TW200306292A - Production of chirally pure α -amino acids and N-sulfonyl α -amino acids - Google Patents
Production of chirally pure α -amino acids and N-sulfonyl α -amino acids Download PDFInfo
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Abstract
Description
五、發明說明(〗) 主發 本發明係關_料性—-胺級及 基酸之新穎製造方法。本發明之化合物有用於= 基二胺 包括用於製藥組成物。 ;夕 的, 5 業已_多種由^絲 =有效彻備刪方 方面,本發明包括_種製借 鏡像異構物。 基馱之手性純s— 10 及两之手‘來製備:胺基醇,駿 胺基苡來製備ν,“· 15 基二供—種用來製備手性^-碍酿 本發==::覽後物_時當可知曉 說明 本發明係關於製備手性㈣基酸之方法。 基酸解離之方法本發8㈣提供-種將手性叫酿基^胺 適當:::=方合物’其可轉化為 胺基醇,路及月亏等想要的標的化合物知基醇或队續酸基2- 20 200306292V. Description of the invention (〗) Main invention The present invention relates to a novel material --- a novel production method of amine grade and basic acid. The compounds of the present invention are useful in dimethyl diamines including in pharmaceutical compositions. In the evening, 5 have been used in various aspects. Effectively and completely deleted aspects, the present invention includes a system of mirror image isomers. Chiral chiral pure s-10 and two hands' to prepare: amine alcohol, succinyl hydrazone to prepare ν, "· 15 radical di-supply-a kind used to prepare chiral ^-hinder the hair == :: 看 后 物 _ When you can know that the present invention is about the method of preparing chiral ammonium acid. The method of dissociation of base acid This article 8 provides-a kind of chirality called amino amine :: == fanghe Compounds' which can be converted into amino alcohols, alcohols, and other deficient target compounds, such as alcohols or acid groups, 2- 20 200306292
於本文中所用之“手性純的,,一詞係指化合物,其用手 性高效能液體色層分離法(HPLC)來測量時含有大於約95 % s-鏡像異構型式,宜為大於約97%。其他測量手性純度 之方法包括習用之分析方法,包括特定之旋光度,以及習As used herein, the term "chiral," refers to a compound that contains greater than about 95% s-mirror isomers when measured by chiral high performance liquid chromatography (HPLC), and is preferably greater than About 97%. Other methods for measuring chiral purity include customary analytical methods, including specific optical rotation, and customary methods.
用之化學方法。然而,用來測量手性純度之技藝並非本發 明之一種限制。 X 於本文中所用之“製藥上有用的,,一詞係指具有一想要 的生物效果之化合物,無論是作為治療劑,免疫刺激劑或 壓制劑’輔助劑,或疫苗試劑。同樣的,有多種化合物, 10 其適用於非製藥應用,例如,診斷劑,標示劑等可藉由本 發明之方法製備。然而,其他製藥上有用之化合物可 此方法生成。 9 15 經濟部智慧財產局員工消費合作社印製 由本毛月所生成之化合物及任何其所轉化成為之標 化合物可以由製藥上或生理上可接受的酸或驗所衍生之踏 類型式來使用。這些鹽類包括但非侷限於下列與有機酸2 無機酸^列如,酷酸,乳酸,棒樣酸,酒石酸,號續, 反式丁烯二酸,順式丁烯二酸,丙二酸,爲桃酸,^ 一酉夂氫亂酉夂,氫填酸,磷酸,頌酸,硫酸,甲燒 甲苯磺酸及類似之已知可接受的酸,及其混合物所形成之 20鹽類。其他鹽類包括與驗金屬或驗土金屬,例如 氫氧_),_(如氫氧化鉀)飼或鎮,形成之鹽類。 W及其他藉由本發明生成之化合 醋類型式,胺基曱_以及其他制之“前藥,,型式,2 此等至式、·、。藥B守,其可於生體内轉化為活性基團。於—神 •4- 200306292 A7 B7 五、發明說明(3 ) 要的具體例中,該前藥為酯類。參見,例如,Β·惕塔及 范威,再訪鈿藥· Ad Hoc” Approach as a Complement to Ligand Design”,藥物研究評論,i6(3) ·· 233_241,ed., John Wiley & Sons (1996)。 5 天然及非天然01 -胺基酸,天然及非天然2-胺基醇 類,以及其中間體可根據本發明來製備。典型的。0_胺 基酸係用式(NH2)(CHR.)(C00H)來描述,其中,R·為一脂 族基團。該根據本發明所製備之α—胺基酸可轉化為队磺 醯基α-胺基酸及其他想要的化合物。此等其他想要的化 10合物包括,而非侷限於,相關之2-胺基醇,醛,肟,及其 製藥上可接文的鹽類,水合物,及前藥。同樣的,天然及 非天然Ν-磺醯基α-胺基酸,天然及非天然磺醯基2_胺 基醇類,及其中間體可根據本發明來製備。因此,可利用 那些精於此方面技藝之人士所已知之技藝,容易的將本文 15中所說明之Ν-確醯基胺基酸還原為2-胺基醇,或轉化 為相關之醛,肟,及其製藥上可接受的鹽類,水合物,及 前藥。 經濟部智慧財產局員Η消費合作社印製 例如,根據本發明之方法所製得之具有式 (R)2CH(CH2)nCH(C〇2H)NH-R’之手性純-胺基酸可容易的 20轉化為手性純2-胺基醇。於另一例中,根據本發明所製得 之具有式(R)2CH(CH2)nCH(C〇2H)NH-S(0)2R,之手性純 Ν· 磺醯基α -胺基酸可容易的轉化為具有式 (R)2CH(CH2)nCH(CH2〇H)NHS(0)2R,之队磺醯基 2_ 胺基 醇。適當的,於上式中,η為〇至約10 ; R為低級烷基, 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公爱了 200306292 A7 B7 五、發明說明(4 ) 經取代之低級烷基,低級烯基,經取代之低級烯基,低級 快基,經取代之低級炔基,環烧基,經取代之環烧基,苯 基,經取代之苯基,苄基,經取代之苄基,環烷基, (¾各吲呼、,CH(低級烷基)-2-吱喃,CH(低級烷基)_4_甲 5氧基本基’ CH(低級烧基)苯基,或ch(〇H)-4-SCH3-苯 基;且R’係於其他適當的基團中選自H,低級烷基,經取代 之低級烷基,低級烯基,經取代之低級烯基,低級炔基,經 取代之低級炔基,雜環基,經取代之雜環基,苯基,經取代 之笨基,苄基,經取代之苄基,環烷基,及經取代之環烷 1〇 基。於另一例中,具有式(R)2CH(CH2)nCH(CH2〇H)NH-S(0)2-2-C4H2S-5-Cl之N-磺醯基2-胺基醇係根據本發明之方法製 備。然而,該根據本發明之方法所製備之手性純化合物並 非侷限於上式。 經濟部智慧財產局員工消費合作社印製 本文中所用之“烷基,,一詞係指直鏈及分支具有一個至 15十個碳原子之飽和脂族烴基。宜為具有一個至八個碳原 子,且最好為具有一個至六個碳原子;“烯基,,意欲包括直 鏈及分支具有至少一個碳-碳雙鍵及二個至八個碳原子, 宜為二個至六個碳原子之烷基;“炔基,,意欲涵蓋直鏈及分 支具有至少一個碳-碳參鍵及二個至八個碳原子,宜為二 20個至六個碳原子之烷基。本文中所用之“低級,,一詞係指任 何具有一個至六個碳原子之上述定義之基團。 “經取代之烷基”,“經取代之烯基,,,“經取代之炔 基’,,“經取代之低級烷基,,,“經取代之低級烯基,,,“經取 代之低級炔基,,一詞係指如前剛說明之烷基,烯基,炔 -6-The chemical method used. However, the technique used to measure chiral purity is not a limitation of the invention. X As used herein, "pharmaceutically useful," the term refers to a compound that has a desired biological effect, whether as a therapeutic agent, immunostimulant or compression agent, 'adjuvant, or vaccine agent. Similarly, There are various compounds, 10 which are suitable for non-pharmaceutical applications, for example, diagnostic agents, labeling agents, etc. can be prepared by the method of the present invention. However, other pharmaceutical useful compounds can be generated by this method. 9 15 Consumption by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Cooperatives print compounds produced by this month and any target compounds that they convert into can be used from pharmaceutical or physiologically acceptable acids or laboratory-derived tread types. These salts include but are not limited to the following With organic acids 2 Inorganic acids ^ Listed as, cool acid, lactic acid, clavulanic acid, tartaric acid, No. cont., Trans-butenedioic acid, cis-butenedioic acid, malonic acid, tauric acid, ^ a 20 salts formed by hydrogen turbidity, hydrogen filling acid, phosphoric acid, sour acid, sulfuric acid, methyl toluene sulfonic acid and similar known acceptable acids, and mixtures thereof. Other salts include metals Soil testing metals, such as hydrogen and oxygen), (such as potassium hydroxide) feed or town, formed salts. W and other types of compound vinegar produced by the present invention, amines and other "prodrugs" ,, type, 2 these to the formula, · ,. Drug B, which can be converted into active groups in vivo. Yu—Shen • 4- 200306292 A7 B7 V. Description of the Invention (3) In the specific example required, the prodrug is an ester. See, e.g., B. Tita and Fanwei, Revisiting Peony · Ad Hoc "Approach as a Complement to Ligand Design", Drug Research Review, i6 (3) · 233_241, ed., John Wiley & Sons (1996 ). 5 Natural and unnatural 01-amino acids, natural and unnatural 2-amino alcohols, and intermediates thereof can be prepared according to the present invention. typical. The 0-amino acid is described by the formula (NH2) (CHR.) (C00H), where R · is an aliphatic group. The α-amino acid prepared according to the present invention can be converted into sulfofluorenyl α-amino acid and other desired compounds. These other desired compounds include, but are not limited to, related 2-amino alcohols, aldehydes, oximes, and their pharmaceutically acceptable salts, hydrates, and prodrugs. Similarly, natural and unnatural N-sulfofluorenyl α-amino acids, natural and unnatural sulfonyl 2-amino alcohols, and intermediates thereof can be prepared according to the present invention. Therefore, the techniques known to those skilled in this field can be used to easily reduce the N-acidamino acids described in this article to 2-amino alcohols, or convert them to related aldehydes, oximes , And its pharmaceutically acceptable salts, hydrates, and prodrugs. Printed by a member of the Intellectual Property Bureau of the Ministry of Economic Affairs and a consumer cooperative. 20 is converted to chiral pure 2-amino alcohol. In another example, a chiral pure N · sulfofluorenyl α-amino acid having the formula (R) 2CH (CH2) nCH (C02H) NH-S (0) 2R prepared according to the present invention may be Easily converted to a sulfonyl 2-amino alcohol having the formula (R) 2CH (CH2) nCH (CH2OH) NHS (0) 2R. Appropriately, in the above formula, η is 0 to about 10; R is a lower alkyl group, and the paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210x297 publicly known 200306292 A7 B7) V. Description of the invention (4) Substituted Lower alkyl, lower alkenyl, substituted lower alkenyl, lower fast radical, substituted lower alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, benzyl, Substituted benzyl, cycloalkyl, (¾ indio, CH (lower alkyl) -2-sweeten, CH (lower alkyl) _4-methyl-5oxybenzyl, CH (lower alkyl) benzene Or ch (〇H) -4-SCH3-phenyl; and R 'is selected from other suitable groups from H, lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower Alkenyl, lower alkynyl, substituted lower alkynyl, heterocyclyl, substituted heterocyclyl, phenyl, substituted benzyl, benzyl, substituted benzyl, cycloalkyl, and substituted A cycloalkanoyl group. In another example, the compound has the formula (R) 2CH (CH2) nCH (CH2OH) NH-S (0) 2-2-C4H2S-5-Cl Amino alcohols are prepared according to the method of the invention. The chiral pure compound prepared by the method according to the present invention is not limited to the above formula. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the term "alkyl," as used herein, refers to straight chains and branches having one to 15 A saturated aliphatic hydrocarbon group of ten carbon atoms. It is preferably one to eight carbon atoms, and preferably one to six carbon atoms; "alkenyl," which is intended to include straight chains and branches with at least one carbon-carbon bicarbonate Bond and two to eight carbon atoms, preferably an alkyl group of two to six carbon atoms; "alkynyl," is intended to cover straight and branched chains with at least one carbon-carbon parameter bond and two to eight carbon atoms , Preferably an alkyl group of 20 to 6 carbon atoms. The term "lower," as used herein, refers to any group having the above definition of one to six carbon atoms. "Substituted alkyl", "Substituted alkenyl," "Substituted alkynyl '," "Substituted lower alkyl,", "Substituted lower alkenyl,", "Substituted lower alkynyl," Refers to the alkyl, alkenyl, alkyne-6- as just described
200306292 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(5 ) --- 基,低級烷基,低級烯基,及低級炔基,其具有一個至三 個選自包括下列基團之取代基:鹵素,CN,〇H,, 胺基,芳基,雜環基,經取代之芳基,經取代之雜環基2, 烷氧基,經取代之烷氧基,芳氧基,經取代之芳氧基二烷 5基羰基,烷基羧基,烷基胺基,及芳硫基。如果連i造成 一穩定的化學基團,這些取代基可連接至烷基,烯基,或 炔基之任何碳原子。 本文中所用之“芳基,,一詞係指一碳環芳族系,其可為 單環,或芳族多環,其係融合或連接一起使得至少該融 1〇合或連接之環的-部分形成了共輛芳族系。該芳基基團包 括,但非侷限於,苯基,萘基,聯苯基,蒽基,四氳萘 基,苯萘基,及氫茚基。 “經取代之芳基”係指如上所剛定義之芳基,其具有一 個至四個選自包含下列基團之取代基··鹵素,CN,OH, 15 N〇2,胺基,烷基,環烷基,烯基,炔基,烷氧基,芳氧 基,經取代之烷氧基,烷基羰基,烷基羧基,烷基胺基, 及芳硫基。 經取代之苄基”係指於苯環上具有一個至五個選自包 含下列基團之取代基的苄基(Bn):齒素,CN,OH, 2〇 N〇2,胺基,烷基,環烷基,烯基,炔基,烷氧基,芳氧 基,經取代之烷氧基,烷基羰基,烷基羧基,烷基胺基, 及芳硫基。 本文中所用之“雜環基,,一詞係指一穩定的‘至孓員單 環或一穩定多環雜環基,其為飽和,部分不飽和,或不飽 -7- 本紙張尺度適用甲國國家標準(CNS)A4 g (21^H97公髮了200306292 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (5) ---, lower alkyl, lower alkenyl, and lower alkynyl, which have one to three selected from the following groups Substituents: halogen, CN, OH, amine, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl 2, alkoxy, substituted alkoxy, aryloxy , Substituted aryloxydioxane 5-ylcarbonyl, alkylcarboxy, alkylamino, and arylthio. These substituents may be attached to any carbon atom of the alkyl, alkenyl, or alkynyl group if the i is a stable chemical group. The term "aryl," as used herein, refers to a carbocyclic aromatic system, which may be a single ring, or an aromatic polycyclic ring, which is fused or linked together such that at least the 10-ring or linked ring -Partially formed a total aromatic system. The aryl group includes, but is not limited to, phenyl, naphthyl, biphenyl, anthryl, tetranaphthyl, benzonaphthyl, and hydroindenyl. "Substituted aryl" means an aryl group as defined immediately above, which has one to four substituents selected from the group consisting of: halogen, CN, OH, 15 N0, amine, alkyl, Cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. Substituted benzyl "system Refers to benzyl (Bn) with one to five substituents selected from the group consisting of: dentin, CN, OH, 20N2, amine, alkyl, cycloalkyl, olefin , Alkynyl, alkoxy, aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. As used herein, the term "heterocyclyl" refers to a stable 'to a member monocyclic or a stable polycyclic heterocyclic group, which is saturated, partially unsaturated, or unsaturated -7- This paper applies to the standard National Standard A (CNS) A4 g (21 ^ H97 issued
200306292 Α7 五、發明說明(6) 10 15 經濟部智慧財產局員工消費合作社印製 20 和且其含有碳原子及由一個至四個選自包括 原子之雜原子。該S原子可被氧化。該’二美= =二Γ;果=任何上述㈣之雜環環基= 方基%上。如果所產生的結構為化學上 =基可連,至任何雜原子或碳原子。此雜 例如,四氳呋喃,六氫吡啶基,六氫吡畊基,2 咐唆基”丫庚因基,料絲,Μ基,_基 基,射基,塔呼基,十坐基,異十坐基,嗎福咐基,吲 喘基’料基’喧吩基,吱喃基,苯並吱喃基,苯並嗟吩 基’嗔嗎福咐基"塞嗎福咐基亞石風,異4咐基,及四氯硫 哌喃。 ’比 本文中所用之“經取代之雜環基,,一詞係用來說明剛定 義如前之雜環基,其具有一個至四個選自包括下列取代 基:鹵素,CN,OH,Ν02,胺基,烷基,經取代之烷 基,環烷基,經取代之環烷基,烯基,經取代之烯基,炔 基,經取代之炔基,烷氧基,經取代之烷氧基,芳氧基, 經取代之芳氧基,烷氧基,經取代之烷氧基,烷基幾基, 經取代之烧基幾基,烧基叛基,經取代之烧基羧基,烧基 胺基,經取代之烷基胺基,芳硫基,或經取代之芳硫基。 本文中所用之“經取代之環烷基”一詞係指一形成一穩 定環之具有多於三個碳原子之碳基環且具有由一個至五個 選自包括下列基團之取代基·· il素,CN,OH,Ν02,胺 基,烷基,經取代之烷基,烯基,經取代之烯基,炔基, 院氧基,芳氧基,經取代之烧氧基,烧基叛基,烧基叛 計 線 本紙張尺度適用中國國家標準(CNS)A4規格(210 X297公釐) 200306292 B7 A7200306292 Α7 V. Description of the invention (6) 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 20 and it contains carbon atoms and consists of one to four heteroatoms selected from the group consisting of atoms. The S atom can be oxidized. The two dimers = = di Γ; fruit = any of the above heterocyclic ring groups = square group%. If the resulting structure is chemically connectable to any heteroatom or carbon atom. For example, tetrahydrofuran, hexahydropyridyl, hexahydropyridyl, 2 hydrazone, yaheptinyl, silk, M-based, yl-based, radio-based, talhuyl, decyl, Hexadecyl, molybdenyl, indoxy, 'material-based', phenanyl, creanyl, benzocreanyl, benzopyridinyl, hydrazone, quot; Shifeng, isoamyl, and tetrachlorothiopiperan. 'Compared to the "substituted heterocyclic group" used herein, the term is used to describe the heterocyclic group just defined, which has one to four Each is selected from the group consisting of the following substituents: halogen, CN, OH, NO2, amine, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl , Substituted alkynyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkoxy, substituted alkoxy, alkylamino, substituted alkyl A few bases, an alkyl group, a substituted alkyl group, an alkyl group, a substituted alkyl group, an arylthio group, or a substituted arylthio group. As used herein, the term "substituted cycloalkyl" refers to a carbon-based ring having more than three carbon atoms forming a stable ring and having from one to five substituents selected from the group consisting of: · Il, CN, OH, NO2, amine, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, oxo, aryloxy, substituted alkoxy, burn Base paper, base paper calculation standard This paper applies Chinese National Standard (CNS) A4 specification (210 X297 mm) 200306292 B7 A7
基,烷基胺基,經取代之烷基胺基,芳硫基,雜環基,經 取代之雜環基,胺基烧基,及經取代之胺基烧基。 當“經取代之烷基環烷基,,,“經取代之烷基〇Bn,,,‘‘經 取代之烷基吡啶基”,“經取代之烷基呋喃基”,“經取代之 5烷基NHR/’,及“苯基(經取代之)烷基,,,“經取代之烷爲 0H” ’及“經取代之烷基SRs”於下列式I及式以中提及 時’取代作用將發生在烷基或相關之基礎化合物上。 於下式I及la中I基團之定義所使用之沭經取代之 六氫吡啶基係定義為一經取代之雜環基。特別想要的取代 10基為N-烷基-,N-芳基-,N-醯基-,及N-磺醯基六氫咄啶 基。特別適當的N-醯基-六氫吡啶基為N-第三丁氧羰基 (BOC)-六氫吡啶。然而,凡精於此方面技藝之人士可容易 的s忍明其他適當的取代基。 經濟部智慧財產局員工消費合作社印製 本文中所用之“烷氧基,,一詞係指0(烷基)基團,其 15中’連接點係經由氧原子且該烧基可任意的被取代。本文 中所用之“芳氧基”一詞係指〇(芳基)基團,其中,連接點 係經由氧原子且該芳基可任意的被取代。本文中所用之 “烧基幾基”一詞係指C0(烷基)基團,其中,該烷基可任意 的被取代且連接點係經由羰基之碳原子。本文中所用之 2〇 “烧基羧基”一詞係指C〇〇(烧基)基團,其中,該烷基可任 意的被取代且連接點係經由羧基之碳原子。本文中所用之 “胺基烷基”一詞係指第二及第三胺,其中,該含有一個至 八個碳原子之烷基或經取代之烷基,其可相同或不同,且 連接點係在氣原子上。 -9- 本紙張尺度適时關家標準(CNS)A4麻—(_21G χ297公爱) 200306292Group, alkylamino group, substituted alkylamino group, arylthio group, heterocyclic group, substituted heterocyclic group, aminoalkyl group, and substituted aminoalkyl group. When "substituted alkylcycloalkyl,", "substituted alkyl 0Bn,", "substituted alkylpyridyl", "substituted alkylfuryl", "substituted 5 Alkyl NHR / ', and "phenyl (substituted) alkyl," "substituted alkane is 0H" and "substituted alkyl SRs" are substituted in the following formula I and formulas mentioned below The action will take place on an alkyl group or related base compound. The definition of the I group in formulae I and la below is used to define a substituted hexahydropyridyl system as a substituted heterocyclic group. Particularly desirable Substituted 10 groups are N-alkyl-, N-aryl-, N-fluorenyl-, and N-sulfonylhexahydropyridinyl. Particularly suitable N-fluorenyl-hexahydropyridyl is N-th Tributoxycarbonyl (BOC) -hexahydropyridine. However, those skilled in this field can easily identify other suitable substituents. The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed the "alkane" used in this article. The term "oxy" refers to a 0 (alkyl) group, wherein the 'connection point' in 15 is via an oxygen atom and the alkyl group can be optionally substituted. As used herein, the term "aryloxy" refers to a 0 (aryl) group, where the point of attachment is via an oxygen atom and the aryl group can be optionally substituted. As used herein, the term "alkynyl" refers to a C0 (alkyl) group, wherein the alkyl group can be optionally substituted and the point of attachment is through the carbon atom of the carbonyl group. As used herein, the term "alkynyl carboxy" refers to a oxo (alkynyl) group in which the alkyl group is optionally substituted and the point of attachment is through the carbon atom of the carboxyl group. As used herein, the term "aminoalkyl" refers to the second and third amines, wherein the alkyl or substituted alkyl group containing one to eight carbon atoms may be the same or different, and the point of attachment Tied to a gas atom. -9- Standard for timely home care (CNS) A4 hemp — (_ 21G χ297 public love) 200306292
_素’,一詞係指α,Br,F,或j。 如,當^另有說明環結構之型式,“環”結構一詞係指,例 構,-振3^ R4於式1中形成—環結構時,包括一單環結 巧冤結構,及融合環結構。 非扮演^親核性驗”一詞係指一非親核性驗性試劑,其並 技蓺中、、親核試劑或黏附在根據本發明所使用之試劑上。 異丙美已知有多種非親核性驗且包括氫化納,氫化舒,二 ,、:人隨胺鋰及六曱基二石夕疊氮化物。 10中已知各水一詞係指一至少含有一驗及水之溶液。技藝 °有多種鹼可容易的溶解於水中且包括鹼金屬氫氧化 於、、 ,氧氧化鋰,氫氧化鈉或氫氧化鉀等。該鹼性水 液中又可含有其他不會干擾本發明之反應的試劑,且包 括有機〉谷劑,例如,四氫呋喃,曱醇,乙醇,或烴溶劑, 鹽類,·例如,氣化鈉,及緩衝液等。 15 合水酸”一詞係指一至少含有一酸及水之溶液。該酸 經濟部智慧財產局員工消費合作社印製 谷液中又可含有其他不會干擾本發明之反應的試劑。 “強酸”或“強鹼,,一詞係指一可於溶液中完全電離之酸 或驗。—般強酸包括HQ,HBr,HI,HN〇3,H2S04,及 HC1〇4。—般強鹼包括鹼金屬(Li,Na,K,Rb,Cs)之氩氧 20化物及重鹼土金屬(ca,Sr,Ba)之氫氧化物。 無機”酸或“無機”驗包括不含破之化合物。 有機溶劑”一詞包括任何已知技藝中之含碳溶劑,其 不會與反應中所用的試劑進行反應且包括飽和烴溶劑,不 飽和few谷劑’包括芳族煙溶劑,醇類,鹵化碟’鱗,及醋 -10~ 本紙張尺度適用T國國家標準(CNS)A4規禧U10x297公釐) " --— 200306292 A7 B7 五、發明說明(9) 酸鹽等。 手性純化合物之合i 該手性純化合物可用說明於下之方法製備。精於此方 面技藝者將可容易的選擇適當的合成方法及試劑,其係為 5精於此方面技藝者所已知於合成之有機技藝或這些方法之 變化。通常’參見,包羅萬象之有機合成法法,“於現代 有機化學之選擇性,策略及功效”,ed·,J•弗萊明,The term _ prime 'refers to α, Br, F, or j. For example, when ^ additionally indicates the type of ring structure, the term "ring" structure refers to, for example, the structure,-Zhen 3 ^ R4 forms a ring structure in Formula 1, including a single ring structure and fusion.环 结构。 Ring structure. The term "non-nuclear nucleophilic test" refers to a non-nucleophilic test reagent that incorporates a nucleophile, nucleophile, or adheres to a reagent used in accordance with the present invention. Isopropyl is known to have a variety of Non-nucleophilic tests and include sodium hydride, hydrogen sulfoxide, di, and: human with amine lithium and hexafluorenyl diazide azide. The word water in 10 is known to mean one containing at least one test and water. Solution. Skills: There are many kinds of alkalis that can be easily dissolved in water and include alkali metal hydroxides, lithium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. The alkaline aqueous solution may contain other substances that will not interfere with the The reagents for the reaction of the invention include organic> cereals, for example, tetrahydrofuran, methanol, ethanol, or hydrocarbon solvents, salts, for example, sodium gasification, and buffers. 15 The term "hydrated acid" means A solution containing at least one acid and water. The acid produced by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs may contain other reagents that do not interfere with the reaction of the present invention. The term "strong acid" or "strong base" refers to an acid or ion that can be completely ionized in solution.-General strong acids include HQ, HBr, HI, HNO3, H2S04, and HC104.-General strong Includes argon oxide 20 compounds of alkali metals (Li, Na, K, Rb, Cs) and hydroxides of heavy alkaline earth metals (ca, Sr, Ba). Inorganic "acid" or "inorganic" tests include compounds that are not broken. The term "organic solvents" includes any known carbon-containing solvents that do not react with the reagents used in the reaction and include saturated hydrocarbon solvents. Unsaturated few cereals include aromatic smoke solvents, alcohols, halogenated dishes. 'Scales, and vinegar-10 ~ This paper scale is applicable to National Standard T (CNS) A4 regulations U10x297 mm) " --- 200306292 A7 B7 V. Description of the invention (9) Acid salts etc. Synthetic chiral pure compounds can be prepared by the methods described below. Those skilled in this field will be able to easily select appropriate synthetic methods and reagents, which are 5 organic compounds known to those skilled in this field Techniques or changes in these methods. Usually 'see, the all-encompassing organic synthesis method, "selectivity, strategy and efficacy in modern organic chemistry", ed., J. Fleming,
Pergamon Press,New York (1991);包羅萬象之有機化學, “有機化合物之合成法及反應”,ed· J.F. S史脫得, 10 Pergamon Press, New York (1979)。 手性純α-胺基酸之,傷 一方面’本發明係提供一種由手性不純α-胺基酸製備 手性純α-胺基酸之方法。於製備手性純α-胺基酸 XXXXVI時,係使用一種新顆的Strecker α-胺基酸之不對 15稱變體合成法(Scheme 14 ;有機化學期刊54 : 1055-1062(1989))。於此途徑(圖示^中,係將醛χχχχνιι與氰 化物鹽與α-甲基苄胺或其鹽以1 : : 1莫耳比例於一適當 經濟部智慧財產局員工消費合作社印制衣 溶劑中進行反應而得到化合物χχχχνιΙΙ。所包括之想要 的氰化物鹽為氰化鈉及氰化鉀。然而,其他適當的氰化物 20鹽可容易的選擇以用於本發明之方法中。溶劑宜為丨:i 之甲醇至水。該反應宜進行約12至約24小時,且最好為 約18小時。然而,亦可使用較長或較短之反應時間。隨 意的,根據這個反應,可形成一含有沉澱之懸浮液,將其 予以過濾並清洗(例如,用水)而得到一粉末。將化合物 -11 - 本紙張尺度適用肀國國家標準(CNS)A4規^(21〇 X 297公釐)__ 200306292 A7 -------_____ B7 五、發明說明(10) 經濟部智慧財產局員工消費合作社印製 XXXXVIII用一強無機酸,其於與化合物合併時要為冷卻 的’以溶解(例如,約〇〇c至約1〇。〇而提供化合物 XXXXIX。可以時,該強無機酸為硫酸。然而,亦可容易 的選擇其他強無機酸。將反應混合物用一無機鹼予以中和 5並用一有機溶劑萃取成為化合物χχχχΐχ。適當的,可用 醋酸乙醋或其他適當的化合物進行萃取反應,且亦包括乾 燥並濃縮得到化合物χχχχιχ。該氫解反應係於一適當的 催化劑存在之下於例如,3大氣壓之pd或RaNi壓力下進 行’過濾、以移除催化劑,接著濃縮以移除溶劑而得到化合 10物XXXXX。然後將化合物χχχχχ用一含水酸溶解以得 到式XXXXVI衍生物。其間,χχχχχ被乾燥形成粉末型 式,將其於高溫時溶解於一強無機酸而得到一手性純…胺 基酸之鹽。例如,可使用於100它之氫氯酸。或者,精於 此方面技藝之人士可輕易的選擇其他酸及其他適當溫度。 15更可以時,該水解步驟係於約12至18小時,或更長期間 進行。於一適當具體例中,該步驟係進行16小時。任意 的,將該產生的反應混合物濃縮得到一產物,其包含胺基 酸鹽及低當量之銨鹽。於此實例中,該產物為胺基酸氩氯 酸鹽及1當量之氣化鈹。將此產物溶解於水中,於其中加 20 入驗’例如,氫氧化鈉或氫氧化銨以形成一溶液。 -12- 本紙張尺度適用ΐ國國家標準(CNS)A4規格(210 Χ297公釐了 200306292 Α7 Β7 五、發明說明(u) 圖示Pergamon Press, New York (1991); All-inclusive Organic Chemistry, "Synthetic Methods and Reactions of Organic Compounds", ed. J.F. S. Stewart, 10 Pergamon Press, New York (1979). One of the problems of chiral pure α-amino acids is to provide a method for preparing chiral pure α-amino acids from chiral impure α-amino acids. In the preparation of chiral pure α-amino acid XXXXVI, a new type of Strecker α-amino acid was used to synthesize a 15-symbol variant (Scheme 14; Journal of Organic Chemistry 54: 1055-1062 (1989)). In this way (in the figure ^, the aldehyde χχχχνιι and the cyanide salt and α-methylbenzylamine or its salt are used in a 1 :: 1 mole ratio in a suitable printing solvent for the clothing consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. The reaction is carried out to obtain the compound χχχχνιΙΙ. The desired cyanide salts included are sodium cyanide and potassium cyanide. However, other suitable cyanide 20 salts can be easily selected for use in the method of the present invention. The solvent is preferred : I: methanol to water. The reaction is preferably carried out for about 12 to about 24 hours, and preferably about 18 hours. However, longer or shorter reaction times can also be used. Optionally, according to this reaction, A suspension containing precipitates is formed, which is filtered and washed (for example, with water) to obtain a powder. Compound-11-This paper size applies the national standard (CNS) A4 ^ (21〇X 297 mm) ) __ 200306292 A7 -------_____ B7 V. Description of the invention (10) Printed by XXXXVIII, a strong inorganic acid used by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, which must be cooled when dissolved with the compound to dissolve (For example, about 〇〇c The compound XXXXIX is provided to about 10.0. Where possible, the strong inorganic acid is sulfuric acid. However, other strong inorganic acids can also be easily selected. The reaction mixture is neutralized with an inorganic base 5 and extracted with an organic solvent. Compound χχχχΐχ. Appropriately, extraction reaction can be performed with ethyl acetate or other suitable compounds, and also includes drying and concentration to obtain compound χχχχχχ. The hydrogenolysis reaction is in the presence of a suitable catalyst under, for example, 3 atm pd or RaNi pressure was used to filter to remove the catalyst, and then concentrated to remove the solvent to obtain compound XXXXX. Then, the compound χχχχχ was dissolved with an aqueous acid to obtain a derivative of formula XXXXVI. Meanwhile, χχχχχ was dried to form a powder form, It is dissolved in a strong inorganic acid at high temperature to obtain a chiral pure ... amino acid salt. For example, it can be used for 100 hydrochloric acid. Or, those skilled in this field can easily choose other acids And other suitable temperatures. 15 If possible, the hydrolysis step is performed for about 12 to 18 hours, or longer. In a suitable embodiment, this step is performed for 16 hours. Optionally, the resulting reaction mixture is concentrated to obtain a product comprising an amino acid salt and a low equivalent ammonium salt. In this example, the product is an amine Acid argon chloride and 1 equivalent of beryllium gaseous. Dissolve this product in water and add 20 'to the test, for example, sodium hydroxide or ammonium hydroxide to form a solution. -12- This paper size applies ΐ National Standard (CNS) A4 Specification (210 × 297 mm 200306292 A7 B7 V. Description of Invention (u)
Λ XXXXVII CN salt Ο CN 人N, Ο 2 strong acid xxxxvm h2n、^〇 0 h2n"Λ XXXXVII CN salt 〇 CN Human N, 〇 2 strong acid xxxxvm h2n, ^ 〇 0 h2n "
XXXXIX 3 H2/catalystXXXXIX 3 H2 / catalyst
OH 10 J R h2n 4 strong inorganic acid xxxxvi h2n^o R 八 h2n xxxxx 15 經濟部智慧財產局員工消費合作社印製 20 根據本發明之方法所生成之這些手性純a_胺基酸可容 易的以所生成之型式來使用,或轉化為想要的標的化合 物。例如’-手性純a-胺基酸可輕易的藉由將^胺基酸還 原古為2-胺基醇並將該2_胺基醇再結晶而得到手性純胺基 性純2-胺基醇。本發明之手性純a-胺基酸之 輕易的為精於此方面技藝者由本文中所 ^供之貝枓及由精於此方面技藝者所已知之資料所顯而易 土埋差L__N-確醯甚胺基酸之擊備艺1 於另-方面,本發明係提供—種解料性不純之且有 β"刀支燒絲代基之Ν•俩基α,級以提供_手性純 Ν-磺醯基α-胺基酸之圖示。可以 ^ XT ^ 〇 才Ν-磧醯基CX-胺基酸 綠 為队㈣基β_乙基原绳胺酸。於另—具體例中,該原 -13- 本商尺度適F中·f^NS)A4規格⑵0χ297 · 200306292 A7 發明說明 胺酸化合物可被選自N_伽基β·乙基賴胺酸,N-错醉 基綠胺酸,及Ν-續酿基卜正_丙基原白胺酸之化合物所取 代。或者,精於此方面技藝之人士可用另—個選擇的具有 β-分支之絲取代基之Ν_雜基α_胺基酸進行根據本發明 之方法以製備相關之手性純化合物。 10 15 經濟部智慧財產局員工消費合作社印製 20 、適當的,可將Ν_俩基β·乙基賴胺酸(或另一個經 選擇的化合物)與手性純麻黃素半水合物於&醇巾以卜」 之莫耳比例此合。然後將混合物加熱以溶解該固體。於一 具體例中,將混合物加熱至約8〇〇c。然而,亦可容易的選 擇其他適當的溫度。之後,將混合物冷卻錢形成沉殿。 此冷卻步驟可於室溫或降低溫度(於约5t)時進行過夜(約 1 /0〗、日小冷4卩步驟之溫度及期間可依照需要或意願各 自往上或往下懸。任意的,可於冷卻後㈣浮液過滤或 清洗、。然後將紐再結晶且然後轉於—_及強含水酸 中。適當的,該再結晶步驟係於海騰的魏乙g旨中進行且 將該再結晶之鹽分離。此可用過濾法或其他習用方法進 打。適當的,該鹽係溶解於一有機溶劑及一強含水酸中。 將有機萃出物清洗,乾燥並濃縮而制手性純酿基 α-胺基酸。於一具體例中,該清洗步驟係用一強含水 酸,例如,氫氯酸進行,且乾燥係用硫酸鈉等進行。 適當的,這些手性純α_胺基酸及胺基酸 可用於多種目的巾。例如,這㈣性H紐及义磺 醯基胺基酸可藉由本文中說明之方法轉化為相關之N_ 磺醯基2-胺基醇。 -14- 本紙張尺度適用中國ii^(CNS)A4規格(210 X 297公gy--—_______________ 一· 200306292 A7 ------ B7 五、發明說明(13) 因此’於一具體例中,該根據本發明生成之手性純α_ 胺基酸可用於合成手性队續醯基胺基酸。這些手性Ν-石頁fe基α-胺基酸之適當製法係提供於本文中。 胺基醇 5 本發明之製法提供合成α-胺基酸及N-磺醯基α-胺基 酸之手性純S鏡像異構物之有效途徑,其可用來製備2-胺 基醇或Ν-磺醯基2-胺基醇,及其中間體,其可用於多種 目的。 經濟部智慧財產局員工消費合作社印製 例如,本文中所提供之實例化合物,Ν-磺醯基2-胺基 10醇及其相關之醛,肟及鹽,可用來調節石-澱粉狀朊之生 成,其係涉及於澱粉狀朊血管病,大腦澱粉狀朊血管病, 全身性澱粉狀變性病,早老性癡呆徵侯群(AD),具德式澱 粉狀朊變性病之遺傳性大腦出血,包括體肌炎,唐氏症候 群等。因此,式(I)化合物可調節罹患AD或其他因大腦中 15石-澱粉狀朊蛋白質之濃度上升所造成之疾病或有此等風 險之個體的-殿粉狀朊之生成。這些化合物及其用途於 2001年12月11曰同時申請之美國專利申請案第 10/014,304號中有更詳細的說明,其係合併於本文中作為 蒼考。式(I)化合物包括製藥上可接受的鹽類及/或其水合 20 物或前藥,其中,式(I)為:OH 10 JR h2n 4 strong inorganic acid xxxxvi h2n ^ o R eight h2n xxxxx 15 Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 20 These chiral pure a-amino acids generated according to the method of the present invention can be easily used The resulting form is used or converted into the desired target compound. For example, '-chiral pure a-amino acid can be easily obtained by reducing ^ amino acid to 2-amino alcohol and recrystallizing the 2-amino alcohol to obtain chiral pure amine pure 2- Amino alcohol. The chiral pure a-amino acid of the present invention is easily shown by the beakers provided by the artisans skilled in this field and by the information known to the artisans skilled in this field. -Determining the Strike Preparation Techniques of Very Amino Acids 1 In another aspect, the present invention provides a kind of N • two-base α, which is impure and has β " blade-burning silk-based radicals, to provide _ hand Schematic representation of a pure N-sulfofluorenyl alpha-amino acid. ^ XT ^ 〇 N-fluorenyl CX-amino acid Green is sulfanyl β-ethyl orthanoline. In another-specific example, the original -13- this quotient is moderate F · NS) A4 specifications ⑵ 0 297 · 200306292 A7 The invention shows that the amino acid compound can be selected from N-gamma β · ethyl lysine, Substituted by N-pyridylchloroamine and N-continuous n-propyl-ortho-leucine. Alternatively, those skilled in the art can perform the method according to the present invention with another selected N-heteroα-amino acid having a β-branched silk substituent to prepare related chiral pure compounds. 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20, where appropriate, N_twoyl β · ethyllysine (or another selected compound) and chiral pure ephedrine hemihydrate can be used in & Alcohol towels are based on the Mohr ratio. The mixture was then heated to dissolve the solid. In a specific example, the mixture is heated to about 800c. However, other suitable temperatures can be easily selected. After that, the mixture was cooled to form a temple. This cooling step can be performed at room temperature or at a reduced temperature (about 5t) overnight (about 1/0), the temperature and duration of the step 4 of the day can be suspended upward or downward as required or desired. Any After cooling, the floating liquid can be filtered or washed, and then recrystallized and then transferred to — and strong aqueous acid. Appropriately, the recrystallization step is performed in Hai Yi's Wei Yi g purpose and The recrystallized salt is separated. This can be filtered by filtration or other conventional methods. Appropriately, the salt is dissolved in an organic solvent and a strong aqueous acid. The organic extract is washed, dried and concentrated to produce chirality. Pure brewing α-amino acid. In a specific example, the washing step is performed with a strong aqueous acid, such as hydrochloric acid, and the drying is performed with sodium sulfate, etc. As appropriate, these chiral pure α_ Amino acids and amino acids can be used for a variety of purposes. For example, this hydrazine and sulphosulfinoamino acid can be converted into related N-sulfofluorenyl 2-amino alcohols by the methods described herein. -14- This paper size applies to China ii ^ (CNS) A4 specification (210 X 297 male gy ---______________ _ I. 200306292 A7 ------ B7 V. Explanation of the invention (13) Therefore, 'In a specific example, the chiral pure α-amino acid generated according to the present invention can be used to synthesize chiral continyl amines. A suitable method for the preparation of these chiral N-leaf-fe-α-amino acids is provided herein. Amino alcohols 5 The method of the present invention provides the synthesis of α-amino acids and N-sulfonyl α-amines. An effective way for the chiral pure S mirror image isomers of amino acids, which can be used to prepare 2-amino alcohols or N-sulfonyl 2-amino alcohols, and their intermediates, which can be used for a variety of purposes. Printed by the Consumer Affairs Cooperative of the Property Bureau. For example, the example compounds provided herein, N-sulfofluorenyl 2-amino 10 alcohol and its related aldehydes, oximes, and salts can be used to regulate the formation of stone-amyloid hydrazone. Involved in amyloid iliac vascular disease, cerebral amyloid iliac vascular disease, systemic amyloidosis, Alzheimer's disease syndrome (AD), hereditary cerebral hemorrhage with German amyloid iliosis, including body muscles Inflammation, Down's syndrome, etc. Therefore, compounds of formula (I) can modulate the development of AD or other 15 stone-starch in the brain The disease caused by the increase in the concentration of 朊 protein or the formation of powdery 朊 in individuals who are at risk of these. These compounds and their uses are in US Patent Application No. 10 / 014,304, which was filed simultaneously on December 11, 2001 There is a more detailed explanation, which is incorporated herein as Cangkao. Compounds of formula (I) include pharmaceutically acceptable salts and / or hydrates or prodrugs thereof, wherein formula (I) is:
⑴ -15- ^»尺度適用國家標準(CNS)A4規格(21^x297^53· 200306292 A7 B7 五、發明說明(14) R3係選自包括氫,烷基,及經取代之烷基之基團; R4係選自包括氫,烷基,經取代之烷基,烷基環烧 基,經取代之烷基環烷基,苯基(經取代之)烷基,烷基 0H,經取代之烷基〇H,烷基OBn,經取代之烷基OBn, 5 烷基吡啶基,經取代之烷基吡啶基,烷基呋喃基,經取代 之烷基呋喃基,CH(OH)苯基,CH(OH)經取代之苯基,烯 基,經取代之烯基,環烷基,經取代之環烷基,N-取代 之-六氫吼唆基,六氫咐《咬基,經取代之六氫吼咬基,四 氫噻哌喃基,經取代之四氫噻哌喃基,2-氫茚,經取代之 10 2-氫茚,苯基,經取代之苯基,烷基NHr7,及經取代之 烷基NHR7 ; 但R3及R4不同時為氫; R7為烷基,經取代之烷基,環烷基,經取代之環烷 基,苄基,經取代之苄基,烷基OH,經取代之烷基OH, 15烷基SR8,或經取代之烷基sr8 ; R8為烷基,經取代之烷基,苄基,或經取代之苄基; 或R3及R4可一起形成一環; 經濟部智慧財產局員工消費合作社印製 R5係選自包括氫,低級烧基,經取代之低級烧基,烯 基,經取代之烯基,炔基,經取代之炔基,cH2環烷基, 20經取代之CH2環烷基,苄基,經取代之苄基,及 ch2ch2qr9 ; Q 為 Ο,NH 或 S ; R9為低級烷基,經取代之低級烷基,苯基,或經取代 之苯基; -16- 200306292 A7 B7 五、發明說明(l5 R6係選自包括氫,鹵素及CF3之基團 T係選自包括下列之基團⑴ -15- ^ »Applicable national standard (CNS) A4 specification (21 ^ x297 ^ 53 · 200306292 A7 B7 V. Description of the invention (14) R3 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkylcycloalkyl, substituted alkylcycloalkyl, phenyl (substituted) alkyl, alkyl 0H, substituted Alkyl OH, alkyl OBn, substituted alkyl OBn, 5 alkylpyridyl, substituted alkylpyridyl, alkylfuranyl, substituted alkylfuranyl, CH (OH) phenyl, CH (OH) substituted phenyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, N-substituted-hexahydrocarbyl, hexahydro Hexahydrocarbyl, tetrahydrothiopiperanyl, substituted tetrahydrothiopiperanyl, 2-hydroindene, substituted 10 2-hydroindene, phenyl, substituted phenyl, alkyl NHr7 , And substituted alkyl NHR7; but R3 and R4 are not hydrogen at the same time; R7 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, benzyl, substituted benzyl, alkyl OH, substituted alkyl OH 15 alkyl SR8, or substituted alkyl sr8; R8 is alkyl, substituted alkyl, benzyl, or substituted benzyl; or R3 and R4 can form a ring together; consumption by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Cooperative printed R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cH2 cycloalkyl, 20 substituted CH2 rings Alkyl, benzyl, substituted benzyl, and ch2ch2qr9; Q is 0, NH or S; R9 is lower alkyl, substituted lower alkyl, phenyl, or substituted phenyl; -16- 200306292 A7 B7 V. Description of the invention (15 R6 is selected from the group including hydrogen, halogen and CF3, T is selected from the group including
〇〇
An 及An and
OH 10 15 經濟部智慧財產局員工消費合作社印製 R!及R2係各自獨立選自包括下列之基團:氫,烷 基,經取代之烷基,CF3,烯基,經取代之烯基,炔基, 經取代之炔基,環烷基,經取代之環烷基,苯基,經ς代 之苯基’及(CH2)n(l,3)二4烷,其中,η為2至5 ; w,y及ζ係各自獨立選自包括下列之基團:c, CRw及N ’但至少一個W,Y及z必須為c ;OH 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R! And R2 are each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, CF3, alkenyl, substituted alkenyl, Alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl 'and (CH2) n (l, 3) di4alkane, where η is 2 to 5; w, y and ζ are each independently selected from the group consisting of: c, CRw and N ', but at least one of W, Y and z must be c;
Rio係選自包括氫及鹵素之基團; X係選自包括〇,s ’ so2,及NRii之基團;Rio is selected from the group including hydrogen and halogen; X is selected from the group including 0, s' so2, and NRii;
Rll係選自包括下列之基團··氫,低級烷基,經取代 之低級烷基,苄基,經取代之苄基,苯基,及經取代之笨 基。 W-X-Y-Z-C雜環基對於S〇2基團之連接點不為本發明 之一項限制。然而,於一較佳具體例中,該環係經由一碳 原子而連接至S〇2基團。然而,該環可經由〇,S,或N 20 雜原子連接。 式(I)化合物中含有一個或多個不對稱碳原子且_此化 合物中含有一個或多個不對稱(手性)中心且因此生成光學 異構物及非對映立體異構物。雖然顯示於式(I)無關於立體 化學,當式(I)化合物含有一個或多個手性中心時,至少 -17- 本紙張尺度適用1^國國家標準(CNS)A4]格(210x297公爱] '~' ___________ 200306292 Α7 Β7 五、發明說明(16) α-胺基酸衍生之手性中心必須為S-立體化學。更佳者, Ν,Τ,R3及R4所連接之碳原子為S-立體化學。 於一具體例中,本發明係關於一種製備具通式la之 N-磺醯基2-胺基醇之手性S鏡像異構物之方法:Rll is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, and substituted benzyl. The point of attachment of the W-X-Y-Z-C heterocyclic group to the S02 group is not a limitation of the present invention. However, in a preferred embodiment, the ring system is connected to the S02 group via a carbon atom. However, the ring may be connected via O, S, or N20 heteroatoms. The compound of formula (I) contains one or more asymmetric carbon atoms and this compound contains one or more asymmetric (chiral) centers and thus generates optical isomers and diastereoisomers. Although shown in formula (I) is not related to stereochemistry, when the compound of formula (I) contains one or more chiral centers, at least -17- this paper size applies to the national standard (CNS) A4] (210x297) Love] '~' ___________ 200306292 Α7 Β7 V. Description of the invention (16) The chiral center derived from α-amino acid must be S-stereochemistry. More preferably, the carbon atoms connected to NR, T, R3 and R4 are S-stereochemistry. In a specific example, the present invention relates to a method for preparing a chiral S image isomer of N-sulfofluorenyl 2-amino alcohol having the general formula la:
RR
R 10R 10
NH (CH2)nNH (CH2) n
OH 經濟部智慧財產局員工消費合作社印製 其中,R為低級烷基,經取代之低級烷基,低級烯 基,經取代之低級烯基,低級炔基,經取代之低級炔基, 環烷基,經取代之環烷基,苯基,經取代之苯基,苄基, 15 經取代之苄基,CH2環烷基,CH2-3-l丨哚,CH(低級烷基)-2-吱喃,CH(低級烧基)-4_甲氧基苯基,CH(低級烧基)苯 基,或CH(OH)-4-SCH3-苯基且η為〇至約10。 如想要,根據本發明之方法所製得之化合物含有至少 一個手性碳中心,其中,R於上述結構中乃相同。於某些 20 想要的具體例中,R基團為甲基,乙基,及正丙基,且更 佳者乃R為乙基。然而,本發明亦包括生產通式之α-胺 基酸及2-胺基醇,惟此處中R基團乃相異。於這些化合物 中,可出現一個或多個其他的手性中心;然而,該其他的 手性中心必須為光學上純的且必須不干擾本發明之手性純 -18- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200306292 A7 B7 五、發明說明(17) α-胺基酸,2-胺基醇,及N-磺醯基2-胺基醇之純s鏡像 異構物的生成。 於另一較佳具體例中,該手性碳中心為生成鏡像異構 純產物之S-立體化學。 5 於一具體例中,本發明之方法係用來生產手性純〇;_胺 基酸’其可容易的轉化為Ν-磺醯基胺基酸。例如,根 據本發明之方法所製得之手性純胺基酸可用來製備式(1) 化合物。特別想要的式(I)化合物包括噻吩胺磺醯,且更想 要的為’ 5-_素17塞吩胺績醯’且最想要的為5-_素。塞吩胺 10 磺醯,其於第一醇側鏈上為冷-分支。因此,關於式(I), 根據本發明所生成之化合物可具有一結構,其中,X為 s,W為C,γ為C(或CR1())且Ζ為C(或CR1G),且胺磺醯 係連接到噻吩環之C2。較佳者,X為S,W為C,Y為 C(或CR10),ζ為C(或〇110)且R6鹵素。最佳的,X為 15 8,^^為〇,丫為〇,2為(:,116為鹵素,丁為 經濟部智慧財產局員工消費合作社印製 C(〇H)RiR2,其中,Ri及R2為氫,R3為Η ’ R4為S-立體 化學之低級烷基,且R5為Η。其他可能的式(I)化合物為 呋喃胺磺醯,其中,X為〇,W為C,Y為C,且Ζ為 C。於一個特別的具體例中,式(I)之呋喃胺磺醯亦可用第 20 一醇之側鏈的/3 -分支來描述。因此,關於式(I)化合物, 於這些化合物中,T為CCOH)!^^,其中,&及r2為 氫,R3為Η,R4為S-立體化學之低級烷基,R5為Η且R6 為鹵素。於試管内及生體内之初步篩選分析中,這些結構 之經選擇的化合物具有不可預期的良好^ -殺粉狀朊抑制 -19- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200306292 A7Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, where R is lower alkyl, substituted lower alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, naphthene , Substituted cycloalkyl, phenyl, substituted phenyl, benzyl, 15 substituted benzyl, CH2 cycloalkyl, CH2-3-1, indole, CH (lower alkyl) -2- Squeeze, CH (lower alkyl) -4-methoxyphenyl, CH (lower alkyl) phenyl, or CH (OH) -4-SCH3-phenyl and η is from 0 to about 10. If desired, the compound prepared according to the method of the present invention contains at least one chiral carbon center, wherein R is the same in the above structure. In certain specific examples, the R group is methyl, ethyl, and n-propyl, and more preferably R is ethyl. However, the present invention also includes the production of α-amino acids and 2-amino alcohols, but the R groups are different here. Among these compounds, one or more other chiral centers may appear; however, the other chiral centers must be optically pure and must not interfere with the chirality of the present invention. Standard (CNS) A4 specification (210 X 297 mm) 200306292 A7 B7 V. Description of the invention (17) Pure s mirror image of α-amino acid, 2-amino alcohol, and N-sulfonyl 2-amino alcohol Formation of isomers. In another preferred embodiment, the chiral carbon center is S-stereochemistry which produces a mirror-isomeric pure product. 5 In a specific example, the method of the present invention is used to produce chiral pure o-amino acid 'which can be easily converted into N-sulfoamidoamino acid. For example, a chiral pure amino acid prepared according to the method of the present invention can be used to prepare a compound of formula (1). Particularly desirable compounds of formula (I) include thienylsulfenium sulfonium, and the more desired is '5-_17 17 cephenamine hydrazone' and the most desired is 5-_. Sedphenamine 10 sulfofluorene, which is cold-branched on the first alcohol side chain. Therefore, regarding formula (I), the compound produced according to the present invention may have a structure in which X is s, W is C, γ is C (or CR1 ()) and Z is C (or CR1G), and the amine Sulfonium is attached to C2 of the thiophene ring. Preferably, X is S, W is C, Y is C (or CR10), ζ is C (or O110), and R6 is halogen. Most preferably, X is 15 8, ^^ is 0, y is 0, 2 is (:, 116 is halogen, and D is printed by C (〇H) RiR2, which is an employee consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Among them, Ri and R2 is hydrogen, R3 is Η 'R4 is a lower alkyl group of S-stereochemistry, and R5 is Η. Other possible compounds of formula (I) are furansulfuron, wherein X is 0, W is C, and Y is C, and Z is C. In a particular specific example, the furansulfuronium of formula (I) can also be described by the / 3-branch of the side chain of the 20th alcohol. Therefore, regarding the compound of formula (I), In these compounds, T is CCOH)! ^^, wherein & and r2 are hydrogen, R3 is Η, R4 is a lower alkyl group of S-stereochemistry, R5 is Η, and R6 is halogen. In the preliminary screening analysis in vitro and in vivo, the selected compounds of these structures have unexpectedly good results. ^ -Powder-like 朊 inhibition-19-This paper is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 200306292 A7
活14,且於許多情況下,較具有其他雜環之式⑴化合物具 有,佳之活性(例如,呋喃,其中,X為〇)。然而,其他 此等式(I)化合物亦有用於本文中說明之目的。 此外,其他藉由本發明所製備之手性純^^胺基酸及 5沐飧醯基2_胺基酸可轉化為所要的N_磺醯基2-胺基醇, 其包括式⑴化合物。式⑴化合物係由⑴之胺磺醯來描述, 其於第一醇基團之側鏈具有分支。因此,關於⑴化合 物,於這些化合物中,T為0:(011)1¾,Rl及R2為氫, R3為Η,FU為S-立體化學之低級烷基,且Rs為η。這些 、及手性純Ν-%醯基α-胺基酸可根據於本文中說明之下 列方法製備。 製法中之第一個方法包括將2-胺基醇Π與適當的磺醯 鹵於一鹼例如三乙胺(TEA)及一適當的溶劑存在之下進行 反應而得到式III化合物。於化合物中之R2及Ri為氫 15 ^ ’將N-磺酸基第一醇用氣鉻酸紕鍵(PCC)或在斯峨條件 經濟部智慧財產局員工消費合作社印制衣 下進行氧化,然後得到相關之醛IV,其可與格利雅試劑 (RMgX,其中,r為一有機基團且X為一鹵素)進行反應 而得到呈一非對映立體異構物之混合物的第二醇V,其可 藉由高效能液體色層分離法(HPLC)來分離(圖示2)。 20 -20- 本紙m八厌迥用甲國國家標準(CNS)A4規格(21〇 χ 297公釐) 200306292 A7 五、發明說明(19 圖示2 OH h2n14 and, in many cases, has better activity than compounds of formula IX having other heterocycles (e.g., furan, where X is 0). However, other such compounds of formula (I) are also useful for the purposes described herein. In addition, other chiral pure amino acids and 5-amino-2-amino acids prepared by the present invention can be converted into the desired N-sulfofluorenyl 2-amino alcohols, which include compounds of formula (I). The compound of formula VII is described by sulfamonium, which has a branch on the side chain of the first alcohol group. Therefore, regarding the amidine compounds, among these compounds, T is 0: (011) 1¾, R1 and R2 are hydrogen, R3 is fluorene, FU is a lower alkyl group of S-stereochemistry, and Rs is η. These and chiral pure N-% fluorenyl alpha-amino acids can be prepared according to the methods described below. The first method in the production process involves reacting 2-amino alcohol Π with an appropriate sulfonium halide in the presence of a base such as triethylamine (TEA) and an appropriate solvent to obtain a compound of formula III. R2 and Ri in the compound are hydrogen 15 ^ 'N-sulfonic acid primary alcohol is oxidized with gas chromate bond (PCC) or printed under the clothing of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, Ministry of Economy and Technology Then the related aldehyde IV is obtained, which can be reacted with Grignard reagent (RMgX, where r is an organic group and X is a halogen) to obtain a second alcohol V which is a mixture of diastereoisomers , Which can be separated by high performance liquid chromatography (HPLC) (Figure 2). 20 -20- This paper is used for National Standard (CNS) A4 specifications (21 × 297 mm) 200306292 A7 V. Description of the invention (19 Picture 2 OH h2n
Ri ΠRi Π
PCC or Swem when in III, R^R^h 10PCC or Swem when in III, R ^ R ^ h 10
15 經濟部智慧財產局員工消費合作社印制衣 製法中之第„個方法包括將^_胺基酸或_ Η與適當 的磺^於-_如三乙胺及_適當溶劑存在之下進行反 應而付到式X化合物(圖示3)。該中間體績酿酸 X(Rx=H)可利用標準方法,例如:謹4,峨或氰尿酿氣 /NaBH4哺化為相關之第_醇vm(Ri=R2=H)。或者,中 間體N-磺醯酯X(RX==烷基,Bn)可用DiBAL而轉化為醛 IV 〇 20 -21- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200306292 A7 B7 五、發明說明(20 ) 圖示315 The first method in the printed clothing manufacturing method of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs includes reacting ^ _amino acid or _ with an appropriate sulfonium in the presence of -_ such as triethylamine and _ appropriate solvents And pay for the compound of formula X (Figure 3). The intermediate Xanthate X (Rx = H) can be used standard methods, such as: Jin 4, E, or cyanuric acid / NaBH4 to feed into the related _ alcohol vm (Ri = R2 = H). Alternatively, the intermediate N-sulfonyl ester X (RX == alkyl, Bn) can be converted to aldehyde IV by DiBAL 〇20 -21- This paper applies Chinese National Standard (CNS) A4 specification (210x297 mm) 200306292 A7 B7 V. Description of invention (20) Picture 3
DiBAL alkyl, BnDiBAL alkyl, Bn
III VIII 經濟部智慧財產局員工消費合作社印製 15 最後,中間體N-磺醯酯X(Rx=烷基,Bn)可與2當量 之格利雅試劑進行反應而得到第三醇ΠΙ,其r1=R2=烧 基。或者,於R!不等於R2之第三醇III時,可製備相關 之N-磺醯酸之Weinreb醯胺(參見圖示11)且隨即與 20 RiMgX及IMgX進行反應。於在CK -胺基酸碳上具有一個 不對稱中心之式X化合物(RX=H)時,該純鏡像異構物可藉 由與多種手性鹼形成之鹽類的再結晶法之標準解析過程而 得到。 於製備第一醇之第二個方法之變化例中,係首先將α_ -22- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200306292 A7III VIII Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 15 Finally, the intermediate N-sulfonyl ester X (Rx = alkyl, Bn) can be reacted with 2 equivalents of Grignard reagent to obtain the third alcohol III, which r1 = R2 = base. Alternatively, at the third alcohol III where R! Is not equal to R2, the relevant Weinreb amide of N-sulfonic acid (see Figure 11) can be prepared and then reacted with 20 RiMgX and IMgX. In the case of a compound of formula X (RX = H) having an asymmetric center on CK-amino acid carbon, the pure mirror isomer can be analyzed by the standard recrystallization method of salts with various chiral bases Process. In the variation of the second method of preparing the first alcohol, the paper size α_-22- is firstly applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200306292 A7
200306292 A7 B7 五、發明說明(22 :) 而得到XV,接㈣原4 胺基醇且隨即石黃醯化得到標的 化合物XVI。見圖示2至5,r5為Η。200306292 A7 B7 V. Explanation of the invention (22 :) Then XV is obtained, followed by primogen 4 amino alcohol, and then the luteinization yields the target compound XVI. See diagrams 2 to 5, r5 is Η.
15 於衣備Ν-烧基化胺續酿viii(r5=烧基等)時,將胺確 醯酯XVII藉由用適當的鹼例如,碳酸鉀接著用烷基化試 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 劑RSX或使用Mitsunobu條件(ioh/DEAD,TPP)處理而 N-烷基化。將該N_烷基化之胺磺醯酯予以UBI^還原而 2〇得到第-醇系列VIII之N-燒基化胺磧醯(圖示6)。這些第 -醇viii可藉由概述於上之化學法而轉化為第二醇v或 醛IV系列。或者,該N_烷基化之胺磺醯酯,或其相關之15 In the preparation of N-alkylated amines viii (r5 = carbonized, etc.), the amine confirmation ester XVII is tested by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs by using an appropriate base such as potassium carbonate followed by alkylation. The consumer cooperative printed formulation RSX or N-alkylated was treated using Mitsunobu conditions (ioh / DEAD, TPP). This N-alkylated sulfamidine is reduced by UBI ^ to obtain N-alkylated amine sulfonium of the -th alcohol series VIII (Figure 6). These first-alcohol viii can be converted to the second alcohol v or aldehyde IV series by the chemical methods outlined above. Alternatively, the N-alkylated sulfasalamide, or related
Weinreb醯胺可藉由用袼利雅試劑處理而得到N_烷基化第 三醇III。 -24-Weinreb ammonium can be obtained by treatment with Zaliya reagent to obtain N-alkylated tertiary alcohol III. -twenty four-
200306292200306292
五、發明說明 23 圖示6V. Description of the Invention 23 Figure 6
ORx Rx= alkyl or Bn xvn or R5OH/DEAD/TPP 2 LiBH4ORx Rx = alkyl or Bn xvn or R5OH / DEAD / TPP 2 LiBH4
1 Base/R5X1 Base / R5X
vm 當該連接至上述醇之胺磺醯的雜環為噻吩時,該相關 之石風衍生物XIX可藉由將噻吩化合物xvm用MCPBA氧 化而製得(圖示7)。 10 圖示7 15 r6·vm When the heterocyclic ring of the sulfamidine connected to the above alcohol is thiophene, the related stone wind derivative XIX can be prepared by oxidizing the thiophene compound xvm with MCPBA (Figure 7). 10 Figure 7 15 r6 ·
r2 Ri MCPBAr2 Ri MCPBA
XVIIIXVIII
XIXXIX
OHOH
經濟部智慧財產局員工消費合作社印製 20 由非天然2-胺基醇所衍生之胺磺醯的變化製法係利用 Strecker α-胺基酸合成之Bucherer修正法(圖示8)。於此途 控中’一搭XX係與氰化物陰離子及碳酸銨進行反應而得 到乙内酿脲XXI,將其水解為胺基酸χχιι。然後將此 化合物還原為ΧΧΙΠ並磺醯化而得到所要的式XXIV化合 物。 -25- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公髮) 200306292 A7 B7 五、發明說明(24 圖示8Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 The change method of amine sulfonium derived from unnatural 2-amino alcohols is the Bucherer correction method using Strecker α-amino acid synthesis (Figure 8). In this way, the ‘Take XX series’ reacts with the cyanide anion and ammonium carbonate to obtain the hydantoin XXI, which is hydrolyzed to the amino acid χχιι. This compound is then reduced to XIXII and sulfonated to give the desired compound of formula XXIV. -25- This paper size applies to China National Standard (CNS) A4 (210x297) 200306292 A7 B7 V. Description of the invention (24 Figure 8
RbRb
RaRa
1 NaCN/(NH4)2C03 9 Rb 2 NaOH1 NaCN / (NH4) 2C03 9 Rb 2 NaOH
RaRa
XXXX
XXI h2n XXII 3 L1AIH4XXI h2n XXII 3 L1AIH4
RbRb
Rb HORb HO
HN—S—Hetar\l II - 〇 4 HetarylS〇2ClHN—S—Hetar \ l II-〇 4 HetarylS〇2Cl
Ra —- HO’ h2nRa —- HO ’h2n
XXIIIXXIII
XXIV 10 於由含有N或O雜原子於側鏈之2-胺基醇所衍生之 胺磺醯時,反應途徑係設計成由D-絲胺酸開始(圖示9)。 於此途徑中,係首先將D-絲胺酸XXV磺醯化為XXVI且 隨即轉化為酮XXVII,將其還原性胺化為式XXVIII之標 的化合物。 15 圖示9XXIV 10 In the case of sulfamonium derived from 2-amino alcohols containing N or O heteroatoms in the side chain, the reaction pathway is designed to start with D-serine (Figure 9). In this route, D-serine XXV is first sulfonated to XXVI and then converted to ketone XXVII, which is reductively aminated to the target compound of formula XXVIII. 15 Figure 9
〇Ή II co2h h2n〇Ή II co2h h2n
OH 〇OH 〇
TEA Y-TEA Y-
co2h , II π x 0 11 LJ 一 HN IIco2h, II π x 0 11 LJ-HN II
經濟部智慧財產局員工消費合作社印製 20Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20
XXVXXV
0 〇H XXVI0 〇H XXVI
BuLiBuLi
RcMgXRcMgX
H κ^νη2 Na(OAc)3BH R . HOAc 6 xx vm -26-H κ ^ νη2 Na (OAc) 3BH R. HOAc 6 xx vm -26-
Rc' II 〇Rc 'II 〇
co - HNco-HN
OH xxvn 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 200306292 Α7 經濟部智慧財產局員工消費合作社印制衣 五、發明說明 ㈣—醇系列(其中R1==H且 2-胺基醇雜時,= 合物細0)之述,設計成_IV«(如圖示2中製^;如騎10所概 圖示10OH xxvn This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 200306292 Α7 Printing of clothing by employees ’cooperatives of the Intellectual Property Bureau of the Ministry of Economy -When the amino alcohol is mixed, = compound fine 0), designed as _IV «(as shown in Figure 2); as shown in Figure 10
XXIX 10 15 20 如於 V之2韻^示2之章節中所提及者,由於第二醇系列 異構混合物之製法中造成了非對映立體 生成之化合物i造14些可造成純非對映立體異構物 的另一個方法則係概述於由L·異白胺酸所衍 σ ^的圖示11中。該方法,其係採用先前由R〇ux 4用之化學法(四面體50:5345d36〇(1994)),包括將格 利雅试劑添加到Weinreb醯胺XXX(由必須α_胺基酸所衍 生)中接著將嗣ΧΧΧΙ予以立體有擇性還原而得到一單一非 對映立體異構之Ν-經保護之2-胺基醇XXXII。將此化合 物去保護接著與磺醯氣進行反應而得到如式XXXIII之純 非對映立體異構之胺磺醯第二醇。 -27- 本紙張尺度適用中國國家標準(CNS)A4規格(210χ297公爱)XXIX 10 15 20 As mentioned in the section of V 2 rhyme ^ 2, due to the diastereoisomeric compounds produced in the preparation of the second alcohol series of isomeric mixtures, making 14 of these can cause pure non-pairing Another method for enantiomeric stereoisomers is outlined in Scheme 11 of σ ^ derived from L. isoleucine. This method uses the chemical method previously used by Roux 4 (tetrahedron 50: 5345d360 (1994)), including the addition of Grignard reagents to Weinreb amine XXX (derived from the essential α-amino acid ) Followed by the stereoselective reduction of YXXXI to give a single diastereoisomeric N-protected 2-amino alcohol XXXII. This compound is deprotected and then reacted with the sulfonium gas to give a pure diastereoisomeric aminesulfonium secondary alcohol of formula XXXIII. -27- This paper size applies to China National Standard (CNS) A4 (210x297 public love)
200306292 A7 B7 五、發明說明(26 ) 圖示11200306292 A7 B7 V. Description of the invention (26) Picture 11
B〇CB〇C
」、 1 I RMgX", 1 I RMgX
B〇C 一B〇C One
NOMe 5NOMe 5
XXXXXX
XXXIXXXI
XXXIIIXXXIII
1 TFA1 TFA
R 2 TEAR 2 TEA
NaBH,NaBH,
XXXII 15 經 濟 部 智 慧 財 產 局 員工 消 費 合 作 社 印 製 20XXXII 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20
當連接到上述醇之胺磺醯上的雜環為噻吩時,該相關 之5-碘及5-氟•噻吩衍生物可藉由將5-溴-噻吩衍生物 XXXIV(如圖示2中得到)轉化為5-三烷基錫·噻吩中間體 XXXV,其可藉由用碘化鈉及氯胺τ處理而轉化為5_蛾 喧吩(XXXVII)或藉由用SELECTFLUORtm(埃銳奇化學公 司)處理而轉化為5-氟-噻吩類似物(XXXVI)(圖示u)。 A -28- 1紙張尺度顧巾⑽ X 297公釐) 200306292 A7 B7 五、發明說明 27 圖示12When the heterocycle attached to the sulfamidine of the above alcohol is thiophene, the related 5-iodine and 5-fluoro • thiophene derivatives can be obtained by adding 5-bromo-thiophene derivative XXXIV (as shown in Figure 2) ) To 5-trialkyltin · thiophene intermediate XXXV, which can be converted to 5-ammonium (XXXVII) by treatment with sodium iodide and chloramine τ or by using SELECTFLUORtm (Eric Chemical Co., Ltd. ) And converted to 5-fluoro-thiophene analog (XXXVI) (u). A -28- 1 Paper size Gu Xun (X 297 mm) 200306292 A7 B7 V. Description of the invention 27 Figure 12
OHOH
ci XXXVci XXXV
(R3Sn)2 R-i ^ Ηβδη r3 Pd(PPh3)4 Nal/Chloramine T(R3Sn) 2 R-i ^ Ηβδη r3 Pd (PPh3) 4 Nal / Chloramine T
XXXVII XXXVI 10 15 裝 經濟部智慧財產局員工消費合作社印製 20 由在環己烷環上之4位置被烷氧基及胺基所取代之環 己基甘胺醇(glycin〇1)所衍生之胺磺醯可根據本文中說明之 方法製備(圖示13)。此途徑係設計成首先將4-L·羥基笨基 甘胺酸XXXVIII氫化,接著磺醯化,將羧酸用乙硼烷予 以還原並生成Ν,Ο-acetonide XXXIX。然後將該4-羥基 acetonide XXXIX用氫化納及一烷基化試劑例如烷基或苄 基溴予以0-烷基化。接著用含水酸處理以移除保護基而 得到式XXXX之4-醚衍生物。或者,該.經基acetonide XXXIX可氧化為4-酮,其可被還原性胺化及去保護而得 到相關之式XXXXI之4-胺基類似物。 -29- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 計 線 200306292 A7 B7 五、發明說明(28 圖示13XXXVII XXXVI 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 20 An amine derived from cyclohexyl glycinol (glycin〇1) substituted at the 4 position on the cyclohexane ring by an alkoxy group and an amine group. Sulfonium can be prepared according to the methods described herein (Figure 13). This pathway is designed to first hydrogenate 4-L · hydroxybenzylglycine XXXVIII, followed by sulfonation, reduce the carboxylic acid with diborane and generate N, 0-acetonide XXXIX. This 4-hydroxyacetonide XXXIX is then 0-alkylated with sodium hydride and a monoalkylating agent such as alkyl or benzyl bromide. It is then treated with an aqueous acid to remove the protecting group to give a 4-ether derivative of the formula XXXX. Alternatively, the .acetonide XXXIX can be oxidized to 4-ketone, which can be reductively aminated and deprotected to obtain the related 4-amine analogue of the formula XXXXI. -29- This paper size applies to China National Standard (CNS) A4 (210x297 mm) line 200306292 A7 B7 V. Description of invention (28 Figure 13
4 DMP/TsOH4 DMP / TsOH
10 r610 r6
NHR XXXXINHR XXXXI
OR 15 經濟部智慧財產局員工消費合作社印製 如果想要,肟XXXXXIV可由相關之醛IV藉由如圖 示14中描述之標準方法衍生。 20 圖示14OR 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. If desired, the oxime XXXXXIV can be derived from the relevant aldehyde IV by the standard method described in Figure 14. 20 Figure 14
〇II -S〆 ,II X 〇 IV〇II-S〆, II X 〇 IV
'Z'Z
nh2oh •30-nh2oh • 30-
pH Y-pH Y-
x o N r3 XXXXXIV 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200306292 A7 B7 五、發明說明(29 ) " 實例 下列K例係用來閑明根據本發明之方法之代表性化合 物的衣法凡精於此方面技藝者會了解到雖然於下列實例 中概述了特定之試劑及條件,這些試劑及條件並非本發明 5 之限制。 實例1 方法1 5-氯-N-[(lS)-2-乙基+曱酿基丁基]喧吩胺石黃醯 10xo N r3 XXXXXIV This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200306292 A7 B7 V. Description of the invention (29) " Examples The following K examples are used to illuminate the representativeness of the method according to the present invention Those skilled in the art of compound chemistry will understand that although specific reagents and conditions are outlined in the following examples, these reagents and conditions are not a limitation of the present invention. Example 1 Method 1 5-Chloro-N-[(lS) -2-ethyl + benzylbutyl] xanthenamine
15 A. 5-(1-乙基-丙基)_咪唑咬-2,4_二酮 經濟部智慧財產局員工消費合作社印製 將氰化鈉(12.0克,244·8毫莫耳)及2_乙基丁基醛 (10.0耄升,81.3毫莫耳)添加到碳酸銨(25·4克,325·3毫 莫耳)於Η2〇(300毫升)中。將乙醇(3〇〇毫升)加入並沉澱出 鹽。將反應混合物加熱至9〇°C。1小時後,混合物成為岣 20勻相並於90°C攪拌U小時。冷卻至25。(:之後,於真空中 移除約500毫升之溶劑。將濃HC1加入以將混合物酸化至 pHl-2並形成一沉澱。將其過濾並將沉澱由Et〇Ac中再結 晶出來而得到5-(1-乙基-丙基)_咪唑啶_2,4_二酮之白色固體 (12.9 克,93% )。質譜(-ESI) : 169(M-H)、 -31- 本紙張尺度適用中國國家標準(CNS)A4規格(21〇χ297公釐) 200306292 A7 B7 五、發明說明(30) Β· Ν·[(5-氯-2-噻吩基)續醯基]-3-乙基原纈胺酸 將5-(1-乙基-丙基)-口米唾唆_2,4-二酿j(12.3克,72.3毫 莫耳)溶解於150毫升NaOH水溶液(π·6克,289.2毫莫耳) 中。將溶液藉由微波於一密封槽中加熱達i小時。(微波 5 條件:15分鐘@1〇〇%強度,15〇°C,50psi,然後5分鐘 〇°/〇強度,然後15分鐘@100%強度,150。〇,50psi,然後 重複順序)。於真空中將水及氫氧化銨由反應混合物中移 除並將產生的粗胺基酸及NaOH混合物不經進一步純化即 使用於下個反應中。 1〇 將粗胺基酸及NaOH混合物溶解於300毫升水中。將 混合物於一冰浴中冷卻至〇°C。將5-氯噻吩-2-磺醯氯(17.3 克,79·5毫莫耳)溶解於1〇〇毫升THF中並於0.5小時期 間逐滴加到反應混合物中。於1小時後,將反應混合物逐 漸回暖至25°C並攪拌16小時。將THF於真空中移除且然 經濟部智慧財產局員工消費合作社印製 15 後將混合物用IN HC1予以酸化至pH 1。約15分鐘後, 沉澱開始由乳白色溶液中迸出。1小時後,將混合物於冰 箱中冷卻1小時且然後過濾。將沉澱用IN HC1清洗得到 呈白色固體之N-[(5-氣-2-噻吩基)磺醯基]-3-乙基原纈胺酸 (18.5 克,78% ) 〇 質譜(-ESI) ·· 325(M-H)-。 20 C. N-[(5-氣-2-噻吩基)磺醯基]-3-乙基-L_原纈胺酸 將(+)-(lS,2R)-麻黃素半水合物(16.7克,95.6毫莫耳) 添加到一含有N-[(5-氣-2-噻吩基)磺醯基]-3-乙基原纈胺酸 (31.2克,95.6毫莫耳)於185毫升EtOH之懸浮液中。將 混合物緩緩加熱以溶解固體並形成一沉澱。於5°C冷卻18 -32- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200306292 A7 B7 五、發明說明(3i) 小時後,將產生的懸浮液過濾出來並將沉殿用冷卻的 EtOH及EtOAc清洗得到27%產量之非對映立體異構鹽。 將該鹽由沸騰的EtOAc(420毫升)中再結晶,然後過濾出 來。然後將產生的白色固體溶解於300毫升EtOAc及300 5毫升1N HC1中。將各層分離並將有機萃出物用IN HC1(2 x 200毫升)清洗,乾燥(NaJCU),並濃縮得到N-[(5-氣_2_ 嗔吩基)¾醯基]-3-乙基-L-原綠胺酸之白色固體(5.6克,18 % )。手性 HPLC[chiralpak AD (25χ〇·46 公分),8 : 2 己烧 (0.1% TFA) ··異丙醇,L-異構物於9.6分鐘洗提且D-異構 10物於13.1分鐘洗提]指出96%手性純度。 [a]D25= +44.5°(c= 1% SOLUTION,MeOH)。 質譜(-ESI) : 325(M-H)·。15 A. 5- (1-ethyl-propyl) _imidazole bite-2,4_dione Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Sodium cyanide (12.0 g, 244.8 mmol) and 2-Ethylbutylaldehyde (10.0 耄, 81.3 mmol) was added to ammonium carbonate (25.4 g, 325.3 mol) in Η20 (300 ml). Ethanol (300 ml) was added and the salt was precipitated. The reaction mixture was heated to 90 ° C. After 1 hour, the mixture became homogeneous and stirred at 90 ° C for U hours. Cool to 25. (After that, about 500 ml of solvent was removed in vacuo. Concentrated HC1 was added to acidify the mixture to pH 1-2 and form a precipitate. It was filtered and the precipitate was recrystallized from EtoAc to give 5- (1-ethyl-propyl) _imidazolidine_2,4_dione as a white solid (12.9 g, 93%). Mass spectrum (-ESI): 169 (MH), -31- This paper is applicable to China Standard (CNS) A4 specification (21 × 297 mm) 200306292 A7 B7 V. Description of the invention (30) Β · Ν · [(5-chloro-2-thienyl) continyl] -3-ethylprovaline Dissolve 5- (1-ethyl-propyl) -oral salivary-2,4-secondary j (12.3 g, 72.3 mmol) in 150 ml of an aqueous NaOH solution (π · 6 g, 289.2 mmol) Ear). The solution was heated by microwave in a sealed tank for i hours. (Microwave 5 conditions: 15 minutes @ 100% strength, 150 ° C, 50 psi, then 5 minutes 0 ° / 〇 intensity, then 15 minutes @ 100% strength, 150.50, 50 psi, then repeat the sequence). Water and ammonium hydroxide were removed from the reaction mixture in vacuum and the resulting crude amino acid and NaOH mixture was used without further purification In the next reaction. 1〇 The mixture of crude amino acid and NaOH was dissolved in 300 ml of water. The mixture was cooled to 0 ° C. in an ice bath. 5-chlorothiophene-2-sulfonyl chloride (17.3 g, 79.5 mmol) was dissolved in 100 ml of THF and added dropwise to the reaction mixture over a period of 0.5 hours. After 1 hour, the reaction mixture was gradually warmed to 25 ° C and stirred for 16 hours. The THF was removed in vacuo and the Ministry of Economic Affairs wisdom The property bureau employee consumer cooperative printed 15 and the mixture was acidified with IN HC1 to pH 1. After about 15 minutes, the precipitate began to scoop out from the milky white solution. After 1 hour, the mixture was cooled in the refrigerator for 1 hour and then filtered. The precipitate was washed with IN HC1 to obtain N-[(5-gas-2-thienyl) sulfonamido] -3-ethylorvaline (18.5 g, 78%) as a white solid. Mass spectrum (-ESI) · 325 (MH)-. 20 C. N-[(5-Gas-2-thienyl) sulfonamido] -3-ethyl-L_orvaline will be (+)-(lS, 2R) -Ephedrine hemihydrate (16.7 g, 95.6 mmol) added to a compound containing N-[(5-gas-2-thienyl) sulfonyl] -3-ethylorvaline (31.2 g, 95.6 mmol) in a suspension of 185 ml of EtOH. The compound is slowly heated to dissolve solids and form a precipitate. Cool at 5 ° C 18 -32- This paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 200306292 A7 B7 V. Description of the invention (3i ) After hours, the resulting suspension was filtered off and Shen Dian was washed with cooled EtOH and EtOAc to give a diastereoisomeric salt in 27% yield. The salt was recrystallized from boiling EtOAc (420 mL) and filtered off. The resulting white solid was then dissolved in 300 ml of EtOAc and 300 5 ml of 1N HC1. The layers were separated and the organic extract was washed with IN HC1 (2 x 200 mL), dried (NaJCU), and concentrated to give N-[(5-Ga_2_fluorenyl) ¾fluorenyl] -3-ethyl -L-orthochloroamino acid as a white solid (5.6 g, 18%). Chiral HPLC [chiralpak AD (25x0.46 cm), 8: 2 hexane (0.1% TFA) · isopropanol, L-isomer was eluted in 9.6 minutes and D-isomer 10 was in 13.1 minutes Elution] indicated a chiral purity of 96%. [a] D25 = + 44.5 ° (c = 1% SOLUTION, MeOH). Mass spectrum (-ESI): 325 (M-H).
CiiH16C1N04S2 之分析: 計算值:C,40.55 ; Η,4·95 ; Ν,4·30。 15 實測值:C,40.30 ; Η,4·78 ; Ν,4·16。 經濟部智慧財產局員工消費合作社印製 D· 5-氯-N-[(lS)-2-乙基-μ(羥基甲基)丁基]噻吩胺磺醯 於〇°C時於一含有Ν-[(5_氯-2_噻吩基)磺醯基乙基_ L-原纈胺酸(5.6克,ΐ7·2毫莫耳)之THF(15〇毫升)中經由 添加漏斗逐滴加入-含有1M甲顺四氮咬喃絡合物於 20 THF(69笔升’ 69宅莫耳)之溶液。15分鐘後,將反應混合 物回暖至25C並擾拌18小時。然後用9〇毫升⑽Ac〇h 於MeOH緩緩的驟冷。於真空中將揮發物移除。然後將殘 質溶解於Et〇Ac(3〇0毫升)中,用飽和含水NaHc〇3(3x 2〇〇毫升)清洗,乾燥(Na2S〇4),並濃縮成一白色沉 -33- 200306292 Α7 Β7 五、發明說明(32) 克’ 96%產率,96%手性純度)。將沉澱用庚烷/EtOAc 4 ·· 1再結晶,得到光學上純的5-氯-N-[(lS)-2-乙基·1-(經基甲 基)丁基]-2-噻吩胺磺醯之白色針狀體(4.4克,81%產率)。 溶點為 113-114Χ:。 5 [aL25= +4.50(c= 1% SOLUTION,DMSO)。 質譜(-ESI) : 310(Μ-Η)-。 ciiH18C1N03S2之分析: 計算值·· C,42.37 ; Η,5·82 ; N,4.49。 實測值·· C,42.37 ; Η,5·79 ; N,4.38。 10 Ε· 5-氯-N-[(lS)-2-乙基-1-曱醯基丁基]噻吩-2-胺磺醯 將重鉻酸Itb旋(2.4克,6.4毫莫耳)添加到一含有5-氯-N-[(lS)-2-乙基-1-(羥基甲基)丁基]-2-噻吩胺磺醯(0.5克, 1·6毫莫耳)於ch2C12(20毫升)之溶液中。18小時後,將反 應混合物經由一寅氏鹽塞過濾。將濾液濃縮並將產生的殘 15 質藉由矽膠管柱色層分離法(洗提液:1 : 4 EtOAC-己烷)予 以純化得到5-氯-N-[(lS)-2-乙基-1-甲醯基丁基]噻吩-2-胺 磺醯之白色固體(303毫克,61% )。 [a]D25= + 136.76°(c= 1% SOLUTION,CHC13)。 經濟部智慧財產局員工消費合作社印製 質譜(-ESI) : 308(M-H)-。 20 ChHkCINC^S]之分析: 計算值:C5 42.64 ; H,5·21 ; N,4.52。 實測值:C,42·57 ; H,5.24 ; N,4·52。 實例2 -34- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) A7 200306292 五、發明說明(33 ) 方法2 5-氯-N-[(lS)-2-乙基-1-曱醯基丁基]噻吩-2-胺磺醯 A. (2S)-3-乙基-2-{[(lS)-l-苯基乙基]胺基}戊腈 於含(S)-(-)-a-甲基苄基胺氫氯酸鹽(1·2克’ 7.6毫莫耳) 5 之80毫升1 : 1 Me0H/H20中將氰化鉀(〇·5克,7.6毫莫 耳)及2-甲基丁醛(0.94毫升,7.6毫莫耳)加入。於30分鐘 後形成一沉澱。於20小時後,將懸浮液過濾並用Η2〇清 洗得到(2S)-3-乙基-2-{[(lS)-l-苯基乙基]胺基}戊腈之白色 粉末(1.29 克,74% ) 〇 10 質譜(+ESI) ·· 310(M+H)+。 C15H22N2之分析· 計算值:C,78·21 ; H,9.63 ; N,12.16。 實測值:C,77.90 ; Η,9·75 ; N,12.32。 Β. 3 -乙基-N2-[(1S)-1-苯基乙基]-L-原顯胺酸酿胺 15 於〇°C時,將(2S)-3-乙基-2-{[(lS)+苯基乙基]胺基} 經濟部智慧財產局員Η消費合作'社印製 戊腈(2.7克,11.6毫莫耳)逐份的加到25毫升之硫酸中。 將混合物回暖至25°C。2天後,將反應混合物倒至約1〇〇 克碎冰中。將濃NEUOH加入以中和酸。將此混合物用 EtOAcPx 100毫升)萃取,於NhSO4上乾燥,過濾出來並 2〇濃縮得到3-乙基苯基乙基]七·原纈胺酸醯胺 (2·6克,90% ),其未經進一步純化即進用於下個步驟。 質譜(+ESI) : 249(Μ+Η)+。 C15H24N2O 之分析: 計算值:C,72.54 ; Η,9·74 ; Ν,11.28。 -35- 錢張尺度通用中關家標準(CNS)A4規格(2〗〇 X 297公釐了 200306292 A7 B7 五、發明說明(34 ) 實測值·· C,72.24 ; H,10.04 ; N,11.01。 C· 3-乙基原線胺酸酿胺 將一含有3-乙基-N2-[(1S)-1-苯基乙基]原纈胺酸醯 胺(2·6克,10·5毫莫耳)及5% Pd/C(800毫克)之混合物於3 5 大氣壓之帕爾裝置中振盈24小時。將混合物經由一寅氏 鹽塞過濾出來並將溶劑於真空中移除,得到3-乙基小原纈 胺酸醯胺之白色固體(1.4克,93% ),其未經進一步純化即 用於下一個反應中。 質譜(+ESI) : 145(M+H)+。 10 D· N-[(5-氯1噻吩基)績醯基]_3·乙基心原纈胺酸 將3-乙基原綠胺酸醯胺(ι·2克,4.8毫莫耳)溶解於 濃HC1(10毫升)中並加熱至100它達16小時。將反應混合 物濃縮成一包括胺基酸氳氯酸鹽及1當量NH4C1之白色固 體’其未經純化即使用於下一個步驟中。 15 將胺基酸氫氣酸鹽與1當量之NH4C1(0.28克,1.19毫 經濟部智慧財產局員工消費合作社印製 莫耳)溶解於6毫升HbO中且然後加入NaOH(0.24克, 6·00毫莫耳)。將溶液冷卻至〇°C且然後將含於6毫升THF 之5_氯喀吩1磺醯氯(0.29克,1.32毫莫耳)逐滴加入。將 此a物回暖至25。〇。19小時後,於真空中將THF移除。 20將剩餘的溶液用10毫升H2〇稀釋並用EtOAc(2x 1〇毫升) 清洗。將溶液用IN HC1予以酸化並形成一沉澱。將其過 濾出來得到N-[(5-氯-2-噻吩基)磺醯基]-3-乙基-L-原纈胺酸 之白色固體(〇·17克,44% )。手性HPLC指出僅出現s鏡 像異構物。 -36- 200306292 A7 B7 五、發明說明(35) 然後根據實例1之方法〗山r 廿# 1由Ν-[(5-氯·2-噻吩基)磺醯 基]-3-乙基-L-賴胺酸製“_氯*__2_乙基__基甲 基)丁基]I嗔吩胺及5-氯*[叫2_乙基小甲醢基丁 基]噻吩-2-胺磺醯。 實例3 5IN-[⑽-2-乙基輕基曱基)丁基峰射胺確醯 10 15 經濟部智慧財產局員工消費合作社印製 20 於一裝設有氮氣通入管,機械攪拌器,及-具有塞子 之添加漏斗的3升3頸燒瓶中加人氫删_M5毫升之於 TOF的2M /合液,〇·29莫耳)。將溶液置放於氮氣中並冷 p至0c將氯二甲基石夕燒(73·8毫升,莫耳)於3〇分 鐘之』間逐滴加人。將切雜且將產㈣生料於饥搜 拌30/鐘。將反應混合物冷卻至叱且將根據美國臨時專 利申π案第60/339,264號所製備之3•乙基心原綠胺酸以 固,型式於15分鐘期間逐份的加人。將反應混合物於冰 浴’合化日守緩緩的回暖至25它。於25°C達3天之後,將反 應此合物冷卻至〇。〇,並於8〇分鐘期間將甲醇(217毫升) 小:的加入。將溶液於25°C再攪拌40分鐘,然後於60°C 減壓之水浴中濃縮。將產生的生料用20%氫氧化鈉(37·5 笔升)予以驗化。將水(37.5毫升)加入,並將整個含水層用 =氯曱燒(3GG毫升)清洗 ,並乾燥(Na2S〇4)。於減壓下濃縮 得到呈一油之3-乙基-L-原纈胺醇(17.3克,91% ),其係立 即使用或儲存於冰箱中過夜:Analysis of CiiH16C1N04S2: Calculated value: C, 40.55; Η, 4.95; N, 4.30. 15 Found: C, 40.30; 30, 4.78; N, 4.16. Printed by D. 5-Chloro-N-[(lS) -2-ethyl-μ (hydroxymethyl) butyl] thiophene sulfonium at 0 ° C in a consumer cooperative of the Ministry of Economic Affairs ’Intellectual Property Bureau. -[(5-Chloro-2_thienyl) sulfoethylethyl-L-orvaline (5.6 g, ΐ7.2 mmol) in THF (150 ml) was added dropwise via an addition funnel- A solution containing 1M metcis tetrazolium complex in 20 THF (69 liters' 69 mol). After 15 minutes, the reaction mixture was warmed to 25C and stirred for 18 hours. It was then slowly quenched with 90 mL of AcOH in MeOH. The volatiles were removed in vacuo. The residue was then dissolved in EtOAc (300 ml), washed with saturated aqueous NaHcO3 (3 x 200 ml), dried (Na2S04), and concentrated to a white precipitate -33- 200306292 Α7 Β7 V. Description of the invention (32) g '96% yield, 96% chiral purity). The precipitate was recrystallized from heptane / EtOAc 4 ·· 1 to obtain optically pure 5-chloro-N-[(lS) -2-ethyl · 1- (transmethyl) butyl] -2-thiophene Amisulfin white needles (4.4 g, 81% yield). The melting point is 113-114X :. 5 [aL25 = +4.50 (c = 1% SOLUTION, DMSO). Mass spectrum (-ESI): 310 (M-VII)-. Analysis of ciiH18C1N03S2: Calculated value · C, 42.37; Η, 5.82; N, 4.49. Measured value · C, 42.37; Η, 5.79; N, 4.38. 10 E. 5-Chloro-N-[(lS) -2-ethyl-1-fluorenylbutyl] thiophene-2-aminesulfonium chloride Itb dichromate (2.4 g, 6.4 mmol) To a solution containing 5-chloro-N-[(lS) -2-ethyl-1- (hydroxymethyl) butyl] -2-thienylsulfonium (0.5 g, 1.6 mmol) in ch2C12 ( 20 ml). After 18 hours, the reaction mixture was filtered through a Yin plug. The filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (eluent: 1: 4 EtOAC-hexane) to obtain 5-chloro-N-[(lS) -2-ethyl 1-Methylmethylbutyl] thiophene-2-aminesulfoniumsulfonate as a white solid (303 mg, 61%). [a] D25 = + 136.76 ° (c = 1% SOLUTION, CHC13). Mass Spectrum (-ESI): 308 (M-H)-printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Analysis of 20 ChHkCINC ^ S]: Calculated: C5 42.64; H, 5.21; N, 4.52. Found: C, 42 · 57; H, 5.24; N, 4.52. Example 2 -34- This paper size applies Chinese National Standard (CNS) A4 (210x297 mm) A7 200306292 V. Description of the invention (33) Method 2 5-Chloro-N-[(lS) -2-ethyl-1 -Fluorenylbutyl] thiophene-2-aminosulfonium A. (2S) -3-ethyl-2-{[((lS) -1-phenylethyl] amino) valeronitrile containing (S) -(-)-a-methylbenzylamine hydrochloride (1.2 g '7.6 mmol) 5 of 80 ml 1: 1 Me0H / H20 potassium cyanide (0.5 g, 7.6 mmol Mol) and 2-methylbutyraldehyde (0.94 ml, 7.6 mmol). A precipitate formed after 30 minutes. After 20 hours, the suspension was filtered and washed with Η20 to give (2S) -3-ethyl-2-{[(lS) -1-phenylethyl] amino} valeronitrile as a white powder (1.29 g, 74%) Mass spectrum (+ ESI) 310 (M + H) +. Analysis and calculation of C15H22N2: C, 78 · 21; H, 9.63; N, 12.16. Found: C, 77.90; Η, 9.75; N, 12.32. Β. 3-Ethyl-N2-[(1S) -1-phenylethyl] -L-orthomelamine 15 at 0 ° C, (2S) -3-ethyl-2- { [(1S) + Phenylethyl] amine} Printed valeronitrile (2.7 g, 11.6 mmol) by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperative, and added to 25 ml of sulfuric acid in portions. Warm the mixture to 25 ° C. After 2 days, the reaction mixture was poured into about 100 grams of crushed ice. Concentrated NEUOH was added to neutralize the acid. This mixture was extracted with EtOAcPx (100 ml), dried over NhSO4, filtered off and concentrated to give 3-ethylphenylethyl] heptavalinate (2.6 g, 90%), which Used in the next step without further purification. Mass spectrum (+ ESI): 249 (M + H) +. Analysis of C15H24N2O: Calculated: C, 72.54; Η, 9.74; Ν, 11.28. -35- Qian Zhang scale General Zhongguanjia Standard (CNS) A4 specification (2) 0X 297 mm 200306292 A7 B7 V. Description of the invention (34) Measured value · C, 72.24; H, 10.04; N, 11.01 C. 3-Ethyl ortholine amino acid amine will contain a 3-ethyl-N2-[(1S) -1-phenylethyl] orthovaline amidine (2 · 6 g, 10 · 5 The mixture of millimolar) and 5% Pd / C (800 mg) was shaken in a Parr apparatus at 35 atmospheres for 24 hours. The mixture was filtered through a Yin's salt plug and the solvent was removed in vacuo to obtain 3-ethyl small orthovalvaline ammonium amine as a white solid (1.4 g, 93%), which was used in the next reaction without further purification. Mass spectrum (+ ESI): 145 (M + H) +. 10 D · N-[(5-Chloro-1thienyl) pyridinyl] _3 · Ethylcardiogenovalinic acid Dissolve the ethyl 3-ethylorthochloroamine amide (ι · 2 g, 4.8 mmol) in concentrated HC1 (10 ml) and heated to 100 it for 16 hours. The reaction mixture was concentrated to a white solid including amino sulfonium chlorate and 1 equivalent of NH4C1 ', which was used without purification in the next step. 15 will Amino acid hydrochloride and 1 equivalent of NH4C1 (0.28 g, 1.19 mmol) The Ministry of Intellectual Property Bureau employee consumer cooperative printed Mohr) was dissolved in 6 ml of HbO and then NaOH (0.24 g, 6.0 mmol) was added. The solution was cooled to 0 ° C and then contained in 6 ml of THF. 5-Chlorophene 1 Sulfachloro (0.29 g, 1.32 mmol) was added dropwise. This substance was warmed to 25. After 19 hours, the THF was removed in vacuo. 20 The remaining solution was used with 10 ml of H20 was diluted and washed with EtOAc (2 x 10 ml). The solution was acidified with IN HC1 and a precipitate formed. It was filtered off to give N-[(5-chloro-2-thienyl) sulfonyl]- 3-ethyl-L-orthovaline acid as a white solid (0.17 g, 44%). Chiral HPLC indicated that only s-image isomers appeared. -36- 200306292 A7 B7 V. Description of the invention (35) Then According to the method of Example 1, rr 廿 # 1 is made from N-[(5-chloro · 2-thienyl) sulfonamido] -3-ethyl-L-lysine to produce "_chloro * __ 2_ethyl_ _Ylmethyl) butyl] I} phenamine and 5-chloro * [named 2-ethyl small methyl fluorenylbutyl] thiophen-2-aminesulfonium. Example 3 5IN- [⑽-2-ethyl light (Based on the base) Butyl amine was confirmed 10 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 Fitted with a nitrogen inlet tube, mechanical stirrer, and - a 3 liter, 3-neck flask with addition funnel stopper of addition of hydrogen in the puncturing _M5 ml in 2M / TOF-prepared solution of 3.29 mole square). The solution was placed under nitrogen and cooled to 0c. Chlorodimethyl sulfite (73.8 ml, mole) was added dropwise between 30 minutes. The chop will be chopped and the raw material will be mixed for 30 / minute. The reaction mixture was cooled to rhenium and the 3 • ethylcardiogenic chlorogenic acid prepared according to US Provisional Patent Application No. 60 / 339,264 was solidified, and added in portions over a period of 15 minutes. The reaction mixture was slowly warmed to 25 ° C in an ice bath ' After 3 days at 25 ° C, the reaction mixture was cooled to zero. And methanol (217 mL) was added over a period of 80 minutes. The solution was stirred for an additional 40 minutes at 25 ° C and then concentrated in a water bath at 60 ° C under reduced pressure. The raw meal produced was tested with 20% sodium hydroxide (37.5 pen liters). Water (37.5 ml) was added, and the entire aqueous layer was washed with chloroform (3GG ml) and dried (Na2SO4). Concentrated under reduced pressure to give 3-ethyl-L-provaline alcohol (17.3 g, 91%) as an oil, which is used immediately or stored in the refrigerator overnight:
Opt. Rot. 25 [a]D t·3·7'!% solution,DMSO); -37- 規格(210x297 公釐) 200306292 A7 B7 五、發明說明(36) 4 NMR (DMSO-d6,500MHz) : δ = 4·38 (廣域 s,1H), 3.35((1(1與一廣域8於5 3.32重疊,了 = 4.5,10.3 1^,311), 3·14 (dd,J =7·9,10·2Ηζ,1H),2.63 (m,1H),1·45 — 1·05 (m, 5Η),0·82 及 0.81(兩個重疊之三峰,J = 7·4Ηζ,6Η); 5 質譜(+ESI) : [Μ+Η]+,132(60% )。 將一含有3-乙基-L-原纈胺醇(34.1克,0·26莫耳)及二 氯曱烷(700毫升)之混合物置於氬氣中,並冷卻至0°C。將 三乙胺(36.2毫升,0.26莫耳)加入,接著將含於二氯甲烷 (400毫升)之5-氯噻吩_2-磺醯氯(56.4克,0.26莫耳)逐滴 10 加入。將反應混合物於冰浴溶化時缓缓的回暖至25°C。於 25°C達3天後,將反應混合物分成兩個0.6升之部分。將 每一部分用醋酸乙酯(1升)稀釋,並用飽和磷酸鉀一水合 物(200毫升)清洗三次,用鹽水(200毫升)清洗一次,並乾 燥(Na2S04)。於減壓下濃縮得到一白色固體(74.5克,92 15 % )。將來自數個路線之產物(87.98克)合併且由熱庚烷: 醋酸乙酯(4 : 1,775毫升)中再結晶出來得到標的化合物 結晶(74.9 克,85% )。 熔點為 115-117.6°C ; Opt· Rot. 經濟部智慧財產局員工消費合作社印製 [a]D25 = +10.81o(l% solution,MeOH); 20 lH NMR (DMSO-d6 ^ 500MHz) : δ = 7·71 (d,J = 8.1 Hz, 1H),7.44 (d,J = 4.1 Hz,1H),7.22 (d,J = 4·1 Hz,1H),4.56 (t, J = 5.2 Hz,OH),3.31 - 3.15 (m,3H),1.40 - 1.15 (m,4H), 1.07 (m,lH),0.79 及 0.76(兩個重疊之三峰,J = 7.3 Hz, 6H); -38- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200306292 A7 B7 五、發明說明(37 ) 13C NMR DMSO-d6, 100 MHz) : δ 141.75, 133,73, 130.95, 127.60, 60.41,56.89, 41·57, 21.31,20.80, 11.79, 11·51; MS (-ESI) : [Μ-Η]-,1 氯同位素型式,310 (100% ),312 (30 % ), 5 CUH18C1N03S2 之分析: 計算值:C,42·37 ; Η,5·82 ; N,4.49。 實測值:C,42·34 ; Η,5·65 ; Ν,4.43。 手性 HPLC(Chiralpak AD,25χ〇·46 公分,洗提液 8 ·· 2 含 有0.1% THF之己烷/異丙醇,流速〇·5毫升/分鐘,於254 10毫微米做UV偵測,S及R異構物之維持時間分別為 10.95分鐘及11.95分鐘)揭示S/R比例為100.0 : 〇.〇。 實例4 5-氯-N-[(lS)-2-乙基-1-(1-羥基乙基)丁基]噻吩·2_胺續酿Opt. Rot. 25 [a] D t · 3 · 7 '!% Solution (DMSO); -37- Specifications (210x297 mm) 200306292 A7 B7 V. Description of the invention (36) 4 NMR (DMSO-d6, 500MHz) : δ = 4.38 (wide area s, 1H), 3.35 ((1 (1 overlaps with a wide area 8 at 5 3.32, == 4.5, 10.3 1 ^, 311), 3.14 (dd, J = 7 · 9,10 · 2Ηζ, 1H), 2.63 (m, 1H), 1.45 — 1.05 (m, 5Η), 0.82 and 0.81 (two overlapping three peaks, J = 7. · 4Ηζ, 6Η) 5 Mass spectrum (+ ESI): [Μ + Η] +, 132 (60%). One containing 3-ethyl-L-provaline alcohol (34.1 g, 0.26 mole) and dichloromethane (700 ml) of the mixture was placed under argon and cooled to 0 ° C. Triethylamine (36.2 ml, 0.26 mole) was added, followed by 5-chlorothiophene in methylene chloride (400 ml). 2-sulfohydrazone (56.4 g, 0.26 mole) was added dropwise 10. The reaction mixture was slowly warmed to 25 ° C when the ice bath melted. After 3 days at 25 ° C, the reaction mixture was divided into two A 0.6 liter portion. Dilute each portion with ethyl acetate (1 liter) and wash three times with saturated potassium phosphate monohydrate (200 ml) and once with brine (200 ml) And dried (Na2S04). Concentrated under reduced pressure to give a white solid (74.5 g, 92 15%). The product from several routes (87.98 g) was combined and heated with hot heptane: ethyl acetate (4: 1, (775 ml) was recrystallized to obtain the crystal of the target compound (74.9 g, 85%). Melting point was 115-117.6 ° C; Opt · Rot. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs [a] D25 = + 10.81o ( l% solution, MeOH); 20 lH NMR (DMSO-d6 ^ 500MHz): δ = 7.71 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 4.1 Hz, 1H), 7.22 (d, J = 4.1 Hz, 1H), 4.56 (t, J = 5.2 Hz, OH), 3.31-3.15 (m, 3H), 1.40-1.15 (m, 4H), 1.07 (m, lH), 0.79 and 0.76 (Three peaks of two overlaps, J = 7.3 Hz, 6H); -38- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 200306292 A7 B7 V. Description of the invention (37) 13C NMR DMSO -d6, 100 MHz): δ 141.75, 133,73, 130.95, 127.60, 60.41, 56.89, 41 · 57, 21.31, 20.80, 11.79, 11.51; MS (-ESI): [Μ-Η]-, 1 Chlorine isotope type, 310 (100%), 312 (30%), 5 CUH18C1N03S2 Analysis: Calculated: C, 42 · 37; Η, 5.82; N, 4.49. Found: C, 42 · 34; Η, 5.65; N, 4.43. Chiral HPLC (Chiralpak AD, 25x0.46 cm, eluent 8 ·· 2, 0.1% THF in hexane / isopropanol, flow rate 0.5 ml / min, UV detection at 254 10 nm, The retention times of the S and R isomers were 10.95 minutes and 11.95 minutes, respectively), revealing that the S / R ratio was 100.0: 0.0. Example 4 5-Chloro-N-[(lS) -2-ethyl-1- (1-hydroxyethyl) butyl] thiophene
經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 將一含有曱基溴化鎂(1·4Μ,7.0毫升,9.7亳莫耳)於 甲苯/THF(75 :功之溶液加到一含有氯叫⑽乙基一 1-曱醯基丁基]噻吩-2-胺磺醯(實例!或2,1〇克,3 2毫 莫耳)於THF(30毫升)之溶液中。將混合物回暖至且 於2小時後小心的用飽和含水氯化銨(25毫升)驟冷。將混 -39- 本紙張尺度適时關家標準(CNS)A4規格χ 297公爱γ 200306292 Α7 Β7 五、發明說明(38) 合物用EtOAc(3x 25毫升)萃取。將有機萃出物於Na2Sc^ 上乾燥,過渡並濃縮得到一無色油。將產物藉由管柱色; 分離法(Biotage)予以純化,洗提液:1 : 4 EtOAc-己烧,而 付到5-氯-N-[(lS)-2-乙基-1-(1-髮基乙基)丁基]嗟吩_2-胺辟 5 醯之白色固體(876毫克,83% )。產物為3 ·· 7比例之非對 映立體異構混合物。熔點為95-98°C。Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, a solution containing fluorenyl magnesium bromide (1.4M, 7.0 ml, 9.7 mol) in toluene / THF (75: work) was added to a solution containing chloroethyl 1-fluorenylbutyl] thiophene-2-aminesulfonium (example! Or 2,10 g, 32 mmol) in THF (30 ml). The mixture was warmed to and within 2 hours After careful quenching with saturated aqueous ammonium chloride (25 ml). Mix -39- This paper size is timely standard (CNS) A4 size χ 297 public love γ 200306292 Α7 Β7 V. Description of the invention (38) The material was extracted with EtOAc (3 x 25 mL). The organic extract was dried over Na2Sc ^, transitioned and concentrated to give a colorless oil. The product was colored by a column; purified by Biotage, eluent: 1 : 4 EtOAc-Hexane, and paid 5-chloro-N-[(lS) -2-ethyl-1- (1-fatylethyl) butyl] pyrene_2-amine 5 white Solid (876 mg, 83%). The product was a diastereoisomeric mixture in a ratio of 3. · 7. The melting point was 95-98 ° C.
Ci2H2GClN03S2 之分析: 計算值:c,44.23 ; H,6.19 ; N,4.30。 實測值:C,44.25 ; Η,6·35 ; N,4.29。 1〇 質譜(-ESI) : 324 (Μ-Η)-。 fill-分析條件 A.半-製備性RP-HPLC條件: 含 Unipoint Software 之 Gilson Semi-Preparative HPLC 系統 15 管柱:Phenomenex C18 Luna 21.6 毫米χ 60 毫米,5μ 溶劑A :水(0.02% TFA缓衝液) 溶劑B :乙腈(0.02% TFA緩衝液) 經濟部智慧財產局員工消費合作社印製 溶劑梯度:時間0 : 10% B ; 2.5分鐘:10% B ; 14分鐘: 90% B。 20 流速:22.5毫升/分鐘 根據UV吸收收集產物高峰並濃縮。 Β·分析性LCMS條件: 含 ChemStation Software 之 Hewlett Packard 1100 MSD 管柱:YMC ODS-AM 2.0毫米χ 50毫米,5μ管柱於23 -40- 本紙張尺度適用中國國家標準(CNS)A4規格(21〇χ297公釐) 200306292 經濟部智慧財產局員工消費合作社印製 Α7 Β7 五、發明說明(39 ) °C ; 3μ微升注射; 溶劑A :水(0.02% TFA緩衝液) 溶劑B ·乙猜(0.02% TFA緩衝液) 梯度:時間0 : 95% A ; 0.3分鐘:95% A ; 4.7分鐘:10% 5 A ; 4.9 分鐘:950/〇 A。 流速:1.5毫升/分鐘; 偵測:254毫微米DAD ; API-ES Scanning Mode Positive 150-700 ; Fragmentor 70 mV o 10 C. 分析性LCMS條件: ZMD (Waters)或 Platform (Micromass)或 LCZ (Micromass) 管柱:Zorbax SB-C8 溶劑:乙腈+ H20(含有0.1% TFA或0.1% FA) 梯度:2·5分鐘15%乙腈-95%乙腈 15 流速:3毫升/分鐘 偵測:ELSD 偵測(SEDEX55) UV 253 债測(Schimadzu) 宜例6 -壓制劑釋放分析(RRA) 20 將如實例1至4中之說明所生成的化合物根據已公開 之技藝進行RRA測試[蘇伊,D.J·,徐飛,ρ·,瓊斯·, D·,柯齊,Μ·Ι·,及昆内,Ε·Μ·(1999),,,壓制劑釋放:〆 種監控哺乳類細胞中澱粉狀朊先質蛋白質(ΑΡΡ)解朊作用 之有用的工具”,神經科學摘要學會,第25冊,神經科學 -41- 本紙張尺度適用肀國國家標準(cns)a4規格(210 X 297公釐)Analysis of Ci2H2GClN03S2: Calculated values: c, 44.23; H, 6.19; N, 4.30. Found: C, 44.25; Η, 6.35; N, 4.29. 10 Mass spectrum (-ESI): 324 (M-VII)-. fill-Analysis conditions A. Semi-preparative RP-HPLC conditions: Gilson Semi-Preparative HPLC System with Unipoint Software 15 Columns: Phenomenex C18 Luna 21.6 mm x 60 mm, 5 μ Solvent A: Water (0.02% TFA buffer) Solvent B: Acetonitrile (0.02% TFA buffer) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Solvent gradient: Time 0: 10% B; 2.5 minutes: 10% B; 14 minutes: 90% B. 20 Flow rate: 22.5 ml / min. Product peaks were collected based on UV absorption and concentrated. Β. Analytical LCMS conditions: ChemStation Software's Hewlett Packard 1100 MSD column: YMC ODS-AM 2.0 mm x 50 mm, 5 μ column at 23 -40- This paper scale applies Chinese National Standard (CNS) A4 specifications (21 〇χ297mm) 200306292 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (39) ° C; 3μl injection; Solvent A: Water (0.02% TFA buffer solution) Solvent B · Ethiopia ( 0.02% TFA buffer) Gradient: Time 0: 95% A; 0.3 minutes: 95% A; 4.7 minutes: 10% 5 A; 4.9 minutes: 950 / 〇A. Flow rate: 1.5 ml / min; Detection: 254 nm DAD; API-ES Scanning Mode Positive 150-700; Fragmentor 70 mV o 10 C. Analytical LCMS conditions: ZMD (Waters) or Platform (Micromass) or LCZ (Micromass) ) Column: Zorbax SB-C8 Solvent: Acetonitrile + H20 (containing 0.1% TFA or 0.1% FA) Gradient: 2.5 minutes 15% acetonitrile-95% acetonitrile 15 Flow rate: 3 ml / min Detection: ELSD detection ( SEDEX55) UV 253 Determining (Schimadzu) Preferential Example 6-Pressure Release Analysis (RRA) 20 The compounds generated as described in Examples 1 to 4 will be subjected to RRA testing according to published techniques [Su Yi, DJ, Xu Fei, ρ ·, Jones ·, D ·, Keqi, M · I ·, and Kunner, E · M · (1999) ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,-,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 制剂, 制剂 1999, 1999, E.M. (1999), F., Phytosome release: monitoring amyloid precursor protein in mammalian cells (APP) A useful tool to resolve the problem ", Abstract Society of Neuroscience, Volume 25, Neuroscience-41- This paper is in accordance with the national standard (cns) a4 (210 X 297 mm)
200306292 A7 B7 五、發明說明(4〇 ) 學會第29次年會,邁阿密海灘,佛羅里達州,1999年10 月23-28日]。簡言之,此分析係如下進行。 A.細胞培養 將CHO-K1細胞於37°C含5% C02之完全DMEM介 5 質(DMEM -含10%牛胎兒血清,1%非必須胺基酸,及1 %青黴素-鏈黴素)之高葡萄糖中培育。於轉染之前24小時 將二百萬個細胞劃至10-公分培養盤中。 短暫的轉染係如Gibco BRL所推薦,用其Lipo-fectamine Plus系統來完成。首先,將6微克pRSVO-luc 10 及6微克APP-lacI構築DNA添加到460微升Opti_Mem 轉染介質中並用30微升Plus試劑培育15分鐘。然後,將 一含有40微升Lipofectamine試劑及460微升Opi-Mem轉 染介質之脂肪混合物與DNA-Plus試劑混合物培育15分 鐘。於DNA-脂肪培育之期間,將CHO-K1細胞清洗一次 15且覆蓋於5·0毫升不含青黴素-鏈黴素之DMEM介質中。 然後將DNA-脂肪製劑層覆於這些細胞上並於37它培育過 夜。 經濟部智慧財產局員工消費合作社印製 將每一孔中1至1.5百萬轉染細胞(100微升總體積)劃 線到於澄清DMEM完全介質(DMEM-不含苯酚紅)之無 20菌,不透明Packard 96-孔培養盤上並於^它含5% c〇2時 培育3-5小時。 、 B·化合物稀釋 將化合物用兩種不同的程序稀釋;一種程序係用於供 應不含溶劑之化合物(用管瓶稱粉末重)而另—程序則係用 -42-200306292 A7 B7 V. Description of Invention (40) 29th Annual Meeting of the Society, Miami Beach, Florida, October 23-28, 1999]. In short, this analysis is performed as follows. A. Cell culture: CHO-K1 cells were completely DMEM 5 containing 37% C02 at 37 ° C (DMEM-containing 10% bovine fetal serum, 1% non-essential amino acids, and 1% penicillin-streptomycin) In high glucose. Two million cells were plated into 10-cm culture plates 24 hours before transfection. Transient transfection, as recommended by Gibco BRL, was performed using its Lipo-fectamine Plus system. First, 6 micrograms of pRSVO-luc 10 and 6 micrograms of APP-lacI construct DNA were added to 460 microliters of Opti_Mem transfection medium and incubated with 30 microliters of Plus reagent for 15 minutes. Then, a fat mixture containing 40 µl of Lipofectamine reagent and 460 µl of Opi-Mem transfection medium and a DNA-Plus reagent mixture were incubated for 15 minutes. During DNA-fat incubation, CHO-K1 cells were washed once 15 and covered with 5.0 ml of penicillin-streptomycin-free DMEM medium. A layer of the DNA-fat preparation was then applied to these cells and incubated overnight at 37 ° C. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, streaking 1 to 1.5 million transfected cells (100 microliters total volume) in each well to 20 bacteria free in clarified DMEM complete medium (DMEM-phenol free) , On an opaque Packard 96-well plate and incubate for 3-5 hours at 5% CO2. B. Compound Dilution Compounds are diluted in two different procedures; one procedure is used to supply a solvent-free compound (weigh the powder in a vial) and the other—the procedure uses -42-
200306292 A7200306292 A7
=乂’合液供給之化合物(2〇^μ於於卯孔培養 i)於兩種程序中,製備新鮮的25mM Hepes及25mM HePes/l/G DMS〇以用作為稀釋劑,該DMS〇係於 所有的實驗培養盤中用作為稀釋控制劑。 下表係記述化合物稀釋之步驟(請注意最後一步驟為將 化合物添加到於組織培養盤上之細胞/介質中): ~-—_ -—------ ZHKH] 稀釋 儲備溶液 --—-- 10亳克/亳升 X毫克化合物(管瓶) 用100% DMSO稀釋 稀釋1 -----— 1亳克/亳升 20微升儲備溶液 180 微升 25mMHepes 稀釋2 200微克/毫升 60微升稀釋1 240 微升 5mM Heroes 稀釋3(於細胞培養盤) 20微克/毫升 11.3微升稀釋2 (於100微升細胞/孔) 由於一些化合物於20mM時在96-孔格式得到結果, 下歹】係代表其稀釋之程序(請注意這些化合物之平均分子 10 $係用來計算這些稀釋且,如上所述,最後一步驟為將化 合物添加到於組織培養盤上之細胞/介質中)·· 經濟部智慧財產局員工消費合作社印製 濃度 稀釋 儲備溶液 -----—(原 >辰唐) - 20mM溶液 稀釋1 ~ 〜200微克/毫升 6微升健備溶液 194 微升 25mM Hepes 稀釋2(於細胞培養盤) 〜20微克/毫升 1L3微升稀釋2 (於100微升細胞/孔) -4 適 度 尺 一張 格 規 A4 S) N (C 準 標 釐 公 97 200306292 A7 B7 五、發明說明(42) -旦化合物被稀釋,將其施用在組織培養盤(如上製備) 之細胞上重複兩次。於3rc含5% c〇2時,將細胞用化合 物再培育36-48小時。 C· 分析測量 5 進行發光酶分析(hcLite試劑,Packard)且於〆= Compound supplied from the mixture (20 ^ μ cultured in spores i) In two procedures, fresh 25mM Hepes and 25mM HePes / l / G DMS were prepared as diluents. The DMS was Used as a dilution control agent in all experimental plates. The following table describes the steps for compound dilution (please note that the last step is to add the compound to the cells / medium on the tissue culture plate): ~ -—_ -—-------- ZHKH] Dilution Stock Solution- --- 10 mg / ml X mg compound (vial) diluted with 100% DMSO 1 -----— 1 mg / ml 20 µl stock solution 180 µl 25mM Hepes diluted 2 200 µg / ml 60 μl dilution 1 240 μl 5 mM Heroes dilution 3 (on cell culture plates) 20 μg / ml 11.3 μl dilution 2 (at 100 μl cells / well) As some compounds get results in 96-well format at 20 mM, Bottom line] represents the procedure of dilution (please note that the average molecular weight of these compounds is 10 $ is used to calculate these dilutions and, as mentioned above, the last step is to add the compound to the cells / medium on the tissue culture plate) ·· Printed Concentration Dilution Stock Solution by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs-(Original > Chen Tang)-20 mM solution diluted 1 ~ ~ 200 μg / ml 6 μl health solution 194 μl 25 mM Hepes Dilute 2 (on cell culture plate) ~ 20 μg / milli 1L 3 microliters diluted 2 (at 100 microliters cells / well) -4 moderate ruler A4 S) N (C quasi-standard centimeter 97 200306292 A7 B7 V. Description of the invention (42)-Once the compound is diluted, The administration was repeated twice on the cells of the tissue culture plate (prepared as above). At 3rc containing 5% co2, the cells were incubated with the compound for another 36-48 hours. C. Analytical measurement 5 Performed luminase analysis (hcLite reagent, Packard)
TopCount儀器讀取。由每一 孔培養盤中移除 介^並於每一孔中用!〇〇微升PBS代替(含Mg+2及 )將寺體積(100微升)之LucLite溶解/酶解物缓衝液 添加到每-個孔中,並於室溫時將培養盤㈣並於黑暗中 10 = —旋轉振盈器上混合分鐘。然後於T〇pC〇unt儀 益上進行發光酶讀取。測量值係以相對光單位(rlu)表示 及計算且如下於MS Excel分析。 D·分析數據 關於本文中舉例說明之化合物的分析結果係提供於下 15表=。如果一化合物於20微W/毫升造成發光酶活性至少 提咼1·5倍且不具有毒性,如藉由訊號消失來測定(提高^ 〇·75倍),該化合物則被認定為在RRA具有活性。ΑΑΑ。 經濟部智慧財產局員工消費合作社印製 SEM代表倍數提高平均之標準偏差(未顯示)。得知所有的 測試化合物均為無毒性。 20 表TopCount instrument reads. Remove the medium from each well and use it in each well! 〇〇Ι of PBS instead of (containing Mg + 2) and added a volume (100 microliters) of LucLite solubilization / enzyme buffer to each well, and the culture plate was incubated at room temperature in the dark Middle 10 = —Mix on mixer. Luminase readings were then performed on a TopCount. Measurements are expressed and calculated in relative light units (rlu) and analyzed in MS Excel as follows. D. Analytical data The results of the analysis of the compounds exemplified herein are provided in Table 15 below. If a compound causes at least 1.5-fold increase in luminase activity and is non-toxic at 20 μW / ml, as determined by the disappearance of the signal (increased by ^ 0.75 ·), the compound is considered to have active. ΑΑΑ. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. SEM stands for the standard deviation of the multiple increase average (not shown). All test compounds were known to be non-toxic. 20 tables
Ex# 濃度(微克/ 亳升) APPI提高倍 數 名稱 1-3 20 4.9 5-氯-N-[(lS)-2-乙基-1-甲醒基丁 基]噻吩-2-胺磺醯 4 20 7.2 5-氯-N-[(lS)-2-乙基-1-(1-經基乙 9.7 基)丁基]σ塞吩-2-胺續酿 -44- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) A7 200306292 B7 五、發明說明(43 ) 於本文中所引用之所有公開案係合併於本文中作為參 考。雖然本發明已用特別佳的具體例來說明,應暸解的是 可不脫離本發明之精神而做成變化例。此等變化例係涵蓋 在所附申請專利範圍之範疇中。 經濟部智慧財產局員工消費合作社印製 -4 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐)Ex # concentration (μg / ml) APPI increase multiples 1-3 20 4.9 5-Chloro-N-[(lS) -2-ethyl-1-methylpentylbutyl] thiophene-2-aminesulfonium 4 20 7.2 5-Chloro-N-[(lS) -2-ethyl-1- (1-Ethylethyl9.7-yl) butyl] σsphen-2-amine Continued-44- This paper is applicable to China Standard (CNS) A4 Specification (210x297 mm) A7 200306292 B7 V. Description of Invention (43) All publications cited herein are incorporated herein by reference. Although the present invention has been described with a particularly good specific example, it should be understood that variations can be made without departing from the spirit of the present invention. These variations are covered by the scope of the attached patent application. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -4 This paper size applies to China National Standard (CNS) A4 (210x297 mm)
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US10/014,304 US6610734B2 (en) | 2000-12-13 | 2001-12-11 | Heterocyclic sulfonamide inhibitors of beta amyloid production |
US10/166,896 US6657070B2 (en) | 2000-12-13 | 2002-06-11 | Production of chirally pure α-amino acids and N-sulfonyl α-amino acids |
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JP (1) | JP4615861B2 (en) |
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CL2004000647A1 (en) | 2003-03-31 | 2005-02-04 | Wyeth Corp | COMPOUNDS DERIVED FROM SULFONAMIDE HETEROCICLES CONTAINING FLUORO AND TRIFLUORO RENT; PHARMACEUTICAL COMPOSITION; PHARMACEUTICAL KIT; PREPARATION PROCEDURE; AND ITS USE AS BETA AMILOID INHIBITORS TO TREAT ALZHEIMER, ANGIOPATIA AM |
JP2007517905A (en) | 2004-01-16 | 2007-07-05 | ワイス | Beta-amyloidogenic heterocyclic sulfonamide inhibitors containing azoles |
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US5968942A (en) * | 1992-08-25 | 1999-10-19 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
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CA2470111A1 (en) | 2003-06-19 |
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WO2003050062A2 (en) | 2003-06-19 |
EP1461332A4 (en) | 2009-10-21 |
AU2002351170B2 (en) | 2009-09-24 |
JP2005511727A (en) | 2005-04-28 |
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AU2002351170A1 (en) | 2003-06-23 |
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