TWI378146B

TWI378146B - Processes for the preparations of optically active cyclopentenones and cyclopentenones prepared therefrom

Info

Publication number: TWI378146B
Application number: TW095101970A
Authority: TW
Inventors: Yu-Chih Yeh; Ming-Kun Hsu; Shih-Yi Wei
Original assignee: Chirogate Int Inc
Priority date: 2006-01-18
Filing date: 2006-01-18
Publication date: 2012-12-01
Also published as: KR101399551B1; JP5554887B2; KR20070076549A; TW200728268A; JP2007224018A

Description

丄J，〇丄4〇九、發明說明：【發明所屬之技術領域】 y及用於製備式（R)_ 1之光學活性環戊婦酮化物的新穎方法，丄J,〇丄4〇 IX. Description of the invention: [Technical field to which the invention pertains] y and a novel method for preparing an optically active cyclopentanone compound of the formula (R)-1,

該等光學活備是有用的酉同化物。These optical activities are useful assimilate compounds.

性環戊烯酮化物對於***素及其類似物之製。本發明還涉及由該等方法製得之新穎環戊稀【先前技術】A cyclopentenone compound is produced for prostaglandins and analogs thereof. The present invention also relates to novel cyclopentene prepared by the methods [Prior Art]

削列腺素及其衍生物具有多種生物學作用，諸如血管舒張作用、致炎性作用、抑制血小板凝集之作用、子宮肌收縮作用、腸收縮作用及降低眼内壓作用，且可用於製備、、台療或預防心肌梗塞、心絞痛、動脈硬化、高血壓或十二^ 腸潰瘍之藥物’其對於人類以及獸醫應用都有價值。 θ 在最近幾十年中，許多學術研究人員及工業機構在開發用於咼效並低成本地合成***素之多種關鍵的中間體以及創新之方法上作出了極大的努力（C〇llines，p w等人 1 993 年，Chem. Rev. 93, 1 533)。 1^〇1」&，0_等人報導’式（11)-1之環戊烯酮化物Adenosine and its derivatives have various biological effects, such as vasodilation, inflammatory effects, inhibition of platelet aggregation, uterine muscle contraction, intestinal contraction, and reduction of intraocular pressure, and can be used for preparation, , Taiwan therapy or drugs to prevent myocardial infarction, angina pectoris, arteriosclerosis, hypertension or 12-intestinal ulcers' are valuable for human and veterinary applications. θ In recent decades, many academic researchers and industrial organizations have made great efforts to develop a variety of key intermediates for innovative and cost-effective synthesis of prostaglandins and innovative methods (C〇llines, pw Et al. 1993, Chem. Rev. 93, 1 533). 1^〇1"&,0_ et al. reported a cyclopentenone of formula (11)-1

H0 (R)-l I07362.doc 1378146 是***素合成中可能之中間體’其中未經取代之直鏈飽和院基（L〇】ja，D.等人，Zh. 〇rg Khim 1985, 21(4) 782)。如在下列流程圖！中所描述，Β^Μί，p g等人使用’ 硝基甲貌絲加成方法將式（RH之環戊烯嶋物轉化為式 II之科裏經（C〇rey aldehyde)，其中Ri為甲基，科裏酸為^ 列腺素合成之一種高級的關鍵中間體（Beraldi， p G等人 1987, Tetrahedron，43, 4669)。流程圖1H0 (R)-l I07362.doc 1378146 is a possible intermediate in the synthesis of prostaglandins 'in which unsubstituted linear saturated homes (L〇) ja, D. et al., Zh. 〇rg Khim 1985, 21 ( 4) 782). As in the following flow chart! As described in the article, Β^Μί, pg et al. used the 'nitroform hair addition method to convert the formula (RH cyclopentene oxime to the formula II C〇rey aldehyde), where Ri is A The kelic acid is a high-level key intermediate for the synthesis of adenine (Beraldi, p G et al. 1987, Tetrahedron, 43, 4669).

HO IIHO II

Beraldi，P. G.等人採用一種如下列流程圖2中展示之製備 (R)-1之光學活性環戊烯酮化物的方法，其中R]為曱基其中藉由將消旋混合物與對掌性試劑（R)_2_胺氧基_4_甲基戍酸反應形成非對映體肟，且從管柱分離中離析並獲得式 (R)-l之理想形式。 107362.doc 1378146 流程圖2Beraldi, PG et al. employ a method of preparing an optically active cyclopentenone compound of (R)-1 as shown in Scheme 2 below, wherein R] is a sulfhydryl group by which the racemic mixture and the palmitic reagent are (R)_2-Aminooxy_4_methylnonanoic acid reacts to form diastereomeric oximes and is isolated from column separation to obtain the desired form of formula (R)-1. 107362.doc 1378146 Flowchart 2

1) 分離 2) TiCl3 v Ο <^J/^CO〇Me1) Separation 2) TiCl3 v Ο <^J/^CO〇Me

Ηό 不幸的是，Beraldi方法產生的非對映體肟中之兩種異構物具有彼此類似之結構及特性，且因此極難將它們使用管柱層析法彼此分離以獲得具有理想光學純度之所需產物。并所品呉構物形式之化合物將廢此外，所存在之約一半某。看來由於上述原因’ Beraldi方法不是很經濟作為替代方案，Veinberga，I.等人利用各種酶方法（包括酶水解（Latv. Kim. Z_ (1-2)，122, 1995 及 Latv. Kim. Z. (1-2),Ηό Unfortunately, the two isomers of the diastereomers produced by the Beraldi process have similar structures and properties to each other, and it is therefore extremely difficult to separate them from each other using column chromatography to obtain the desired optical purity. The desired product. And the compound in the form of the 呉 structure will be scrapped. In addition, about half of it exists. It seems that for the above reasons, the Beraldi method is not very economical as an alternative. Veinberga, I. et al. use various enzymatic methods (including enzymatic hydrolysis (Latv. Kim. Z_ (1-2), 122, 1995 and Latv. Kim. Z). (1-2),

1 16, 1995))及兩步驟之酶反應（Latv Kim z (1), ι〇3, ι992) 以後付式（R)-1之光學活性環戊烯酮化物，其中Ri僅為甲基。不幸的是，Veinberga，〗·等人所使用之這些酶反應或生物催化劑對党質未表現出可能之光學選擇性。因此，具有高於跳e.e.(對映體過量）光學純度之光學活性環戊稀嗣化物的製備是難以達到的。已採用共輛加成方法以建立***素環戍1 16, 1995)) and the two-step enzyme reaction (Latv Kim z (1), ι〇3, ι992) followed by the optically active cyclopentenone of formula (R)-1, wherein Ri is only methyl. Unfortunately, these enzymatic reactions or biocatalysts used by Veinberga, et al. do not exhibit possible optical selectivity for the party. Therefore, the preparation of optically active cyclopentenes having an optical purity higher than that of e.e. (enantiomeric excess) is difficult to achieve. A co-additive method has been used to establish prostaglandin

之立體化學。力分圭广上I 于在共軛加成之過程中，如流程圖3之描诚，形成兩個新的對掌性中心。圓之描述 107362.doc 1378146 流程圖3Stereochemistry. In the process of conjugate addition, such as the description of Flowchart 3, two new pairs of palm centers are formed. Description of the circle 107362.doc 1378146 Flowchart 3

PO POPO PO

儘管由於動力學平衡，反應有利於在環戊烷環上以反式方向分別形成三個取代基，但不可避免地會形成具有順式方向之立體異構物。最主要的問題集中於怎樣移除殘留在共軛產物中之立體異構物或怎樣減少共軛加成過程中產生之立體異構物。為便於這些立體異構物之移除，預期h應使得化合物之結晶度更高，以便能夠更容易地藉由結晶: 從共軛產物中分離順式異構物。或者，建議採用具有：大取代基之環戊烯酮化物^)·〗以進行反應，因為更大之將使順式異構物的產生最小化。不幸的《，關於環戊婦嗣化物(R)-1之習知技術已限制1為未經取代之直鏈飽和烷基，其或非大體積或具有低的結晶度。關於〜為大烧基、芳基或芳烧基之研究’以前從未進行過。【發明内容】本發明提供製備光學活性環戊稀_化物（叫之新賴方法，該等方法沒有習知方法遇到之缺點。更重要地，本文揭示之方法更易操作、經濟且對工業生產目的有用。此外，本發明還藉由引入新賴之Ri基團(其更大或能產生更高結晶度之光學活性環戊稀酮化物（叫）提供在醋官能基上更廣範圍的選擇。 f實施方式】 I07362.doc 1378146 ι.定義本文所使用之術語"烷基"是指含有1到30個碳原子之直鏈或支鏈fe基，諸如甲基、乙基、異丙基、第三丁基及其類似物；或具有3到1 〇個碳原子之環狀飽和烴基，諸如環丙基、環戊基、環己基、薄荷基及其類似物。本文所使用之術語"低碳烷基”是指含有1到6個碳原子之烷基，諸如甲基、乙基、丙基及其類似物。本文所使用之術語”烯基，，是指含有3到20個碳原子及一或多個碳碳雙鍵之直鏈或支鏈烴基，諸如戊烯基、丙稀基及其類似物’或具有5到2 0個碳原子及一或多個碳碳雙鍵之環狀不飽和烴基’諸如環戊烯基、環己烯基及其類似物。本文所使用之”炔基"是指含有3到20個碳原子及一或多個碳碳三鍵之直鏈或支鏈烴基，諸如戊炔基、丙炔基及其類似物；或具有6到20個碳原子及一或多個碳碳三鍵之環狀不飽和煙基。本文所使用之術語"芳基"是指單環或多環芳族煙基，諸如苯基 '萘基.、蒽基、菲基及其類似物。芳基可視情況被一或多個取代基取代，取代基包括（但不限於）_素、烷氧基、硫烷氧基、烷基及芳基。本文所使用之術§吾”务烧基"是指含有1到2 〇個碳原子及一或多個如上文所描述之芳基之直鏈或支鏈烴基，諸如苯甲基、二苯曱基、芴基曱基及其類似物。每一上文提及之烷基、烯基、炔基、芳基及芳烷基可視情況被一或多個選自由鹵素、烷基、芳基、烷氧基、芳氧 I07362.doc 1378146 基、硫烷氧基、硫芳氧基、烷胺基、芳胺基、氰基、烷氧羰基、芳基羰基、芳胺基羰基、烷胺基羰基及羰基組成之群的取代基或選自由吡啶基、噻吩基、呋喃基、咪唑基、嗎啉基、啰唑啉基、哌啶基、哌嗪基、四氫哌喃基、吡咯啶基、。比咯啶酮基及其類似物組成之群的雜環基取代。術語”保護基團”具有在有機合成化學中定義之習知涵 -義，即能夠保護化合物之官能基或部分免受一化學反應攻 φ 擊之基團。保護基團之實例包括（但不限於）甲氧基甲基、甲氧基硫甲基、2·甲氧基乙氧基甲基、雙（2_氣乙氧基）甲基、四氫哌喃基、四氫噻喃基、4_甲氧基四氫哌喃基、4_甲氧基四氫噻喃基、四氫呋喃基、四氫噻吩基、2 _乙氧基乙基、 • 卜甲基〒氧基乙基、三苯基甲基、烯丙基、苯曱基、經 • 取代之苯甲基及SiRaRbRc，其中Ra、Rb及Rc每-者分別為 C,.4烷基 '苯基、苯f基、經取代之苯基或經取代之苯甲基。在整個本說明書給出之化合物描述中，—加粗的錐料 •()指示一在β-方向（在分子或頁之平面的上方）上之取代Although the reaction favors the formation of three substituents in the trans direction on the cyclopentane ring due to the kinetic equilibrium, a stereoisomer having a cis direction is inevitably formed. The main problem is focused on how to remove the stereoisomers remaining in the conjugated product or how to reduce the stereoisomers produced during the conjugate addition. To facilitate the removal of these stereoisomers, it is expected that h should be such that the crystallinity of the compound is higher so that it can be more easily crystallized: the cis isomer is separated from the conjugated product. Alternatively, it is recommended to use a cyclopentenone compound having a large substituent to carry out the reaction because the larger one will minimize the production of the cis isomer. Unfortunately, the conventional technique for cyclopentanthene (R)-1 has restricted 1 to an unsubstituted linear saturated alkyl group which is either non-bulk or has low crystallinity. Studies on ~ is a large alkyl, aryl or aryl group have never been done before. SUMMARY OF THE INVENTION The present invention provides the preparation of optically active cyclopentenes (known as new methods) which do not have the disadvantages encountered by conventional methods. More importantly, the methods disclosed herein are easier to operate, economical, and industrially produced. The purpose is also useful. In addition, the present invention provides a wider range of choices on vinegar functional groups by introducing a new Ri group (which is more or more optically active cyclopentenone). f Embodiments I07362.doc 1378146 ι. Definitions The term "alkyl" as used herein refers to a straight or branched fe group containing from 1 to 30 carbon atoms, such as methyl, ethyl, isopropyl. a base, a third butyl group, and the like; or a cyclic saturated hydrocarbon group having 3 to 1 carbon atoms, such as a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a menthyl group, and the like. "Lower alkyl" means an alkyl group containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl and the like. The term "alkenyl" as used herein, means 3 to 20 a straight chain or branch of one carbon atom and one or more carbon-carbon double bonds a hydrocarbon group such as a pentenyl group, an acryl group and the like 'or a cyclic unsaturated hydrocarbon group having 5 to 20 carbon atoms and one or more carbon-carbon double bonds' such as a cyclopentenyl group or a cyclohexenyl group. And its analogs. As used herein, "alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 3 to 20 carbon atoms and one or more carbon-carbon triple bonds, such as pentynyl, propynyl and An analog; or a cyclic unsaturated smoky group having 6 to 20 carbon atoms and one or more carbon-carbon triple bonds. The term "aryl" as used herein refers to a monocyclic or polycyclic aromatic smoki group. , such as phenyl 'naphthyl., fluorenyl, phenanthryl and the like. The aryl group may be optionally substituted by one or more substituents including, but not limited to, _, alkoxy, thioalkoxy Base, alkyl and aryl. As used herein, a singular or branched hydrocarbon group containing from 1 to 2 carbon atoms and one or more aryl groups as described above. , such as benzyl, diphenyl fluorenyl, fluorenyl fluorenyl and the like. Each of the above-mentioned alkyl, alkenyl, alkynyl, aryl and aralkyl groups can be visualized. One or more selected from the group consisting of halogen, alkyl, aryl, alkoxy, aryloxy I07362.doc 1378146, thioalkoxy, thioaryloxy, alkylamino, arylamino, cyano, alkane a substituent of the group consisting of an oxycarbonyl group, an arylcarbonyl group, an arylaminocarbonyl group, an alkylaminocarbonyl group, and a carbonyl group, or a pyridyl group, a thienyl group, a furyl group, an imidazolyl group, a morpholinyl group, an oxazoline group, a piperidine a heterocyclic group substituted with a group consisting of a piperazine group, a tetrahydropyranyl group, a pyrrolidinyl group, a pyrrolidinyl group, and the like. The term "protecting group" has a conventional meaning defined in organic synthetic chemistry. - a meaning that is capable of protecting a functional group or a moiety of a compound from a chemical reaction. Examples of protecting groups include, but are not limited to, methoxymethyl, methoxythiomethyl, 2· Methoxyethoxymethyl, bis(2-methoxyethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetra Hydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2-ethoxyethyl, • methyl methoxyethyl, triphenylmethyl, allyl , phenyl fluorenyl, trans-substituted benzyl and SiRaRbRc, wherein Ra, Rb and Rc are each C, .4 alkyl 'phenyl, benzene f, substituted phenyl or substituted benzene methyl. Throughout the description of the compounds given in this specification, the thickened cones () indicate a substitution in the β-direction (above the plane or the plane of the page).

基，一間斷的火炬形線（..""丨丨士如 .,^ L )才日不一在α-方向（在分子或頁之平面的下方）上之取代基。 II.本發明之第一態樣 ΙΙ-1.製備式1之消旋環戊烯酮化物的方法如流程圖辑示’式1之環戊稀酮化物由2-糠路製備，其中R,為烷基、烯基、炔基、芳基或芳烷基，其每一者未被取代或由-或多個選自由齒素、烧基、芳基、烧氧基、芳氧基、硫烧氧基、硫芳氧基、㈣基、芳胺基n & l07362.doc ., 11 - 〆川 8146 氣羰基、芳基羰基、芳基胺基羰基、烷胺基羰基及羰基組成之群的取代基或選自由°比咬基、嗟吩基、咬喃基、σ米。坐基、嗎啉基、哼唑啉基、哌啶基、哌嗪基、四氫哌喃基、比咯啶基及吡咯啶酮基組成之群的雜環基或羧基之保護基團取代。Base, a broken torch-shaped line (.."" gentleman such as ., ^ L) is not a substitute in the α-direction (below the plane of the molecule or page). II. The first aspect of the invention ΙΙ-1. The method for preparing the racemic cyclopentenone of Formula 1 is as shown in the flow chart. The cyclopentanone of Formula 1 is prepared by 2-lane, wherein R, An alkyl group, an alkenyl group, an alkynyl group, an aryl group or an arylalkyl group, each of which is unsubstituted or selected from - or a plurality selected from the group consisting of dentate, alkyl, aryl, alkoxy, aryloxy, sulfur Alkoxy group, thioaryloxy group, (tetra)yl group, arylamine group n & l07362.doc., 11 - 〆川8146 Group of gas carbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl and carbonyl The substituent is alternatively selected from the group consisting of a thiol group, a porphinyl group, a thiol group, and a σ meter. Substituted by a protecting group of a heterocyclic group or a carboxyl group of a group consisting of a pendant group, a morpholinyl group, an oxazoline group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a pyrrolidinyl group and a pyrrolidinone group.

流程圖A ΟΗ Ο 众丄 XOOR,Flowchart A ΟΗ 丄 Public 丄 XOOR,

η 2 步驟(b)η 2 step (b)

COOR, OHCOOR, OH

AcOR, 步驟(a)AcOR, step (a)

COOR, ^!rCH0 ΟCOOR, ^!rCH0 Ο

HO 在流程圖A之步驟（a)中，2_糠酸與式Ac〇R】之化合物反應以獲得式2之呋喃甲醇，其中心如上文之定義。HO In step (a) of Scheme A, 2_decanoic acid is reacted with a compound of the formula Ac〇R] to obtain furanmethanol of the formula 2, the center of which is as defined above.

在步驟（b)中，式2之呋喃甲醇經轉化（或重排）以獲得式3 及1之環戊烯酮化物的混合物。在步驟(c)中，該混合物進一步經歷-異構化反應以將式3之環戊_化物轉化成式k 環戊烯酮化物。在流程圖A中，步驟（a)為與式化合物之間链醇縮合反應，其中R,如上文之^義，該反應可在一較為二異丙醯胺鋰（LDA)之鹼的在力幻仔在下進行。步驟（b)為一化（即重排）反應，其可在一含1〇〇0/ p ^ 3 iUO/o水之水性介質或水與量有機溶劑之混合液中進行。用一用有機或無機酸性或驗物質將pH值維持在約2.5到約6 5夕铲m丄 , • 3之靶圍中，較佳用磷酸 -12. I07362.docIn step (b), the furan methanol of formula 2 is converted (or rearranged) to obtain a mixture of the cyclopentenone compounds of formulas 3 and 1. In step (c), the mixture is further subjected to an isomerization reaction to convert the cyclopentate of formula 3 to the formula k cyclopentenone. In Scheme A, step (a) is an alcohol condensation reaction with a compound of the formula wherein R, as defined above, is reactive with a base of lithium diisopropylamide (LDA). The phantom is going on. The step (b) is a one-step (i.e., rearrangement) reaction which can be carried out in an aqueous medium containing 1 〇〇 0 / p ^ 3 iUO / water or a mixture of water and an organic solvent. Using a organic or inorganic acid or test substance to maintain the pH at about 2.5 to about 65 shovel m 丄, in the target range of 3, preferably phosphoric acid -12. I07362.doc

鉀S文緩衝洛液。進行重排反應之溫度較佳在約6〇。〇到勺200 C之範圍中，更佳在約8〇。〇到約丨4〇它之範圍中。在一個較佳實施例中’由重排反應產生之式…之環戊烯酮化物的現合物無需進-步純切可直接進行步驟⑷。步驟⑷ 為異構化反應、，其可在水合氣路及三乙胺之存在下進仃藉由異構化反應，式3之環戊烯酮化物被異構化為式i 之環戊稀嗣化物。所得粗製式1之環戊稀酮化物是消旋的。班式i之環戊稀酮化物（其中Rl如上文之定義）也可由心，之 f戊烯酮化物（r2為低碳貌基）藉由酿交換反應製備。根據本發明，式；!，之環戊稀酮化物到式i之環戍稀酉同化物的酯交換反應在流程圖B中展示。Potassium S text buffer Loose solution. The temperature at which the rearrangement reaction is carried out is preferably about 6 Torr. It is better to be in the range of 200 C, preferably about 8 inches. It is about 4 〇 in its range. In a preferred embodiment, the present invention of the cyclopentenone compound of the formula (produced by the rearrangement reaction) can be directly subjected to the step (4) without further cutting. Step (4) is an isomerization reaction which can be carried out in the presence of a hydrated gas path and triethylamine by isomerization reaction, and the cyclopentenone compound of the formula 3 is isomerized to the cyclopentanthene of the formula i Compound. The resulting cyclopentanone of the crude formula 1 is racemic. The cyclopentenone compound of formula i (wherein R1 is as defined above) can also be prepared from the heart by the f-pentenone (r2 is a low carbon base) by a brewing exchange reaction. According to the present invention, the transesterification of a cyclopentenone to a hydrazine oxime of the formula i is shown in Scheme B.

流程圖BFlowchart B

步驟(f)Step (f)

PO 4 、⑽r2,⑷）V-COOR2步驟⑻》r、c〇〇hPO 4 , (10) r2, (4)) V-COOR2 step (8) "r, c〇〇h

RjOHRjOH

COOR,步驟(g)COOR, step (g)

COOR, '仙·程圖B之步驟（d)中夕&庙之反應為一保護反應。較佳之保蠖基團為鹼穩定的，其包括 ° 基甲臭、2… 不限於)甲氧基甲基、甲氧基硫丞〒暴 2 -曱氧基乙氢其田盆 ^ . '"甲基、又（2-氯乙氧基）曱基、四氫哌喃基、四氫噻喃基、4 虱唭喃美 ”土 f氧基四氧哌喃基、4-甲氧基四氫 :南基，咬喃基、四氫售吩基、u乙氧基乙基 ―1-曱氡基乙基、三苯甲其、、路二甲基甲基及SiRRR ▲ 基、苯曱基、經取代之笨 …、、中、、、及、每-者分別為燒基、 107362.doc 1378146 苯基、笨甲基、經取代之苯基或經取代之苯曱基。進行保護之反應條件在此項技術中是為人們所熟知的。合適之保護基團之實例於 T_ W. Greene 在，，Protective Groups in Organic Synthesis”（J〇hn Wiley & Sons公司，1981年）中有所描述。例如，將式1，之環戊烯酮化物溶解在二氯甲烷中並向其中加入催化量之對甲苯磺酸。使反應混合物經冰浴，並 : 加入合適量之3,4-二氫-2H-哌喃，接著在室溫下攪拌約1〇 φ 分鐘到約10小時以獲得式4之受保護之環戊烯酮化物。流程圖B之步驟（e)中之反應為在酶存在下進行的水解反應，該酶較佳為在一水相（水或緩衝液）及/或一有機溶劑中之一假絲酵母南極脂肪酶。流程圖B的步驟（f)中之反廡為一 • 用式R|〇h醇對經水解之環戊烯酮化物之羧基的酯化反 _ 應，该反應在用於活化羧基或醇部分之縮合試劑及鹼的存在下進行。縮合試劑之實例包括（但不限於）1，3-二環己基碳一亞胺、氣化物、碘化2-氣-1-曱基-吼啶鏽、氣化2_氯_4,5_ 藝二氫-1，3-二子基_m-咪唑鏽、氣化N，N_二苯基氣苯基曱基 • 亞銨及其類似物，且鹼之實例包括於一合適溶劑中之吡 • 啶、二乙胺 '二異丙基乙胺、N，N-二曱胺基吡啶及其類似物，合適溶劑包括二氯甲烷、四氫呋喃及丨，2•二氣乙烷以及其混合物。流程圖B之步驟（g)中之反應為—去保護反應，其可以一習知方式進行。例如，將式6之環戊烯酮化物（其中&為2_ 奈基，且P為四氫哌喃基保護基團）溶解在一諸如甲醇之合適溶劑中，用一諸如氯化氫、對甲苯磺酸或對甲苯磺酸。比 I07362.docCOOR, 'Shen Cheng Cheng B's step (d) Mid-Autumn & Temple reaction is a protective reaction. Preferably, the oxime group is alkali-stable, and includes a base odor, 2... not limited to) methoxymethyl, methoxy sulfoxime 2 - methoxy ethoxyhydrogen hydride pot ^ . '" Methyl, (2-chloroethoxy)indenyl, tetrahydropentanyl, tetrahydrothiopyranyl, 4 oxime, "foxytetraoxypyrano, 4-methoxytetrahydro : Nanji, thiol, tetrahydro phenyl, u ethoxyethyl 1-nonylethyl, trityl, dimethylmethyl and SiRRR ▲, phenyl fluorenyl, Substituted stupid...,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, It is well known in the art. Examples of suitable protecting groups are described in T_W. Greene,, Protective Groups in Organic Synthesis" (J〇hn Wiley & Sons, Inc., 1981). . For example, the cyclopentenone of Formula 1, is dissolved in dichloromethane and a catalytic amount of p-toluenesulfonic acid is added thereto. The reaction mixture is subjected to an ice bath, and: a suitable amount of 3,4-dihydro-2H-pyran is added, followed by stirring at room temperature for about 1 〇 φ minutes to about 10 hours to obtain a protected cyclopentane of formula 4. Ketone. The reaction in the step (e) of the scheme B is a hydrolysis reaction carried out in the presence of an enzyme, preferably an Candida antarctic fat in one aqueous phase (water or buffer) and/or an organic solvent. Enzyme. The reaction in step (f) of Scheme B is: • The esterification of the carboxyl group of the hydrolyzed cyclopentenone by the R|〇h alcohol, which is used to activate the carboxyl or alcohol moiety. The condensation reaction is carried out in the presence of a base. Examples of condensation reagents include, but are not limited to, 1,3-dicyclohexylcarbodiimide, vapor, 2-oxa-1-indenyl-acridine rust, gasification 2_chloro-4,5_ Dihydro-1,3-diyl-m-imidazole rust, gasified N,N-diphenyl phenylphenylmercapto-immonium and its analogs, and examples of the base include pyridyl in a suitable solvent. Suitable solvents include pyridine, diethylamine 'diisopropylethylamine, N,N-diguanidinyl pyridine and the like. Suitable solvents include dichloromethane, tetrahydrofuran and hydrazine, 2 • di- ethane and mixtures thereof. The reaction in step (g) of Scheme B is a deprotection reaction which can be carried out in a conventional manner. For example, a cyclopentenone of formula 6 (wherein & is 2-nine and P is a tetrahydropyranyl protecting group) is dissolved in a suitable solvent such as methanol, using a reagent such as hydrogen chloride or p-toluene Acid or p-toluenesulfonic acid. Than I07362.doc

1378146 。定钂之合適去保護劑處理’在室溫下攪拌ίο分鐘到ίο小時以獲得式1之去保護產物。 Π_2·消旋醇（R)-l之對映選擇性（R)-酯化作用如在流程圖C中所示，式1之消旋環戊稀酮化物與式A之醯基供體 0 R41378146. It is suitable to remove the protective agent treatment. Stir at room temperature for ίο minutes to ίο hours to obtain the deprotected product of Formula 1. Enantioselective (R)-esterification of Π_2· racemic alcohol (R)-1 as shown in Scheme C, racemic cyclopentanone of formula 1 and thiol donor of formula A R4

AA

在一對映選擇性脂肪酶之存在下反應，其中R3&R4分別為一低奴烷基’其中醯基供體較佳與（R)-型之環戊烯酮化物反應，從而產生由式（R)-7之光學活性酯及式（S)·；!之未反應醇組成的混合物（流程圖C)。Reacting in the presence of a pair of selective lipases wherein R3 & R4 are each a non-n-alkyl group, wherein the thiol donor is preferably reacted with the (R)-type cyclopentenone, thereby producing A mixture of an optically active ester of (R)-7 and an unreacted alcohol of formula (S)·! (Scheme C).

流程圖CFlow chart C

1 ⑻-1 R3A) (R)-7 根據本發明，所得式（汉)_7之酯擁有至少為85% e e之光學活性，較佳地至少為9〇% e e，最佳至少為95% e e且高達99% e.e.。此外，根據本發明之較佳實施例，在式1中， I為eve"炫基、苯曱基、萘基或苯基，其每一者為未被取代或被取代的，且更佳地，係選自甲基、乙基、苯甲基、萘基或三氯乙基。在一個實施例中，本發明中使用之對映選擇性脂肪酶衍生自豬肝臟、豬胰臟或微生物，例如無色桿菌屬 (AChr〇mobacter spp·)、產驗桿菌屬⑷⑶丨^⑽spp )、黑麯 107362.doc 1378146 徽（Aspergillus niger)、南極假絲酵母（Candida antarcitica)、皺褶假絲酵母（Candida rugosa)、解脂假絲酵母（Candida lypolytica) “viscosum色桿菌（Chromobacterium viscosum)、 Mucor janvanicus、米黑毛黴（Mucor miehei)、卡門培爾乾路青黴（Penicillum Camenberti),、Penicillium roqueforteii、1 (8)-1 R3A) (R)-7 According to the invention, the resulting ester of the formula (H)-7 has an optical activity of at least 85% ee, preferably at least 9% ee, optimally at least 95% ee And up to 99% ee. Further, in accordance with a preferred embodiment of the present invention, in Formula 1, I is eve" leucoyl, benzoinyl, naphthyl or phenyl, each of which is unsubstituted or substituted, and more preferably , selected from methyl, ethyl, benzyl, naphthyl or trichloroethyl. In one embodiment, the enantioselective lipase used in the present invention is derived from pig liver, porcine pancreas or microorganism, such as Agrobacterium spp., A. genus (4) (3) 丨^(10)spp),黑曲107362.doc 1378146 emblem (Aspergillus niger), Candida antarcitica, Candida rugosa, Candida lypolytica "Chromobacterium viscosum", Mucor Janvanicus, Mucor miehei, Penicillum Camenberti, Penicillium roqueforteii,

洋蔥假單胞菌（Pseudomonas cepacia)、螢光假單胞菌 (Pseudomonas flU0rescence)、假單胞菌屬、stutzud假單胞菌（Pseudomonas stutzuri)、Rhiz〇pus Delmar、黴白根黴 (Rh1Z〇pus Niveus).、RhiZOpus oryze及根黴屬（Rhiz〇pus SPP·)。更佳地，立體選擇性脂肪酶衍生自南極假絲酵母、無色桿菌屬、產驗桿菌屬、螢光假單胞g、Stutzd假單胞菌或洋蔥假單胞菌。脂肪酶在本發明之方法中可以任何形式存在，包括純化形式或粗產物形式或與脂肪酶所衍生之微生物本身相關的自然形式’只要其光學選擇性在酿化作用中保#。脂肪酶之化學穩定性、活性或對映選擇性可藉由基因料、繼重組或固定進—步提高。在較佳實施例中，脂肪酶為名為二κ ’或”PS"之假單胞菌脂肪酶(其可從A_〇製藥公司購生：無色桿菌屬之脂肪酶、或衍生自產驗桿菌屬，之：肪…從NovoN。，得之名為 Nov〇zyme”的脂肪酶。Pseudomonas cepacia, Pseudomonas flU0rescence, Pseudomonas, Pseudomonas stutzuri, Rhiz〇pus Delmar, Rhizopus oryzae (Rh1Z〇pus Niveus) ), RhiZOpus oryze and Rhizopus SPP. More preferably, the stereoselective lipase is derived from Candida antarctica, Achromobacter, Aureus, Fluorescent pseudomonas g, Stutzd Pseudomonas or Pseudomonas cepacii. The lipase may be present in any form in the process of the invention, including the purified form or the crude form or the natural form associated with the microorganism from which the lipase is derived, as long as its optical selectivity is maintained during brewing. The chemical stability, activity or enantioselectivity of the lipase can be increased by genetic material, subsequent recombination or immobilization. In a preferred embodiment, the lipase is a Pseudomonas lipase named κ' or "PS" (which can be purchased from A_〇 Pharmaceutical Company: a lipase of the genus Achromobacter, or derived from a test Bacillus, which is: fat... from NovoN., named after the enzyme "Nov〇zyme".

對映選擇性酯化作用 nD 中進粁了在早-有機溶劑或混合有機溶劑甲進仃，溶劑選自己抆乙基綱、甲基里丁心苯、四氫咬喃、甲基 τ丞，、丁基g同、乙_、《石並亦丄，異丙基醚、甲基異丙基醚 107362.doc 丁基尹基醚以及其混合物。所使用之脂肪酶的量隨 '如脂肪酶之活性、受質之量或所使用之溶劑的許多因素在本發明之一個實施例中，脂肪酶之量，係每質量 “之式1環戊烯酮化物使用〇.〇1質量當量到1〇質量當量之範圍。應將反應混合物不斷授拌、搖動或超聲波振盪以確保反應物與脂肪酶之間良好的接觸。另外，適於反應之溫度在入〇 C之間’ & ^圭為環境溫度。此外’當獲得起始物質。適轉化時’藉由將脂肪酶從反應混合物中移除，可終止對映異構選擇性酿化作用。在一個實施例中，當轉化率達到观雜/Q之間，較佳在約5G%時，移除脂肪酶以終止酶促0曰化作用。在一個實施例中’本發明使用之醯基供體包含乙酸乙缔酿、乙酸異丙烯雖、戊酸乙烯酿、戊酸異丙烯S曰、丁酸乙烯酯 '或丁酸異丙烯酯或其混合物。 Π-3·未經處理之（s)_醇之移除 ❿ 未經處理之⑻·醇之移除包含直接將來自步驟⑻的反應混合物中式（R)_7之酿與未反應之醇⑻q分離。由於式⑻ 之酿的結構及特性與式⑻]之醇的結構及特性明顯不同，因而式（Rpm可藉由諸如㈣急驟層析法的習知方法從混合物中容易地分離出來：Enantioselective esterification nD is introduced into an early-organic solvent or a mixed organic solvent, and the solvent is selected from the group consisting of ethyl sulfonate, methyl butyl benzene, tetrahydroethylene, and methyl τ. , butyl g, B, "stone and oxime, isopropyl ether, methyl isopropyl ether 107362.doc butyl ylide and mixtures thereof. The amount of lipase used depends on, for example, the activity of the lipase, the amount of the substrate, or the solvent used. In one embodiment of the present invention, the amount of lipase is per gram of The ketene is used in the range of from 1 mass equivalent to 1 〇 mass equivalent. The reaction mixture should be continuously stirred, shaken or ultrasonically shaken to ensure good contact between the reactant and the lipase. In addition, the temperature suitable for the reaction. Between the 〇C and the 'environmental temperature'. In addition, 'when the starting material is obtained. Suitable for transformation', the enantioselective brewing can be terminated by removing the lipase from the reaction mixture. In one embodiment, the lipase is removed to terminate the enzymatic deuteration when the conversion is between spectroscopy/Q, preferably at about 5 G%. In one embodiment, 'the invention is used 醯The base donor comprises acetic acid, isopropene acetate, vinyl valerate, isopropene valerate, vinyl butyrate or isopropenyl butyrate or mixtures thereof. Π-3·untreated ( s) _ alcohol removal ❿ untreated (8) · alcohol removal The separation of the unreacted alcohol (8) q from the reaction mixture from the step (8) is directly separated from the unreacted alcohol (8) q. Since the structure and characteristics of the formula (8) are significantly different from those of the alcohol of the formula (8), the formula (Rpm) It can be easily separated from the mixture by a conventional method such as (iv) flash chromatography:

〇〇

COOR, 】^Y^COOR 丨 ° 驟(μ) 〈丨| 分離 R人(R)-7 I07362.doc 丄丄4() 或者’根據本發明之-個實施例，藉由一合適溶劑中之偶氮-日及二芳基膦存在下，以式R5C〇〇h之酸氧基供體將QH基團轉化—氧基，而將未反應之醇⑻」轉化為式（R)_7或式（R)·?之s旨，其中^之^義係如〜或^之定義。較佳地，偶氮二m酸二烧g|為偶氮二㈣二乙醋、偶氮二羧酸二異丙酯或偶氮二羧酸二苯甲酯，及/或三芳基膦為二苯基膦’及/或溶劑為曱苯，及/或酿氧基供體為叛酸及COOR, 】^Y^COOR 丨° ((μ) 〈丨| Isolation R human (R)-7 I07362.doc 丄丄4() or 'in accordance with an embodiment of the invention, by a suitable solvent In the presence of azo-day and diarylphosphine, the QH group is converted to an oxy group by an acid oxy donor of the formula R5C〇〇h, and the unreacted alcohol (8)" is converted to the formula (R)_7 or (R)·?? s, where ^^^ is defined as ~ or ^. Preferably, the azobismuth acid dicalcined g| is azobis(tetra)diethyl acrylate, diisopropyl azodicarboxylate or diphenylmethyl azodicarboxylate, and/or triarylphosphine is two Phenylphosphine' and/or solvent is toluene, and/or the oxy-donor is tareized and

/或R5為低碳烷基或R3。在步驟（1_2)中，混合物中幾乎1〇〇% 之式（S)-l之醇轉化成為式（R)_7,之酯。/ or R5 is lower alkyl or R3. In the step (1-2), almost 1% of the alcohol of the formula (S)-1 in the mixture is converted into an ester of the formula (R)-7.

或/及 Ο ^J^COOR, R3 人 0 (R)-7 為獲得本發明之式（R)-1之光學活性環戊烯酮化物，不必從在步驟（h)所獲得的混合物中離析式（R)-7之酯或移除式 (S)-1之醇。取而代之的’混合物可直接經歷步驟（1-2)之轉換反應以獲得式（R)_7及（R)·7'之酯混合物。 II-4.式（R)-7及/或式（R)-7,之酯的去醯基化作用 I07362.doc • 18· 1^/8146 Ο ^J^COOR, (R)-l (R)-7 或/及 7’Or / and Ο ^J^COOR, R3 human 0 (R)-7 is to obtain the optically active cyclopentenone of the formula (R)-1 of the present invention, and does not have to be isolated from the mixture obtained in the step (h) An ester of formula (R)-7 or an alcohol of formula (S)-1. Instead, the mixture can be directly subjected to the conversion of step (1-2) to obtain an ester mixture of formula (R)-7 and (R)·7'. II-4. Demethylation of an ester of the formula (R)-7 and/or (R)-7, I07362.doc • 18· 1^/8146 Ο ^J^COOR, (R)-l ( R)-7 or / and 7'

據本發明，步驟（J)為_去醯基化反應。在本發明之— 個實知例中，去醯基化反應為在醇及酸催化劑（諸如磷酸、對甲本嶒酸、氫溴酸、鹽酸、硝酸或硫酸或其混合物）存在下之化學水解或醇解，用以裂解（R)-7及/或（R)_7,之酯以獲知式（R)-1之環戊烯酮化物。較佳地，酸為硫酸且醇為 Ri〇H，其中尺丨如上文之定義。According to the invention, step (J) is a de-thiolation reaction. In a preferred embodiment of the invention, the dethiolation reaction is a chemical hydrolysis in the presence of an alcohol and an acid catalyst such as phosphoric acid, p-capric acid, hydrobromic acid, hydrochloric acid, nitric acid or sulfuric acid or mixtures thereof. Or alcoholysis to cleave the ester of (R)-7 and/or (R)-7, to obtain the cyclopentenone of formula (R)-1. Preferably, the acid is sulfuric acid and the alcohol is Ri〇H, wherein the size is as defined above.

COOK〗步驟⑺ ΟCOOK step (7) Ο

在本發明之另一實施例中，步驟⑴中之去酿基化反應為一酶促裂解反應。酶促裂解反應或為水解或為醇解，且可在水、緩衝液、水飽和或緩衝液飽和之有機溶劑、烷基或芳基醇或含醇水性或非水㈣統，存在下進行4外了用於酶促去醯基化作用之反應系統，可為均質或含有水或緩衝液和不溶於水之溶劑的兩相系統。g旨應溶解或細微地分散於反應系統中’以提供與其中之脂肪酶的良好接觸。若必要’可向系統中’加人-例如鹽或界面活性劑之相轉移催化劑，w增加反應速率H容劑可與水不互溶，或鹿該用水或緩衝液或諸如醇之溶於水的有機溶劑飽和。：：之緩衝液包括(但不限於)由齒化物、碳酸鹽，酸鹽、硫酸鹽、硝酸鹽、碳酸氫鹽及/或醋酸鹽製備且較佳在5到8之Η 值範圍内的緩衝液。反應中使用之合適有機溶劑可為互溶之溶劑，其包括㈣限峨基醇、芳基醇、歸基醇' 丨07362.doc _19· 〇丄斗Ο 鱼甲亞砜、丙酮、二甲基甲醯胺、乙腈及其混合物，或為與水不互溶之溶劑，其包括（但不限於）己烷、曱苯、***、由醚異丙基醚、甲基第三丁基醚、四氫呋喃、甲基乙土酮甲基異丁基酮、二啰烷及其混合物。斤採用之酶為適於酯之水解或醇解之脂肪酶。較佳地，在步驟⑺中所用之脂肪酶射自南極假絲酵母、無色桿菌屬：產鹼桿菌屬、螢光假單胞菌、stutzri假單胞菌或洋葱饭單胞菌。更佳地，脂肪酶衍生自南極假絲酵母、假單胞菌屬或無色桿菌屬’且最佳地，衍生自南極假絲酵母。反應由HPLC使用一對掌性管柱監控，且較佳地當產物之光學純度降低到約95%e.e.時由移除脂肪酶終止反應。視情況，式W-7及/或⑻_7，之未反應的醋可在去醯基化作用之後移除。根據本發明，式⑻]之醇以至少95% e.e之光學活性產生，較佳為至少98% e e。 Η 5.式（R)_i之光學活性環戊烯酮化物之酯交換作用在本發明之一個實施例中，式（R)_】之環戊烯酮化物進行知父換反應，使得環戊烯酮化物中之由另一取代基置換。除起始物質為光學活性環戍烯酮化物而非消旋物；之外，根據本發明之式⑻]光學活性環戊烤酮化物的黯交換作用，係以與IM節（流程圖B)中所示之相同的方式進行。在酯交換反應尹，受質之光學純度保持不變。 III.本發明之第二態樣本發明進一步提供式！八之化合物 I07362.doc •20- !378146In another embodiment of the invention, the de-branching reaction in step (1) is an enzymatic cleavage reaction. The enzymatic cleavage reaction is either hydrolysis or alcoholysis, and can be carried out in the presence of water, buffer, water-saturated or buffer-saturated organic solvent, alkyl or aryl alcohol or alcohol-containing aqueous or non-aqueous (tetra). A reaction system for enzymatic demethylation can be used as a two-phase system that is homogeneous or contains water or a buffer and a water-insoluble solvent. g is intended to be dissolved or finely dispersed in the reaction system to provide good contact with the lipase therein. If necessary, 'additional to the system' - a phase transfer catalyst such as a salt or a surfactant, w increase the reaction rate H. The agent may be immiscible with water, or deer should be dissolved in water or a buffer or such as an alcohol. The organic solvent is saturated. :: Buffers include, but are not limited to, buffers prepared from dentates, carbonates, acid salts, sulfates, nitrates, bicarbonates, and/or acetates, preferably within a range of 5 to 8 liquid. Suitable organic solvents for use in the reaction may be mutually miscible solvents, including (iv) mercapto alcohols, aryl alcohols, decyl alcohols '丨07362.doc _19· 〇丄 Ο 甲甲、, acetone, dimethyl ketone Indoleamine, acetonitrile and mixtures thereof, or solvents which are immiscible with water, including but not limited to hexane, toluene, diethyl ether, ether isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, Benbendone methyl isobutyl ketone, dioxane and mixtures thereof. The enzyme used in the jin is a lipase suitable for hydrolysis or alcoholysis of the ester. Preferably, the lipase used in step (7) is injected from Candida antarctica, A. genus: Alcaligenes, Pseudomonas fluorescens, Pseudomonas stutzri or Oryza sativa. More preferably, the lipase is derived from Candida antarctica, Pseudomonas or Achromobacter' and is optimally derived from Candida antarctica. The reaction is monitored by HPLC using a pair of palmarity columns, and preferably the reaction is terminated by removal of lipase when the optical purity of the product is reduced to about 95% e.e. Depending on the case, unreacted vinegar of formula W-7 and/or (8)_7 may be removed after demethylation. According to the invention, the alcohol of formula (8)] is produced with an optical activity of at least 95% e.e, preferably at least 98% e e. Η 5. Transesterification of an optically active cyclopentenone compound of the formula (R)_i In one embodiment of the present invention, the cyclopentenone of the formula (R)_] is subjected to a reaction of a parent, such that a cyclopentane The ketene is replaced by another substituent. The oxime exchange of the optically active cyclopentanone according to the formula (8) of the present invention is in addition to the IM section (flowchart B), except that the starting material is an optically active cyclic ketene ketone compound rather than a racemate; The same is done in the same way as shown. In the transesterification reaction, the optical purity of the substrate remains unchanged. III. Second Aspect of the Invention The present invention further provides a formula! Eight compounds I07362.doc •20- !378146

其中1為}1或羥基之保護基團，且心為烷基、烯基、块基、务基或方烧基’其母一者未被取代或由一或多個選自由鹵素、烷基、芳基、烷氧基、芳氧基、硫烷氧基、硫芳氧基、烷胺基、芳胺基、氰基、烷氧羰基、芳基羰基、芳基胺基羰基、烷胺基羰基及羰基組成之群之取代基或選自由吡啶基、噻吩基、呋喃基、咪唑基、嗎啉基、嘮唑啉基、哌啶基、哌嗪基、四氫哌喃基、吡咯啶基及吡咯啶酮基組成之群的雜環基，或羧基之保護基團取代，限制條件為&不為直鏈、未經取代之烷基。根據一個實施例，式1A之化合物富含R組態，且具有至少為95%對映體過量之光學純度。特定而言，本發明提供式以之化合物’其中心為支鏈烷基、烯基或炔基，其每一者未被取代或由一或多個選自由 _素燒基、芳基、烧氧基、芳氧基、硫烧氧基、硫芳氧土烷胺基、芳胺基、氰基、烷氧羰基、芳基羰基、芳基胺基幾I、院Μ幾基及幾基組成之群的取代基或選自由比定基、嗟令基“夫喃基、味嗤基、嗎琳基”号。坐琳基、 :定基、哌嗪基、四氫哌喃基、吡咯啶基及吡咯啶酮基組之群的雜環基，缝基的保絲團取代，且較佳地^為 :院基，其未被取代或經一或多個選自由函素、烧基、芳土、说氧基、芳氧基、硫貌氧基、硫芳氧基、院胺基、芳 107362.docWherein 1 is a protecting group of 1 or a hydroxy group, and the core is an alkyl group, an alkenyl group, a aryl group, a aryl group or a aryl group, the parent thereof is unsubstituted or one or more selected from the group consisting of halogen and alkyl , aryl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, alkylamino, arylamino, cyano, alkoxycarbonyl, arylcarbonyl, arylaminocarbonyl, alkylamino The substituent of the group consisting of a carbonyl group and a carbonyl group is alternatively selected from pyridinyl, thienyl, furyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl And a heterocyclic group of a pyrrolidinyl group or a protecting group of a carboxyl group, and the restriction is & not a linear, unsubstituted alkyl group. According to one embodiment, the compound of Formula 1A is enriched in R configuration and has an optical purity of at least 95% enantiomeric excess. In particular, the present invention provides a compound of the formula wherein the center is a branched alkyl, alkenyl or alkynyl group, each of which is unsubstituted or consists of one or more selected from the group consisting of aryl, aryl and pyrene. Oxygen, aryloxy, sulfur alkoxy, thioaryloxyalkylamine, arylamine, cyano, alkoxycarbonyl, arylcarbonyl, arylamine, I, and several groups The substituent of the group may be selected from the group consisting of a specific group, a sulfonyl group, a "fumantyl group, a misoyl group, a morphine group". a heterocyclic group of a group of a group consisting of: a group, a piperazinyl group, a tetrahydropyranyl group, a pyrrolidinyl group and a pyrrolidinone group, a silk-retaining group of a slit group, and preferably a hospital base , which is unsubstituted or one or more selected from the group consisting of a functional element, an alkyl group, a aryl group, an oxy group, an aryloxy group, a thiol oxy group, a thioaryloxy group, a aryl group, an aromatic 107362.doc

-21 - 1378146 胺基、氰基、烷氧羰基'芳基羰基、芳基胺基羰基、烷胺基羰基及羰基組成之群的取代基取代，且較佳地芳烷基為笨甲基’其未被取代或經一或多個選自由鹵素、烷基、芳土院氧基、芳氧基、硫院氧基、硫芳氧基、烧胺基、芳胺基、氰基、烷氧羰基、芳基羰基、芳基胺基羰基、烷胺基羰基及羰基組成之群的取代基取代；或為芳基，其未被 : 取代或經一或多個選自由_素、烷基、烷氧基、硫烷氧基、 • 烷氧羰基、羰基及氰基組成之群的取代基取代；較佳地芳基選自由苯基、萘基、芘基及菲基組成之群，其每一者未被取代或經一或多個選自由鹵素、烷基、烷氧基硫烷氧基、烷氧羰基、羰基及氰基組成之群的取代基取代。 • 更特定而言，本發明提供式1A的化合物，其中1為萘基、 • 苯甲基、2·氰乙基、薄荷基、甲氧基苯甲基、胡椒基、苯基、烷氧羰基苯基、三氣乙基或二苯甲基。本發明將在下列實例中作進一步描述。然而這些實例將 • 不對本發明之範疇作任何限制。可由一般技術者容易地完 - 成之t改或變更都包含在本說明書之揭示内容及附隨的申請專利範圍中。實例實例1 2 -乙氧基羰基曱基-4-羥基_2_環戊烯q —酮〇-21 - 1378146 Substituted by a substituent of the group consisting of an amino group, a cyano group, an alkoxycarbonyl 'arylcarbonyl group, an arylaminocarbonyl group, an alkylaminocarbonyl group and a carbonyl group, and preferably the aralkyl group is a stupid methyl group' It is unsubstituted or one or more selected from the group consisting of halogen, alkyl, aryloxy, aryloxy, thioloxy, thioaryloxy, acrylamine, arylamine, cyano, alkoxy Substituted by a substituent of a group consisting of a carbonyl group, an arylcarbonyl group, an arylaminocarbonyl group, an alkylaminocarbonyl group, and a carbonyl group; or an aryl group which is not substituted: or one or more selected from the group consisting of _, alkyl, Substituted with a substituent of a group consisting of an alkoxy group, a thioalkoxy group, an alkoxycarbonyl group, a carbonyl group and a cyano group; preferably, the aryl group is selected from the group consisting of a phenyl group, a naphthyl group, an anthracenyl group and a phenanthryl group, each of which One is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxythioalkoxy, alkoxycarbonyl, carbonyl and cyano. More specifically, the present invention provides a compound of Formula 1A wherein 1 is naphthyl, • benzyl, 2·cyanoethyl, menthyl, methoxybenzyl, piperonyl, phenyl, alkoxycarbonyl Phenyl, tri-g-ethyl or diphenylmethyl. The invention will be further described in the following examples. However, these examples will not impose any limitation on the scope of the invention. It can be easily modified by a person skilled in the art or incorporated in the scope of the present disclosure and the accompanying claims. EXAMPLES Example 1 2-Ethoxycarbonylmercapto-4-hydroxy_2_cyclopentene q-one oxime

HO O7362.doc -22- 1378146 此實例根據流程圖B中展示之程序進行。步驟（a) ·’ 將-反應燒瓶(2升)在真空中火焰乾燥並於氮氣中架設。於反應燒瓶中加入400 ml之無水THF、59 68 g之二異丙胺及約352 π^Κ6 _正丁基經的己貌溶液，並在_坑到屹之範圍的溫度下授拌約一個小時。接著，使用乾冰/丙㈣HO O7362.doc -22- 1378146 This example was performed according to the procedure shown in Flowchart B. Step (a) -' The reaction flask (2 liters) was flame dried in vacuo and erected in nitrogen. Add 400 ml of anhydrous THF, 59 68 g of diisopropylamine and about 352 π^Κ6-n-butyl hexane to the reaction flask, and mix for about one hour at a temperature ranging from _ pit to 屹. . Next, use dry ice / C (four)

使反應溫度降低到約.贼。用滴液漏斗向反應混合物中加 ^^1〇〇 ml 2 〇混合物中加人51々之„，且—旦反應完成，就用氯化敍之飽和水溶液對反應混合物中止，並接㈣拌—小時一旦完成，相便會分離，用乙酸乙酉旨（2χ5〇〇叫萃取水相兩次。組合有機層並用鹽水（500 ml)洗務，經無水硫酸鎮乾燥’過遽、，並在真空（4(TC，2 _Hg)中濃縮。獲得暗淺黃色到褐色之油（約120 g)。步驟（b) : 將步驟um得之產物用於步驟（b)中而無需進—步純化。在裝有一攪拌器及一冷凝器之三頭燒瓶中，饋入來自步驟⑷之產物、水（4800 g)及磷酸氫二鉀（51 g)並授拌。使用磷酸將反應溶液之pH值調到約3。在⑽。c左右或高於 100C之溫度下一氮流中對反應混合物進行回流。當回流反應完成時，冷卻反應混合物並使用乙酸乙酿萃取直至I相中不含所需產⑯。從萃取產物中蒸發出乙酸乙§|以生成含有2-乙氧基数基曱基-4-羥基_2_環戊烯酮及2_乙氧基^ 基曱基-3-羥基-4-環戊烯-1-酮之混合物（總量約12〇 g)。 107362.doc •23 · 1378146 步驟（C): 向從步驟（b)獲得之反應混合物（約120 g)中，加入6 g三乙胺、0.6g單水合氯醛及25〇ml甲苯。室溫下將混合物攪拌1 到24個小時直至2_乙氧基羰基曱基_3_羥基_4_環戊烯·ι_酮元全轉化為2-乙氧基羰基曱基_4_羥基_2環戊烯_丨酮其中轉化由一薄層層析法（TLC)監控。將反應混合物進—步濃縮以獲得一暗褐色油狀產物，其隨後經受一急驟層析，其中官柱中充滿石夕膠，並用含有不同比率之己烷及乙酸乙酯之溶劑混合物溶離。最後，獲得純化形式之標題化合物2-乙Reduce the reaction temperature to about thieves. Add a solution of 51 々ml 2 〇 to the reaction mixture with a dropping funnel, and once the reaction is completed, stop the reaction mixture with a saturated aqueous solution of chlorinated chloride, and then mix with (4). Once the hour is completed, the phase will be separated, and the aqueous phase will be extracted twice with acetic acid. The organic layer is combined and washed with brine (500 ml), dried over anhydrous sulfuric acid, dried, and vacuumed ( Concentrate in 4 (TC, 2 _Hg) to obtain a dark-yellow-yellow oil (about 120 g). Step (b): The product from step um is used in step (b) without further purification. In a three-headed flask equipped with a stirrer and a condenser, the product from the step (4), water (4800 g) and dipotassium hydrogen phosphate (51 g) were fed and mixed. The pH of the reaction solution was adjusted to using phosphoric acid. About 3. The reaction mixture is refluxed in a nitrogen stream at a temperature of about (10) c or above 100 C. When the reflux reaction is completed, the reaction mixture is cooled and extracted with acetic acid until the desired phase is not contained in the I phase. Evaporating acetic acid from the extracted product to form 2-ethoxygen A mixture of a decyl fluorenyl-4-hydroxy-2-cyclohexenone and a 2-ethoxylated hydrazino-3-hydroxy-4-cyclopenten-1-one (a total amount of about 12 Å). 107362.doc •23 · 1378146 Step (C): To the reaction mixture obtained from step (b) (about 120 g), 6 g of triethylamine, 0.6 g of chloral monohydrate and 25 ml of toluene were added. The mixture is stirred for 1 to 24 hours until the 2-ethoxycarbonyl fluorenyl_3_hydroxy_4_cyclopentene·ι-ketone element is fully converted to 2-ethoxycarbonyl fluorenyl _4_hydroxy-2 Cyclopentene-fluorenone wherein the conversion is monitored by a thin layer chromatography (TLC). The reaction mixture is further concentrated to give a dark brown oily product which is subsequently subjected to flash chromatography. Ethylene gel, and is dissolved in a solvent mixture containing hexane and ethyl acetate in different ratios. Finally, the title compound 2-B in purified form is obtained.

氧基数基甲基·4_羥基-2-環戊烯-1-酮（約57 g)。^-NMR (CDCI3/TMS)： δ 7.44 (s,lH), 4.98 (m, 1H), 4.16 (q； 2H)5 3.25 (s52H), 3.11 (brj 1H), 2.83 (dd, 1H), 2.34 (dd, 1H),1.27 (t，3H)。實例2 2-甲氧基幾基甲基_4_羥基_2_環戊烯酮〇 ^jj^COOMeOxyl group methyl 4-hydroxy-2-cyclopenten-1-one (about 57 g). ^-NMR (CDCI3/TMS): δ 7.44 (s, lH), 4.98 (m, 1H), 4.16 (q; 2H)5 3.25 (s52H), 3.11 (brj 1H), 2.83 (dd, 1H), 2.34 (dd, 1H), 1.27 (t, 3H). Example 2 2-Methoxymethylmethyl_4_hydroxy_2_cyclopentenone 〇 ^jj^COOMe

HO 重複實例1之程序，除了使用乙酸曱酯（40 g)而非乙酸乙酉旨。獲得黑色油狀之標題化合物（24 g)。h-NMR (CDCI3/TMS): δ 7.45 (s,lH), 5.01 (m, 1H), 3.72 (s, 3H)S 3.28 (s,2H), 2.85 (dd，1H)，2.35 (dd，1H)，1.67 (brs, 1H)。實例3 2-苯甲氧基羰基甲基_4_羥基_2_環戊烯酮HO The procedure of Example 1 was repeated except that decyl acetate (40 g) was used instead of ethyl acetate. The title compound (24 g) was obtained as a white oil. h-NMR (CDCI3/TMS): δ 7.45 (s, lH), 5.01 (m, 1H), 3.72 (s, 3H)S 3.28 (s, 2H), 2.85 (dd, 1H), 2.35 (dd, 1H) ), 1.67 (brs, 1H). Example 3 2-Benzyloxycarbonylmethyl_4_hydroxy_2_cyclopentenone

I07362.doc -24- 1378146 οI07362.doc -24- 1378146 ο

COOBn 重複實例1之程成 Μ 序’除了使用乙酸苯曱酯（80.8 g)而北r 酸乙酯。獲得愛备4t 外^ …、色油狀之標題化合物（55 g)。ih_n (CDC13/TMS): δ 7 μ 7 〇 , ·!5~7.55 (m, 6Η), 5.17 (s5 2H), 5.〇ι，（如’ 實例4COOBn repeats the procedure of Example 1 except that phenyl decyl acetate (80.8 g) is used instead of ethyl urate. The title compound (55 g) was obtained as a color oil. Ih_n (CDC13/TMS): δ 7 μ 7 〇 , ·!5~7.55 (m, 6Η), 5.17 (s5 2H), 5.〇ι, (eg’ example 4

2_乙氧基羰基甲基·4_四氫哌喃氧基_2_環戊烯+酮〇 ^j^COOEt 將100 g 2-乙氧基羰基甲基_4_羥基_2_環戊烯_丨酮溶柃 1000阳1二氣甲烧中’加入55§3,4_二氫_2化〇底。南及2請甲苯磺酸單水合物，並隨後在室溫下攪拌約3個小時。一旦反應完成，就用400 ml飽和碳酸氫鈉水溶液洗滌反應混合物’經無水硫酸鎂乾燥，並濃縮以獲得2_乙氧基幾美四氫略喃氧基-2-環戊烯-1-酮（1 38 5 g)。lH_N]^ (CDCl3/TMS):5 7.40〜7.68(m，lH)，4.70〜5-02(m，2H)，4is (q，2H)，3.88 (m，1H)，3.54 (m，lH)，3.23 (q，2H), 2 (m，lH)，2.37 (m, 1H)，1.77 (m, 2H), ι·55 (m，4H)】25 (t 3H)。 5 實例5 2-經基叛基甲基-4-四氣略味氧基—2-環戊烯_1_嗣 I07362.doc •25· ^781462_ethoxycarbonylmethyl·4_tetrahydropiperidinyloxy-2-cyclopentene+ketone oxime^j^COOEt 100 g 2-ethoxycarbonylmethyl-4_hydroxy-2_cyclopentane The ene-ketone is dissolved in 1000 yang 1 and the second gas is burned in the '55 § 3, 4 _ dihydro 2 oxime bottom. South and 2 are benzsulfonate monohydrate and then stirred at room temperature for about 3 hours. Once the reaction is complete, the reaction mixture is washed with 400 ml of a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated to afford 2- ethoxy thiol. (1 38 5 g). lH_N]^ (CDCl3/TMS): 5 7.40~7.68(m,lH), 4.70~5-02(m,2H),4is (q,2H),3.88 (m,1H),3.54 (m,lH) , 3.23 (q, 2H), 2 (m, lH), 2.37 (m, 1H), 1.77 (m, 2H), ι·55 (m, 4H)] 25 (t 3H). 5 Example 5 2-Pylorylmethyl-4-tetrazole slightly oxy-2-cyclopentene_1_嗣 I07362.doc •25· ^78146

將50 g從實例4獲得之2·乙氧基羰基甲基_4_四氫哌喃氧基-2-環戊烯-1-酮及5 g南極假絲酵母脂肪酶懸浮在500 ml 鱗酸鹽緩衝液mM, pH 6.5-7.5)中並在室溫下攪拌。用IN 氣氧化鈉溶液維持溶液之pH值並最終一旦反應完成後就調 ί 8 · 0用3 0 0 m 1乙酸乙醋洗蘇反應混合物兩次β進一步使用飽和硫酸氫鈉溶液將水層之pH值調到3·0。再次用300 ml 乙酸乙醋洗滌水層兩次。組合有機層並經無水硫酸鎂乾燥’過濾’並濃縮以獲得2-羥基羰基甲基_4-四氫哌喃氧基 •2-% 戊烯-i_酮（31 5 g，產率 75%)。1h_NMr (ce>ci3/TmS): 6 7·45~7·61 (m, 1H), 4.73-5.02 (m, 2H), 3.88 (m, 1H), 3.55 (m，lH)，3.31 (m，2H)，2.82 (m，lH)，2.38 (m，1H)，1.42〜1.88 (m, 6H)。實例6 (I’l’l-二氯乙氧基羰基甲基）_4_羥基_2_環戊烯·酮 Ο ^J^COOChiCC\350 g of 2·ethoxycarbonylmethyl-4·tetrahydropiperanyloxy-2-cyclopenten-1-one obtained from Example 4 and 5 g of Candida antarctica lipase were suspended in 500 ml of squaric acid Salt buffer mM, pH 6.5-7.5) and stirred at room temperature. Maintain the pH of the solution with IN gas sodium oxide solution and finally adjust the pH of the solution after the reaction is completed. The reaction mixture is washed twice with 300 ml of acetic acid in ethyl acetate. Further, the aqueous layer is further treated with saturated sodium hydrogen sulfate solution. The pH is adjusted to 3.0. The aqueous layer was washed twice more with 300 ml of ethyl acetate. The organic layers were combined and dried <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> to <RTI ID=0.0> ). 1h_NMr (ce>ci3/TmS): 6 7·45~7·61 (m, 1H), 4.73-5.02 (m, 2H), 3.88 (m, 1H), 3.55 (m, lH), 3.31 (m, 2H), 2.82 (m, lH), 2.38 (m, 1H), 1.42 to 1.88 (m, 6H). Example 6 (I'l'l-Dichloroethoxycarbonylmethyl)_4_hydroxy_2_cyclopentene ketone Ο ^J^COOChiCC\3

HO 將5 g從實例5獲得之2-羥基羰基甲基_4_四氫哌喃氧基_2-衣戍稀小酮、2,2,2·三氣乙醇（4.7 g)、二氣曱烧（5〇 mi)及0.2 8 (―甲胺）。比啶一同加入30 ml含有1，3_二環己基碳二亞女士 g之—氣甲烷溶液中。在室溫下攪拌反應混合物約4 小％。過濾去掉沉澱。用2〇 ml稀鹽酸溶液、水洗滌濾液， 107362.docHO 5 g of 2-hydroxycarbonylmethyl_4_tetrahydropiperidinyloxy-2-insulphonic ketone obtained from Example 5, 2,2,2·trisethanol (4.7 g), dioxane Burn (5 〇 mi) and 0.2 8 ("methylamine"). Add 30 ml of a 1,3-dicyclohexylcarbazide-containing m-gas methane solution together with the pyridine. The reaction mixture was stirred at room temperature for about 4% by weight. The precipitate was removed by filtration. Wash the filtrate with 2 〇 ml of dilute hydrochloric acid solution and water, 107362.doc

-26- 1378146 經無水硫酸鎂乾燥’過濾，並在真空中蒸發。將粗產物溶解在30 ml丙酮及6 ml水中，再加入3…3NHc](水溶液）並攪拌過仪。一旦反應完成，就將丙酮蒸發，並用乙酸乙酯稀釋反應混合物，且用碳酸氣納水溶液及鹽水溶液洗務。有機液體進行先前之處理程序，包括脫水、過濾及蒸發，並藉由石夕勝層析法純化以獲得標題化合物（4.8 g，80%)。 ]H-NMR (CDC13/TMS): δ 7.49 (m, 1H), 5.02 (m, lH)j 4.75 • (s, 2H), 3.42 (s5 2H), 2.86 (dd, 1H), 2.35 (dd, 1H), 1.78 (brs 1H)。，實例7 2-(2-萘氧基羰基甲基）_4_羥基_2·環戊烯酮〇-26- 1378146 was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude product was dissolved in 30 ml of acetone and 6 ml of water, then 3...3 NHc] (aqueous solution) was added and stirred. Once the reaction was complete, the acetone was evaporated and the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium carbonate and brine. The organic liquid was subjected to the previous procedures, including dehydration, filtration, and evaporation, and purified by chromatography to afford the title compound (4.8 g, 80%). H-NMR (CDC13/TMS): δ 7.49 (m, 1H), 5.02 (m, lH)j 4.75 • (s, 2H), 3.42 (s5 2H), 2.86 (dd, 1H), 2.35 (dd, 1H), 1.78 (brs 1H). , Example 7 2-(2-Naphthyloxycarbonylmethyl)_4_hydroxy_2·cyclopentenone 〇

HO 將5 g從實例5獲得之羥基羰基曱基_4_四氫哌喃氧基·2_ 環戊烯-1-酮（21mmol)、2_ 萘酚（47g，32mm〇1)、二氣曱烷 (〇 ml)及0.2 g 4-( 一甲胺）°比。定一同加入5〇 m丨含有ι，3_二環己基妷二亞胺（7 g，34 mm〇l)之二氣曱烷溶液中。在室溫下攪拌反應混合物約4小時。過濾去掉沉澱，用2〇 ml之稀鹽酸溶液、水洗滌濾液，經無水硫酸鎂乾燥，過濾，並在真玉中蒸發。將粗產物溶解在3〇 ml丙酮及6 ml水中，再加入〇·3 g對曱苯磺酸並攪拌過夜。一旦反應完成，就蒸發出丙酮並用乙酸乙酯稀釋反應混合物，且用碳酸氫鈉水溶液及鹽水溶液洗滌。有機液體進行先前之處理程序，包括脫水' 107362.docHO 5 g of hydroxycarbonylindenyl-4-isohydroperoxycarbonyl-2-cyclopenten-1-one (21 mmol), 2-naphthol (47 g, 32 mm 〇1), dioxane obtained from Example 5. (〇ml) and 0.2 g 4-(monomethylamine) ° ratio. A solution of 5 〇 m丨 containing ι,3_dicyclohexyldiimide (7 g, 34 mm 〇l) in dioxane was added. The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was removed by filtration, and the filtrate was washed with 2 ml of a dilute hydrochloric acid solution and water, dried over anhydrous magnesium sulfate, filtered, and evaporated. The crude product was dissolved in 3 ml of acetone and 6 ml of water, then 〇·3 g of terephthalic acid was added and stirred overnight. Once the reaction was completed, acetone was evaporated and the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate and brine. Organic liquids for previous treatment procedures, including dehydration' 107362.doc

•27· 、濾及崧夯，並藉由矽膠層析法桿題化人铷 ^ t以獲侍如白色固體之知趨化合物。熔點：81t (4 2 ΤΜ^ δ, 1/〇) H-NMR (CDCI3/ S). δ 7.82 (m，2H)，7.78 (d，1H) 7 2H) 7 91 叫’ 7.W (m，2H)，7.46 (m， 2H)，7·21 (dd，1H)，5.04 (m，1H) 3.56 2 38 ΓΗΗ 1 (s, 2H), 2.89 (dd, 1H), 2.38 (dd, 1H)，1.60 (brs，1H)。實例8 (RR苯甲氧純基甲基_4_乙酿氧基_2_環戊w (s)-2-苯甲氧基叛基曱基_心經基2環戊稀小嗣之混合物〇• 27·················································· Melting point: 81t (4 2 ΤΜ^ δ, 1/〇) H-NMR (CDCI3/ S). δ 7.82 (m, 2H), 7.78 (d, 1H) 7 2H) 7 91 is called ' 7.W (m, 2H), 7.46 (m, 2H), 7·21 (dd, 1H), 5.04 (m, 1H) 3.56 2 38 ΓΗΗ 1 (s, 2H), 2.89 (dd, 1H), 2.38 (dd, 1H), 1.60 (brs, 1H). Example 8 (RR Benzyloxymethyl-4-4-ethoxycarbonyl-2_cyclopenta(s)-2-benzyloxycarbenyl-peripheryl 2 cyclopentanthene mixture 〇

COOBn 將1〇 g從實例3獲得之2-苯甲氧基羰基甲基_4羥基_2環戊烯-1-酮、10 ml乙酸乙烯酯、1 §來自洋慧假單胞菌之脂肪酶及100 ml甲基異丁基酮（下文中稱為"MIBK")加入25〇 m】反應燒瓶中並在〇。〇到5〇。〇之溫度下攪拌。當完成約45% 到5 5 %之酯化反應時，藉由移除脂肪酶終止反應。在真空蒸發（50°C，20 mmHg)下濃縮反應混合物，形成暗褐色油狀產物’其含有（R)-酯（即（R)-2-苯甲氧基羰基曱基-心乙醯氧基-2-環戊烯-1-酮）及未反應之（s)-醇（即（S)-2-苯曱氧基羰基曱基-4-羥基-2-環戊烯-1 -酮）。視情況，藉由一快速管枉將（R)-酯（4.8 g，99% e.e.)與未反應之（S)-醇（4.2 g，99% e.e.) 分離。實例9到26 實例9到26係以與實例8描述之相同方式進行，除了使用 I07362.doc -28- 1378146 符號”---"代表沒有加入溶劑或豨釋劑。縮寫詞"MIBK"是指曱基異丁基酮。縮寫詞"IPE"是指異丙基醚。實例27及28 (R)-2·苯甲氧基羰基甲基_4_乙醯氧基_2_環戊烯纲〇 • A^l^^COOBnCOOBn 1 〇g of 2-benzyloxycarbonylmethyl-4 hydroxy-2-cyclopenten-1-one obtained from Example 3, 10 ml of vinyl acetate, 1 § lipase from Pseudomonas syringae And 100 ml of methyl isobutyl ketone (hereinafter referred to as "MIBK") was added to the 25 〇m reaction flask and was in hydrazine. Go to 5〇. Stir at the temperature of the crucible. When about 45% to 55% of the esterification reaction is completed, the reaction is terminated by removing the lipase. The reaction mixture was concentrated under vacuum evaporation (50 ° C, 20 mmHg) to give the product as a dark brown oil, which contains (R)-ester (i.e., (R)-2-benzyloxycarbonyl fluorenyl-cardiamine Benz-2-cyclopenten-1-one) and unreacted (s)-alcohol (ie (S)-2-benzoquinoneoxycarbonylmercapto-4-hydroxy-2-cyclopenten-1-one ). Optionally, (R)-ester (4.8 g, 99% e.e.) is separated from unreacted (S)-alcohol (4.2 g, 99% e.e.) by a flash tube. Examples 9 to 26 Examples 9 to 26 were carried out in the same manner as described in Example 8, except that the use of I07362.doc -28-1378146 symbol "---" represents no solvent or release agent added. Abbreviation "MIBK" Refers to decyl isobutyl ketone. The abbreviation "IPE" means isopropyl ether. Examples 27 and 28 (R)-2·Benzyloxycarbonylmethyl_4_ethyloxy-2-_2 ring Pentene 〇• A^l^^COOBn

AcO • 實例27 將從實例8獲得之未經反應之（S)·醇（即（s)_2_苯甲氧基羰基曱基-4-羥基-2-環戊烯_；!_酮）（4.2 g，980/〇 e.e.)、醋酸（1 54 、 §，I.5莫耳當量）及三苯基膦（6.74 g，1.5莫耳當量）_同溶解在—封閉反應燒瓶之甲苯中。接著，將反應混合物冷卻到約〇到1 0 C之溫度，且隨後緩慢加入偶氮二羧酸二異丙酯 (4.5 g，1.3莫耳當量）。溫度維持在〇到1〇。〇直至反應完成， • 並隨後將反應混合物變為室溫。所得沉澱經過濾且濾液在真空下蒸發以去除甲苯。獲得粗產物’即（R)_2_苯甲氧基羰基曱基-4-乙醯氧基_2·環戊烯小酮（54 g, 98% 'Ή-NMR (CDCVTMS): δ 7.43 (ms 1H), 7.33 (m5 5H)3 5 78 5.13(3, 2H), 3.31 (s52H), 2.87 (dd5lH)52.3i(dd 1 H)，2.06 (s，3H)。 ’ 實例28 將從貫例15獲得之含有（R)_g旨：2•苯甲氧基幾基甲基乙酿氧基-2-環戊稀酮及未經反應之⑻-醇：2_苯甲氧基 I07362.doc /0140 叛基甲基-4_窥基-2·環戊稀-卜酮之混合物（5.75 g)與曱苯 {=、醋酸（1.06匕丨·5莫耳當量）及三苯基膦（4.6 g，1.5 莫耳當量）組合。在室溫下攪拌反應混合物直至形成一均質此D物。冷卻反應混合物並逐漸加入偶氮二羧酸二異曰3」g，1.3莫耳當量）。反應完成後，將反應混合物加二丨裒兄血度並攪拌一天。所得沉澱經過濾且將濾液在真下蒸發以去除甲苯。獲得含有（R)-酯、殘餘物及Mitsunobu 反應副產物之粗產物（97 g)。粗產物直接用於下述反應或撸由快速管柱稍微純化。獲得之標題化合物（約4 8 g)具有約99% e.e.之光學純度。實例29 (R)-2·乙氧基羰基甲基_4•乙醯氧基_2_環戊烯巧-酮〇 ^jJ^^COOEtAcO • Example 27 The unreacted (S)·alcohol obtained from Example 8 (i.e., (s)_2_benzyloxycarbonylmercapto-4-hydroxy-2-cyclopentene_;!-one) 4.2 g, 980 / 〇 ee), acetic acid (1 54 , §, I.5 molar equivalents) and triphenylphosphine (6.74 g, 1.5 mole equivalents) were dissolved in toluene in a closed reaction flask. Next, the reaction mixture was cooled to a temperature of about 10 C, and then diisopropyl azodicarboxylate (4.5 g, 1.3 mol equivalent) was slowly added. The temperature is maintained at 1 〇. 〇 until the reaction is completed, • and then the reaction mixture is allowed to reach room temperature. The resulting precipitate was filtered and the filtrate was evaporated in vacuo to remove toluene. Obtained the crude product 'i(R)_2_benzyloxycarbonylmercapto-4-ethyloxy-2-cyclopentanone (54 g, 98% 'Ή-NMR (CDCVTMS): δ 7.43 (ms 1H), 7.33 (m5 5H)3 5 78 5.13(3, 2H), 3.31 (s52H), 2.87 (dd5lH)52.3i(dd 1 H), 2.06 (s,3H). 'Example 28 will be from Example 15 The obtained (R)_g is intended to be: 2: benzyloxymethylmethylethyloxy-2-cyclopentanone and unreacted (8)-alcohol: 2_benzyloxy I07362.doc /0140 a mixture of thiomethyl-4-peptidyl-2.cyclopentan-one (5.75 g) with anthracene {=, acetic acid (1.06 匕丨·5 molar equivalent) and triphenylphosphine (4.6 g, 1.5 molar equivalent) combination. The reaction mixture was stirred at room temperature until a homogenous D was formed. The reaction mixture was cooled and diazonium diazodicarboxylate 3"g, 1.3 mole equivalents) was gradually added. After the reaction was completed, the reaction mixture was added to the second blood and stirred for one day. The resulting precipitate was filtered and the filtrate was evaporated in vacuo to remove toluene. The crude product (97 g) containing the (R)-ester, the residue and the by-product of the Mitsunobu reaction was obtained. The crude product was used directly in the reaction described below or was slightly purified from a flash column. The title compound obtained (about 48 g) had an optical purity of about 99% e.e. Example 29 (R)-2·Ethoxycarbonylmethyl-4·Ethyloxy_2_cyclopentene-ketone 〇 ^jJ^^COOEt

Ac〇將含有（R)-酯：2-乙氧基歟基曱基_4_乙醯氧基·2環戊烯 -1-酮及（S)-酵.2-乙氧基羰基甲基_4•羥基_2_環戊烯酮之混合物進行實例28中描述之程序以獲得標題化合物（7 2 g)。H-NMR (CDC13/丁MS): δ 7.44 (s，1H), 5.79 (ds 1H), 4.15 (q，2H)，3.25 (s，2H)，2.88 (dd，1H)，2.37 (dd, 1H)，2.07 (s, 3H)，1.25 (s，3H)。實例30Ac〇 will contain (R)-ester: 2-ethoxyindolyl-4-4-ethenyloxy-2-cyclopenten-1-one and (S)-fermented 2-ethoxycarbonylmethyl A mixture of _4 hydroxy-2-cyclopentenone was subjected to the procedure described in Example 28 to give the title compound (7 2 g). H-NMR (CDC13/butyl MS): δ 7.44 (s, 1H), 5.79 (ds 1H), 4.15 (q, 2H), 3.25 (s, 2H), 2.88 (dd, 1H), 2.37 (dd, 1H) ), 2.07 (s, 3H), 1.25 (s, 3H). Example 30

107362.doc 1378146 根據實例28之程序進行實例3Ο ’除了此反應使用之是丁酸而不為醋酸。獲得之標題混合物為一黑色油狀物（產率：約 90%)。實例31到33 (R)-2-乙氧基羰基曱基_4_羥基-2-環戊稀_ι_酮〇 <^jJ/VCO〇Et H0 貫例3 1 ·將5 g (R)-2-乙氧基羰基甲基_4_乙醯氧基_2_環戊烯酮（96% e.e·)溶解在40 ml乙醇中。向反應混合物中逐漸加入5 g硫酸並接著在4〇°C攪拌4到5個小時。將反應混合物幻入冰水中並使用飽和碳酸氫鈉水溶液將溶液之pH值調到約4到6。在真空中濃縮反應混合物以蒸發掉乙醇，進— 步用300 ml乙酸乙酯稀釋以進行萃取，靜置以允許相分離用、力1 〇〇 ml乙酸乙酯洗滌水層兩次。收集有機溶液，組合並分別用飽和碳酸氫鈉溶液和鹽水溶液洗滌。用無水硫酸鎖乾燥反應混合物並在真空中濃縮。藉由謂急驟層析純化殘餘物以得到如油狀物之標題化合物(4ι & 96% e.e.) 〇實2室m下在一反應燒瓶中加入5 g (r)_2-乙氧基羰107362.doc 1378146 Example 3 was carried out according to the procedure of Example 28 except that butyric acid was used instead of acetic acid. The title mixture obtained was a black oil (yield: about 90%). Examples 31 to 33 (R)-2-Ethoxycarbonylindenyl_4-hydroxy-2-cyclopentene_ι-ketone oxime <^jJ/VCO〇Et H0 Example 3 1 · 5 g (R 2-Ethoxycarbonylmethyl_4_acetoxy-2-cyclopentenone (96% ee·) was dissolved in 40 ml of ethanol. 5 g of sulfuric acid was gradually added to the reaction mixture and then stirred at 4 ° C for 4 to 5 hours. The reaction mixture was immersed in ice water and the pH of the solution was adjusted to about 4 to 6 using a saturated aqueous solution of sodium hydrogen carbonate. The reaction mixture was concentrated in vacuo to evaporate ethanol, and then extracted with 300 ml of ethyl acetate to extract, and allowed to stand for separation, and the aqueous layer was washed twice with ethyl acetate. The organic solutions were collected, combined and washed separately with saturated sodium bicarbonate solution and brine solution. The reaction mixture was dried with anhydrous sulphuric acid and concentrated in vacuo. The residue was purified by flash chromatography to give the title compound (4m & 96% e.e.) as an oil. 5 g (r) 2 -ethoxy carbonyl was added to a reaction flask at room 2 m

基甲基_4_乙酿氧基環戊婦-1-酮（96。/〇 e.e.)連同5〇 mI M IBKn5 Q 7 tx n c . Η G扛及0.5 g南極假絲酵母脂肪酶（從 I:dUSt城得），„起攪拌。反應由肌C監控，直到反應受、之先學純度降到99% e.e，時，藉由濾出脂肪酶而終止。濃 I07362.doc •32· 1378146 標題化縮反應混合物以移除溶劑且進—步經過一短管桎以移反應之酯，獲得具有高光學純度（42 g，99% e之牙、合物。了使用衍生 °獲得之標實例33 :根據實例32之程序進行實例33,除自無色桿菌之脂肪酶而非南極假絲酵母脂肪酶題化合物具有高光學純度(4·1 g，99%e.e.)。實例34及35Methyl-4-4-ethoxycyclopentan-1-one (96./〇ee) together with 5〇mI M IBKn5 Q 7 tx nc . Η G扛 and 0.5 g Candida antarctica lipase (from I :dUSt City), „Agitated. The reaction is monitored by muscle C until the reaction is reduced, and the purity is reduced to 99% ee, which is terminated by filtering out the lipase. Concentration I07362.doc •32· 1378146 Title The reaction mixture was condensed to remove the solvent and passed through a short tube to shift the reacted ester to obtain a tooth having a high optical purity (42 g, 99% e. The standard example obtained using the derivative ° 33 Example 33 was carried out according to the procedure of Example 32 except that the lipase from Achromobacter sinensis but not the Candida antarctica lipase compound had high optical purity (4.1 g, 99% ee). Examples 34 and 35

本甲氧基幾基甲基_4_經基_2•環戊稀小綱 QBen methoxymethylmethyl_4_trans-base_2•cyclopentene small class Q

C〇〇Br H0 實例34 ·根據實例32之程序進行實例％，除了使用起始物質W-2-苯甲氧基裁基甲基乙酼氧基心環戊稀小酮(4 g，，e.e.)及苯甲醇而非(R)_2-乙氧基幾基甲基_4_乙醯氧基2 %戊稀·及乙醇。獲得之標題化合物具有高光學純度（3,4 g，99% e.e.)。C〇〇Br H0 Example 34 • Example % was carried out according to the procedure of Example 32 except that the starting material W-2-benzyloxymethylmethyl ethoxycyclopentanone (4 g, ee) was used. And benzyl alcohol instead of (R) 2 -ethoxymethylmethyl 4 - ethyl oxy 2% pentane and ethanol. The title compound obtained has a high optical purity (3, 4 g, 99% e.e.).

實例35 抑實例35:將5 g (R)_2•苯甲氧基幾基甲基冬乙酿氧基衣戊烯1-_(5 g，98% e.e)、〇 5 g南極假絲酵母脂肪酶及 ml碟酸鹽緩衝液（1()mM，pH7)_同加人並在室溫下㈣。氫氧化鈉/谷液將反應混合物之值維持在約65到 7.5匕約3到4小時後’藉由過濾掉脂肪酶終止反應。用乙酸 -曰（5 0 ml)從水相中兩次萃取產物。隨後，用飽和碳酸氫納浴液及鹽水溶液分別洗料收集之有機層，經無水硫酸 107362.doc •33- 1378146 鎂乾燥，並在真空中蒸發。藉由矽膠急驟層析純化殘餘物以生成如油狀物之標題化合物（3.2 g, 98% e.e.)。實例36 (R)-2-乙氧基幾基f基-4-三乙基石夕烧氧基_2•環戊婦小嗣 0 ^jJ^'COOEt TES0 將25 g之（R)-2-乙氧基羰基甲基·4_羥基·2_環戊烯酮（5 g，98% e.e.)溶解在乙酸乙酯中並將此溶液置於—氮淨化燒瓶中。加入畔唑（U.87 g，204 mm〇i)。將溶液冷卻到〇1並緩慢加入三乙基氯石夕烧（26.6 g，！ 76 mm〇1)。允許反應混合物溫至室溫並再攪拌15小時。過濾後，用飽和碳酸氫鈉溶液及鹽水溶液分別洗務遽液，經無水硫酸鎖乾燥，並濃縮以獲得標題化合物（38.5 g，95%)。[a]D: + 27 8。& ! ch3cn)。 Ή-NMR (CDC13/TMS): δ 7.36 (s, 1H), 4.96 (ms lH)j 4.16 (q, 2H), 3.23 (dd, 2H), 2.84 (dd, lH)j 2.32 (dd5 1H), 1.26 (t, 3H)，0,99 (t，9H)，0.65 (q，6H)。實例37 W-2-經基基_4•三乙基錢氧基_2•環戊稀小嗣Example 35 Example 35: 5 g of (R)_2•benzyloxymethylbutanyl-ethoxylated pentene 1--(5 g, 98% ee), 〇5 g of Candida antarctica fat Enzyme and ml disc acid buffer (1 () mM, pH 7) _ with the addition and at room temperature (four). The sodium hydroxide/guar solution maintains the value of the reaction mixture at about 65 to 7.5 Torr for about 3 to 4 hours. The reaction is terminated by filtering out the lipase. The product was extracted twice from the aqueous phase with acetic acid - hydrazine (50 mL). Subsequently, the organic layer collected was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous succinic acid, EtOAc, <RTIgt;</RTI> The residue was purified by EtOAc EtOAc (EtOAc) Example 36 (R)-2-Ethoxyl group fyl-4-triethyl oxalate alkoxy _2•Cyclopentanyl quinone 0 ^jJ^'COOEt TES0 25 g of (R)-2- Ethoxycarbonylmethyl 4-hydroxy-2icyclopentenone (5 g, 98% ee) was dissolved in ethyl acetate and this solution was placed in a nitrogen purge flask. Add torazole (U.87 g, 204 mm〇i). The solution was cooled to 〇1 and triethyl chlorite (26.6 g, ! 76 mm 〇1) was slowly added. The reaction mixture was allowed to warm to rt and stirred for additional 15 h. After filtration, the residue was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sulfate, and concentrated to give the title compound (38.5 g, 95%). [a]D: + 27 8. & ! ch3cn). Ή-NMR (CDC13/TMS): δ 7.36 (s, 1H), 4.96 (ms lH)j 4.16 (q, 2H), 3.23 (dd, 2H), 2.84 (dd, lH)j 2.32 (dd5 1H), 1.26 (t, 3H), 0, 99 (t, 9H), 0.65 (q, 6H). Example 37 W-2-Substituted _4•Triethyl hydroxyoxy-2•cyclopentanthene

C〇〇H TES0 將.2〇g從實•例35獲.得之（R)_2.乙氧基幾基甲基冬三乙基㈣氧基’及2 g南極假絲酵母脂肪酶懸浮在 200 ml填酸鹽緩衝液（1〇成阳6.5七）中並在室溫下攪 I07362.doc •34· 1378146 拌。用INil氧化鈉溶液維持溶液之阳值並在反應完成時將其最終調整到7.0且藉由過遽去除脂肪酶。用⑽mi乙酸乙 -曰萃取反應/tb s物兩次。使用一飽和硫酸氫鈉溶液將水層之pH值進纟5周到6 〇。使用⑽乙酸乙自旨再次萃取水層兩人.·且口有機層，經無水硫酸鎮乾燥，過滤，並濃縮以纹侍（R)-2-h基釦基甲基_4_三乙基矽烷氧基_2·環戊烯-卜 -嗣（12 g，65/。產率）。[a]D: + 19 8。（c i 〇, ch〕cn) ; 1h_nmr -· (CDCI3/TMS): δ 7.35 (m5lH)j 4.93 (m5lH)5 3.26 (m5 2H), 2.78 (dd，1H)，2.31 (dd，1H)，G_95 (t，9H)，0.64 (q, 6H)。實例38 (R)-2-[2-(4m氧基叛基甲基）]_4_三6基石夕烧氧基_2環戍稀-1 ·嗣C〇〇H TES0 obtained from .2〇g from Example 35. (R)_2. Ethoxymethylmethyl-tert-triethyl (tetra)oxyl and 2 g of Candida antarctica lipase were suspended at 200 Ml sate buffer (1 〇 Chengyang 6.5) and mix at room temperature I07362.doc •34· 1378146. The positive value of the solution was maintained with INil sodium oxide solution and finally adjusted to 7.0 upon completion of the reaction and the lipase was removed by hydrazine. The reaction/tb s was extracted twice with (10) mi acetic acid ethyl bromide. The pH of the aqueous layer was ramped for 5 weeks to 6 Torr using a saturated sodium bisulfate solution. The (10) acetic acid was used to re-extract the aqueous layer from the two. The organic layer was dried over anhydrous sulfuric acid, filtered, and concentrated to give (R)-2-h-methylmethyl 4-[3-ethyl矽 alkoxy 2·cyclopentene-b-oxime (12 g, 65% yield). [a]D: + 19 8. (ci 〇, ch]cn) ; 1h_nmr -· (CDCI3/TMS): δ 7.35 (m5lH)j 4.93 (m5lH)5 3.26 (m5 2H), 2.78 (dd,1H), 2.31 (dd,1H), G_95 (t, 9H), 0.64 (q, 6H). Example 38 (R)-2-[2-(4moxyheptylmethyl)]_4_3-6-based oxalate-oxy-2 ring 戍-1 -嗣

將5 g(18.5 mmol)從實例37獲得之2羥基羰基曱基_4·三乙基石夕院氧基-2-環戊稀_ι_酮（21 mm〇i)、4_(2羥基乙基）_ 嗎啉（2.9 g，22_1 mmol)、二氯甲烷（5〇 mlu〇2 g 4_(二甲胺）-吡啶一同加入含有L3-二環己基碳二亞胺（6 g，29 mmol)之30 ml二氣甲院溶液中。在室溫下授拌反應混合物約4小時。將沉澱過濾掉。用—飽和碳酸氫納溶液洗縣據液，經無水硫酸鎂乾燥，過濾，並在真空中蒸發。藉由矽膠急驟層析純化殘留物以得到如一油狀物之標題化合物 (4.4 g，62%)。[a]D: + 26.〇。（c 1〇, CH3Cn); 1h nmr I07362.doc •35* 1378146 (CDCfSh δ 7.40 (m，1H)，4 97 (m，1Η)，4 Μ (t， 3.75 (t5 4H), 3.28 (q5 2H), 2.80 (dd, 1H), 2.69 (t, 2H), 2.57 (s，4H)，2.33 (dd，1H)，(t, 9H)，〇 68 (q，6h)。實例39 (R)-2-(2-氰乙氧基幾基甲其 — ^基·4-二乙基矽烷氧基-2-環戊稀 -1-酮〇5 g (18.5 mmol) of 2-hydroxycarbonylmercapto- 4·triethyl oxacillinyloxy-2-cyclopentene ketone (21 mm〇i), 4-(2-hydroxyethyl) obtained from Example 37 ) _ morpholine (2.9 g, 22_1 mmol), dichloromethane (5 〇mlu 〇 2 g 4 _(dimethylamine)-pyridine was added together with L3-dicyclohexylcarbodiimide (6 g, 29 mmol) 30 ml of the second gas chamber solution. The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was filtered off. The county liquid was washed with a saturated sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, filtered, and placed in vacuo. Evaporation. The residue was purified byjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Doc •35* 1378146 (CDCfSh δ 7.40 (m,1H), 4 97 (m,1Η), 4 Μ (t, 3.75 (t5 4H), 3.28 (q5 2H), 2.80 (dd, 1H), 2.69 (t , 2H), 2.57 (s, 4H), 2.33 (dd, 1H), (t, 9H), 〇 68 (q, 6h). Example 39 (R)-2-(2-Cyanoethoxymethyl Its —^·4-diethylnonyloxy-2-cyclopentan-1-one oxime

、CN <^jJ/XCOO> THS0 根據實例3 8之步驟7丨。κ ^ /哪進订貫例39，除了在反應中使用3_羥基丙猜而非4-(2-經某;7 土乙基）嗎啉。獲得之標題化合物為一油狀物（產率：64%)。 [a]D. + 30.9 (c 1.0, CH3CN)； 'H-NMR (CDC13/TMS): δ 7.37 (s，H)，4.96 (m，1H)，4.30 (t，2H)，3 3〇 ⑷ 2H)，2 79 ⑽， IH)，2.72 (ί，2H)，2.3I (dd，】H)，0.98 (t，9H)，0.65 (q，6H) 實例40 (R)-2-(3-乙氧幾基苯氧羧基甲基）4三乙基矽烷氧基環戊烯-1 -酮, CN <^jJ/XCOO> THS0 according to step 7 of Example 38. κ ^ / Where to proceed to Example 39, except that 3_hydroxypropyl guess was used instead of 4-(2-trans-; 7-t-ethyl)morpholine in the reaction. The title compound obtained was an oil (yield: 64%). [a]D. + 30.9 (c 1.0, CH3CN); 'H-NMR (CDC13/TMS): δ 7.37 (s, H), 4.96 (m, 1H), 4.30 (t, 2H), 3 3 〇 (4) 2H), 2 79 (10), IH), 2.72 (ί, 2H), 2.3I (dd,]H), 0.98 (t, 9H), 0.65 (q, 6H) Example 40 (R)-2-(3- Ethoxy phenoxyphenoxymethyl) 4 triethyldecyloxycyclopenten-1-one

COOB TES0 根據貝例38之程序進行實例4〇，除了在反應中使用3_羥基苯曱乙S日而非4_(2_經基乙基）嗎琳。獲得之標題化合物為一油狀物（產率：67%)。㈤D: + 2L0。（c u，CH3CN); I07362.doc -36- 1378146 'H-NMR (CDCI3/TMS): δ 7.96 (m, 1H), Ί.19 (m, 1H), 7.49 (m5 2H)5 7.32 (m, 1H), 5.03 (m, 1H), 4.41 (q, 2H), 3.56 (qs 2H), 2.87 (dd, 1H), 2.40 (dd, 1H), 1.43 (t, 3H), 1.03 (t, 9H), 0.70 (q, 6H) 〇實例41 2-[(lR，2S，5R)-薄荷氧基羰基曱基卜羥基_2_環戊烯-卜酮COOB TES0 Example 4 was carried out according to the procedure of Example 38 except that 3_hydroxyphenyl hydrazine S was used instead of 4_(2_ylidylethyl) morphin in the reaction. The title compound obtained was an oil (yield: 67%). (5) D: + 2L0. (cu, CH3CN); I07362.doc -36- 1378146 'H-NMR (CDCI3/TMS): δ 7.96 (m, 1H), Ί.19 (m, 1H), 7.49 (m5 2H)5 7.32 (m, 1H), 5.03 (m, 1H), 4.41 (q, 2H), 3.56 (qs 2H), 2.87 (dd, 1H), 2.40 (dd, 1H), 1.43 (t, 3H), 1.03 (t, 9H) , 0.70 (q, 6H) 〇 Example 41 2-[(lR,2S,5R)-menthyloxycarbonylindolyl hydroxy-2-cyclopentene- ketone

mm

將5 g(18.5 mmol)從實例37獲得之2_羥基羰基甲基_4_三乙基矽烷氧基-2-環戊烯酮（21 mmo丨）、（111，28,511)_(-)_薄荷醇（3.44 g，22.0 mmol)、二氣曱烷（50 ml)及〇 2 g 4_(二曱胺）-吡啶一同加入含有二環己基碳二亞胺（6 g，29 mmol)之3 0 ml二氣甲烷溶液中。在室溫下攪拌反應混合物約4小時。將沉澱過濾掉。用一飽和碳酸氫鈉溶液洗滌濾液，經無水硫酸鎂乾燥，過濾，並在真空中蒸發。將粗產物溶解在50 ml THF及5 ml水中，再加入！ ml 3Ν Ηα(水溶液）並在室溫下挽拌丨小時。一旦反應完成，就用乙酸乙醋稀釋反應混合物並用碳酸氫鈉水溶液及鹽水溶液洗滌。使有機液體進行先前描述之處理程序，包括過濾及蒸發。藉由矽膠急驟層析純化殘留物以得到如一油狀物之標題化合物（4,3 g, 79 %)。實例42 -2-環戊烯-1-酮 (R)-2-(4-曱氧苯基甲氧羰基甲基）_4_羥基 107362.doc -37· ^/81465 g (18.5 mmol) of 2-hydroxycarbonylmethyl-4-triethyldecyloxy-2-cyclopentenone (21 mmo丨), (111, 28, 511) _ (-)_ obtained from Example 37 Menthol (3.44 g, 22.0 mmol), dioxane (50 ml) and g2 g 4_(diamine)-pyridine were added together with dicyclohexylcarbodiimide (6 g, 29 mmol). Ml two gas methane solution. The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was filtered off. The filtrate was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated. Dissolve the crude product in 50 ml THF and 5 ml water and add! Mol 3 Ν (α (aqueous solution) and mix at room temperature for several hours. Once the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium hydrogen carbonate and brine. The organic liquid is subjected to the previously described processing procedures, including filtration and evaporation. The residue was purified by EtOAc (EtOAc) elute Example 42 -2-cyclopenten-1-one (R)-2-(4-indoleoxyphenylmethoxycarbonylmethyl)_4_hydroxy 107362.doc -37·^/8146

OMe 根據實例41之程序進行實例42，除了在反應中使用4-甲氧基苯甲醇而不為（-)_薄荷醇。獲得之標題化合物為油狀物 (產率：67%)。 H-NMR (CDC13/TMS): δ 7.39 (s, 1H), 7.25 (d, 2H), 6.87 (d,OMe Example 42 was carried out according to the procedure of Example 41 except that 4-methoxybenzyl alcohol was used instead of (-)-menthol in the reaction. The title compound obtained was an oil (yield: 67%). H-NMR (CDC13/TMS): δ 7.39 (s, 1H), 7.25 (d, 2H), 6.87 (d,

2H)，5.06 (s，3H)，4.95 (m，1H)，3.79 (s，3H)，3.26 (s，2H)， 2.81 (dd，1H)，2.3 1 (d，1H)。實例43 (R)-2-(2-奈氧基羰基甲基）_4_第三丁基二甲基矽烷氧基 -2-環戊烯-1 _酮2H), 5.06 (s, 3H), 4.95 (m, 1H), 3.79 (s, 3H), 3.26 (s, 2H), 2.81 (dd, 1H), 2.3 1 (d, 1H). Example 43 (R)-2-(2-N-oxycarbonylmethyl)_4_t-butyldimethylammoniooxy-2-cyclopentene-1 ketone

將5 g(27.1 mm〇i，98% e.e.)(R)_2-乙氧基羰基甲基_4·羥基 -2-¼戊烯-1-酮溶解在乙酸乙酯中並將溶液置於一氮淨化之燒瓶中。加入咪唑（2.77 g，40.7 mmol)。將溶液冷卻到〇。〇並分批加入第三丁基二甲基氣石夕烧（5·3 g，35 mm〇i)。允許反應混合物溫至室溫’域拌15小時。過濾後，用飽和碳酸氮納溶液及鹽水溶液分別洗«液，經無水硫酸錢乾燥’過濾並蒸發至乾燥。將殘留物及lg南極假絲酵母脂肪酶懸浮在⑽㈣酸鹽緩衝液（1〇_，阳6 5 7 5)中並在室溫下搜拌。藉由m氫氧化鋼溶液維持溶液之pH值並在反應完成時最終將PH值調到7.〇’且藉由過濾移除脂肪酶。用50 l07362.doc •38· 13781465 g (27.1 mm〇i, 98% ee)(R)_2-ethoxycarbonylmethyl-4'hydroxy-2-1⁄4penten-1-one was dissolved in ethyl acetate and the solution was placed in one In a nitrogen purged flask. Imidazole (2.77 g, 40.7 mmol) was added. Cool the solution to hydrazine.第三 Add the third butyl dimethyl gas stone (5·3 g, 35 mm〇i) in batches. The reaction mixture was allowed to warm to room temperature for 15 hours. After filtration, it was washed with a saturated solution of sodium nitrite and a brine solution, dried over anhydrous sulphuric acid, and evaporated to dryness. The residue and lg Anguillas angustifolia lipase were suspended in (10) (tetra) acid salt buffer (1 〇 _, cation 6 5 7 5) and mixed at room temperature. The pH of the solution was maintained by m hydroxide steel solution and the pH was finally adjusted to 7. 〇' at the completion of the reaction and the lipase was removed by filtration. With 50 l07362.doc •38· 1378146

m丨甲本卒取反應滿合物兩次。使用硫酸氫納飽和水溶液將水層之pH值進一步調到6.0。使用1〇〇 ml乙酸乙酯再次萃取水層兩次。組合有機層’經無水硫酸鎂乾燥，過濾並濃縮。將殘留物及2-萘酷（5.0 g，34.7 mmol)溶解在二氣甲烧（5〇中’且連同〇,2g4-(二甲胺）u比。定加入到一 3〇mi含有ι，3_ —環己基碳二亞胺（7.5 g，36 mmol)之二氯曱院溶液中。在至皿下檀拌反應混合物約4小時。過濾、掉沉澱。用飽和碳酸氫納溶液洗滌濾液，經無水硫酸鎂乾燥，過濾並在真空中病發。藉由矽膠急驟層析純化殘留物以得到如白色固體之標題化合物（5.2 g, 48 %)。 Ή-NMR (CDC13/TMS): δ 7.78 (m, 2H), 7.74 (d, 1H), 7.50 (s5 1H), 7.42 (m, 3H), 7.17 (dd, 1H), 4.95 (m, 1H), 3.50 (q, 2H), 2.77 (dd} 1H), 2.30 (dd, 1H), 0.82 (s, 9H), 0.08 (s, 6H) 〇實例44 (R)-2-羥基羰基曱基四氫哌喃氧基_2_環戊烯酮m 丨本本卒卒反应反应反应满满The pH of the aqueous layer was further adjusted to 6.0 using a saturated aqueous solution of sodium hydrogen sulfate. The aqueous layer was extracted twice more with 1 mL of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue and 2-naphthol (5.0 g, 34.7 mmol) were dissolved in two gas (5 〇 ' and together with 〇, 2 g 4-(dimethylamine) u ratio. Add to a 3 〇mi containing ι, 3_-cyclohexylcarbodiimide (7.5 g, 36 mmol) in diclofenac solution. Mix the reaction mixture for about 4 hours under the dish. Filter and remove the precipitate. Wash the filtrate with saturated sodium bicarbonate solution. The residue was dried over MgSO4, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj m, 2H), 7.74 (d, 1H), 7.50 (s5 1H), 7.42 (m, 3H), 7.17 (dd, 1H), 4.95 (m, 1H), 3.50 (q, 2H), 2.77 (dd} 1H), 2.30 (dd, 1H), 0.82 (s, 9H), 0.08 (s, 6H) 〇 Example 44 (R)-2-Hydroxycarbonylmercaptotetrahydropiperanyloxy-2-cyclopentenone

^J^COOH thp<5 根據實例4及實例5之程序進行實例44，除了在反應中使用光學活性2-乙氧基羰基曱基_4羥基_2•環戊 e.e.)而非外消旋2-乙氧基羰基甲基_4_羥基_2_環戊烯·；!_ 酉同。獲得之標題化合物為—油狀物。實例45 (R)-2-(2-奈氧基爹炭基甲基）_心四i旅喃氧基_2-環戍稀小酮 107362.doc -39· 1378146^J^COOH thp<5 Example 44 was carried out according to the procedure of Example 4 and Example 5 except that the optically active 2-ethoxycarbonylcarbonyl- 4 hydroxy-2-cyclopentane ee was used in the reaction instead of racemic 2 -ethoxycarbonylmethyl_4_hydroxy_2_cyclopentene·;__ 酉. The title compound obtained was an oil. Example 45 (R)-2-(2-naphthyloxycarbylmethyl)_heart four i brityloxy-2-cyclononanthone ketone 107362.doc -39· 1378146

ΤΗΡ0 將5 g從實例44獲得之2-羥基羰基甲基_4(R)_四氫哌喃氧基-2-環戊烯-1-酮（21 mmol)、2-萘酚（4.7 g, 32 mmol)、二氣甲烧（5 0 ml)及0.2 g 4-(二曱胺）吡啶一同加入5〇 ml含有1，3· 二環己基碳二亞胺（7 g，34 mmol)之二氯曱烷溶液中。室溫下攪拌反應混合物約4小時。過濾掉沉澱。用2〇 ml稀鹽酸溶液及水洗滌濾液，經無水硫酸鎂乾燥，過濾並在真空中蒸發。藉由矽膠急驟層析純化殘留物以得到如白色固體之標題化合物（3_8 g, 64%)。熔點：75°C; [a]D + 29.3。（c 1.0, CH3CN);丨 H-NMR (CDC13/TMS): δ 7_10 〜7.90 (m，8H), 4.72~5_ll(m，2H)，3.90(m，lH)，3.60(m，3H)，2.89(m,lH)， 2.35〜2.60 (m，1H), 1.40〜1.92 (m，6H)。實例46 2-薄荷氧基羰基甲基四氫哌喃氧基_2_環戊稀_丨_酮ΤΗΡ0 5 g of 2-hydroxycarbonylmethyl-4(R)-tetrahydropentanyloxy-2-cyclopenten-1-one (21 mmol), 2-naphthol (4.7 g, obtained from Example 44). 32 mmol), aerobic (50 ml) and 0.2 g of 4-(diamine)pyridine were added together with 5 μml of 1,3·dicyclohexylcarbodiimide (7 g, 34 mmol). In a chlorodecane solution. The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was filtered off. The filtrate was washed with 2 mL of aq. The residue was purified by EtOAc EtOAc (EtOAc) Melting point: 75 ° C; [a] D + 29.3. (c 1.0, CH3CN); 丨H-NMR (CDC13/TMS): δ 7_10 ～7.90 (m,8H), 4.72~5_ll(m,2H), 3.90 (m,lH), 3.60 (m,3H), 2.89 (m, lH), 2.35 to 2.60 (m, 1H), 1.40 to 1.92 (m, 6H). Example 46 2-menthyloxycarbonylmethyltetrahydropyranooxy-2_cyclopentene_丨-ketone

除了反應中使用之等莫耳濃度之受質為（1R,2s，5R)_(_)_ 薄荷醇而非2-萘酚外’根據實例45 _描述之相同程序可势備並得到如一油.狀物之標題化合物。 i-NMR (CDC13/TMS): δ 7.44〜7.58 (m，1H)，4.65〜5 〇4 (m， 3H), 3.91 (m，1H)，3.57 (m，1H)，3.24 (m，2H)，2.以〜之別⑽， 107362.doc •40· 1378146 1Η), 2.35-2.54 (m, 1H) 實例47 W-2-二苯基甲⑽基甲基四氫㈣氧基環戊稀相Except that the molar concentration of the reaction used in the reaction is (1R, 2s, 5R) _ (_) _ menthol instead of 2-naphthol, the same procedure as described in Example 45 _ can be prepared and obtained as an oil The title compound of the title. i-NMR (CDC13/TMS): δ 7.44~7.58 (m,1H), 4.65~5 〇4 (m, 3H), 3.91 (m,1H), 3.57 (m,1H), 3.24 (m,2H) , 2. to ~ (10), 107362.doc • 40· 1378146 1Η), 2.35-2.54 (m, 1H) Example 47 W-2-diphenylmethyl(10)-methyltetrahydro(tetra)oxycyclopentadiene

除了反應中使用之等莫耳濃度的受質為_ ^ v 一本基甲醇而非 2-萘酚之外，根據實例45中描述之相同程』^-備如一油狀物的標題化合物。]H-NMR (CDCh/TMSV S， ) 〇 7.20-7.42 (m 11H)，6.81 (s，1H)，4·85 (m，1H)，4 68 (m，1H)，3 ⑷， 3.46 (m，1H)，3.30 (m，2H)，2·74 (m，1H)，2 2〇〜2 4 ，， 1.15〜1.90 (m，6H)。、’川)，實例48 (R)-2-(3,4·亞甲二氧基苯基甲氧叛基甲基M，氫^ -2-環戍烯-1-_The same procedure as described in Example 45 was followed for the title compound as an oil, except that the molar concentration of the solvent used in the reaction was _^v-based methanol instead of 2-naphthol. H-NMR (CDCh/TMSV S, ) 〇 7.20-7.42 (m 11H), 6.81 (s, 1H), 4·85 (m, 1H), 4 68 (m, 1H), 3 (4), 3.46 (m , 1H), 3.30 (m, 2H), 2·74 (m, 1H), 2 2〇~2 4 ,, 1.15 to 1.90 (m, 6H). , 'Chuan', Example 48 (R)-2-(3,4·Methylenedioxyphenylmethoxymethylmethyl M, hydrogen-2-cyclodecene-1-_

ΤΗΡ0 除了反應中使用之等莫耳濃度的受質為胡椒醇而非2_萘盼之外’根據實例45中描述之相同程序可製備並得到如一油狀物之標題化合物。 H-NMR (CDCVTMS): δ 7·42〜7.6〇 (m，1Η)，6 81 _肩 5.98 (s, 2H), 5.05 (s5 2H), 4.97 (m5 ιΗ), 4.80 (rn, 1H)s 3.9i (m，1H)，3.57 (m，1H)，3.31 (m, 2H)，2.8G (m，m)，2 3〇〜2.55 (m，1H)，1,45〜2.04 (m，6H) o 107362.doc 41ΤΗΡ0 The title compound was obtained as an oily product, which was obtained from the same procedure as described in Example 45, except that the molar concentration of the solvent used in the reaction was hexane. H-NMR (CDCVTMS): δ 7·42~7.6〇(m,1Η),6 81 _shoulder 5.98 (s, 2H), 5.05 (s5 2H), 4.97 (m5 ιΗ), 4.80 (rn, 1H)s 3.9i (m, 1H), 3.57 (m, 1H), 3.31 (m, 2H), 2.8G (m, m), 2 3〇~2.55 (m, 1H), 1, 45~2.04 (m, 6H) ) o 107362.doc 41

Claims

~w -»r-v〇- 年月日修(更)正本_〇9510197〇號專利申請案 >文申够-專利範圍喈換本(!丨01年8月）、申請專利範圍：~w -»r-v〇- 年月日修(更)本本_〇9510197〇 Patent application >文申够-Patent scope 喈换本(!丨01年月01), application patent scope:

一種用於製備式1之化合物的方法含(R)-對映異構物且具有至少為95%對映體過量之光學純度，A process for the preparation of a compound of formula 1 contains a (R)-enantiomer and has an optical purity of at least 95% enantiomeric excess,

其中Rl為烷基、苯曱基、萘基或苯基，其每一者未經取代或經一或多個選自由齒素、烷基、芳基、烷氧基、芳氧基、硫烷氧基、硫芳氧基、烷胺基、芳胺基及氰基組成之群的取代基或選自由。比啶基、噻吩基、呋喃基、咪唑基、嗎啉基、吟唑啉基、哌啶基、哌嗪基、四氫哌喃基、咄咯啶基及吡咯啶酮基組成之群的雜環基所取代，其中各基團中之烷基為含有1到10個碳原子之直鏈或支鏈烴基或具有3到i 〇個碳原子之環狀飽和烴基，及芳基係選自由苯基、萘基、蒽基及菲基所組成之群’該方法包含下列步驟： (a)用醯基供體及第一脂肪酶對映選擇性地（R)-酯化該式 1化合物之消旋醇混合物，以獲得第一（R)_酯及未反應的（S)醇’其中該第一脂肪酶係衍生自由南極假絲酵母、無色桿菌屬、產鹼桿菌^、螢光假單胞菌、絲德特瑞（stutzri)假單胞菌或洋慧假單胞菌組成之群的菌種； (b) 移除未反應的（s)_醇；及 (c) 在式R1〇H之醇的存在下，以第二脂肪酶將所得（r)_ 107362-1010809.doc 酉日去醯基化，其中該第二脂肪酶包含一衍生自假單胞菌屬、無色桿菌屬或南極假絲酵母之脂肪酶；或在式 Rl〇Ii之醇的存在下，以酸催化劑將所得（R)-酯去醯基 4匕’其中尺丨如上文之定義。 ’ 清求項1之方法，其中移除該未反應的（s)_醇之步驟包括將邊未反應的（S)-醇’藉由在偶氮二羧酸二烷基酯及三芳基鱗的存在下，該未反應的（S)-醇與醯基供體間之反應，而轉化為（R)·酯。 •如明求項1之方法，其中該醯基供體為乙酸乙稀酯、乙酸異丙歸'戊酸乙烯酯、戊酸異丙烯酯、丁酸乙烯酯、或丁酸異丙烯酯。 4·如請求項2之方法，其中該偶氮二羧酸二烷基酯為偶氮二叛酸二乙酯、偶氮二羧酸二異丙酯或偶氮二羧酸二苯甲酯。 5. 如請求項2之方法，其中該三芳基膦為三苯基膦。 6. 如請求項1之方法，其中該第二脂肪酶包含一衍生自南極假絲酵母之脂肪酶。 7. 如凊求項1之方法’其中該酸催化劑包含—選自由填酸、對甲苯磺酸、氫溴酸、鹽酸 '硝酸及硫酸及其混合物組成之群的酸。 8. —種式1A之化合物，其富含（R)-對映異構物且具有至少為 95%對映體過量之光學純度， 107362-1010809.doc -2- ΓΙ378146Wherein R1 is alkyl, benzoinyl, naphthyl or phenyl, each of which is unsubstituted or one or more selected from the group consisting of dentate, alkyl, aryl, alkoxy, aryloxy, sulfane The substituent of the group consisting of an oxy group, a thioaryloxy group, an alkylamino group, an arylamine group, and a cyano group is selected or selected from the group consisting of. a group consisting of a group consisting of a pyridyl group, a thienyl group, a furyl group, an imidazolyl group, a morpholinyl group, an oxazoline group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, an anthranilyl group, and a pyrrolidinyl group. Substituted by a cyclic group wherein the alkyl group in each group is a linear or branched hydrocarbon group having 1 to 10 carbon atoms or a cyclic saturated hydrocarbon group having 3 to i carbon atoms, and the aryl group is selected from benzene a group consisting of a base group, a naphthyl group, a fluorenyl group and a phenanthryl group. The method comprises the steps of: (a) enantioselectively (R)-esterifying a compound of the formula 1 with a thiol donor and a first lipase. a racemic alcohol mixture to obtain a first (R)-ester and an unreacted (S) alcohol, wherein the first lipase is derived from Candida antarctica, Achromobacter, Alcaligenes, and fluorescent a strain of a group consisting of a bacterium, a stutzri Pseudomonas or a Pseudomonas syringae; (b) removing unreacted (s)-alcohol; and (c) at the formula R1〇 In the presence of an alcohol of H, the resulting (r)_107362-1010809.doc is demethylated by a second lipase, wherein the second lipase comprises a derivative derived from Pseudomonas Genus Achromobacter or the Candida antarctica lipase; or in the presence of an alcohol of the formula Rl〇Ii, the acid catalyst resulting (R) - ester to acyl dagger 4 'as defined above wherein the foot Shu. The method of claim 1, wherein the step of removing the unreacted (s)-alcohol comprises reacting the unreacted (S)-alcohol' with a dialkyl azodicarboxylate and a triaryl squama In the presence of the unreacted (S)-alcohol and the mercapto donor, it is converted to the (R) ester. The method of claim 1, wherein the thiol donor is ethyl acetate, isopropyl acetate, vinyl valerate, isopropenyl valerate, vinyl butyrate, or isopropenyl butyrate. 4. The method of claim 2, wherein the dialkyl azodicarboxylate is diethyl azodicarboxylate, diisopropyl azodicarboxylate or dibenzoyl azodicarboxylate. 5. The method of claim 2, wherein the triarylphosphine is triphenylphosphine. 6. The method of claim 1, wherein the second lipase comprises a lipase derived from Candida antarctica. 7. The method of claim 1, wherein the acid catalyst comprises - an acid selected from the group consisting of acid-filling, p-toluenesulfonic acid, hydrobromic acid, hydrochloric acid, nitric acid, and sulfuric acid, and mixtures thereof. 8. A compound of formula 1A which is enriched in the (R)-enantiomer and has an optical purity of at least 95% enantiomeric excess, 107362-1010809.doc -2- ΓΙ 378146

其中Χι為Η或經基之保護基團；且R丨為院基、稀基、炔基、方基或务烧基’其每一者未經取代或經一或多個選自由齒素、烧基、芳基、烷氧基、芳氧基、硫烷氧基、硫芳氧基、燒胺基、芳胺基、氰基、炫氧幾基、芳基幾基、 ^•胺基幾基、烧胺基幾基及幾基組成之群的取代基或選自由β比咬基、嗟吩基、咬痛基、味β坐基、嗎琳基、巧峻啉基、哌啶基、哌嗪基、四氫哌喃基、吡咯啶基及吡咯啶酮基組成之群的雜環基’或羧基之保護基團所取代，限制條件為R,不為直鏈、未經取代之烷基；其中各基團中之貌基為含有1到10個碳原子之直鏈或支鏈烴基或具有3到10個碳原子之環狀飽和烴基；烯基為含有3到2〇個碳原子及一或多個碳碳雙鍵之直鏈或支鏈烴基，或含有5 到20個碳原子及一或多個碳碳雙鍵之環狀不飽和烴基；炔基為含有3到20個碳原子及一或多個碳碳三鍵之直鏈或支鏈挺基’或含有6到20個碳原子及一或多個碳碳三鍵之環狀不飽和烴基；及芳基選自由苯基、萘基、蒽基及菲基所組成之群。 9·如請求項8之化合物，其中該保護基團係對鹼具安定性者，且係選自甲氧基曱基、曱氧基硫曱基、2•甲氧基乙氧基甲基、曱氧基曱基、二（2_氣乙氧基）甲基、四氫哌喃基、四氫呋喃基、四氫硫代呋喃基、丨_乙氧基乙基、丨甲基-卜 107362-1010809.doc 1378146 曱氧基乙基、三苯甲基'烯丙基' 苯甲基、經取代苯甲基及SiRaRbRc ’其中Ra、Rl^Rc各為Cl_c4烷基、苯基、笨曱基、經取代苯基或經取代苯甲基。 10.如請求項8之化合物，其中h為支鏈烷基、烯基或炔基，其每一者未經取代或經一或多個選自由齒素、烧基、芳基、统氧基、^氧基、硫炫氧基、硫芳氧基、烧胺基、芳胺基、氰基、烷氧羰基、芳基羰基、芳胺基羰基、貌胺基幾基及幾基組成之群的取代基或選自由^比咬基、。塞吩基' 呋喃基、咪唑基、嗎啉基、呤唑啉基、哌咬基、派嗪基、四氫哌喃基、吡咯啶基及吡咯啶酮基組成之群的雜環基，或羧基之保護基團所取代。 11 ‘如請求項8之化合物’其中R!為芳烧基，其未經取代或經 —或多個選自由函素、烧基、芳基、烧氧基 '芳氧基、硫烷氧基、硫芳氧基、烧胺基、芳胺基 '氰基、院氧幾基、芳基羰基、芳胺基羰基及烷胺基羰基組成之群的取代基所取代。 12. 如請求項8之化合物，其中R!為芳基，其未經取代或經一或多個選自由齒素、烷基、烷氧基、硫烷氧基、烷氧幾基及氰基組成之群的取代基所取代。 13. 如請求項η之化合物，其中該芳烷基為苯甲基，其未經取代或經一或多個選自由函素、烷基、芳基 '烷氧基' 芳氧基、硫烷氧基、硫芳氧基、烷胺基、芳胺基、氰基、烧氧羰基、芳基羰基、芳胺基羰基及烷胺基羰基組成之群的取代基所取代。 107362-1010809.doc -4 - 1378146Wherein Χ is a protecting group of a hydrazine or a thiol group; and R 丨 is a fenium group, a dilute group, an alkynyl group, a aryl group or a carbyl group, each of which is unsubstituted or selected from one or more selected from the group consisting of dentate, An alkyl group, an aryl group, an alkoxy group, an aryloxy group, a thioalkoxy group, a thioaryloxy group, an acridine group, an arylamine group, a cyano group, a oxy-oxy group, an aryl group, an amine group a substituent of a group consisting of a group of an amino group and a group of a plurality of groups or a group selected from the group consisting of a β-bite group, a porphinyl group, a biting group, a taste group, a phenanthrenyl group, a phenanthrenyl group, a piperidinyl group, Substituted by a heterocyclic group of the piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinyl groups or a protecting group of a carboxyl group, the restriction is R, not a linear, unsubstituted alkane a base; wherein the base group in each group is a linear or branched hydrocarbon group having 1 to 10 carbon atoms or a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms; and the alkenyl group has 3 to 2 carbon atoms And a linear or branched hydrocarbon group of one or more carbon-carbon double bonds, or a cyclic unsaturated hydrocarbon group having 5 to 20 carbon atoms and one or more carbon-carbon double bonds; an alkynyl group having 3 to 20 carbons Atomic and one or a linear or branched thiol of a carbon-carbon triple bond or a cyclic unsaturated hydrocarbon group having 6 to 20 carbon atoms and one or more carbon-carbon triple bonds; and an aryl group selected from the group consisting of phenyl, naphthyl, anthracene A group of bases and phenotypes. 9. The compound of claim 8, wherein the protecting group is stable to a base and is selected from the group consisting of methoxyindenyl, decyloxythiol, 2:methoxyethoxymethyl,曱曱曱, bis (2- ethoxyethoxy) methyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, oxime ethoxyethyl, oxime methyl-bu 107362-1010809 .doc 1378146 methoxyethyl, trityl 'allyl' benzyl, substituted benzyl and SiRaRbRc ' wherein Ra, Rl^Rc are each Cl_c4 alkyl, phenyl, alum, and Substituted phenyl or substituted benzyl. 10. The compound of claim 8, wherein h is a branched alkyl, alkenyl or alkynyl group, each of which is unsubstituted or one or more selected from the group consisting of dentate, alkyl, aryl, oxy Group of oxy, thioxyloxy, thioaryloxy, acrylamine, arylamino, cyano, alkoxycarbonyl, arylcarbonyl, arylaminocarbonyl, amido group and several groups The substituent is selected from the group consisting of. a heterocyclic group of the group consisting of a pyrenyl group, a furyl group, an imidazolyl group, a morpholinyl group, an oxazoline group, a piperidine group, a pyrazinyl group, a tetrahydropyranyl group, a pyrrolidinyl group, and a pyrrolidinone group, or Substituted by a protecting group for a carboxyl group. 11 'A compound of claim 8 wherein R! is an aryl group which is unsubstituted or via- or a plurality selected from a functional group, an alkyl group, an aryl group, an alkoxy group, an aryloxy group, a thioalkoxy group. Substituted by a group consisting of a thioaryloxy group, an acrylamine group, an arylamino group 'cyano group, an aristolooxy group, an arylcarbonyl group, an arylaminocarbonyl group, and an alkylaminocarbonyl group. 12. The compound of claim 8, wherein R! is aryl, unsubstituted or one or more selected from the group consisting of dentate, alkyl, alkoxy, thioalkoxy, alkoxy, and cyano Substituted by a group of substituents. 13. The compound of claim η, wherein the aralkyl group is benzyl, unsubstituted or one or more selected from the group consisting of a functional element, an alkyl group, an aryl 'alkoxy' aryloxy group, a sulfane group Substituted by a group consisting of an oxy group, a thioaryloxy group, an alkylamino group, an arylamine group, a cyano group, a oxycarbonyl group, an arylcarbonyl group, an arylaminocarbonyl group, and an alkylaminocarbonyl group. 107362-1010809.doc -4 - 1378146

14. 如請求項12之化合物，纟中該芳基選自由苯*、萘基、隸及菲基所組成之群，其每—者未經取代或經一或多個選自由齒素、烷基、烷氧基'硫烷氧基、烷氧羰基及亂基組成之群的取代基所取代。 15. 如凊求項8之化合物，其中R!為蔡基、笨曱基、2_氰乙基、薄荷基、甲氧苯曱基、胡椒基、笨基、烷氧羰基苯基、三氯乙基或二苯甲基。 I07362-1010809.doc14. The compound of claim 12, wherein the aryl group is selected from the group consisting of benzene*, naphthyl, and phenanthryl groups, each of which is unsubstituted or one or more selected from the group consisting of dentate and alkane. Substituents of the group consisting of a group, an alkoxy 'thioalkoxy group, an alkoxycarbonyl group and a chaotic group are substituted. 15. The compound of claim 8, wherein R! is caiji, alum, 2-cyanoethyl, menthyl, methoxybenzoyl, piperonyl, strepyl, alkoxycarbonylphenyl, trichloro Ethyl or diphenylmethyl. I07362-1010809.doc