionate, which was further saponified in a similar manner to that described in Example 20f] to give [racemic]-3-{4-[2-(4-chlorobenzene) as a colorless solid. Base)-5-methylcarbazol-4-ylmethoxy] __- 1PR -_____ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 public)
裝 訂Binding
線 1328585 A7 B7 五、發明説明(192 ) 苯并呋喃-7-基} - 2-乙氧基丙酸。 MS ·· 454.2 (M-Η).,408.1,299.1,249.1。 NMR : (DMSO-d6, 1H, 400ΜΗζ, ά , TMS) 0.99 (t, J=7.2, 3H), 2.46 (s, 3H), 3.06 (dxd, J=15.2, J=8, 1H), 3.19 (dxd, J=15.2, J=6.4, 1H), 3.23-3.45 (m, 1H), 3.47-3.55 (m, 1H), 4.10 (t, i=1.2, 1H), 5.13 (s, 2H), 6.89 (d, J=8, 1H), 6.90 (d, J=1.6, 1H), 7.12 (d, J=8, 1H), 7.60 (d, J=8.8, 2H), 7.90 (d, J=1.6, 1H), 7.96 (d, J=8.8, 2H)U12.90 (br.s, 1H) 〇 實例137 - Γ夕卜Ά旋4生1-3-{4-[~2-(4-氣笨基)-5-甲基p号峰·4_某甲氣 某1-2-甲基苽某丨-2-乙氧某丙醢 在類似於實例2 1 f]說明的步驟中,-將[外消旋性卜2_乙氧 基-3-(4-¾基-2-甲基苯基)丙酸乙酿(實例129c])與[2-(4-氯 甲基)-5-曱基呤唑-4-基]曱醇(R. C. Self, W. E. Barber, J. P. Machin, J. M. Osbond, C. E. Smithen, B. P. Tong J. C. Wickens, D. P. Bloxham, D. Bradshaw, C. H. Cashin B. B. Dodge, E. J. Lewis, D. Westmacott, J. Med. Chem. 1991, 34, 772-777)在二本鱗及偶氮二幾酸二乙g旨的存在下反應,% 產生[外消旋性]-3- {4-[ 2-(4-氣苯基)-5-甲基呤唑-4-基甲 氧基]-2-甲.基笨基}_2_乙氧基丙酸乙g旨,將其以類似於實 例120f]說明的步驟進一步-包化,以產生成為無色固體之 [外消旋性]-3- {4-[2-(4-氣苯基)-5-曱基。号唑_4_基曱氣 基]-2-甲基苯基}-2-乙氧基丙酸。 MS : 428.32 (M-H)·,384.1,349.0, 255.4。 196 本紙乐尺度適用中國圉家標準(CMS) A4規格(210X297公釐) 1328585 A7 ______B7 五、發明説明(193) NMR : (CDCI3, 1H, 400MHz, (5 , TMS) 1.06 (t, J=7.2, 3H), 2.23 (s, 3H), 2.36 (s. 3H), 2.88 (dxd, J=15.2, J=8, 1H), 3.05 (dxd, J=15.2, J=4.8, 1H), 3.22-3.31 (m, 1H), 3.43-3.51 (m, 1H), 3.94 (dxd, J=8, J=4.8, 1H), 4.88 (s, 2H), 6.73 (dxd, J=8, J=1.6, 1H), 6.76 (d, J=1.6, 1H), 7.06 (d, J=8, 1H), 7.34 (d, J=8, 2H), 7.88 (d, J=8, 2H)。 實例138 J:外消旋性1-3- {4-「2-(3.5-二-甲氳某苽某)-5-甲其,诎- 4-羞•甲氧基1苯并咭喃-7-基卜2-乙氣基丙酸 在類似於實例12〇f]說明的步驟中,將[外消旋性]_ 2_乙氧 基_3·(4-羥基苯并呋喃-7-基)丙酸甲酯(實例120e])與4-氣 甲基-2-(3:5-二甲氧基苯基)_5_甲基-哼唑(在類似於實例21a) 及b]說明的步驟中,以3,5_二甲氧基苯醛及二乙醯基單 月亏,接著以POCI3處理製得的)在碳酸鉀及碘化鉀的存在下 反應,以產生[外消旋性]_3_{4_ [2_(3,5_二甲氧基苯基)_5_ 曱基号吐-4-基甲乳基]苯并吱喃-7-基丨-2-乙氧基丙酸甲 醋,將其以類似於實例12〇f]說明的步驟進—步皂化,以產 生成為無色固體之[外消旋性]_3- {4- [2-(3,5-二甲氧基苯 基)-5-甲基呤唑-4-基甲氧基]苯并呋喃-7_基卜2_乙氧基丙 酸。 MS : 480.2 (M-H).,434.3,-390.2, 249.1。 NMR : (DMSO-d6, 1H, 400MHz, δ , TMS) 1.00 (t, J=7.2, 3H), 2.46 (s, 3H), 3.08 (dxd, J=15.2, J=8, 1H), 3.19 (dxd, J=15.2, J=6.4, 1H), 3.26-3.32 (m, 1H), 3.47-3.55 (m, 1H), __ - 197 - 本纸張尺度適用中g國家標準(CNS) A4規格㈣x297公爱) -- 裝 訂Line 1328585 A7 B7 V. Description of the Invention (192) Benzofuran-7-yl}-2-ethoxypropionic acid. MS ·· 454.2 (M-Η)., 408.1, 299.1, 249.1. NMR : (DMSO-d6, 1H, 400 ΜΗζ, ά, TMS) 0.99 (t, J = 7.2, 3H), 2.46 (s, 3H), 3.06 (dxd, J = 15.2, J = 8, 1H), 3.19 ( Dxd, J=15.2, J=6.4, 1H), 3.23-3.45 (m, 1H), 3.47-3.55 (m, 1H), 4.10 (t, i=1.2, 1H), 5.13 (s, 2H), 6.89 (d, J=8, 1H), 6.90 (d, J=1.6, 1H), 7.12 (d, J=8, 1H), 7.60 (d, J=8.8, 2H), 7.90 (d, J=1.6 , 1H), 7.96 (d, J=8.8, 2H)U12.90 (br.s, 1H) 〇Example 137 - Γ Ά Ά 4 4 1-3-{4-[~2-(4-气Stupid base) -5-methyl p-peak · 4_ a certain gas 1-2-methyl 苽 a 丨 -2- ethoxy propyl hydrazine in a step similar to the example 2 1 f], - [Racemic 2 -ethoxy-3-(4-3⁄4yl-2-methylphenyl)propionic acid ethyl (example 129c)) and [2-(4-chloromethyl)-5- Mercaptoin-4-yl] sterol (RC Self, WE Barber, JP Machin, JM Osbond, CE Smithen, BP Tong JC Wickens, DP Bloxham, D. Bradshaw, CH Cashin BB Dodge, EJ Lewis, D. Westmacott , J. Med. Chem. 1991, 34, 772-777) reacts in the presence of two scales and arsenic acid diethylene g, % yields [racemic]-3- {4-[ 2 -(4-phenylphenyl)-5-methylcarbazole -4-ylmethoxy]-2-yl.ylamino}_2-ethoxypropionic acid B, which was further-encapsulated in a similar manner to that described in Example 120f] to give a colorless solid. [Racecycling]-3-{4-[2-(4-Phenylphenyl)-5-fluorenyl. No. azole_4_ylindole group]-2-methylphenyl}-2-ethoxypropionic acid. MS: 428.32 (M-H)·, 384.1, 349.0, 255.4. 196 This paper scale applies to China National Standard (CMS) A4 specification (210X297 mm) 1328585 A7 ______B7 V. Invention description (193) NMR: (CDCI3, 1H, 400MHz, (5, TMS) 1.06 (t, J=7.2 , 3H), 2.23 (s, 3H), 2.36 (s. 3H), 2.88 (dxd, J=15.2, J=8, 1H), 3.05 (dxd, J=15.2, J=4.8, 1H), 3.22- 3.31 (m, 1H), 3.43-3.51 (m, 1H), 3.94 (dxd, J=8, J=4.8, 1H), 4.88 (s, 2H), 6.73 (dxd, J=8, J=1.6, 1H), 6.76 (d, J=1.6, 1H), 7.06 (d, J=8, 1H), 7.34 (d, J=8, 2H), 7.88 (d, J=8, 2H). Example 138 J : racemic 1-3- {4-"2-(3.5-di-methyl 氲) ----, 诎- 4-- • methoxy 1 benzopyran-7-yl 2-Ethylpropionic acid in a procedure similar to that described in Example 12〇f], [racemic] _ 2 ethoxy _ 3 · (4-hydroxybenzofuran-7-yl) propyl Methyl ester (Example 120e)) with 4-methylmethyl-2-(3:5-dimethoxyphenyl)-5-methyl-carbazole (in a similar manner to Example 21a) and b] Reacting in the presence of potassium carbonate and potassium iodide with a single monthly loss of 3,5-dimethoxybenzaldehyde and diethylhydrazine, followed by treatment with POCI3 to produce [racemic]_3 _{4_[2_(3,5-Dimethoxyphenyl)_5_ fluorenyl oxa-4-ylmethyl] benzopyran-7-yl hydrazine-2-ethoxypropionic acid methyl vinegar, It was further saponified in a procedure similar to that described in Example 12, to give [racemic]_3-{4-[2-(3,5-dimethoxyphenyl) as a colorless solid. -5-Methyloxazol-4-ylmethoxy]benzofuran-7-yl-2-ethoxypropane acid MS: 480.2 (MH)., 434.3, -390.2, 249.1. NMR: (DMSO -d6, 1H, 400MHz, δ, TMS) 1.00 (t, J=7.2, 3H), 2.46 (s, 3H), 3.08 (dxd, J=15.2, J=8, 1H), 3.19 (dxd, J= 15.2, J=6.4, 1H), 3.26-3.32 (m, 1H), 3.47-3.55 (m, 1H), __ - 197 - This paper size applies to the Chinese National Standard (CNS) A4 specification (4) x297 public) - - Binding
線 1328585 A7 B7 五、發明説明(194 3.82 (s, 6H), 4.13 (dxd, J=8, J=6.4, 1H), 5.12 (s, 2H), 6.64 (t, J=0.8, 1H), 6.89 (d, J=8, 1H), 6.91 (d, J=1.6, 1H), 7.06 (d, J=〇.8,2H),7.12 (d, J=8, 1H), 7.90 (d, J=1.6,1H), 12,70 (br.s,1H)。 實例139 22-乙氩某-3-{4-丨2-(4-異丙某笨某)-5-甲某„^^坐_4_基甲氧. 基1-2-甲某苽基丨-丙烯酸 在類似於實例120f]說明的步-寧中,將4-羥基-2-曱基苯醛 (關於4-經基-2-甲基苯醛的製備作用,參考:η.. H. Hodgson, T. A. Jenkinson, J. Chem. Soc. 1929, 469, 1639-1641)與4-氯甲基-2-( 4-異丙基苯基)-5 _甲基哼唑(在類似於 實例21a]及b]說明的步驟中,以4-異丙基苯醛及二乙醯基 單肟,接著以P 0 C13處理製得的)在碳酸鉀的存在下反應, 以產生4-[2-(4-異丙基苯基)_5-曱基σ号吐_4_基甲氧基]_2_ 甲基苯醛。在類似於實例12〇c]說明的步驟中,將4_ [ 2_ (4_ 異丙基苯基)-5-甲基"号唑-4-基甲氧基]_2_甲基苯醛與氯化 (乙氧基乙氧羰基甲基)三苯錡(關於氣化(乙氧基乙氧羰基 甲基)三苯鱗的製備作用,參考:κ.κ·Bach,H.R.EI-Seedi, Η. M. Jensen, Η. B. Nielsen, I. Thomson, K. B. G.Line 1328085 A7 B7 V. Description of invention (194 3.82 (s, 6H), 4.13 (dxd, J=8, J=6.4, 1H), 5.12 (s, 2H), 6.64 (t, J=0.8, 1H), 6.89 (d, J=8, 1H), 6.91 (d, J=1.6, 1H), 7.06 (d, J=〇.8,2H), 7.12 (d, J=8, 1H), 7.90 (d, J=1.6,1H), 12,70 (br.s,1H). Example 139 22-Ethyl argon-3-{4-丨2-(4-isopropyl some stupid)-5-A „^ ^坐_4_基methoxy. base 1-2-methyl hydrazino-acrylic acid in a step similar to that described in Example 120f], 4-hydroxy-2-mercaptobenzaldehyde (about 4- Preparation of benzyl-2-methylbenzaldehyde, reference: η.. H. Hodgson, TA Jenkinson, J. Chem. Soc. 1929, 469, 1639-1641) and 4-chloromethyl-2-(4- Isopropylphenyl)-5-methylcarbazole (in a procedure similar to that described in Examples 21a) and b], treated with 4-isopropylbenzaldehyde and diethylindenyl, followed by P0C13 The resulting compound is reacted in the presence of potassium carbonate to produce 4-[2-(4-isopropylphenyl)-5-indenyl σ. 吐-4-ylmethoxy]_2-methylbenzaldehyde. Similar to the procedure illustrated in Example 12〇c], 4_[ 2_(4-isopropylphenyl)-5-methyl "oxazol-4-ylmethoxy]_2-methylbenzene Aldehyde and chlorinated (ethoxyethoxycarbonylmethyl)triphenylhydrazine (for the preparation of gasified (ethoxyethoxycarbonylmethyl) triphenyl scales, reference: κ.κ·Bach, HREI-Seedi , Η. M. Jensen, Η. B. Nielsen, I. Thomson, KBG
Torssell’ Tetrahedron 1994, 50, 7543-7556)在 DBU 的存在下 反應,以得到2Z-乙氧基_3_{4_[2_(4·異丙基苯基)·5甲基 ρ可唑-4-基甲氧基]-2-甲基苯基卜丙烯酸乙酯,將其以類似 於貫例1 20f]說明的步驟進_步皂化,以產生成為淺綠色固 體之2Z-乙氧基-3- {4-[2-(4-異丙基苯基)-5-甲基呤唑_4_基 1 本纸張·尺度適用中國國豕標準(CNS) A4規格(210X291^^) ~ 1328585 A7 B7 195 五、發明説明 甲氧基]-2-甲基苯基}-丙烯酸。 MS : 434.3 (M-H)·,362.2,_293.2。 NMR : (DMSO-d6, 1H, 400ΜΗζ, δ , TMS) 1.21 (t, J=8, 3H), 1.23 (d, 1=1.2, 6H), 2.32 (s, 3H), 2.45 (s, 3H), 2.95 (sept·, J=7.2, 1H), 3.90 (q, J=7.2, 2H), 5.01 (s, 2H), 6.92 (dxd, J=8, J=0.8, 1H), 6.95 (d, J=〇.8, 1H), 7.03 (s, 1H), 7.40 (d, J=8, 2H), 7.87 (d, J=8, 2H), 8.00 (d, J=8, 1H), 12.80 (br.s, 1H)。 -- 實例140 L外确旋.j生卜2-乙氡基- 3- f3_甲某-氧基)笨基1-丙酸 在類似於實例1 08c]說明的步驟中,以在N N_二甲基甲醯 胺中的4-氣甲基-2-苯基-呤唑[以苯醯胺及〖,3_二氣基丙酮 如 Bioorg. Med_ Chem. Lett.(20〇〇),1〇(17),2041-2044的說 明製備的]及氫化鈉處理[外消旋性]_2•乙氧基·3_4_(羥基· 3-甲基苯基)丙酸乙酯[PCT Int Αρρ丨(2〇〇1),w〇 01/40172A1],以產生[外消旋性]_2_乙氧基·3[3甲基_4· (2-苯基-十坐_4·基甲氧基)苯基丙酸乙§旨,將其以類似於 實例9U]說明的步鄉進一步琶化,以產生成為無色膠之[外 消旋性]-2·乙氧基-3-[3-曱基-4-(2-苯基-呤唑_4_基甲氧基 苯基]-丙酸。 . MS : 380.2 (M-H)* 〇 NMR : (CDC13> 1H, 2-25 (s, 3H), 2.92 400MHz,TMS) L18 J=?〇j 3h)j (dxd. J=14.4j J=7.6, 1H), 3.06 (dxd. 本纸張尺度適时g g家料(CNS) A4規格--------- 1328585 A7 B7Torssell' Tetrahedron 1994, 50, 7543-7556) reacts in the presence of DBU to give 2Z-ethoxy_3_{4_[2_(4·isopropylphenyl)·5 methyl ρ-axazole-4- Ethyl methoxy]-2-methylphenyl acrylate, which is saponified in a similar manner to that described in Example 1 20f] to give 2Z-ethoxy-3- as a light green solid. {4-[2-(4-Isopropylphenyl)-5-methylcarbazole_4_yl 1 Paper · Scale applicable to China National Standard (CNS) A4 Specification (210X291^^) ~ 1328585 A7 B7 195 V. DESCRIPTION OF THE INVENTION Methoxy]-2-methylphenyl}-acrylic acid. MS: 434.3 (M-H)·, 362.2, _293.2. NMR : (DMSO-d6, 1H, 400 ΜΗζ, δ, TMS) 1.21 (t, J=8, 3H), 1.23 (d, 1 = 1.2, 6H), 2.32 (s, 3H), 2.45 (s, 3H) , 2.95 (sept·, J=7.2, 1H), 3.90 (q, J=7.2, 2H), 5.01 (s, 2H), 6.92 (dxd, J=8, J=0.8, 1H), 6.95 (d, J=〇.8, 1H), 7.03 (s, 1H), 7.40 (d, J=8, 2H), 7.87 (d, J=8, 2H), 8.00 (d, J=8, 1H), 12.80 (br.s, 1H). - Example 140 L is externally rotated. j shengb 2-ethyl fluorenyl-3-f3_methyl methoxy) phenyl 1-propionic acid in a procedure similar to that described in Example 1 08c], in N N 4-oxomethyl-2-phenyl-oxazole in dimethylformamide [in terms of benzoguanamine and [3-3-dicarbylacetone] such as Bioorg. Med_Chem. Lett. (20〇〇), 1〇(17), prepared by the description of 2041-2044] and sodium hydride treatment [racemic]_2•ethoxy3_4_(hydroxy-3-methylphenyl)propionate ethyl ester [PCT Int Αρρ丨(2〇〇1), w〇01/40172A1], to produce [racemate]_2_ethoxy-3 [3 methyl_4·(2-phenyl-tensole_4·ylmethoxy) Phenylpropionate, which was further deuterated in a similar manner to that described in Example 9U] to give [racemic]-2·ethoxy-3-[3- Mercapto-4-(2-phenyl-carbazole-4-ylmethoxyphenyl)-propionic acid. MS : 380.2 (MH)* NMR: (CDC13 > 1H, 2-25 (s, 3H) ), 2.92 400MHz, TMS) L18 J=?〇j 3h)j (dxd. J=14.4j J=7.6, 1H), 3.06 (dxd. This paper size is timely gg material (CNS) A4 specification -- ------- 1328585 A7 B7
^14·4, J=4, 1Η), 3.48 (dxq. J=13.6, J=7.2, 1H), 3.56 (dxq, 2 '6> J-7.2, 1H), 4.05 (dxd. J=8, J=4.4, 1H), 5.07 (s, 2H),6.86 (d,J=8.8,ih),7.04 (ar〇m. H,2H),7 45 7 48 m· Η, 3H), 7.71 (s, 1H), 8.05 (m, arom. Η, 2H), 8-11 (非常寬,1H)。 實例141 丙氣甚雨 ge ' 在類似於-實例lla]至llc]說明的步驟中,將3,5二甲基_ 4·[2-(5-甲基-2-苯基-哼唑-4-基)-乙氧基卜苯醛(實例117) 與(S)、4-苄基-3-丙氧基乙醯基》号唑燒_2_酮(實例26)及 nBu2B〇Tf 反應,以產生(s)_4-苄基 _3_((23,311)_3_丨3,5_二 曱基-4-[2,(5-曱基-2-苯基-哼唑-4-基)·乙氧基]•苯基}·3_ 羥基-2-丙氧基丙醯基)呤唑烷_ 2-酮(根據NMR,四個異構 物的其中之一極佔優勢;根據D· Haigh,h. c. BirrelU b. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron^14·4, J=4, 1Η), 3.48 (dxq. J=13.6, J=7.2, 1H), 3.56 (dxq, 2 '6> J-7.2, 1H), 4.05 (dxd. J=8, J=4.4, 1H), 5.07 (s, 2H), 6.86 (d, J=8.8, ih), 7.04 (ar〇m. H, 2H), 7 45 7 48 m· Η, 3H), 7.71 (s , 1H), 8.05 (m, arom. Η, 2H), 8-11 (very wide, 1H). Example 141: Propane gas rain ge 'In a procedure similar to that described in -Examples 11a to 11], 3,5-dimethyl-4-4[2-(5-methyl-2-phenyl-oxazole- 4-yl)-ethoxybenzaldehyde (Example 117) with (S), 4-benzyl-3-propoxyethenyl oxazolidine 2-ketone (Example 26) and nBu2B〇Tf To produce (s)_4-benzyl_3_((23,311)_3_丨3,5-dimercapto-4-[2,(5-mercapto-2-phenyl-oxazol-4-yl) · Ethoxy]•phenyl}·3_hydroxy-2-propoxypropionyl)oxazolidine-2-one (according to NMR, one of the four isomers is predominant; according to D· Haigh , hc BirrelU b. CC Cantello, DS Eggleston, RC Haltiwanger, RM Hindley, A. Ramaswamy, NC Stevens, Tetrahedron
Asymmetry 1999,10,1353- 1367 ’ 暫時將組態以 2s,3R 命 名)。以在三氟醋酸中的三乙基甲石夕貌還原(S)_ 4_芊基_ 3_ ((2S,3R)-3-{3,5-二甲基- 4-[2-(5-曱基-2-苯基-号吐 _4· 基)-乙氧基]-苯基}-3 -經基-2-丙氧基丙酿基)„号峻.烷-2· 酮’以得到(S)-4-^ 基- 3- ((2S)-3-{3,5-二甲基-4-(2-(5-甲 基-2-苯基号唑-4 -基)-乙氧基]-笨基}_ 2-丙氧基丙醯基)呤 唑烷-2-酮。接著將(S)-4-笮基-3-((2S)-3-{3,5-二甲基-4- ____- 200 - 本紙張尺度適用中S S家標準(CNS) A4規格(210X297公釐)Asymmetry 1999,10,1353- 1367 ’ temporarily configures the 2s, 3R name). Reduction of (S)_ 4_mercapto-3_((2S,3R)-3-{3,5-dimethyl-4-[2-(5) with triethylmethionine in trifluoroacetic acid - mercapto-2-phenyl-form _4·yl)-ethoxy]-phenyl}-3-transyl-2-propoxypropyl) „ 峻 . 烷 烷 烷 · ketone To give (S)-4-^yl-3-((2S)-3-{3,5-dimethyl-4-(2-(5-methyl-2-phenyloxazole-4-yl) )-ethoxy]-styl}_ 2-propoxypropionyl)oxazolidin-2-one. Next, (S)-4-mercapto-3-((2S)-3-{3 ,5-Dimethyl-4- ____- 200 - This paper size is applicable to the SS standard (CNS) A4 specification (210X297 mm)
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線 1328585 A7 B7 五、發明説明(197) [2-(5-甲基-2-苯基-哼唑-4-基)-乙氧基]-笨基}-2-丙氧基 丙醯基)σ号唑烷-2-酮以在THF中的1克分子量NaOH皂化,以 產生成為無色固體之(S)-3- {3,5-二甲基-4-[2-(5-甲基- 2-苯基号唑-4-基)-乙氧基]-苯基}-2-丙氧基丙酸》 MS : 436.4 (M-Η) , 376.3, 251.1,217.1。 NMR : (DMSO-d6, 1H,400MHz, 5,TMS) 0.87 (t,J=7.2, 3H),1.56 (sext.,J=7.2,2H),2.18 (s,6H),2.39 (s,3H), 2.86 (dxd, J=15.2, J=8, 1H), 2'.98 (t, 1=7.2, 2H), 3.02 (dxd, J=15.2, J=4.8, 1H), 3.31-3.37 (m, 1H), 3.44-3.50 (m, 1H) 4.01-4.04 (m, 3H), 6.85 (s, 2H), 7.40-7.45 (m, 3H), 7.98 (dxd, J=8, J=0.8, 2H) « 實例142 . a~| 2 -丁- 3-缔氣基-3-{3,5 -二甲基-4-Γ2-(5-甲某-2-策举- 唑-4-基)-乙氧基卜笨基丨-3-蕤某丙酸乙酯Line 1328085 A7 B7 V. Description of the Invention (197) [2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2-propoxypropyl fluorenyl σ oxazolidin-2-one is saponified with 1 gram of molecular weight NaOH in THF to give (S)-3-{3,5-dimethyl-4-[2-(5-A) as a colorless solid Benzyl-2-phenyloxazol-4-yl)-ethoxy]-phenyl}-2-propoxypropionic acid MS: 436.4 (M-Η), 376.3, 251.1, 217.1. NMR : (DMSO-d6, 1H, 400MHz, 5, TMS) 0.87 (t, J = 7.2, 3H), 1.56 (sext., J = 7.2, 2H), 2.18 (s, 6H), 2.39 (s, 3H) ), 2.86 (dxd, J=15.2, J=8, 1H), 2'.98 (t, 1=7.2, 2H), 3.02 (dxd, J=15.2, J=4.8, 1H), 3.31-3.37 ( m, 1H), 3.44-3.50 (m, 1H) 4.01-4.04 (m, 3H), 6.85 (s, 2H), 7.40-7.45 (m, 3H), 7.98 (dxd, J=8, J=0.8, 2H) « Example 142 . a~| 2 - Butyl-3-cyclohexyl-3-{3,5-dimethyl-4-indole 2-(5-methyl-2-pyrox-oxazol-4-yl )-ethoxy bromide 丨-3-蕤ethyl propionate
將在THF(3毫升)中的丁 - 3-埽氧基醋酸乙酯(12〇毫克, 0.76¾莫耳)之溶液在-78 °C下加入在THF中檟;拌的2克分子 量之LDA溶液(0.38¾升,0.76毫莫耳)中(關於丁-3_烯氧基 醋酸乙醋的製備作用’參考:A. F. Noe丨s,A. Dem〇nceau,NA solution of ethyl 3-methoxyacetate (12 mg, 0.763⁄4 mol) in THF (3 mL) was added to THF at -78 °C; 2 g of molecular weight LDA Solution (0.383⁄4 liter, 0.76 mmol) (for preparation of buty-3_alkoxyacetic acid ethyl vinegar) Reference: AF Noe丨s, A. Dem〇nceau, N
Petiniot, A..J. Hubert, P. Teyssie, Tetrahedron 1982, 38, 2733-2739)。將洛液授拌l〇分鐘,並接著加入在thf(3毫升) 中的3,5 甲基- 4-[2-(5-甲基-2-苯基号嗅_4_基)_乙氧 基]-表链(254¾克’ 0.76¾莫耳’實例ip)之溶液。將反應 混合物在-7 8 C下攪拌3 0分鐘,接著以在-7 § t下加入飽和 NHjCl中止。將溶液以水及醋酸乙酯稀釋,將層分離,並將 __- 7Π1 -___ 本纸俵尺度適用中國國家標準(CNS) A4規格(210X297公釐) 'Petiniot, A..J. Hubert, P. Teyssie, Tetrahedron 1982, 38, 2733-2739). The solution was stirred for 1 minute and then added to the 3,5 methyl 4-[2-(5-methyl-2-phenyl) _4_yl)-B in thf (3 mL) A solution of oxy]- bracelet (2543⁄4 gram '0.763⁄4 mole' example ip). The reaction mixture was stirred at -7 8 C for 30 minutes, then quenched by the addition of saturated NHjCl at -7 §. The solution was diluted with water and ethyl acetate to separate the layers, and the __- 7Π1 -___ paper size was applied to the Chinese National Standard (CNS) A4 specification (210X297 mm).
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線 1328585 A7 B7 五、發明説明(198 水相以醋酸乙醋萃取兩次。將合併的有機層以食鹽水清洗 及經硫納乾燥。以蒸發溶劑得到黃色油,將其以管柱色 層分離法(矽膠’己烷/Ac〇Et= 9/1)純化,以得到成為無色 油之160毫克(0.32毫莫耳,43%)成為立體異構物混合物之 標題化合物° MS : 494.2 (M+H) +,476.3, 446.3, 402.4, 186.4。 NMR : (CDC13,1H,300MHz,<? ’ TMS) 1.16 (t,J=7.2, 3H), 2.20 (s, 6H), 2.25-2.35 (m, 2H),. 2.39 (s, 3H), 2.87 (d, J=4.8, 0.7H-), 2.98 (t, J=7.2, 2H), 3.30-3.44 (m, 1H), 3.63-3.75 (m, 1H), 3.88 (d, J=7.2, 0.3H), 3.98-4.03 (m, 2H), 4.16 (q, J=7.2, 2H), 4.76 (t, J=6.4, 0.3H), 4.84 (t, J=6.4, 0.7H), 4.99-5.13 (m, 2H), 5.63-5.82-(m, 1H), 6.98 (s, 2H), 7.40-7.45 (m, 3H), 7.97-8.00 (m,2H)。 bl 2Z- 丁 - 3-# 氧基-3 - {夂5·二甲某-4- Γ2-( 5-甲甚黎某- °号唑-4 ·基)-乙氧基1 -苯某丨·雨掄齡Λ龅 將三乙胺(55微升,〇.4毫莫耳)及曱烷磺酸氣化物(42微 升’ 0_3 6毫莫耳)在0°C下連續加入在二氣甲烷(2毫升)中的 2- 丁-3-烯氧基-3-{ 3,5-二甲基-4-[2-(5-甲基-2-苯基-崎 哇-4-基)-乙氧基]-苯基}-3-經基丙酸乙酯(150毫克,0.3毫 莫耳)之溶液中。允許反應經隔夜溫熱至室溫,並接著以加 入飽和NaHCO;中止。將層分離,並將水相以二氯甲烷萃取 兩次。將合併的有機層經较酸鈉乾燥及在真空中濃縮,以 供給粗丁 - 3 -締氧基-3 - { 3,5-二甲基-4- [2-( 5-甲基-2-苯基_ °号唑-4 -基)-乙氧基]-苯基卜3_甲烷磺醯氧基丙酸乙酯,將 _- - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(199) 其溶解在THF(2毫升)中。在室溫下加入DBU(139微升,0.9 毫莫耳)’並將混合物在501下攪拌8小時》以加入水中止 反應,將層分離,並將水相以二氯甲烷萃取兩次。將合併 的有機層經硫酸鈉乾燥,並在減壓下除去溶劑,以供給棕 色油’將其以管柱色層分離法(矽膠,己烷/ AcOEt= 9/1)純 化,以得到成為鮮黃色油之79毫克(0.1 66毫莫耳,55%)標 題化合物及成為鮮黃色油之29毫克(6 1微莫耳,20% ) 2E-丁 ·3-締氧基-3-{3,5-二甲基-·4二[2,(5-甲基-2-苯基-哼唑-4 -基)-乙氧-基]-苯基}-丙締酸乙g旨。 Ζ-異構物之數攄: MS : 476.3 (Μ+Η) +,328.4, 293.4, 186.3。 NMR : (CDC13, 1H, 400MHz, ¢5 , TMS) 1.35 (t, J=8, 3H), 2.22 (s, 6H), 2.40 (s, 3H), 2.51 (q, J=7.2, 2H), 2.99 (t, J=7.2, 2H), 3.94 (t, J=7.2, 2H), 4.08 (t, J=7.2, 2H), 4.28 (q, J—8, 2H), 5.09 (dxd, J=8.8, J=0.8, 1H), 5.16 (dxd, J=16.8, J=0.8, 1H), 5.84-5.94 (m, 1H), 6.89 (s, 1H), 7.39-7.46 (m, 5H),7.99 (dxd,J=8, J= 1.6, 2H)。 £]_22-丁-3-烯氧基-3-{3.5-二甲基-4-[2-(5-甲某-2-苯某-唑-4-基)·乙氣基1-苽某丨-丙烯酸 在類似於實例120f]說明的步騾中,將2Z- 丁 - 3-烯氧基-3-{3,5- —甲基- 4-[2-(5-甲基--2-苯基号嗅-4-基)-乙氧基]· 苯基}-丙烯酸乙酯皂化’以產生成為無色固體之2Z-丁 - 3_ 少布氧基- 3- {3,5 - 一甲基- 4- [2-(5-甲基-2-苯基号哇-4-基)_ 乙氧基]-苯基}-丙烯酸。 ______- 70^ - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1328585 A7 B7 五、發明説明(200 ) MS : 446.0 (M-H)-,391.7, 327.1, 256.9, 212.9,185.6 ° NMR : (CDC13, 1H, 400MHz,5 , TMS) 2.23 (s, 6H), 2.40 (s, 3H), 2.51 (q, J=7.2, 2H), 3.01 (t, J=7.2, 2H), 3.96 (t, J=7.2, 2H), 4.09 (t, J=7.2, 2H), 5.12 (dxd, J=8.8, J=0.8, 1H), 5.18 (dxd, J= 16.8, J=0.8, 1H), 5.84- 5.94 (m, 1H), 7.03 (s, 1H), 7.41-7.46 (m, 5H), 7.99 (dxd, J=8, J=l.6, 2H)。 實例143 2E- 丁 - 3-烯氣某-3- {3,5-二甲-4.-「2-(5-甲某-2-笨某-吟 唑-4 -基)-乙氣基1 -笨基丨-丙烯酸 在類似於實例1 20f]說明的步驟中,將2E- 丁 - 3-烯氧基-3-{ 3,5-二曱基- 4-[2-(5-曱基-2-苯基-吟唑-4-基)-乙氧基]-苯基卜丙烯酸乙酯(實例142b])皂化?以產生成為無色油之 2E- 丁 - 3-烯氧基-3- {3,5-二甲基-4-[2-(5-甲基-2-苯基-咩 哇-4-基)-乙氧基]-苯基}-丙稀酸。 MS : 446.1 (Μ·Η)·,392.0, 384.4, 253.2, 216.6,161.5 ° NMR : (CDC13, 1H, 400MHz, (5 , TMS) 2.17 (s, 6H), 2.39 (s, 3H), 2.55 (q, J=7.2, 2H), 2.98 (t, J=7.2, 2H), 3.93 (t, J=7.2, 2H), 4.03 (t, J=7.2, 2H), 5.15 (dxd, J=8.8, J=0.8, 1H), 5.19 (dxd, J= 16.8, J=0.8, 1H), 5.83-5.91 (m, 1H), 6.20 (s, 1H), 7.02 (s, 2H), 7.42-7.51 (m, 3H), 7.98 (dxd, J=8, J= 1.6, 2H)。 - 實例144 al丨外消旋性1-3-丨4-f 2-( 2-氣笨某)-5-甲某哼唑-4-某甲氧. 基卜2-甲基笨某}-2-乙氣基丙酸乙酯 _- 2Q4 -_ 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐)Line 1328085 A7 B7 V. Description of the invention (198 The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried with thios. to evaporate solvent to give a yellow oil, which was separated by column chromatography Purification by the method (j. hexanes / EtOAc / EtOAc / EtOAc / EtOAc / EtOAc) H) +, 476.3, 446.3, 402.4, 186.4. NMR: (CDC13, 1H, 300MHz, <? 'TMS) 1.16 (t, J=7.2, 3H), 2.20 (s, 6H), 2.25-2.35 (m , 2H),. 2.39 (s, 3H), 2.87 (d, J=4.8, 0.7H-), 2.98 (t, J=7.2, 2H), 3.30-3.44 (m, 1H), 3.63-3.75 (m , 1H), 3.88 (d, J=7.2, 0.3H), 3.98-4.03 (m, 2H), 4.16 (q, J=7.2, 2H), 4.76 (t, J=6.4, 0.3H), 4.84 ( t, J=6.4, 0.7H), 4.99-5.13 (m, 2H), 5.63-5.82-(m, 1H), 6.98 (s, 2H), 7.40-7.45 (m, 3H), 7.97-8.00 (m , 2H). bl 2Z-butyl- 3-# oxy-3 - {夂5·dimethyl-4-pyrene-2-(5-methyl sulphur- ° azole-4 ·yl)-ethoxy 1 - Benzene 抡 抡 抡 Λ龅 三 三 triethylamine (55 μl, 〇. 4 mmol) and decane sulfonate gas (42 μl of '0_3 6 mmol) was continuously added at 0 ° C to 2-but-3-enyloxy-3-{ 3,5-dimethyl- in di-methane (2 mL). 4-[2-(5-Methyl-2-phenyl-samily-4-yl)-ethoxy]-phenyl}-3-ylpropanoic acid ethyl ester (150 mg, 0.3 mmol) The solution was allowed to warm to room temperature overnight, and then was added with saturated NaHCO; the layer was separated and the aqueous phase was extracted twice with dichloromethane. Concentrated in vacuo to supply crude 1,3- 3 -amino-oxy-3 - { 3,5-dimethyl-4-[2-( 5-methyl-2-phenyl_ ° azole-4-yl )-Ethoxy]-phenyl phenyl 3_methanesulfonyloxypropionic acid ethyl ester, _- - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 Five Inventive Note (199) It was dissolved in THF (2 mL). DBU (139 μL, 0.9 mmol) was added at room temperature and the mixture was stirred at 501 for 8 hours. The reaction was quenched by addition of water, the layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvent was evaporated under reduced pressure to afford a brown oil, which was purified by column chromatography (yield, hexane / AcOEt = 9/1). 79 mg of yellow oil (0.1 66 mmol, 55%) of the title compound and 29 mg (6 1 micromolar, 20%) as a bright yellow oil. 2E-butyl 3-conoxy-3-{3, 5-Dimethyl-·4 bis[2,(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy-yl]-phenyl}-propionate acid. Number of oxime-isomers: MS: 476.3 (Μ+Η) +, 328.4, 293.4, 186.3. NMR : (CDC13, 1H, 400MHz, ¢5, TMS) 1.35 (t, J=8, 3H), 2.22 (s, 6H), 2.40 (s, 3H), 2.51 (q, J=7.2, 2H), 2.99 (t, J=7.2, 2H), 3.94 (t, J=7.2, 2H), 4.08 (t, J=7.2, 2H), 4.28 (q, J-8, 2H), 5.09 (dxd, J= 8.8, J=0.8, 1H), 5.16 (dxd, J=16.8, J=0.8, 1H), 5.84-5.94 (m, 1H), 6.89 (s, 1H), 7.39-7.46 (m, 5H), 7.99 (dxd, J=8, J= 1.6, 2H). £]_22-but-3-enyloxy-3-{3.5-dimethyl-4-[2-(5-methyl-2-benzene-oxazol-4-yl)·ethane group 1-苽A hydrazine-acrylic acid in a step similar to that described in Example 120f], 2Z-but-3-enyloxy-3-{3,5-methyl-4-[2-(5-methyl-- 2-phenylnosyl-4-yl)-ethoxy]-phenyl}-ethyl acrylate saponified to give 2Z-butyl- 3 _ lesseoxy- 3- {3,5 - one as a colorless solid Methyl-4-[2-(5-methyl-2-phenyl-wow-4-yl)-ethoxy]-phenyl}-acrylic acid. ______- 70^ - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1328585 A7 B7 V. Invention description (200) MS : 446.0 (MH)-, 391.7, 327.1, 256.9, 212.9, 185.6 ° NMR : (CDC13, 1H, 400MHz, 5 , TMS) 2.23 (s, 6H), 2.40 (s, 3H), 2.51 (q, J=7.2, 2H), 3.01 (t, J=7.2, 2H), 3.96 (t, J=7.2, 2H), 4.09 (t, J=7.2, 2H), 5.12 (dxd, J=8.8, J=0.8, 1H), 5.18 (dxd, J= 16.8, J=0.8, 1H) , 5.84- 5.94 (m, 1H), 7.03 (s, 1H), 7.41-7.46 (m, 5H), 7.99 (dxd, J=8, J=l.6, 2H). Example 143 2E-butyl-3-ene gas -3-{3,5-dimethyl-4.-"2-(5-methyl-2-methyl-oxazol-4-yl)-ethane group 1 - Stupid hydrazine-acrylic acid in a procedure similar to that described in Example 1 20f], 2E-but-3-enyloxy-3-{ 3,5-dimercapto-4-[2-(5-曱) Ethyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenylethyl acrylate (Example 142b)) saponified to give 2E-but-3-enoxy-3 as a colorless oil - {3,5-Dimethyl-4-[2-(5-methyl-2-phenyl-indol-4-yl)-ethoxy]-phenyl}-acrylic acid. MS : 446.1 ((················· =7.2, 2H), 2.98 (t, J=7.2, 2H), 3.93 (t, J=7.2, 2H), 4.03 (t, J=7.2, 2H), 5.15 (dxd, J=8.8, J=0.8 , 1H), 5.19 (dxd, J= 16.8, J=0.8, 1H), 5.83-5.91 (m, 1H), 6.20 (s, 1H), 7.02 (s, 2H), 7.42-7.51 (m, 3H) , 7.98 (dxd, J=8, J= 1.6, 2H). - Example 144 al丨 racemic 1-3-丨4-f 2-(2-gaso)-5-methyl-carbazole- 4- Some methoxy. Kebu 2-methyl stupid}-2-Ethyl propyl propionate _- 2Q4 -_ This paper scale applies to China Standard (CNS) A4 size (210 X 297 mm)
線 1328585 A7 B7 五、發明説明(2()1) 將跋酸絶(97毫克,300微莫耳,1.5當量)及少量琪化鉀加 入在丙酮(4毫升)中的[外消旋性]-2-乙氧基-3- (4-羥基-2-甲基苯基)丙酸乙酯(50毫克,200微莫耳,1當量,實例 129c))及4-氣甲基-2-(2-氯苯基)-5-甲基咩唑(72毫克,3〇〇 微莫耳,1 ·5當量,在類似於實例2 1 a]及b]說明的步驟中, 以2-氯基苯醛及二乙醯基單肟,接著以P〇Cl3處理製得的) 之溶液中。將混合物在回流下加熱1 2小時,過滤及在真空 中蒸發過濾物。將殘餘物以醋楚乙.酿及冰冷的1克分子量氫 氯酸處理。將有機層以食鹽水清洗兩次及經硫酸鈉乾燥。 在減壓下除去溶劑,以得到黃色油,將其以管拄色層分離 法(矽膠,己烷/AcOEt=9/l)純化,以得到成為無色油之72 毫克(160微莫耳,79%)標題化合物^ MS : 458.3 (M+H) + , 414.1, 384.1, 247.1, 206.1, 179.1 <· NMR : (CDC13, 1H, 300MHz, δ , TMS) 1-15 (t, J=7.2, 3H), 1.22 (t, J=8, 3H), 2.33 (s, 3H), 2.46 (s, 3H), 2.97 (d, J=7.2 2H), 3.25-3.37 (m, 1H), 3.52-3.62 (m, 1H), 3.96 (t, J=7.2, 1H), 4.16 (q, J=8, 2H), 5.00 (s, 2H), 6.79 (dxd, J=8, J=l.6> 1H), 6.83 (d, J=1.6, 1H), 7.10 (d, J=8, 1H), 7.33-7.37 (mj 2H), 7.47-7.50 (m, 1H), 7.95-7.98 (m,1H)。 bl『外消旋性1 - 3- M-丨2- (2-氣笨某)-5-甲基p号唑-4-基甲i 基1-2-甲基笨基丨-2-乙氩某-丙醢 在類似於實例120f]說明的步驟中,將[外消旋性]-3- { 4-[2-(2-氣苯基)-5-甲基呤唑-4-基甲氧基]-2-甲基苯基} - 2-乙氧基丙酸乙酯皂化,以產生成為無色油之[外消旋性]-3_Line 1328085 A7 B7 V. Description of the invention (2()1) Adding citric acid (97 mg, 300 micromolar, 1.5 equivalents) and a small amount of potassium citrate to [racemicity] in acetone (4 ml) Ethyl 2-ethoxy-3-(4-hydroxy-2-methylphenyl)propanoate (50 mg, 200 micromoles, 1 equivalent, example 129c)) and 4-methylmethyl-2- (2-Chlorophenyl)-5-methylcarbazole (72 mg, 3 Torr micromolar, 1.5 eq., in a procedure similar to that described in Example 2 1 a) and b], with 2-chloro A solution of the base benzaldehyde and the diethylindenyl monohydrazine followed by the P?Cl3 treatment. The mixture was heated under reflux for 12 hours, filtered and the filtrate evaporated in vacuo. The residue was treated with vinegar, brewed, and ice-cold 1 g of molecular weight hydrochloric acid. The organic layer was washed twice with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow oil, which was purified by EtOAc (EtOAc, EtOAc/EtOAc/EtOAc) %) title compound ^ MS : 458.3 (M+H) + , 414.1, 384.1, 247.1, 206.1, 179.1 <· NMR : (CDC13, 1H, 300MHz, δ , TMS) 1-15 (t, J=7.2, 3H), 1.22 (t, J=8, 3H), 2.33 (s, 3H), 2.46 (s, 3H), 2.97 (d, J=7.2 2H), 3.25-3.37 (m, 1H), 3.52-3.62 (m, 1H), 3.96 (t, J=7.2, 1H), 4.16 (q, J=8, 2H), 5.00 (s, 2H), 6.79 (dxd, J=8, J=l.6> 1H ), 6.83 (d, J=1.6, 1H), 7.10 (d, J=8, 1H), 7.33-7.37 (mj 2H), 7.47-7.50 (m, 1H), 7.95-7.98 (m, 1H). Bl "racemic 1 - 3- M-丨2- (2-qi 某)-5-methyl p azole-4-yl yl i 1-2-methyl phenyl -2- Argon-propionin in a procedure similar to that described in Example 120f], [racemic]-3-{4-[2-(2-phenylphenyl)-5-methyloxazol-4-yl Ethyl methoxy]-2-methylphenyl}-2-ethoxypropionate is saponified to give [racemic]-3_ as a colorless oil
裝 訂Binding
線 ------- 9〇cj - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(2〇2) {4-[2-(2-氣苯基)-5-甲基哼唑-4-基甲氧基]-2-甲基苯基卜 2-乙氧基丙酸。 MS : 428.2 (M-H)*, 382.0. 222.7, 176.8 ° NMR : (CDC13, 1H, 300MHz, 5 , TMS) 1.13 (t, J=7.2, 3H), 2.34 (s, 3H), 2.46 (s, 3H), 2.93 (dxd, J=15.2, J=8.8, 1H), 3.13 (dxd, J=15.2, J=4, 1H), 3.31-3.37 (m5 1H), 3.48-3.56 (m, 1H), 4.01 (dxd, J=8.8, J=4.8, 1H), 5.30 (s, 2H), 6.81 (dxd, J=8, J=1.6, 1H), 6.85 d 1H), 7.13 (d, J=8, 1H), 7.33-7.37 (m, 2H), 7.47-7.51 (m, 1H), 7.95-7.98 (ms 1H)。 實例145 『外消旋,座1-3- Μ-Γ2-(3-氣苽某)-·5-甲某哼崦其甲y 基1-2-甲基苽基卜2-乙氳墓丙酸 在類似於實例144a]說明的步驟中,將[外消旋性]_ 2-乙氧 基-3-(4-羥基-2-甲基苯基)丙酸乙酯(實例129c])與4-氯甲 基- 2-(3-氯苯基)-5-甲基1>号吐(在類似於實例21a)及b]說明 的步驟中,以3-氯基苯醛及二乙醯基單肪,接著以P〇ci3處 理製得的)在碳酸铯及碘化鉀的存在下反應,以產生[外消 旋性]-3-{4-[2-(3-氯苯基)-5-甲基呤唑-4-基曱氧基卜2-甲 基苯基}-2-乙氧基丙酸乙醋’將其以類似於實例12〇 f]說明 的步驟進一步皂化,以產生成為白色固體之[外消旋性]_ 3_ {4-[2-(3 -氣苯基)-5-甲基β号岐-4-基曱氧基]-2-甲基苯基)_ 2-乙氧基丙酸。 MS : 428.2 (Μ-Η)·,382.1,337.7, 223.0, 176.2。 -206 - '本纸張尺度適财S S家標準(CNS) A4規格(21GX297公茇) 'Line ------- 9〇cj - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (2〇2) {4-[2-( 2-Phenylphenyl)-5-methyloxazol-4-ylmethoxy]-2-methylphenyl- 2-ethoxypropionic acid. MS : 428.2 (MH)*, 382.0. 222.7, 176.8 ° NMR : (CDC13, 1H, 300MHz, 5 , TMS) 1.13 (t, J=7.2, 3H), 2.34 (s, 3H), 2.46 (s, 3H ), 2.93 (dxd, J=15.2, J=8.8, 1H), 3.13 (dxd, J=15.2, J=4, 1H), 3.31-3.37 (m5 1H), 3.48-3.56 (m, 1H), 4.01 (dxd, J=8.8, J=4.8, 1H), 5.30 (s, 2H), 6.81 (dxd, J=8, J=1.6, 1H), 6.85 d 1H), 7.13 (d, J=8, 1H ), 7.33-7.37 (m, 2H), 7.47-7.51 (m, 1H), 7.95-7.98 (ms 1H). Example 145 『racemic, seat 1-3- Μ-Γ2-(3-气苽)-·5-甲甲哼崦甲甲 y base 1-2-methyl 苽基卜 2-乙氲墓Acid in a similar procedure to that described in Example 144a], [[R)-2-ethoxy-3-(4-hydroxy-2-methylphenyl)propanoate (Example 129c)) 3-Chloromethyl-2-(3-chlorophenyl)-5-methyl 1> No. (in a procedure similar to Example 21a) and b], 3-chlorobenzaldehyde and diethyl hydrazine The reaction is carried out in the presence of cesium carbonate and potassium iodide to produce [racemic]-3-{4-[2-(3-chlorophenyl)-5. -methylcarbazol-4-yloxy-2-ethyl-3-phenyl}-ethoxypropionic acid vinegar's further saponified in a similar manner to that described in Example 12, to give [Racecycling]_ 3_ {4-[2-(3-(phenylphenyl)-5-methylβ-indol-4-yloxy)-2-methylphenyl)_ 2 - ethoxypropionic acid. MS: 428.2 (Μ-Η)·, 382.1, 337.7, 223.0, 176.2. -206 - 'This paper scale is suitable for S S standard (CNS) A4 specification (21GX297 public) '
裝. 訂Packing
線 1328585 A7 ________B7五、發明説明(~~" — NMR : (CDC13, 1H, 300MHz, 5 , TMS) 1.13 (t, J=8, 3H), 2.34 (s, 3H), 2.44 (s, 3H), 2.93 (dxd, J=15.2, J=8.8, 1H), 3.14 (dxd, J=15.2, J=4, 1H), 3.31-3.39 (m, 1H), 3.49-3.57 (m, 1H), 4.02 (dxd, J=8.8, J=4, 1H), 4.96 (s, 2H), 6.80 (dxd, J=8, J=0.8, 1H), 6.83 (d, J=〇.8, 1H), 7.13 (d, J=8, 1H), 7.34- 7.42 (m, 2H), 7.90 (dxt, J=7.2, J=0.8, 1H), 8.01-8.02 (m,1H)。 實例146 fill消旋性卜2-乙氧某-3- {2-甲基_4_「3_is_甲基·2苽基.-17号 咬-4-基)丙氣基1菜基丨-丙醢 在類似於實例2 1 f]說明的步驟中,將[外消旋性]_ 2乙氧 基-3-(4-羥基-2-甲基苯基)丙酸乙酯(實例129{;])與3_(5甲 基-2-苯基-十圭_4_基)丙-】-酵(J 乂 c〇1Hns,m』以心,j A. Oplinger, A. Jeffrey, T. M. Willson, International Patent Appl’’ Publication No. W00008002 (Al),2000)在三苯膦及 偶氮二羧酸二乙酯的存在下反應,以產生[外消旋性卜2·乙 氧基-3- {2-甲基-4-[3-(5-曱基-2-苯基唑_4-基)丙氧美] 苯基}-丙酸乙酯,將其以類似於實例1 20f]說明的步騾進一 步皂化’以產生成為無色油之[外消旋性卜2·乙氧基3 ( 2 曱基-4-[3-(5-甲基-2·苯基·咩唑-4-基)丙氧基]笨基丨丙 酸。 _ MS : 422.2 (M-H),,375,9, 308.7, 222.8, 179.4。 NMR : (CDC13, 1H, 300MHz,<5 , TMS) 1.13 (t’ j=7 2 冲 2.14 (qUint·,J=7.2, 2H), 2 28 (s,3Η),2·32 (s 3h), 2 的 〇 本纸張尺度適用中國國家標毕(CNS) A4規格(21QX297公愛) -----Line 1328085 A7 ________B7 V. Description of the invention (~~" - NMR: (CDC13, 1H, 300MHz, 5, TMS) 1.13 (t, J=8, 3H), 2.34 (s, 3H), 2.44 (s, 3H ), 2.93 (dxd, J=15.2, J=8.8, 1H), 3.14 (dxd, J=15.2, J=4, 1H), 3.31-3.39 (m, 1H), 3.49-3.57 (m, 1H), 4.02 (dxd, J=8.8, J=4, 1H), 4.96 (s, 2H), 6.80 (dxd, J=8, J=0.8, 1H), 6.83 (d, J=〇.8, 1H), 7.13 (d, J=8, 1H), 7.34- 7.42 (m, 2H), 7.90 (dxt, J=7.2, J=0.8, 1H), 8.01-8.02 (m, 1H). Example 146 fill racemability卜2-ethoxyxo-3-{2-methyl_4_"3_is_methyl·2 yl. -17 -4--4-) propyl group 1 菜 丨 - 醢 醢 in similar to Example 2 In the procedure described in 1 f], [racemic] 2 ethyl ethoxy-3-(4-hydroxy-2-methylphenyl)propanoate (example 129 {;]) and 3_(5 Methyl-2-phenyl-十圭_4_yl)------- (J 乂c〇1Hns,m) heart, j A. Oplinger, A. Jeffrey, TM Willson, International Patent Appl'' Publication No. W00008002 (Al), 2000) is reacted in the presence of triphenylphosphine and diethyl azodicarboxylate to give [racemic 2·ethoxy-3-{2-methyl-4] -[3-(5- Ethyl-2-phenylazole-4-yl)propoxyl]phenyl}-propionic acid ethyl ester, which was further saponified in a similar manner to that described in Example 1 20f] to give a colorless oil. Cyclosyl 2·ethoxy 3 ( 2 decyl-4-[3-(5-methyl-2.phenyl)oxazol-4-yl)propoxy]pyridylpropionic acid. _ MS : 422.2 (MH),, 375, 9, 308.7, 222.8, 179.4. NMR: (CDC13, 1H, 300MHz, <5, TMS) 1.13 (t' j=7 2 rushed 2.14 (qUint·, J=7.2, 2H ), 2 28 (s, 3Η), 2·32 (s 3h), 2 The size of the paper is applicable to the China National Standard (CNS) A4 specification (21QX297 public) -----
裝 訂Binding
線 1328585 A7 B7 五、發明説明(2〇4) J=7.2, 2H), 2.92 (dxd, J=15.2, J=8.8, 1H), 3.13 (dxd, J=15.2, J=4, 1H), 3.29-3.40 (m, 1H), 3.47-3.58 (m, 1H), 3.95 (t, J=7.2, 2H), 4.03 (dxd, J=8.8, J=4, 1H), 6.68 (dxd, J=8, J=1.6, 1H), 6.71 (d, J=1.6, 1H), 7.10 (d, J=8, 1H), 7.40-7.46 (m, 3H),7.98 (dxd, J=8, J=〇.8, 2H)。 實例147 「外」肖祿性]-3- f 4-Γ 2-(4-氣甚-3-甲某茇甚、-5-甲某呤咄_4-基五氧基1-2-甲某笔其丨_高酩 在類似於實例144a]說明的步驟中,將[外消旋性]_2_乙氧 基-3-(4-羥基-2-甲基苯基)丙酸乙酯(實例129c])與4-氯甲 基-2-(4-氟基-3-甲基苯基)_5-甲基。号吐(在類似於實例21 a] 及b]說明幻步驟中,以私氟基-3·甲基苯醛及二乙醯基單 月亏,接著以POCI3處理製得的)在碳酸铯及碘化鉀的存在下 反應’以產生[外消旋性]_3-{4-[2-(4-氟基-3-甲基苯基)_ 5-甲基《号唑-4-基甲氧基]-2-甲基苯基}-丙酸乙酯,將其以 類似於實例120f]說明的步驟進一步皂化,以產生成為無色 固體之[外消旋性]-3-{4-[2-(4-氟基-3-甲基苯基)_5_甲基 呤唑-4-基甲氧基]-2-甲基苯基卜丙酸。 MS : 426.2 (M-H)·,380.1,336.5, 283.3, 255.4。 NMR : (DMSO-d6,1H,300MHz,5,TMS) 1.02 (t,j=72 3H), 2.27 (s, 3H), 2.31 (s-, 3H), 2.43 (s, 3H), 2.79 (dxd J=15.2, J=8, 1H), 2.89 (dxd, J=15.2,J=6.4, 1H), 3.20-3 32 (m, 1H), 3.45-3.52 (m, 1H), 3.91 (dxd, J=8, J=6.4, iH) 4.94 (s, 2H), 6.78 (dxd, J=8, J=0.8, 1H), 6.83 (d, J=〇g • 208 - 本纸張尺度適用中國國家標準(CNS) A4規格(210X297公爱)Line 1328085 A7 B7 V. Description of invention (2〇4) J=7.2, 2H), 2.92 (dxd, J=15.2, J=8.8, 1H), 3.13 (dxd, J=15.2, J=4, 1H), 3.29-3.40 (m, 1H), 3.47-3.58 (m, 1H), 3.95 (t, J=7.2, 2H), 4.03 (dxd, J=8.8, J=4, 1H), 6.68 (dxd, J= 8, J=1.6, 1H), 6.71 (d, J=1.6, 1H), 7.10 (d, J=8, 1H), 7.40-7.46 (m, 3H), 7.98 (dxd, J=8, J= 〇.8, 2H). Example 147 "External" Xiaolu sex]-3- f 4-Γ 2-(4- gas very-3-A certain 茇,-5-A 呤咄4-4-pentaoxy1-2-A In the procedure described in analogy to Example 144a], a certain amount of [racemic] 2 -ethoxy-3-(4-hydroxy-2-methylphenyl)propanoic acid ethyl ester ( Example 129c]) with 4-chloromethyl-2-(4-fluoro-3-methylphenyl)-5-methyl. No. (in a similar manner to Example 21 a) and b] A fluorinated 3-methylbenzaldehyde and a dihydrazino group is lost in a single month, followed by treatment with POCI3) in the presence of cesium carbonate and potassium iodide to produce [racemic] _3-{4- [2-(4-Fluoro-3-methylphenyl)_ 5-methyl "oxazol-4-ylmethoxy]-2-methylphenyl}-propionic acid ethyl ester, which is similar Further saponification was carried out in the procedure illustrated in Example 120f] to give [racemic]-3-{4-[2-(4-fluoro-3-methylphenyl)-5-methylcarbazole as a colorless solid. 4--4-methoxy]-2-methylphenylpropanoic acid MS: 426.2 (MH)·, 380.1, 336.5, 283.3, 255.4. NMR: (DMSO-d6, 1H, 300 MHz, 5, TMS) 1.02 (t,j=72 3H), 2.27 (s, 3H), 2.31 (s-, 3H), 2.43 (s, 3H), 2.79 (dx d J=15.2, J=8, 1H), 2.89 (dxd, J=15.2, J=6.4, 1H), 3.20-3 32 (m, 1H), 3.45-3.52 (m, 1H), 3.91 (dxd, J=8, J=6.4, iH) 4.94 (s, 2H), 6.78 (dxd, J=8, J=0.8, 1H), 6.83 (d, J=〇g • 208 - This paper size applies to China Standard (CNS) A4 specification (210X297 public)
裝 訂Binding
線 1328585 A7 B7 五、發明説明(2〇5) 1H), 7.07 (d, J=8, 1H), 7.29 (t, J=8, 1H), 7.77-7.82 (m> 1H),7.89 (dxd, J=8, J=0.8, 1H),12.65 (br.s,1H)。 實例148 ί外消差.性卜2-乙氪某-3- {4_丨2-(2-甲氣基甲其〇罢 峻_4_羞甲氧基卜2-甲某苽某丨-丙酸 在類似於實例144a]說明的步驟中,將[外消旋性]-2-乙氧 基-3-(4-羥基-2-甲基苯基)丙酸乙酯(實例129c))與4·氯甲 基-2-(2-甲氧基苯基)_5_甲基1吱(在類似於實例213]及1)] 說明的步驟中,以2-曱氧基苯醛及二乙醯基單肟,接著以 POCI3處理製得的)在碳酸铯及碘化鉀的存在下反應,以產 生[外消旋性]-2-乙氧基-3-{4-[2-(2-曱氧基苯基)_5_甲基 哼唑_4_基甲氧基]_2_甲基苯基卜丙酸乙酯,將其以類似於 實例120f]說明的步驟進一步皂化,以產生成為白色固體之 [外消旋性]-2-乙氧基-3_{4_[2_(2_甲氧基苯基)_5_甲2噚 唑-4-基曱氧基]-2-甲基苯基卜丙酸。 MS : 424.3 (M-H)·,380.3, 334.8, 299.3, 255 NMR : (CDC13, 1H,400MHz,d,TMS) 1.12 (t,J=7 2 3H) 2.33 (s,3H),2.44 (S,3H),2.91 (dxd,J叫5 2, J=8’ iH)’ 3.10 (dxd, J=15.2, J=4, 1H), 3.29-3.36 (m, 1H), 3.49-3.57 (m, 1H), 3.94 (s, 3H), 3.99 (dxd, J=8, J=4, iH), 4.99 〇 2H)’ 6.79 (dxd, J=8, 1H),6.83 (d,J叫·6, 1H)· 7 w 7.05 (m,2H),7.12 (d,J=8, 1H),7.41 (dxt,J=8,,J=〇 : ih 7.90 (dxd, J=8, J=0.8, 1H) 〇 ’ 實例149 -209 -Line 1328085 A7 B7 V. Description of the invention (2〇5) 1H), 7.07 (d, J=8, 1H), 7.29 (t, J=8, 1H), 7.77-7.82 (m> 1H), 7.89 (dxd , J=8, J=0.8, 1H), 12.65 (br.s, 1H). Example 148 ί external consumption. Sexuality 2 2- 氪 -3- -3- {4_丨2-(2-甲甲基甲〇〇峻_4_羞methoxy-4-E-A certain 丨- Propionic acid In a similar procedure to that described in Example 144a], [R-[rho]-2-ethoxy-3-(4-hydroxy-2-methylphenyl)propanoic acid ethyl ester (Example 129c)) With 4· chloromethyl-2-(2-methoxyphenyl)-5-methyl 1 oxime (in a similar manner to Examples 213) and 1)], 2-nonyloxybenzaldehyde and Ethyl oxime, followed by treatment with POCI3) is reacted in the presence of cesium carbonate and potassium iodide to give [racemic]-2-ethoxy-3-{4-[2-(2- Ethyloxyphenyl)_5-methylcarbazole-4-yloxy]_2-methylphenylpropionic acid ethyl ester, which was further saponified in a procedure similar to that described in Example 120f] to give white Solid [racemate]-2-ethoxy-3_{4_[2_(2-methoxyphenyl)-5-methyl-2-oxazol-4-yloxy]-2-methylphenyl Propionic acid. MS : 424.3 (MH)·, 380.3, 334.8, 299.3, 255 NMR : (CDC13, 1H, 400 MHz, d, TMS) 1.12 (t,J=7 2 3H) 2.33 (s,3H),2.44 (S,3H ), 2.91 (dxd, J is 5 2, J=8' iH)' 3.10 (dxd, J=15.2, J=4, 1H), 3.29-3.36 (m, 1H), 3.49-3.57 (m, 1H) , 3.94 (s, 3H), 3.99 (dxd, J=8, J=4, iH), 4.99 〇2H)' 6.79 (dxd, J=8, 1H), 6.83 (d, J is 6.6, 1H) · 7 w 7.05 (m, 2H), 7.12 (d, J=8, 1H), 7.41 (dxt, J=8,, J=〇: ih 7.90 (dxd, J=8, J=0.8, 1H) 〇 'Example 149 -209 -
•摹 訂•摹定
1328585 A7 B7 五、發明説明(2〇6) f外消旋性卜3-(4-{2-」^£^氩苯基)·5_甲甚碍地-4·基1乙 氧i..}.-5,6,7,8-四氫萘二基Λ氧某丙龄 在類似於實例17a]說明的步驟中,將[外消旋性]_2乙氧 基-3-(4-羥基-5,6,7,8-四氫莕_1_基)丙酸乙酯(實例1〇81)]) 與2-[2-(4-氯苯基)-5-曱基噚唑_4•基]乙醇(以類似於實例 21a]至e]說明的順序,將4-氯基苯盤轉化成2· [2_(4_氣苯 基)-5-甲基哼唑-4-基]乙醇)在三苯膦及DEAD(偶氮二羧酸 二乙酯)的存在下反應,以產生』外消旋性]_3_(4{2[2(4_ 氯苯基)-5-甲基嘮唑-4-基]乙氧基}-5,6,7,8_四氫莕_丨_.基)_ 2-乙氧基丙酸乙酯,將其以類似於實例9〗e]說明的步驟進 一步皂化,以產生成為無色油之[外消旋性]_ 3_ ( 4丨 (4-氯苯基)-5-甲基吟唑-4-基]乙氧基卜5,6,7,8_四氫莕·卜 基)-2-乙氧基丙酸。 MS : 484.3 (M+H) + , 506.2 (M+Na)+ 〇 NMR : (CDC13, 1H, 6 , TMS, 300MHz) 1.12 (t, J=7.2, 3H) 1.73- 1.79 (m, 4H), 2.37 (s, 3H), 2.60-2.74 (m, 4H), 2.91, 3.05 (m., 4H), 3.32-3.35 (m, 1H), 3.50-3.56 (m, 1H)} 3 9g_ 4.01 (m, 1H), 4.19 (t, J=6.3, 2H), 6.61 (d, J=8.4, 1H), 6.98 (d, J=8.4, 1H), 7.39 (d, J=6.9, 2H), 7.90 (d, 8.7, 2H) COOH非常寬。 ’ 實例150 - _「外Ά旋性1-2-乙乳基-3-(4 -轉基篇-〗·基)两酸乙酿. 在類似於實例93a]說明的步驟中,將4-芊氧基萘·丨·幾遂 (以在N,N-二甲基甲醯胺中的4-羥基莕-i_羧醛、苄基氯及 -210 - 本纸張尺度適用中國國家標準(CMS) A4規格(210 X 297公釐) ' ~— 1328585 A7 _______B7 五、發明説明(2()7) 碳酸奸在室溫下製得的)與氣化(乙氧基乙氧羰基甲基)三苯 鱗[Tetrahedron 50(25),7543-56( 1994)]反應,以產生 3-(4- 卞氧基茶-1 -基)-2-乙氧基·( Z,E)-丙烯酸乙酯。如實例91 d] 的說明,以3-(4-苄氧基萘-丨·基)_2_乙氧基_(Z,E)_丙烯酸 乙醋的氫化作用產生成為淺棕色油之[外消旋性]_ 2_乙氧 基-3-(4-經基莕-1 -基)丙酸乙醋。 MS : 288.3 (M),242.2, 215.3, 157.2。 NMR : (CDC13, 1H, 5 , TMS, 3Ό〇ΜΗζ) : 1.11 (t, J= 7.0, 3Η), 1.17 (t, J=7.1, 3H), 3.26-3.60 (m, 4H), 4.10-4.19 (m, 3H), 5.67 (s, 1H), 6.82 (d, J=7.6, 1H), 7.20 (d, J=7.6, 1H), 7.46-7.58 (m, 2H), 8.03 (d, J=7.8, 1H), 8.24 (d, J=7.9, 1H) 〇 bl『外消旋性1 - 2-乙氣某-3 甲某-2·苯基-崎唑-4·某 甲氧基)笨-1 -某1 -丙龄 在類似於實例1 08c]說明的步驟中,以在N,N_二甲基甲醯 胺中的4-氯甲基-5-甲基· 2-苯基-咩唑及氫化鈉處理[外消 旋性]-2-乙氧基-3- ( 4-羥基莕-1 -基)丙酸乙酯,以產生[外 消旋性]-2-乙氧基-3-[4-(5 -甲基-2-苯基-哼唑-4-基甲氧基) 茶-1 -基]-丙酸乙酯,將其以類似於實例9丨e]說明的步驟進 一步t化,以產生成為無色固體之[外消旋性2_乙氧基· 3-[ 4-(5-甲基-2-苯基号唑·4-基甲氧基)莕_丨_基]-丙酸。 MS : 430.3 (Μ·Η)·。 - NMR : (CDC13, 1H, δ, TMS, 300MHz) 1.01 (t, J=7.0, 3H), 2.47 (s, 3H), 3.15-3.25 (m, 2H), 3.41-3.63 (m, 2H), 4.16 (dxd. J, = 3.9, J2=6.9, 1H), 5.17 (s, 2H), 6.90 (d. J=7.9, 1H), - —— · / I i 本纸張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585 A7 B71328585 A7 B7 V. Description of the invention (2〇6) f racemic property 3-(4-{2-"^^^^^^^^^^^^^^^^^^^^^^^^^^ ..,-5,6,7,8-tetrahydronaphthalenyloxyl, a certain age, in a procedure similar to that described in Example 17a], [racemic] _2 ethoxy-3-(4- Ethyl hydroxy-5,6,7,8-tetrahydroindole-1-ylpropionate (Example 1〇81)]) with 2-[2-(4-chlorophenyl)-5-mercaptocarbazole _4•yl]ethanol (in a sequence similar to that described in Examples 21a) to e], the 4-chlorobenzene disk was converted to 2·[2_(4-_phenylphenyl)-5-methylcarbazole-4- (ethanol) reacts in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to produce "racemicity" _3_(4{2[2(4_chlorophenyl)-5-A) Ethyl oxazol-4-yl]ethoxy}-5,6,7,8-tetrahydroindole_丨_.yl) 2-ethyl ethoxypropionate, which is similar to Example 9 The procedure described is further saponified to give [racemic]_3_(4丨(4-chlorophenyl)-5-methyloxazol-4-yl]ethoxy brom 5,6 as a colorless oil. , 7,8_tetrahydroindole·buki)-2-ethoxypropionic acid. MS : 484.3 (M+H) + , 506.2 (M+Na) + NMR: (CDC13, 1H, 6 , TMS, 300 MHz) 1.12 (t, J=7.2, 3H) 1.73- 1.79 (m, 4H), 2.37 (s, 3H), 2.60-2.74 (m, 4H), 2.91, 3.05 (m., 4H), 3.32-3.35 (m, 1H), 3.50-3.56 (m, 1H)} 3 9g_ 4.01 (m, 1H), 4.19 (t, J=6.3, 2H), 6.61 (d, J=8.4, 1H), 6.98 (d, J=8.4, 1H), 7.39 (d, J=6.9, 2H), 7.90 (d , 8.7, 2H) COOH is very wide. 'Example 150 - _ "External Cyclonic 1-2-Ethyl-3-(4-trans-base-)-based diacids. In a procedure similar to that described in Example 93a], 4-芊 萘 萘 萘 以 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( CMS) A4 size (210 X 297 mm) ' ~-1328585 A7 _______B7 V. Description of invention (2()7) Carbonated at room temperature) and gasification (ethoxyethoxycarbonylmethyl) Tritene scale [Tetrahedron 50 (25), 7543-56 (1994)] reaction to produce 3-(4-decyloxy tea-1 -yl)-2-ethoxy(Z,E)-acrylic acid Ester. As illustrated in Example 91 d], hydrogenation of 3-(4-benzyloxynaphthalenyl-fluorenyl)-2-ethoxylate-(Z,E)-ethyl acrylate afforded a light brown oil. Racemic] _ 2_ethoxy-3-(4-pyridin-1-yl)propionic acid ethyl acetate MS: 288.3 (M), 242.2, 215.3, 157.2. NMR: (CDC13, 1H, 5, TMS, 3Ό〇ΜΗζ): 1.11 (t, J= 7.0, 3Η), 1.17 (t, J=7.1, 3H), 3.26-3.60 (m, 4H), 4.10-4.19 (m, 3H), 5.67 (s, 1H), 6.82 (d, J=7.6, 1H), 7.20 (d, J= 7.6, 1H), 7.46-7.58 (m, 2H), 8.03 (d, J=7.8, 1H), 8.24 (d, J=7.9, 1H) 〇 bl 『racemic 1 - 2-ethane- 3 甲-2 phenyl-s-azol-4- methoxy) stupid-1 - some 1 - propylene in a procedure similar to that described in Example 1 08c], in N, N-dimethyl Treatment of 4-chloromethyl-5-methyl-2-phenyl-oxazole and sodium hydride in guanamine [racemic]-2-ethoxy-3-(4-hydroxyindole-1-yl) Ethyl propionate to give [racemic]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy) tea-1 -yl]-propionic acid ethyl ester, which was further t-formed in a similar manner to that described in Example 9 丨e] to give a racemic 2- ethoxy 3-(4-(5) -Methyl-2-phenyloxazole·4-ylmethoxy)indole-yl]-propionic acid MS: 430.3 (Μ·Η)·· - NMR : (CDC13, 1H, δ, TMS, 300MHz) 1.01 (t, J=7.0, 3H), 2.47 (s, 3H), 3.15-3.25 (m, 2H), 3.41-3.63 (m, 2H), 4.16 (dxd. J, = 3.9, J2=6.9 , 1H), 5.17 (s, 2H), 6.90 (d. J=7.9, 1H), - —— · / I i This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1328585 A7 B7
五、發明説明(2Q8) 7.30 (d. J-7.9,1H),7.44-7.57 (m,5H),8 〇2_8 〇5 (m,3H), 8.34 (d,J=8.2, 1H),COOH非常寬。 實例1 5 1 『外4旋性丄-2-乙氧棊-3二基苯# [blg塞吩_4某1丙醢 甲酯 * 在類似於貫例9 1 b]說明的步驟中,將7_苄氧基苯并[b]噻 吩(以在N,N-二曱基曱醯胺中的苯并[b]嘧吩_7 •醇[1^£111· Soc. Perkin Trans. 1( 1983),(12、2973 7]、爷基氯及碳酸鉀 在室溫下製-得的)與在二氣甲烷中的二氯甲基甲醚在〇。〇下 反應,以得到7-卞氧基苯并[b]嘍吩· 4_羧醛。在類似於實 例9.3a]說明的步驟中,以在2_丙醇中的氣化(乙氧基乙氧窥 基甲基)三苯鱗處理7_节氧基苯并[_吩_4·Μ,以得到 3-(7·爷氧基苯并[b]4吩·4•基)_2(z,e)·乙氧基丙缔酸乙 酿。在類似於實例93b]說明的步财,以在THF/Me〇H(i:i) 中的鎂在:(TC下還原3_(7_苄氧基苯并…噻吩_4-基)_ 2(Z’E)-乙氧基丙缔酸乙醋,以產生[外消旋性]节氧 基苯并[b]塞>% ·4-基) 2-乙氧基丙烯酸甲酯,接著在類似 於實例93c]說明的步驟中,以在二氯甲烷中的二甲硫及三 氟Μ二乙_在室溫下除去爷基保護基,以得到成為淺黃 色油之[外消旋性卜2-乙氧基-3_(7_經基笨并[b]〇塞吩_4基) 丙酸甲酯。 MS : 279.0 (M-Η)·。 ' NMR : (CDC13, 1H,(5, TMS,300MHz) 1.12 (t,j=7 〇, 3H), 3.230.36 (m3 3H), 3.56-3.61 (m, 1H), 3.68 (s> 3H)/4.11- 本紙張尺度適用中國國豕標準(CNS) A4規格(210 X — 1 ~ -- 丄:^如V. INSTRUCTIONS (2Q8) 7.30 (d. J-7.9, 1H), 7.44-7.57 (m, 5H), 8 〇2_8 〇5 (m, 3H), 8.34 (d, J=8.2, 1H), COOH Very wide. Example 1 5 1 "Exocyclyl-2-oxoindole-3-diylbenzene # [blg stopper _4 1 propyl hydrazine * in a step similar to the example 9 1 b], will 7-Benzyloxybenzo[b]thiophene (as benzo[b]sulfonyl-7-ol in N,N-didecylguanamine [1^£111· Soc. Perkin Trans. 1 ( 1983), (12, 2973 7], stearyl chloride and potassium carbonate produced at room temperature) and dichloromethyl methyl ether in di-methane methane are reacted under hydrazine to obtain 7-卞Oxybenzo[b] porphin-4-carboxylic aldehyde. Gasification (ethoxyethoxypyrimylmethyl)triphenyl in 2-propanol in a procedure similar to that described in Example 9.3a] Squamous treatment of 7-hydroxy benzo[_pheno-4·Μ to give 3-(7-yloxybenzo[b]4 phen·4•yl)_2(z,e)·ethoxypropane Acidic acid. In a similar manner to that described in Example 93b], the magnesium in THF/Me〇H(i:i) was reduced at 3:(7_benzyloxybenzo...thieno-4 -yl)_ 2(Z'E)-ethoxypropionic acid ethyl acetoacetate to give [racemic] oxy benzo[b] plug >% ·4-yl) 2-ethoxyl Methyl acrylate, followed by a step similar to that described in Example 93c] Dimethyl sulphate and trifluoromethane in the alkane remove the aryl protecting group at room temperature to obtain a racemic 2-ethoxy-3-(7- [b]Deuterophene-4-yl) methyl propionate MS: 279.0 (M-Η)·. 'NMR: (CDC13, 1H, (5, TMS, 300MHz) 1.12 (t,j=7 〇, 3H ), 3.230.36 (m3 3H), 3.56-3.61 (m, 1H), 3.68 (s> 3H)/4.11 This paper scale applies to China National Standard (CNS) A4 specification (210 X — 1 ~ -- 丄:^如
4·15 (dxd,J| = 5.5,J2=7 7 im ζ 〇, 7ns …2 ,1H)’5.83(s,lH),6.63(d,J=7.8, ),7.〇8(d,J=7.8, IH),7.45(s,2h)。 里巩棊)+并吩-4-甚 /類似於實例職]說明的步驟中,以在Ν,Ν·^基甲驢 胺中的4氯—曱基-5-甲基_2_苯基·气峻及氫化鋼處理[外消 旋性]-2-乙乳基-3_(7·經基苯并[小塞吩心基)丙酸甲醋, 以產生[外消旋性]-2·乙氧基义[7♦甲基·2苯基…圭_ 4」基甲氧基)苯并[b]P塞吩_4_基]丙酸甲醋,將其以類似於 貫例91e]說明的步驟進一步琶化以產生成為無色固體之 ^卜消旋性]-2-乙氧基_3_[7_(5-甲基·2苯基十坐_4_基甲 氧基)私并[b] <»塞吩-4-基]-丙酸。 MS : 436.2 (M-Η)' 〇 NMR : (CDC13, 1H, TMS, 300MHz) 1.07 (t, J=7.0, 3H), 2.47 (s, 3H), 3.19-3.33 (m, 2H), 3.40- 3.55 (m, 2H), 4.10- 4.15 (dxd. J, = 4.1, J2=8.3, 1H), 5.20 (s, 2H), 6.87 (d. J=8.0, 1H), 7.19 (d. J=8.0, 1H), 7.43- 7.48 (m, 5H), 8.00-8.03 (m, 2H),COOH非常寬》 實例152 L_外-消旋性卜2-乙氧奚丙氩某竿其甲基 呤唑-4-基甲氣某1苽砰fblp盡略_4-基}_丙醢 在類似於實例1 〇8c]說明的步驟中,以在N,N_二甲基甲醯 胺中的4-氯甲基-2-(4-異丙氧基苯基)-5-曱基呤唑(在類似 於實例2 1 a)及b)說明的步驟中,以4_異丙氧基苯醛及二乙 - 本紙張尺度適用中國固家標準(CNS) A4規格(210X297公爱) 1328585 A7 _____B7 五、發明説明 1基單柄,接著以P0C13處理製得的)及氫化納處理[外消 旋性]-2-乙氧基_3_(7_羥基苯并[b]噻吩_4基)丙酸甲酯(實 例151a]),以產生[外消旋性]_2乙氧基_3_{7[2(4異丙 氧基苯基)-5-甲基呤唑_4_基甲氧基]苯并[b]p塞吩_4_基卜丙 S父甲酯,將其以類似於實例9丨e]說明的步驟進一步皂化, 以產生成為無色固體之[外消旋性]-2-乙氧基-3- { 7- [2-(4- 異丙氧基苯基)_5_曱基嘮唑_4_基甲氧基]苯并[b]嘍吩_4_ 基}-丙酸。 MS : 494.1 .( Μ- Η)' 〇 NMR . (CDC13, 1H, δ , TMS, 300MHz) 1.07 (t, J=6.9, 3H), 1-36 (d, J=6.3, 6H), 2.44 (s, 3H), 3.18-3.30 (m, 2H), 3.38-3-44 (dxd, J, = 4.2, J2=14.1, 1H), 3.49- 3.55 (m, 1H), 4.09-4.13 (dxd, J, = 3.9, J2=8.15 1H), 4.58-4.66 (m, 1H), 5.17 (s, 2H), 6.86 (d, J=7.8, 1H), 6.93 (d. J=8.7, 2H), 7.18 (d, J-7.8, 1H), 7.42-7.47 (dxd, J,= 5.4, J2=9.9, 2H), 7.91-7.94 (dxd, J2=6.9, 2H), COOH非常寬。 實例153 1^1^性卜2-乙氧幕-3-(7-{立1£2_(2_乙1某_4_|1笨某)_ U_基0号唑_4·基1乙氧基丨苯并[bl忒吩_4·其)而醋 在類似於實例17a]說明的步驟中,將[外消旋性]_2_乙氧 基- 3-(7-羥基苯并[b]p塞吩-4-基)丙酸曱酯(實例i51a))與2_ [2- ( 2-乙氧基-4-乳苯基)-5-甲基》号。全基]乙醇(實例95) 在二苯鱗及DEAD(偶氮一幾酸二乙酯)的存在下反應,以產 生[外消旋性]-2-乙氧基- 3-(7- {2-[2-(2_乙氧基-4-氟苯 L______- 214 - 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(211) 基)-5-曱基亏唑-4-基]乙氧基}苯并[b]嘍吩_4•基)丙酸曱 酯,將其以類似於實例9 1 e]說明的步驟進一步皂化,以產 生成為無色固體之[外消旋性卜2-乙氧基-3-(7- {2-[2-(2-乙 氧基-4-氟苯基)-5-甲基咩唑-4-基]乙氧基丨苯并[b]噻吩_4_ 基)丙酸。 MS : 5 12.2 (M-Η)-。 NMR : (DMSO-d6, 1H, δ , TMS, 300MHz) 0.99 (t, J=6.9, 3H),1.33 (t,J=6.9, 3H),2.3(T〔s,3H), 2.98 (t, J=6.3, 2H), 3.17-3.33 (m, 3H), 3.46-3.57 (m, iH), 3.99-4.04 (dxd,4·15 (dxd, J| = 5.5, J2=7 7 im ζ 〇, 7ns ... 2 , 1H) '5.83(s,lH), 6.63(d,J=7.8, ),7.〇8(d, J = 7.8, IH), 7.45 (s, 2h). In the step described in the example, the method is as follows: in the step described in the example, the 4-chloro-indolyl-5-methyl-2-phenyl group in the indole ·Surface and hydrogenated steel treatment [racemic]-2-ethyl lactyl-3_(7· mercaptobenzo[small-septyl)-propionic acid methyl vinegar to produce [racemic]-2 · Ethoxy ethoxy [7 ♦ methyl · 2 phenyl ... qi 4 4 methoxy) benzo [b] P ceto _ 4 yl] propionic acid methyl vinegar, similar to the example 91e The steps described are further deuterated to produce a racemic nature of 2-methyloxy_3_[7-(5-methyl-2-phenyl-s-___ylmethoxy) as a colorless solid. [b] <»cephen-4-yl]-propionic acid. MS : 436.2 (M-Η)' NMR: (CDC13, 1H, TMS, 300MHz) 1.07 (t, J=7.0, 3H), 2.47 (s, 3H), 3.19-3.33 (m, 2H), 3.40- 3.55 (m, 2H), 4.10- 4.15 (dxd. J, = 4.1, J2=8.3, 1H), 5.20 (s, 2H), 6.87 (d. J=8.0, 1H), 7.19 (d. J=8.0 , 1H), 7.43- 7.48 (m, 5H), 8.00-8.03 (m, 2H), COOH is very wide. Example 152 L_Exo-racemic 2- 2-ethoxypropane argon 竿 呤 methyl oxazole-4 - a group of gas, a 1 苽砰fblp, _4-base}_ propyl hydrazine in a procedure similar to that described in Example 1 〇8c], with 4-chloroform in N,N-dimethylformamide Base-2-(4-isopropoxyphenyl)-5-mercaptocarbazole (in a procedure similar to that described in Examples 2 1 a) and b), 4-isopropoxybenzaldehyde and diethyl - This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1328585 A7 _____B7 V. Invention description 1 base single handle, followed by P0C13 treatment) and sodium hydride treatment [racemic] - Methyl 2-ethoxy_3_(7-hydroxybenzo[b]thiophene-4-yl)propionate (Example 151a)) to give [racemic] _2 ethoxy _3_{7[2( 4isopropoxyphenyl)-5-methylcarbazole_4_ylmethoxy]benzo[b]p-septene _4_Kibupro-S parent methyl ester, which was further saponified in a procedure similar to that described in Example 9丨e] to give [racemic]-2-ethoxy-3-{ 7- as a colorless solid. [2-(4-Isopropoxyphenyl)-5-indolylcarbazole-4-yloxy]benzo[b]porphin_4_yl}-propionic acid. MS : 494.1 .( Μ- Η)' NMR (CDC13, 1H, δ, TMS, 300MHz) 1.07 (t, J=6.9, 3H), 1-36 (d, J=6.3, 6H), 2.44 ( s, 3H), 3.18-3.30 (m, 2H), 3.38-3-44 (dxd, J, = 4.2, J2=14.1, 1H), 3.49- 3.55 (m, 1H), 4.09-4.13 (dxd, J , = 3.9, J2=8.15 1H), 4.58-4.66 (m, 1H), 5.17 (s, 2H), 6.86 (d, J=7.8, 1H), 6.93 (d. J=8.7, 2H), 7.18 ( d, J-7.8, 1H), 7.42-7.47 (dxd, J, = 5.4, J2 = 9.9, 2H), 7.91-7.94 (dxd, J2 = 6.9, 2H), COOH is very wide. Example 153 1^1^性卜2-ethoxy curtain-3-(7-{立1£2_(2_乙一某_4_|1笨某)_ U_基0号 _4·基1乙Oxyquinone [bl忒 _4·) and vinegar in a procedure similar to that described in Example 17a], [racemic]_2_ethoxy-3-(7-hydroxybenzo[b] ] p-Phen-4-yl) decyl propionate (example i51a)) and 2-[2-(2-ethoxy-4-lactophenyl)-5-methyl". All-base]ethanol (Example 95) is reacted in the presence of diphenyl scales and DEAD (diethyl azo-monoacid) to give [racemic]-2-ethoxy-3-(7- { 2-[2-(2_ethoxy-4-fluorobenzene L___- 214 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Description of invention (211) )--5-mercapto-oxazol-4-yl]ethoxy}benzo[b]porphin-4-yl)propionate, which is further saponified in a similar manner to that described in Example 9 1 e] To produce a racemic 2-ethoxy-3-(7-{2-[2-(2-ethoxy-4-fluorophenyl)-5-methylcarbazole 4-yl]ethoxy benzobenzo[b]thiophene-4-yl)propanoic acid. MS: 5 12.2 (M-Η)-. NMR : (DMSO-d6, 1H, δ, TMS, 300MHz) 0.99 (t, J = 6.9, 3H), 1.33 (t, J = 6.9, 3H), 2.3 (T[s, 3H), 2.98 (t, J=6.3, 2H), 3.17-3.33 (m, 3H), 3.46-3.57 (m, iH), 3.99-4.04 (dxd,
Ji = 5.4, J2=7.5, 1H), 4.09-4.16 (q, J=6.9, 2H), 4.37 (t, J-6.3, 2H), 6.83-6.91 (m, 2H), 7.04-7.08 (dxd, 1, = 2.1, J2=11.4, 1H), 7.15 (d, J=8.1, 1H), 7.49 (d, J=5.4, 1H), 7.71 (d, J=5.4, 1H), 7.76-7.81 (dxd, J, = 6.9, J2=12, 1H), 12.67 (s, 1H) » 實例154 f外. >肖旋性.1 - 3- ( 7- { 2-『2- (4-氟笨某).5·甲基4 P全-4-基·]乙 氧基丨苯并「bl嘧吩-4-基)-2-乙氳甚呙酩 在類似於實例1 7a]說明的步驟中,將[外消旋性]_ 2_乙氧 基-3-(7-羥基苯并[bp塞吩-4-基)丙酸曱酯(實例i5ia))與2-[2- (4-氯苯基)-5-甲基呤唑· 4-基]乙醇(以類似於實例2 1 a) 至2 1 e]說明的順序,將4-氯基苯醛轉化成2_ [2-(4-氯苯 基)-5-甲基吟唑-4-基]乙醇)在三苯膦及DEAD(偶氮二羧酸 二乙酯)的存在下反應’以產生[外消旋性]-3· ( 7_ { 2- [ 2· ( 4_ 氣苯基)-5-甲基哼唑-4-基]乙氧基}笨并[b]p塞吩-4·基)·2_ __- 21S -___ 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 1328585 212 五、發明説明( ^乳基丙酸"旨’將其以類似於實例. 步4化,以產生成為無色油之[外消旋性] ^進一 氣苯基)-5-甲基七坐-4•基]乙氧基}笨并[㈣吩1 = -乙乳基丙酸。 土)-2- MS : 484.2 (M-Η).。 NMR:(CDC,3,1H, ,,TMs,3〇〇MH2)1〇7(t j=7〇 2 44 (s,3H),3.〇5(t,Jas6,,2H) 3 22 3 3 i(m 2H) 3.45 (dxd, J, = 4.4, J2=u.2> 1HL 3 513 57 >8.0, 1H),7.i6(d,J=8 〇, π)」” H ’ 7·91 (m,2H),COOH非常寬。 ’ ),7.87- 實例155 ^類似於實例臟]說明的步驟中,以在心二甲基甲酷 ::4'乱〒基_2_(4_第三丁基苯基)-5,基㈣在類似 ;:例2U)及b)說明的步驟中,以4第三丁基苯醛及二乙 =基早H矣著以p〇cl3處理製得的)及氮化韵處理[外消旋 〔氧基-3· ( 7-輕基苯并[b] n塞吩_ 4基)丙酸甲醋(實例 a]) ’以產生[外消旋性]3{7七(4第三丁基苯基 甲基十坐-4·基甲氧基]苯并[小塞吩·4-基"·乙氧基丙酸 :醋,將其以類似於實例91e]說明的步驟進一步惠化,以 f成為無色非晶形固體之[外消旋性]-3-{7-[2-(4-第三 丁基笨基)·5·甲基十坐-4-以氧基]笨并㈤違吩-4-基}士 1328585 A7 B7 ___ 五、發明説明(213) 乙氧基丙酸。 MS : 492.2 (M-H)', 448.2 〇 NMR : (CDC13, 1H, 6, TMS, 300MHz) 1.07 (t, J=7.2, 3H), 1.35 (s, 9H), 2.46 (s, 3H), 3.26 (m, 2H), 3.51 (m, 2H), 4.13 (m, 1H), 5.20 (s, 2H), 6.87 (d, J=8.1, 1H), 7.19 (d, J=8.1, 1H),7.45-7.48 (m, 4H), 7.94 (d,J=8.7,2H),COOH 非常 寬。 實例丨56 . (S)-2-乙氩基-3“ 3-甲某-4-『2-(5-甲某-2-笨基-°号唑- 4-基)-乙氧基卜笨某丨-丙醢 在類似於實例1 1 a]至1 1 c]說明的步驟中,將3-甲基-4- [ 2-(5-曱基-2-苯基等唑-4-基)-乙氧基]-苯醛(實例114b])與 (S)-4-卞基-3-乙氧基乙驢基0等坐燒-2-酮及nBi^BOTf反 應’以產生(S)-4-;基-3-((2S,3R)-2-乙氧基-3-羥基-3-{3-甲基-4-[2-(5-甲基-2-苯基·呤唑-4-基)-乙氧基卜苯基} 丙醯基)咩唑烷-2-酮(根據NMR,四個異構物的其中之_ 極 4占優勢;根據Tetrahedron Asymmetry 1999,1353,暫時 將組態以2S,3R命名)。以在三氟醋酸中的三乙基甲矽烷還 原(S)-4-苄基-3-((2S,3R)-2-乙氧基-3-羥基-3· {3-甲基-4_ [2-(5-甲基-2-苯基-哼唑-4-基)-乙氧基]-苯基丨丙醯基)。号 唑烷-2-酮’接著得到(s)-4-芊基-3-((2S)-2-乙氧基_3_{3· 甲基-4-[2-(5-甲基-2-苯基-吟唑-4-基)-乙氧基卜苯基}丙 醯基)噚唑烷-2-酮。接著將(S)-4-苄基-3-((2S)-2-乙氧基_ 3-{3-曱基·4· [2-(5-甲基-2-苯基-哼唑-4-基)·乙氧基]_笨 -;-----217 ___ 本紙張尺度適用中國國家標準(QMS) A4規格(210X29^爱) — 1328585 A7 B7五、發明説明(214) 基}丙醯基)。号唑烷-2-酮以在THF中的iN Na〇H息化,以產 生成為典色固體之(S)-2-乙乳基-3-{3 -甲基- 4_[2-(5-甲奉_ 2-苯基-吟唑-4 -基)-乙氧基]-笨基卜丙酸。根據對掌性 HPLC (Chiralpak-AD)鑑定過量的對映異構物係99 3〇/〇。 MS : (M+H+广 410.5。NMR (DMSO-d6,1H,5, TMS) : 1‘〇3 (t,3H),2.06 (s,3H), 2.35 (s, 3H), 2.75 (dxd, 1H), 2.82 (dxd, 1H), 2.91 (t, 2H), 3.23-3.32 (m, 1H), 3.45-3.52 Cm, 1H), 3.90 (dxd, 1H), 4.18 (t, 2H), 6.69 (dxd, 1H), 6.95-6.99 (ms 2H), 7.47- 7.52 (m, 3H), 7.92 (dxd,2H),12_6 (s, 1H)。 實例157 (5)-3-{3,5-二甲某-4-『2-(5-甲基-2-.宏甚、碟地-4-某)-乙氫 基1-笨基丨-2-乙氣.某丙齡 在類似於實例1 1 a]至1 1C]說明的步驟中,將3,5-二甲基-4-[2-(5-曱基-2-苯基号唑-4-基)-乙氧基]-苯醛(實例117) 與(S)-4-苄基-3-乙氧基乙醯基呤唑烷-2-酮及nBu2BOTf反 應’以產生(S)-4-苄基-3-((2S,3R)-3-{3,5-二甲基-4-[2-(5-甲基-2-苯基-哼唑-4-基)-乙氧基]·苯基}-2-乙氧基-3-羥基丙醯基)呤唑烷-2-酮(根據NMR,四個異構物的其中 之一極佔優勢;根據Tetrahedron Asymmetry 1999,1 353, 暫時將組態以2S,3R命名)。_以在三氟醋酸中的三乙基甲矽 烷還原(3)-4-芊基-3-((23,311)-3-{3,5-二甲基-4-[2-(5-甲 基-2-苯基-呤唑-4 -基)-乙氧基]•苯基}· 2-乙氧基-3-羥基丙 醯基)°号唑烷-2-酮,接著得到(s)-4·芊基-3-((2S)-3-{3,5-Ji = 5.4, J2=7.5, 1H), 4.09-4.16 (q, J=6.9, 2H), 4.37 (t, J-6.3, 2H), 6.83-6.91 (m, 2H), 7.04-7.08 (dxd, 1, = 2.1, J2=11.4, 1H), 7.15 (d, J=8.1, 1H), 7.49 (d, J=5.4, 1H), 7.71 (d, J=5.4, 1H), 7.76-7.81 (dxd , J, = 6.9, J2=12, 1H), 12.67 (s, 1H) » Example 154 f. > Cyclonic. 1 - 3- ( 7- { 2-『2- (4-Fluoro .5·Methyl 4 P all-4-yl·]ethoxy benzobenzo < ld <RTI ID=0.0>>>> [Racecyclo]_ 2_ethoxy-3-(7-hydroxybenzo[bp-desphen-4-yl)propanoate (example i5ia)) with 2-[2-(4-chloro) Phenyl)-5-methylcarbazole-4-yl]ethanol (in a sequence similar to that described in Examples 2 1 a) to 2 1 e], converting 4-chlorobenzaldehyde to 2_ [2-(4- Chlorophenyl)-5-methyloxazol-4-yl]ethanol) is reacted in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to produce [racemic]-3. ( 7_ { 2- [ 2· ( 4_ phenyl)-5-methyloxazol-4-yl]ethoxy} benzo[b]p-cephen-4-yl)·2_ __- 21S -___ This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210X297 mm) 1328585 212 V. Description of the invention (^-lactyl propionic acid "" is similar to the example. Step 4 to produce [racemic] ^1 phenyl)-5-methyl as a colorless oil Seven-spin-4•yl]ethoxyl} stupid and [(tetra)-pheno- 1 =-ethyllactylpropionic acid. Soil)-2-MS: 484.2 (M-Η).. NMR: (CDC, 3,1H, , , TMs, 3〇〇MH2)1〇7(tj=7〇2 44 (s,3H),3.〇5(t,Jas6,,2H) 3 22 3 3 i(m 2H) 3.45 (dxd, J , = 4.4, J2=u.2> 1HL 3 513 57 >8.0, 1H), 7.i6(d, J=8 〇, π)”” H '7·91 (m, 2H), COOH is very wide '), 7.87- Instance 155 ^similar to the example dirty] explained in the steps to the heart of dimethyl methyl:: 4' chaotic base 2_(4_t-butylphenyl)-5, base (four) In a similar procedure; in the steps described in Examples 2U) and b), 4: butyl benzaldehyde and diethyl 2: H) are treated with p〇cl3) and fluorinated [racemic] [oxy-3·(7-light-based benzo[b]n-secret-4-yl)-propionic acid methyl vinegar (example a]) 'to produce [racemic] 3 {7 seven (4 third butyl Phenylmethyl-methyl-n-yl-yloxy]benzo[small snail-4-yl"-ethoxypropionic acid: vinegar, The procedure illustrated in Example 91e] is further enhanced to give [racemic]-3-{7-[2-(4-t-butylphenyl)-5.methyl as a colorless amorphous solid. Ten sitting -4- to oxy] stupid and (five) violent -4-yl} 士1328585 A7 B7 ___ V. Description of invention (213) ethoxypropionic acid. MS: 492.2 (MH)', 448.2 NMR: (CDC13, 1H, 6, TMS, 300 MHz) 1.07 (t, J=7.2, 3H), 1.35 (s, 9H), 2.46 (s, 3H), 3.26 ( m, 2H), 3.51 (m, 2H), 4.13 (m, 1H), 5.20 (s, 2H), 6.87 (d, J=8.1, 1H), 7.19 (d, J=8.1, 1H), 7.45- 7.48 (m, 4H), 7.94 (d, J = 8.7, 2H), COOH is very wide. Example 丨 56 . (S)-2-Ethyl aryl-3" 3-methyl-4-"2-(5-methyl-2-yl-2-yl-2-yl)-ethoxy b In a step similar to that described in Examples 1 1 a] to 1 1 c], 3-methyl-4-[2-(5-mercapto-2-phenylisoxazole-4- ))-ethoxy]-benzaldehyde (Example 114b)) reacts with (S)-4-mercapto-3-ethoxyethyl oxime 0 and the like ketone-2-one and nBi^BOTf to produce S)-4-;yl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl) · oxazol-4-yl)-ethoxy phenyl} propyl hydrazide) oxazolidin-2-one (according to NMR, _ pole 4 of the four isomers predominate; according to Tetrahedron Asymmetry 1999, 1353, temporarily configured with 2S, 3R). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-) with triethylformane in trifluoroacetic acid 3-hydroxy-3·{3-methyl-4_[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenylindenyl). Alkan-2-one' followed by (s)-4-mercapto-3-((2S)-2-ethoxy_3_{3·methyl-4-[2-(5-methyl-2-) Phenyl-oxazol-4-yl)-ethoxyphenyl}nonyl) oxazolidine-2-one. Next (S) 4-benzyl-3-((2S)-2-ethoxy-3- 3-{3-indolyl·4· [2-(5-methyl-2-phenyl-oxazol-4-yl) ·Ethoxy]_stupid;-----217 ___ This paper scale applies to Chinese National Standard (QMS) A4 Specification (210X29^Love) — 1328585 A7 B7 V. Invention Description (214) Base} The oxazolidin-2-one is acetylated with iN Na〇H in THF to give (S)-2-ethyllacyl-3-{3-methyl-4_[2-( 5-methyl -2-phenyl-oxazol-4-yl)-ethoxy]- phenylpropionic acid. Identification of excess enantiomeric line 99 3 according to HPLC (Chiralpak-AD) 〇/〇. MS : (M+H+ 广410.5. NMR (DMSO-d6,1H,5, TMS): 1'〇3 (t,3H), 2.06 (s,3H), 2.35 (s, 3H), 2.75 (dxd, 1H), 2.82 (dxd, 1H), 2.91 (t, 2H), 3.23-3.32 (m, 1H), 3.45-3.52 Cm, 1H), 3.90 (dxd, 1H), 4.18 (t, 2H ), 6.69 (dxd, 1H), 6.95-6.99 (ms 2H), 7.47- 7.52 (m, 3H), 7.92 (dxd, 2H), 12_6 (s, 1H). Example 157 (5)-3-{3,5-dimethyl-4-(2-(5-methyl-2-. macro, dish-4-a)-hydrogenyl 1-styl -2-E gas. A certain age of 3,5-dimethyl-4-[2-(5-mercapto-2-phenyl) in a procedure similar to that described in Examples 1 1 a] to 1 1C] Zyzol-4-yl)-ethoxy]-benzaldehyde (Example 117) is reacted with (S)-4-benzyl-3-ethoxyethyl oxazolidin-2-one and nBu2BOTf to produce (S)-4-benzyl-3-((2S,3R)-3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-carbazole-4- ()-ethoxy]-phenyl}-2-ethoxy-3-hydroxypropionyl)oxazolidin-2-one (according to NMR, one of the four isomers is predominant; Tetrahedron Asymmetry 1999, 1 353, temporarily named 2S, 3R). _Reducing (3)-4-mercapto-3-((23,311)-3-{3,5-dimethyl-4-[2-(5-A) with triethylformane in trifluoroacetic acid Benzyl-2-phenyl-oxazole-4-yl)-ethoxy]•phenyl}·2-ethoxy-3-hydroxypropanyl) ° oxazolidine-2-one, followed by (s )-4-mercapto-3-((2S)-3-{3,5-
裝 訂Binding
線 _ - 218 - 本紙張尺度適用中國國家標準(CNS) A4规格(210 X 297公釐) 1328585Line _ - 218 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1328585
二甲基-4-[2-(5-甲基-2-笨基-呤唑-4_基)·乙氧基]_苯基卜 2-乙氧基丙醯基广号唑烷_2酮。接著將(s)-4_芊基·3_ ((2S)-3-{3,5-二曱基·4·[2·(5_ 甲基 _2· 苯基-σ号唑·4 基 )· 乙氧基]-苯基} · 2-乙氧基丙醯基)„号唑烷—2酮以在THF中的 IN NaOH皂化,以產生成為無色固體之(s)_3_{3,5•二甲基_ 4-[2·(5-曱基-2-苯基-喝唑_4·基)_乙氧基]苯基}·2乙氧 基丙§又。根據對掌性HPLC ( Chiralpak· ad)鑑定過量的對 映異構物係98.8%。 -- MS : (M-Η)· 422.2 〇 NMR (DMS〇-d6, 1H, TMS) : l.〇3 (t, 3H), 2.09 (s, 6H), 2- 38 (s, 3H), 2.72 (dxd, 1H), 2.80 (dxd, 1H), 2.91 (t, 2H), 3- 23- 3.32 (m, 1H), 3.45-3.52 (m, iH), 3.90-4.02 (m, 3H), 6.84 (s, 2H), 7.47-7.52 (m, 3H), 7.92 (dxd, 2H), 12 8 (s 1H)。 ’ 實例158 f夕上消旋性1-2-乙氧基_3_丨%氣ι^_「2·(5甲甚芊芊 _哇-4 -基)-乙氣基1 _装其丨·丙醢 在類似於實例114b]、c]及d]說明的步驟中,將3_氟基_4_ 羥基苯醛與.甲烷磺酸2-(5-甲基-2_苯基-呤唑基)乙酯 [PCT Int. APP1.(2000) W00008002]反應.以得到 3·氟基 _4· [2-(5-甲基-2-苯基-呤唑·4·基)·乙氧基]•苯醛。以氣化(苄 氧羰基乙氧基甲基)三苯鎢(以類似於在實例n 4a)中合成氣 化(苄氧羰基甲氧基甲基)三苯鑄所說明的步驟製得的)處^ 3-氟基-4-[2-(5-甲基-2-苯基-呤唑_4_基)_乙氧基】苯醛,Dimethyl-4-[2-(5-methyl-2-indolyl-oxazol-4-yl)-ethoxy]-phenyl b-2-ethoxypropenylpolyoxazolidine_2 ketone. Next, (s)-4_芊基·3_((2S)-3-{3,5-dimercapto-4·[2·(5_methyl_2·phenyl-σ-azole·4 base) · Ethoxy]-phenyl} 2-ethoxypropenyl) oxazolidine-2-one is saponified with IN NaOH in THF to produce (s)_3_{3,5• as a colorless solid. Dimethyl_ 4-[2·(5-fluorenyl-2-phenyl-benzazosin-4-yl)-ethoxy]phenyl}·2 ethoxy propyl § again. According to the palmar HPLC ( Chiralpak·ad) identified 98.8% of the excess enantiomeric system. -- MS : (M-Η)· 422.2 〇NMR (DMS〇-d6, 1H, TMS): l.〇3 (t, 3H), 2.09 (s, 6H), 2- 38 (s, 3H), 2.72 (dxd, 1H), 2.80 (dxd, 1H), 2.91 (t, 2H), 3- 23- 3.32 (m, 1H), 3.45- 3.52 (m, iH), 3.90-4.02 (m, 3H), 6.84 (s, 2H), 7.47-7.52 (m, 3H), 7.92 (dxd, 2H), 12 8 (s 1H). 'Example 158 f On the eve of the race, 1-2-ethoxy _3_丨% gas ι^_"2·(5A 芊芊 芊芊 _ wow-4 - yl)- ethane group 1 _ 丨 丨 · 醢 醢 in a similar In the steps illustrated in Examples 114b], c] and d], 3-fluoro-4-tetrahydroxybenzaldehyde and 2-(5-methyl-2-phenyl-carbazolyl)ethyl methanesulfonate [ PCT Int. APP1. (2000) W00008002] Reaction. To get 3·fluoroyl_4·[2-(5-methyl-2-phenyl-carbazole·4·yl)·ethoxy]benzaldehyde. Gasification (benzyloxycarbonylethoxymethyl) 3-trifluoro-4-[2-() prepared by the procedure described for the synthesis of gasified (benzyloxycarbonylmethoxymethyl)triphenyl cast in a similar manner as in Example n 4a) 5-methyl-2-phenyl-carbazole _4_yl)-ethoxyl]benzaldehyde,
裝 ίτInstall ίτ
1328585 A7 B7 五、發明説明(1328585 A7 B7 V. Description of invention (
216 接著得到2(2/)-乙氧基-3-{3-氟基-4-[2-(5_甲基_2_苯其216 followed by 2(2/)-ethoxy-3-{3-fluoro-4-[2-(5-methyl-2-phenylene)
呤唑-4 -基)-乙氧基]-苯基卜丙烯酸苄酯,將其f . I y s l y人產 生成為無色固體油之[外消旋性]-2-乙氧基·3_丨3_氣其4 [2-(5-甲基-2-苯基-哼唑-4-基)-乙氧基卜笨基卜丙酸f · MS : (M-H)· 412.2 〇 NMR (DMSO-d6, 1H, TMS) : 1.03 (t, 3H), 2.35 (s, 3H) 2.78 (dxd, 1H), 2.88 (dxd, 1H), 2.95 (t, 2H), 3.23-3.32 (m 1H), 3.45- 3.52 (m, 1H),3.95:1.00 (m,iH),4 26 (t,2H)’ 6.95 (d,1H),7.04-7.10 (m, 2H),7.47-7.52 (m,3H),7 92’ (dxd,2H),12.7 (s, 1H)。 實例159 1_外..消祿性卜2-乙氣基-3-{4-【2-(5-甲1^苯基-喵〇4^^ 乙氧基1-3-丙某芨某}-兩百会 在類似於實例1 14b]、c]及d]說明的步驟中,將3_缔丙其 4·羥基苯醛與甲烷磺酸2- ( 5-甲基-2-苯基-呤唑_ 4_基)乙酉t [PCT Int. Appl.(2000) W00008002]反應,以得到3_ 缔丙 基- 4- [2-(5-甲基-2-私基-11亏0坐-4-基)-乙氧基]-苯链。以氣 化(r氧幾基乙氧基甲基)三苯鱗(以類似於在實例1丨4a]中合 成氣化(爷氧碳基甲氧基曱基)三苯鱗所說明的步驟製得的) 處理3-烯丙基-4-[2-(5-曱基-2-苯基-呤唑·4-基)-乙氧基 苯醛’接著得到3-{3-烯丙-基-4-[2-(5-甲基-2-苯基-呤唾_ 4-基)-乙氧基]-苯基卜2(Ζ,Ε)-乙氧基丙烯酸芊酯,將其氫 化’以產生成為無色固體油之[外消旋性]_ 2-乙氧基-3-丨4_ [2-(5-甲基-2-苯基-哼唑-4-基)乙氧基]-3-丙基苯基}_丙 220 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1328585 A7 B7 五、發明説明(217) 酸。 MS : (M-H)· 436.3。 NMR (DMSO-d6, 1H, <5, TMS) : Ο.77 (t> 3H), 1.03 (t, 3H), 1.32- 1.42 (m, 2H), 2.35 (s, 3H), 2.35-2.45 (m, 2H), 2.76 (dxd, 1H), 2.85 (dxd, 1H), 2.92 (t, 2H), 3.23-3.32 (m, 1H), 3.45-3.52 (m, 1H), 3.90 (dxd,1H),4.19 (t,2h),6.82 (d, 1H), 6.92 (d, 1H), 6.97 (dxd, 1H), 7.47-7.52 (m, 3H), 7.92 (dxd, 2H), 12.7 (s, 1H)。 二 實例160 - (2.S)-2-乙我基士{ 3 -甲氧基-4_ [ 甲某_2_苯基_ g号咬- 4 '基)-乙乳基1-笨基}-丙酸 在類似於實例lla]至lie]說明的步驟中,將3_甲氧基_4_ [2-(5-甲基-2-苯基等唑-4-基)-乙氧基卜苯醛(在類似於貪 例1 14b]說明的步驟中,以4-羥基_3-曱氧基苯醛及曱烷磺 酸2-(5-甲基-2-苯基-呤唑-4-基)乙酯製得的)與(s)_4·苄 基-3-乙氧基乙醯基》号〇坐燒_2_酮及nBU2B〇Tf反應,以產生 (5)-4-芊基-3-((23,311)-2-乙氧基-3-羥基-3-{3-甲氧基_4- [2-(5-甲基-2-苯基-哼唑-4-基)-乙氧基]-苯基}丙醯基)哼 唑烷-2-酮(根據NMR,四個異構物的其中之一極佔優勢; 根據 Tetrahedron Asymmetry 1999,1353,暫時將組態以 2 5,311命名)。以在三氟醋酸中的三乙基甲矽烷還原(3)_4-芊基-3-((23,311)-2-乙氧基-3-羥基-3-{3-甲氧基-4-[2-(5-甲基-2-苯基-吟唑-4-基)-乙氧基]-苯基}丙醯基)呤唑烷-2-酮’接著得到(S)-4-芊基-3-((2S)-2-乙氧基-3-{3-甲氧基- ___- 221 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)Benzyl-4-yl)-ethoxy]-phenyl benzyl acrylate, which is produced as a colorless solid oil [racemic]-2-ethoxy·3_丨3 _ gas 4 [2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy bupidopropionic acid f · MS : (MH) · 412.2 NMR (DMSO-d6 , 1H, TMS) : 1.03 (t, 3H), 2.35 (s, 3H) 2.78 (dxd, 1H), 2.88 (dxd, 1H), 2.95 (t, 2H), 3.23-3.32 (m 1H), 3.45- 3.52 (m, 1H), 3.95: 1.00 (m, iH), 4 26 (t, 2H)' 6.95 (d, 1H), 7.04-7.10 (m, 2H), 7.47-7.52 (m, 3H), 7 92' (dxd, 2H), 12.7 (s, 1H). Example 159 1_外..消禄性卜2-乙气基-3-{4-[2-(5-甲一^Phenyl-喵〇4^^ ethoxyl 1-3-propyl 芨 some }- two hundred will be in a procedure similar to that described in Examples 1 14b], c] and d], 3- propyl propyl 4-hydroxybenzaldehyde and 2-( 5-methyl-2-phenyl methanesulfonate -carbazole _ 4_yl) acetamidine t [PCT Int. Appl. (2000) W00008002] reaction to obtain 3_ propyl-4-(2-(5-methyl-2- ingyl-11-deficient 0 sitting 4-yl)-ethoxy]-benzene chain. Gasification by gasification (r-oxy-ethoxymethyl)triphenyl scale (similar to in Example 1丨4a) 3-methoxy-4-[2-(5-fluorenyl-2-phenyl-oxazol-4-yl)-ethoxylate prepared by the procedure described for methoxyfluorenyltriphenyl scales Benzoaldehyde' then gives 3-{3-allyl-yl-4-[2-(5-methyl-2-phenyl-indenyl-4-yl)-ethoxy]-phenyl b 2 ( Ζ,Ε)-decyl ethoxy acrylate, hydrogenated to produce [racemic]_2-ethoxy-3-indole-4_[2-(5-methyl-2) as a colorless solid oil -Phenyl-oxazol-4-yl)ethoxy]-3-propylphenyl}_propene 220 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 13285 85 A7 B7 V. INSTRUCTIONS (217) Acid MS: (MH)·436.3. NMR (DMSO-d6, 1H, <5, TMS): Ο.77 (t> 3H), 1.03 (t, 3H) , 1.32- 1.42 (m, 2H), 2.35 (s, 3H), 2.35-2.45 (m, 2H), 2.76 (dxd, 1H), 2.85 (dxd, 1H), 2.92 (t, 2H), 3.23-3.32 (m, 1H), 3.45-3.52 (m, 1H), 3.90 (dxd, 1H), 4.19 (t, 2h), 6.82 (d, 1H), 6.92 (d, 1H), 6.97 (dxd, 1H), 7.47-7.52 (m, 3H), 7.92 (dxd, 2H), 12.7 (s, 1H). Example 160 - (2.S)-2-B I Keshi { 3 -Methoxy-4_ [A _2_Phenyl-g-biting - 4 'yl)-ethyllacyl 1-styl}-propionic acid in a procedure similar to that illustrated by Examples lla] to lie], 3-methoxy_4_ [2 -(5-methyl-2-phenylisoxazin-4-yl)-ethoxybenzaldehyde (in a procedure similar to that of greek 1 14b), 4-hydroxy-3-methoxybenzene (2-) 5-(4-methyl-2-phenyl-oxazol-4-yl)ethyl acetate 〇 烧 _2 _2 ketone and nBU2B 〇 Tf reaction to produce (5)-4-mercapto-3-((23,311)-2-ethoxy-3-hydroxy-3-{3-methoxy _4- [2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl} Acyl) Well-2-one (according to NMR, one of the four isomers of the dominant pole; according to Tetrahedron Asymmetry 1999,1353, configured to temporarily named 2 5,311). Reduction of (3)- 4-mercapto-3-((23,311)-2-ethoxy-3-hydroxy-3-{3-methoxy-4-[3] with triethylformane in trifluoroacetic acid 2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}propenyl)oxazolidin-2-one' followed by (S)-4-芊Base-3-((2S)-2-ethoxy-3-{3-methoxy- ___- 221 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)
訂Order
線 1328585 A7 B7 五、發明説明(218) 4-[ 2-(5-甲基-2·苯基-咩唑-4-基)-乙氧基卜苯基}丙醢基) 11号唑烷-2-酮。接著將(S)-4-芊基-3-((2S)-2-乙氧基_3_{3-甲氧基-4-[2-(5-甲基-2-苯基-哼唑-4-基)_乙氧基]苯基) 丙醯基)哼唑烷-2-酮以在THF中的IN NaOH皂化,以產生成 為無色固體之(S)-2-乙氧基- 3-{3-甲氧基·4-[2-(5-甲基- 2-苯基-°咢°坐-4 -基)-乙氧基]-苯基}-丙酸。根據對掌性hplC (Chiralcel-OJ)鑑定過量的對映異構物係98.7%。 MS : (M-Η)· 424‘3。 乙. NMR (DMSO-d6, 1ΗΓ δ , TMS) : l.〇4 (t, 3Η), 2.36 (s, 3H), 2.75-2.87( 2xdxd, 2xlH), 2.91 (t, 2H), 3.27-3.32 (m, 1H), 3.49-3.52 (m, 1H), 3.72 (s, 3H), 3.94-3.96 (m, 1H), 4.14 (t, 2H), 6.71 (dxd, 1H), 6.84-6.87 (m, 2H), 7.48-7.50 (m, 3H), 7.90-7.92 (m, 2H), 12.7 (s,1H)。 實例1 6 1 (2S)-2-乙氣基-3- (2-甲氳某-4-Γ2-Η-甲某·2-米早_p署岫_ 4 -基乙氣某1-笨某卜丙酸 在類似於實例1 1 a]至11 c]說明的步驟中,將2·甲氧基-4-[2-(5-甲基-2-苯基-哼唑-4-基)-乙氧基]•笨醛(在類似於實 例1 14b]說明的步驟中,以4-羥基-2·甲氧基苯醛及甲烷磺 酸2- ( 5-甲基-2-苯基-°号咬-4-基)乙酯製得的)與(s)_ 4-芊 基-3-乙氧基乙醯基β号吐炫-2-酮及nBi^BOTf反應,以產生 (5)-4-芊基-3-((2 5,311)-2-乙氧基-3-經基_3-{2-曱氧基-4-[2-(5-甲基-2-苯基-呤唑-4-基)-乙氧基]•苯基丨丙醯基)呤 唑烷-2-酮(根據NMR,四個異構物的其中之一極佔優勢; _____-000 -___________ 本紙張尺财目S家料(CNS) A4規格(21G X 29ϋ "" 1328585 A7 B7 五、發明説明(219) 根據 Tetrahedron Asymmetry 1999,1 353,暫時將組態以 2S,3R命名)》以在三氟醋酸中的三乙基甲矽烷還原(s)_4_ 苄基-3-((25,311)-2-乙氧基-3-羥基-3-{2-曱氧基-4-[2-(5- 甲基-2-苯基号唑-4-基)-乙氧基]-苯基}丙醯基号唑虎_2_ 酮’接著得到(S)-4-笮基-3-((2S)-2-乙氧基-3-{2-甲氧基· 4-[2-(5-甲基-2-苯基号η坐·4 -基)-乙氧基]-苯基丨丙酸基) 呤唑烷-2-酮。接著將(S)-4-芊基-3-((2S)-2-乙氧基-3_ρ· 甲氧基-4- [2- ( 5-甲基-2-苯基-·5唑-4 -基)-乙氧基]•苯基} 丙醯基)噚唑烷-2-酮以在THF中的IN NaOH皂化,以產生成 為無色固體之(S)-2-乙氧基-3- {2-甲氧基-4-[2-(5-甲基-2- 冬基-吟°全-4-基)-乙氣基]-苯基}-丙酸。 MS : (Μ- H)- 424.5。 NMR (DMSO-d6, 1H, (5, TMS) : 1.01 (t, 3H), 2.36 (s, 3H), 2.72 (dxd, 1H), 2.84 (dxd, 1H), 2.92 (t, 2H), 3.22-3.29 (m, 1H), 3.41-3.49 (m, 1H), 3.75 (s, 3H), 3.89-3.92 (m, 1H), 4.19 (t, 2H), 6.44 (dxd, 1H), 6.50 (d, 1H), 6.99 (d, 1H), 7.48- 7.50 (m, 3H), 7.90-7.92 (m, 2H), 12.6 (s, lH)。 實例1 62 i外消旋性1 - 2-異丙氣基-3- M-丨2-( 5-甲基-2-苽某-哼唑-4-基)-乙氧基1-笨并fbl·»实吩-7-某丨-而齡 以類似於實例68的方式製備成為熔點146- 147。之灰白色 固體’但是在丁間醇醛步驟中使用未經取代之4_[2_(5_甲 基-2-苯基号吐-4-基)-乙氧基]-苯并[b]e塞吩·7-幾链[以在 四氫呋喃中的4-羥基苯并[b]。塞吩-7-羧醛[Ger. Offen.( 1998) _- 223 - 本紙張尺度適用中圉留家標準(CNS) A4規格(210X 297公爱) ~ 一Line 1328085 A7 B7 V. Description of the Invention (218) 4-[2-(5-Methyl-2.phenyl-oxazol-4-yl)-ethoxyphenyl}propenyl) 11-oxazolidine -2-ketone. Next, (S)-4-mercapto-3-((2S)-2-ethoxy_3_{3-methoxy-4-[2-(5-methyl-2-phenyl-carbazole) 4-yl)-ethoxy]phenyl)propanyl)oxazolidin-2-one is saponified with IN NaOH in THF to give (S)-2-ethoxy-3 as a colorless solid. -{3-Methoxy-4-[2-(5-methyl-2-phenyl-)-yl-4-yl]-ethoxy]-phenyl}-propionic acid. The excess enantiomer was 98.7% identified based on palmitic hplC (Chiralcel-OJ). MS: (M-Η)· 424'3. NMR (DMSO-d6, 1ΗΓ δ , TMS) : l.〇4 (t, 3Η), 2.36 (s, 3H), 2.75-2.87 ( 2xdxd, 2xlH), 2.91 (t, 2H), 3.27-3.32 (m, 1H), 3.49-3.52 (m, 1H), 3.72 (s, 3H), 3.94-3.96 (m, 1H), 4.14 (t, 2H), 6.71 (dxd, 1H), 6.84-6.87 (m , 2H), 7.48-7.50 (m, 3H), 7.90-7.92 (m, 2H), 12.7 (s, 1H). Example 1 6 1 (2S)-2-Ethyl-3- (2-methyl 氲 -4- Γ Η 甲 甲 甲 2- 2- 2- 2- 4 4 4 4 4 4 4 4 4 4 4 a certain propionic acid in a procedure similar to that described in Examples 1 1 a] to 11 c], 2·methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl) )-ethoxy]-stanoaldehyde (in a procedure similar to that described in Example 1 14b), 4-hydroxy-2.methoxybenzaldehyde and 2-(5-methyl-2-phenylmethanesulfonate) - (#) 4-yl) ethyl ester prepared by reacting with (s) 4- 4-mercapto-3-ethoxyethyl ketone beta oxet-2-one and nBi^BOTf to produce 5) 4-mercapto-3-((2 5,311)-2-ethoxy-3-carbyl-3-{2-decyloxy-4-[2-(5-methyl-2-benzene) Base-oxazol-4-yl)-ethoxy]-phenylpyridinyl)oxazolidin-2-one (according to NMR, one of the four isomers is predominant; _____-000 - ___________ This paper ruler S (materials) S (materials) A4 specifications (21G X 29ϋ "" 1328585 A7 B7 V, invention description (219) According to Tetrahedron Asymmetry 1999, 1 353, the configuration will be temporarily named 2S, 3R) Reduction of (s)_4_benzyl-3-((25,311)-2-ethoxy-3-hydroxy- by triethylformane in trifluoroacetic acid 3-{2-decyloxy-4-[2-(5-methyl-2-phenyloxazol-4-yl)-ethoxy]-phenyl}propanyl oxazol-2_ketone Next, (S)-4-mercapto-3-((2S)-2-ethoxy-3-{2-methoxy-4--[2-(5-methyl-2-phenyl) Sodium 4-(yl)-ethoxy]-phenylpropionate) oxazolidin-2-one followed by (S)-4-mercapto-3-((2S)-2-ethoxy -3_ρ·methoxy-4-[2-(5-methyl-2-phenyl-·5oxa-4-yl)-ethoxy]•phenyl}propenyl)oxazolidine-2- The ketone is saponified with IN NaOH in THF to give (S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-whenyl) as a colorless solid - 吟 ° all-4-yl)-ethane group]-phenyl}-propionic acid MS: (Μ-H)- 424.5. NMR (DMSO-d6, 1H, (5, TMS): 1.01 (t, 3H), 2.36 (s, 3H), 2.72 (dxd, 1H), 2.84 (dxd, 1H), 2.92 (t, 2H), 3.22-3.29 (m, 1H), 3.41-3.49 (m, 1H), 3.75 (s, 3H), 3.89-3.92 (m, 1H), 4.19 (t, 2H), 6.44 (dxd, 1H), 6.50 (d, 1H), 6.99 (d, 1H), 7.48- 7.50 (m, 3H ), 7.90-7.92 (m, 2H), 12.6 (s, lH). Example 1 62 i Racemic 1- 2 -isopropenyl-3-M-indole 2-(5-methyl-2-indole-carbazol-4-yl)-ethoxy 1-stup Fbl·» 实-7-7- 丨- and aged to a melting point of 146-147 in a manner similar to Example 68. An off-white solid' but using an unsubstituted 4_[2_(5-methyl-2-phenylno-4-yl)-ethoxy]-benzo[b]e in the aldol process吩7-chain [to 4-hydroxybenzo[b] in tetrahydrofuran. Cerebral-7-carboxaldehyde [Ger. Offen. ( 1998) _- 223 - This paper scale applies to the Chinese Standard (CNS) A4 specification (210X 297 public) ~ one
裝 訂Binding
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DE 1971 1617 A1]及2-(5- 苯膦及DEAD(偶氮二羧酸 電子性偶合夥伴》 甲基-2-苯基号唑_4基)乙醇在二 二乙酯)的存在下製得的]作為親 ISN-MS : 464.1 (M-H)+ 〇 實例163DE 1971 1617 A1] and 2-(5-phenylphosphine and DEAD (Azodicarboxylic acid electronic coupling partner methyl-2-phenyloxazole-4-yl)ethanol in the presence of diethylene ester) Derived as a pro-ISN-MS: 464.1 (MH) + 〇 instance 163
Ll)-2-異丙裹.某-3-(4-「om 计 a -~~~苽某-呤唑-4_ 其i . 氧基1 -苯并f b 塞吩-7 -某卜丙咕— 以類似於實例η的方式製備、為熔點167_168。之灰白色 晶體’但是-在步驟a]中使用(s)_4m·異丙氧基乙醯基 十至垸-2-鲷代替(SM4基_3·甲氧基乙醯基七坐燒上嗣 ,為偶合夥伴。在類似於以上實例65說明的方法,以異丙 氧基醋酸及(S)- 4-芊基-2-呤唑烷酮製備前者。 ISN-MS : 464.2 (M-H)+。 實例1 6 4 ill外消旋性1 - 3_ ( 3-埽羥某芏-丨·美V 2-乙氫某而酩 乙酯 將0.87公克(2.65毫莫耳)[外消旋性]_3·(4-烯丙氧基莕 基)-2-.乙氧基丙酸乙酯[以[外消旋性]_2•乙氧基3_(4•羥基 茶· 1 -基)丙酸乙酯(實例丨50a])及晞丙溴與在丙酮中的碳酸 钟在60°C下製成的]在160 °C下不與任何溶劑攪拌2小時。將 暗色殘餘物以閃蒸色層分離法(妙膠,己炫/ AcOEt= 4: 1)純 化’以產生成為黃色油之0.82公克(94%)[外消旋性]-3-(3-烯丙基-4-羥基莕-1-基)-2-乙氧基丙酸乙酯。 MS : 327.2 (M-Η).。 L------ 79Λ - 本紙張尺度適用中國国家標準(CNS) Α4規格(210 X 297公釐) 1328585 A7 B7 221 五、發明説明( NMR : (CDCI3, 1H, <5, TMS) 1.1〇 (t, J=7, 3H), 1.18 (t, J-7, 3H), 3.23- 3.35 (m, 3H), 3.42-3.44 (d, J=5, 1H), 3.53-3.57 (m, 2H), 4.10-4.18 (m, 3H), 5.20-5.27 (m, 2H), 5.47 (s, 1H), 6.02-6.11 (m, 1H), 7.13 (s, 1H), 7.47-7.54 (m, 2H), 8.00-8.03 (m, 1H),8.20- 8.23 (m,1H)。 kl—L1K.消旋性1 - 3- Π-烯而葚-1甲某-2-苽某-噚唑-4 -基)·乙氧基卜萘-1 -..1卜2_乙盡其兩醢 在類似於實例1 7a]說明的步驟<中,將[外消旋性]-3- (3-烯 丙基-4-羥基莕-1-基)-2-乙氧基丙酸乙酯與在四氫呋喃中 的2-(5-甲基-2-苯基-喝唑_4_基)乙醇在三苯膦& DBad(偶 氮二羧酸二特丁酯)的存在下反應,以產生[外消旋性卜夂 {3-晞丙基-4-[2-(5-甲基-2-苯基_嘮-哇_4_基卜乙氧基卜萘 1-基卜2-乙氧基丙酸乙酯,將其以類似於實例91e]說明的 步驟進一步皂化,以產生成為無色固體之[外消旋性卜3 { 3-烯丙基-4- [2- ( 5-甲基-2-苯基-呤唑_4_基)_乙氧基萘 1-基}-2-乙氧基丙酸。 MS : 484.3 (M-Η).。 NMR : (CDC13, 1H, TMS) 0.97- 1.02 (t, J=7 3m 0 (s, 3H), 3.08-3.22 (m, 4H), 3.43-3.59 (m, 4H), 4.12 * ^ · 1 6 (dxd, J, = 3.5, J2=9, 1H), 4.23-4.27 (t, J=6.5, 2H), 5.〇〇.5 〇6 (m, 2H), 5.92-6.01 (m, 1H), 7.22 (s, 1H), 7.40-7 / υ (m, 5H),8.00-8.10 (m, 4H),COOH非常寬。Ll)-2-isopropyl wrap. -3-(4-"om a-~~~苽- oxazole-4_ its i. oxy 1 -benzofb sept-7 - a certain propyl hydrazine - prepared in a manner similar to the example η, as the melting point 167-168. The off-white crystal 'but- in step a] is replaced with (s) _4m·isopropoxyacetinyl 10 to 垸-2-鲷 (SM4 base _ 3. Methoxyethyl sulfhydryl sulphide is a coupling partner. In a manner similar to that described in Example 65 above, isopropoxyacetic acid and (S)-4-mercapto-2-oxazolidinone Prepare the former. ISN-MS: 464.2 (MH)+. Example 1 6 4 ill racemic 1 - 3_ ( 3-埽 芏 芏 丨 丨 美 美 2- 2- 2- 2- 2- 2- 2- 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 2.65 millimoles) [racemic] _3·(4-allyloxyindenyl)-2-.ethyl ethoxypropionate [as [racemic]_2•ethoxy 3_(4 • Hydroxy tea · 1-yl) ethyl propionate (example 丨 50a)) and guanidinium bromide with carbonic acid in acetone at 60 ° C] stirred at 160 ° C for 2 hours without any solvent The dark residue was purified by flash chromatography (yield, EtOAc/EtOAc: 4:1) to yield a yield of 0.82 g (94%) as a yellow oil. Ethyl 3-(3-allyl-4-hydroxyindol-1-yl)-2-ethoxypropanoate MS: 327.2 (M-Η). L------ 79Λ - This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1328585 A7 B7 221 V. Description of the invention (NMR: (CDCI3, 1H, <5, TMS) 1.1〇(t, J=7, 3H), 1.18 (t, J-7, 3H), 3.23- 3.35 (m, 3H), 3.42-3.44 (d, J=5, 1H), 3.53-3.57 (m, 2H), 4.10-4.18 (m , 3H), 5.20-5.27 (m, 2H), 5.47 (s, 1H), 6.02-6.11 (m, 1H), 7.13 (s, 1H), 7.47-7.54 (m, 2H), 8.00-8.03 (m , 1H), 8.20- 8.23 (m, 1H). kl-L1K. Racemic 1-3-Π-ene-ene-1 某-2- 苽- oxazol-4-yl)·ethoxy萘naphthalene-1 -..1卜2_B, in the same step as described in Example 1 7a], [racemic]-3-(3-allyl-4-hydroxyl) Ethyl phthal-1-yl)-2-ethoxypropionate with 2-(5-methyl-2-phenyl-oxazolyl-4-yl)ethanol in tetrahydrofuran in triphenylphosphine & DBad ( Reaction in the presence of di-tert-butyl azodicarboxylate) to give [racemic oxime {3-晞propyl-4-[2-(5-methyl-2-phenyl-唠-wow) _4_Kib ethoxy bnaphthalene 1-yl b 2-ethoxyl Ethyl acetate, which was further saponified in a similar manner to that described in Example 91e] to give a racemic, 3, 3- allyl-4-[2-(5-methyl-2) -Phenyl-carbazole-4-yl)-ethoxynaphthalene 1-yl}-2-ethoxypropionic acid. MS: 484.3 (M-Η). NMR : (CDC13, 1H, TMS) 0.97- 1.02 (t, J=7 3m 0 (s, 3H), 3.08-3.22 (m, 4H), 3.43-3.59 (m, 4H), 4.12 * ^ · 1 6 (dxd, J, = 3.5, J2=9, 1H), 4.23-4.27 (t, J=6.5, 2H), 5.〇〇.5 〇6 (m, 2H), 5.92-6.01 (m, 1H) , 7.22 (s, 1H), 7.40-7 / υ (m, 5H), 8.00-8.10 (m, 4H), COOH is very wide.
實例A 可以熟知的方式製造含有以下成份之藥片·· 本纸張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1328585 A7 B7 五、發明説明(222 ) 成份 每一個藥片 式I化合物 10.0-100.0 毫克 乳糖 125.0毫克 玉米澱粉 75.0毫克 滑石粉 4.0毫克 硬脂酸鎂 1.0毫克 實例B 可以熟知的方式製造含有以又成份之膠囊: 成份 - 每一個膠囊 式I化合物 25.0毫克 乳糖 150.0毫克 玉米澱粉 20.0毫克 滑石粉 5.0毫克 實例C 注射溶液可以具有以下組合物: 式I化合物 3.0毫克 白明膠 150.0毫克 酚 4.7毫克 用於注射溶液的水 約1.0毫升 -??β - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐)Example A A tablet containing the following ingredients can be manufactured in a well-known manner. · This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1328585 A7 B7 V. Invention Description (222) Ingredients Each tablet type I Compound 10.0-100.0 mg Lactose 125.0 mg Corn starch 75.0 mg Talc powder 4.0 mg Magnesium stearate 1.0 mg Example B Capsules containing the ingredients can be made in a well-known manner: Ingredients - Each capsule I compound 25.0 mg lactose 150.0 mg corn Starch 20.0 mg talc 5.0 mg Example C The injection solution may have the following composition: Compound of formula I 3.0 mg of gelatin 150.0 mg of phenol 4.7 mg of water for injection solution about 1.0 ml -?? β - This paper scale applies to Chinese national standards (CNS) A4 size (21〇x 297 mm)
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