TW200536828A

TW200536828A - 2-oxo-1-pyrrolidine derivatives, process for preparing them and their uses

Info

Publication number: TW200536828A
Application number: TW94125252A
Authority: TW
Inventors: John Surtees; Violeta Marmon; Edmond Differding; Vincent Zimmermann
Original assignee: Ucb Farchim Sa
Priority date: 2001-04-03
Filing date: 2001-04-03
Publication date: 2005-11-16

Abstract

The invention concerns 2-oxo-1-pyrrolidine derivatives and a process for preparing them and their uses. The invention also concerns a process for preparing α-ethyl-2-oxo-1-pyrrolidine acetamide derivatives from unsaturated 2-oxo-1-pyrrolidine derivatives. Particularly the invention concerns novel intermediates and their use in methods for the preparation of S-α-ethyl-2-oxo-1-pyrrolidine acetamide.

Description

200536828 九、發明說明：【發明所屬之技術領域】本發明係有關2 _氧基—i _吡咯啶衍生物及其製法及其用途。本發明亦係關於由未飽和2 _氧基-1 -吡咯啶衍生物製備α -乙基-2 -氧基—i -吡咯啶乙醯胺衍生物之方法。【先前技術】特別本發明係有關新穎中間物及其用於製備（S)-(-)_ α -乙基-2-氧基-i-吡咯啶乙醯胺之方法，其於國際非專屬名稱命名爲左堤拉西坦（Levetiracetam)、其右旋對映異構物及相關化合物。左堤拉西坦顯示爲具有如下結構式：200536828 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a 2_oxy-i_pyrrolidine derivative, a preparation method thereof, and a use thereof. The present invention also relates to a method for preparing an α-ethyl-2 -oxy-i-pyrrolidineacetamide derivative from an unsaturated 2-oxy-1 -pyrrolidine derivative. [Prior art] In particular, the present invention relates to a novel intermediate and a method for preparing (S)-(-) _ α-ethyl-2-oxy-i-pyrrolidinacetamidine, which is not exclusive internationally. The name is Levetiracetam, its dextro-enantiomer and related compounds. Levetiracetam is shown to have the following structural formula:

左堤拉西坦左堤拉西坦爲一種左旋化合物，於歐洲專利案第1 6203 6 號揭示作爲中樞神經系統之缺氧及缺血型發作的治療及預防。此種化合物也可用於治療癲癇，癲癇爲一種治療適應症而已經驗證本發明之右旋對映異構物（R)-( + )_ α -乙基- 2-氧基-1-吡咯啶乙醯胺完全缺乏活性（A. J. GOWER等人，歐洲藥理期刊，2 2 2，（ 1 9 9 2 )，1 9 3 - 2 0 3 )。最後，歐洲專利申請案第〇 64 5 1 3 9號顯示此種化合物具有解除焦慮活性非對稱碳原子帶有一個位在紙張平面上的氫原子（圖中未顯示）。左堤拉西坦之製備述於歐洲專利案第〇 1 6 2 0 3 6 200536828 號以及英國專利案第2 2 2 5 3 2 2號’二案皆讓與本發明之受讓人。右旋對映異構物（R) - (+)_ α _乙基-2 -氧基-α比略啶乙醯胺之製備揭示於歐洲專利案第0 1 6 5 9 1 9號。雖言如此，此等辦法無法全然滿足工業製程的需求。因此’透過新穎前驅物之非對稱氫化反應開發新辦法。【發明内容】於一特徵方面，本發明提供一種具有通式（Α)化合物及其醫藥可接受性鹽之化合物。Levetiracetam Levetiracetam is a L-compound that was disclosed in European Patent No. 162036 as a treatment and prevention of hypoxic and ischemic attacks in the central nervous system. This compound can also be used to treat epilepsy, which is a therapeutic indication and the dextroenantiomer (R)-(+) _ α-ethyl-2-oxy-1-pyrrolidine of the present invention has been verified Acetamide is completely inactive (AJ GOWER et al., European Journal of Pharmacology, 22, 2 (19 2 2), 19 3-2 0 3). Finally, European Patent Application No. 0 64 5 139 shows that this compound has an anxiolytic activity. The asymmetric carbon atom has a hydrogen atom (not shown) on the plane of the paper. The preparation of Levetiracetam is described in European Patent No. 06 2 0 3 6 200536828 and British Patent No. 2 2 5 3 2 2 'both assigned to the assignee of the present invention. The preparation of the d-enantiomer (R)-(+) _ α_ethyl-2 -oxy-α-pyrididimidine is disclosed in European Patent No. 0 1 6 5 9 1. Having said that, these methods cannot fully meet the needs of industrial processes. Therefore, a new approach was developed through the asymmetric hydrogenation of novel precursors. SUMMARY OF THE INVENTION In one aspect, the present invention provides a compound having a compound of general formula (A) and a pharmaceutically acceptable salt thereof.

其中，X 爲-CONR5R6 或-COOR7 或-CO-R8 或 CN ; R1爲氫或烷基，芳基，雜環烷基，雜芳基’鹵原子’ 羥基，胺基，硝基，氰基； R2、R3、R4爲相同或相異，且各自分別爲氫或鹵原子，羥基，胺基，硝基，氰基，醯基，醢氧基，磺醯基，亞磺醯基，烷基胺基，羧基，酯基，醚基，醯胺基’磺酸基，磺醯胺基，烷基磺醯基，芳基磺醯基，烷氧羰基、烷基亞磺醯基、芳基亞磺醯基，烷硫基，芳硫基，烷基，烷氧基，氧酯基，氧醯胺基，芳基，芳基胺基，芳氧基，雜環烷基，雜芳基，乙烯基； R5、R6、R7爲相同或相異，且各自分別爲氫’羥基，烷基，芳基，雜環烷基’雜芳基，烷氧基，芳氧基；以及 200536828 r8爲氫，羥基，锍基，鹵原子，烷基，芳基，雜環烷基 ^雜方基’院硫基’方硫基。烷基一詞用於此處包括具有直鏈、分支或環狀部分或其組合且含有1-20個碳原子及較佳1-5個碳原子之飽和一價烴基。烷基可選擇性經以1至5個分別選自鹵原子、羥基、锍基、胺基、硝基、氰基、醯基、醯氧基、磺醯基、亞磺醯基、烷基胺基、羧基、酯基、醚基、醯胺基、磺酸基、磺醯胺基、烷基磺醯基、芳基磺醯基、烷氧羰基、院基亞磺醯基、芳基亞磺醯基、烷硫基、芳硫基、氧酯基、氧醯胺基、雜環烷基、雜芳基、乙烯基、（C^CJ烷氧基、 (C6-C1())芳氧基、（C6-C1())芳基組成的組群之取代基取代。較佳烷基爲甲基、乙基、丙基、異丙基、丁基、異-或第三-丁基、2,2,2-三甲基乙基或經以至少一個選自鹵原子、羥基、锍基、胺基、硝基、氰基組成的組群之基取代，例如三氟甲基，三氯甲基，2，2,2-三氯乙基，1,1-二甲基_2,2 二溴乙基，1，1-二甲基-2,2，2 -三氯乙基。「雜環烷基」一詞用於此處表示如前定義之「（C^C6)環烷基」，帶有至少一個0、S及/或N原子岔斷碳環系環結構例如四氫呋喃基，四氫D比喃基，六氫批D定基，六氫啦口井基，嗎啉基，吡咯啶基或經以至少一個選自鹵原子、經基、酼基、胺基、硝基、氰基組成的組群之基取代。「烷氧基」一詞用於此處包括-0 -烷基，其中「烷基」定義如前。較佳烷基爲甲基、乙基、丙基、異丙基、丁基 200536828 、異-或第三-丁基、2,2,2 -三甲基乙基或經以至少一個鹵基取代之基，例如三氟甲基，三氯甲基，2,2,2 -三氯乙基，1，1-二甲基- 2,2 -二溴乙基，丨，卜二甲基_2,2，2-三氯乙基〇「烷硫基」一詞用於此處包括-S -烷基，其中「烷基」定義如前。較佳烷基爲甲基、乙基、丙基、異丙基、丁基、異-或第三-丁基、2,2,2 -三甲基乙基或經以至少一個_ 基取代之基，例如三氟甲基，三氯甲基，2,2,2 -三氯乙基，1，卜二甲基-2,2-二溴乙基，1，1_二甲基-2,2,2-三氯乙基〇「院基胺基」一詞用於此處包括-Ν Η院基或-N (院基）2 基，其中「烷基」定義如前。較佳烷基爲甲基、乙基、丙基、正丙基、異丙基、丁基、異-或第三-丁基、2，2,2 -三甲基乙基或經以至少一個鹵基取代之基。「芳基」一詞用於此處包括經由去除一個氫原子而衍生自芳族烴之有機基團，例如苯基，苯氧基，萘基，芳烷基，苄基，選擇性經以1至5個分別選自鹵原子、羥基、锍基、胺基、硝基、氰基、醯基、醯氧基、磺醯基、亞擴醯基、烷基胺基、羧基、酯基、醚基、醯胺基、磺酸基、磺醯胺基、烷基磺醯基、烷氧羰基、烷基亞磺醯基、烷硫基、氧酯基、氧醯胺基、芳基、（CVC6)烷氧基、（C6-C1Q)芳氧基及（c6-c1())芳基組成的組群之取代基取代。芳基係由 1-3個環組成，較佳由1個環組成，且含有2-30個碳原子 200536828 且較佳爲6 - 1 0個碳原子。較佳芳基爲苯基基苯基、硝基苯基、甲氧苯基、萘基、苄基基平基、甲氧午基、硝基平基、2 -苯基乙基「芳基胺基」一詞用於此處包括-ΝΗ芳基基，其中「芳基」定義如前。較佳芳基爲苯氰基苯基、硝基苯基、甲氧苯基、萘基、鹵基、甲氧苄基、硝基苄基、2 -苯基乙基。「芳氧基」一詞用於此處包括-0-芳基，3 定義如前。較佳芳基爲苯基、鹵苯基、氰基基、甲氧苯基、苄基、鹵苄基、氰基苄基、基苄基、2_苯基乙基。「芳硫基」一詞用於此處包括-S-芳基，| 定義如前。較佳芳基爲苯基、鹵苯基、氰基基、甲氧苯基、平基、鹵亨基、氨基平基、基苄基、2-苯基乙基。Among them, X is -CONR5R6 or -COOR7 or -CO-R8 or CN; R1 is hydrogen or alkyl, aryl, heterocycloalkyl, heteroaryl 'halogen' hydroxyl, amine, nitro, cyano; R2, R3, and R4 are the same or different, and each is a hydrogen or halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a fluorenyl group, a fluorenyl group, a sulfonyl group, a sulfinyl sulfenyl group, and an alkylamine, respectively. Group, carboxyl group, ester group, ether group, sulfonylamino group's sulfonyl group, sulfonylamino group, alkylsulfonyl group, arylsulfonyl group, alkoxycarbonyl group, alkylsulfinyl group, arylsulfinyl group Fluorenyl, alkylthio, arylthio, alkyl, alkoxy, oxyester, oxamino, aryl, arylamino, aryloxy, heterocycloalkyl, heteroaryl, vinyl ; R5, R6, R7 are the same or different, and each is hydrogen 'hydroxyl, alkyl, aryl, heterocycloalkyl' heteroaryl, alkoxy, aryloxy; and 200536828 r8 is hydrogen, hydroxyl , Fluorenyl, halogen atom, alkyl, aryl, heterocycloalkyl ^ heterosyl ', "thio" and thio. The term alkyl is used herein to include saturated monovalent hydrocarbon groups having a linear, branched or cyclic moiety, or a combination thereof, containing 1 to 20 carbon atoms, and preferably 1 to 5 carbon atoms. Alkyl can be optionally selected from 1 to 5 by halogen, hydroxyl, fluorenyl, amine, nitro, cyano, fluorenyl, fluorenyl, sulfonyl, sulfinyl, and alkylamine Group, carboxyl, ester, ether, amido, sulfonyl, sulfonamido, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylsulfinyl, sulfinyl Fluorenyl, alkylthio, arylthio, oxyester, oxamido, heterocycloalkyl, heteroaryl, vinyl, (C ^ CJ alkoxy, (C6-C1 ()) aryloxy And (C6-C1 ()) aryl group substituents. Preferred alkyl group is methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2 2,2,2-Trimethylethyl or substituted with at least one group selected from the group consisting of halogen atom, hydroxyl group, fluorenyl group, amine group, nitro group, and cyano group, such as trifluoromethyl, trichloromethyl Group, 2,2,2-trichloroethyl, 1,1-dimethyl_2,2 dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl. The term "cycloalkyl" is used herein to mean "(C ^ C6) cycloalkyl" as previously defined, with at least one 0, S, and / or N atomic carbocyclic ring Ring structures such as tetrahydrofuranyl, tetrahydro D-pyranyl, hexahydropyridyl, hexahydrolatoyl, morpholinyl, pyrrolidinyl, or at least one selected from the group consisting of halogen atoms, vials, fluorenyl, Amino groups, nitro groups, and cyano groups are substituted. The term "alkoxy" is used herein to include -0-alkyl, where "alkyl" is as defined above. Preferred alkyl is methyl , Ethyl, propyl, isopropyl, butyl 200536828, iso- or third-butyl, 2,2,2-trimethylethyl or a group substituted with at least one halo group, such as trifluoromethyl Methyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 丨, dimethyl_2,2,2-trichloro Ethyl. The term "alkylthio" is used herein to include -S-alkyl, where "alkyl" is as defined above. Preferred alkyl is methyl, ethyl, propyl, isopropyl, butyl , Iso- or third-butyl, 2,2,2-trimethylethyl or a group substituted with at least one radical, such as trifluoromethyl, trichloromethyl, 2,2,2-tri Chloroethyl, 1,2-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl The term "amino" is used herein to include -NΗ, or -N (radical) 2, where "alkyl" is as defined above. Preferred alkyl is methyl, ethyl, propyl, n-propyl Group, isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl or a group substituted with at least one halo group. The term "aryl" is used herein Including organic groups derived from aromatic hydrocarbons by removing one hydrogen atom, such as phenyl, phenoxy, naphthyl, aralkyl, benzyl, and optionally selected from 1 to 5 halogen atoms, hydroxyl groups , Fluorenyl, amine, nitro, cyano, fluorenyl, fluorenyl, sulfonyl, fluorenylene, alkylamino, carboxyl, ester, ether, sulfonyl, sulfonyl, Sulfonylamino, alkylsulfonyl, alkoxycarbonyl, alkylsulfinyl, alkylthio, oxyester, oxamino, aryl, (CVC6) alkoxy, (C6-C1Q) The group consisting of an aryloxy group and a (c6-c1 ()) aryl group is substituted with a substituent. The aryl system is composed of 1-3 rings, preferably 1 ring, and contains 2-30 carbon atoms 200536828 and preferably 6-10 carbon atoms. Preferred aryl groups are phenylphenyl, nitrophenyl, methoxyphenyl, naphthyl, benzylpentyl, methoxypentyl, nitropentyl, 2-phenylethyl "arylamine The term "radical" is used herein to include -N-aryl, where "aryl" is as defined above. Preferred aryl groups are phenylcyanophenyl, nitrophenyl, methoxyphenyl, naphthyl, halo, methoxybenzyl, nitrobenzyl, and 2-phenylethyl. The term "aryloxy" is used herein to include -0-aryl, 3 as defined above. Preferred aryl groups are phenyl, halophenyl, cyano, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, benzyl, and 2-phenylethyl. The term "arylthio" is used herein to include -S-aryl, as defined above. Preferred aryl groups are phenyl, halophenyl, cyano, methoxyphenyl, pentyl, halohenyl, aminopinyl, benzyl, 2-phenylethyl.

「鹵原子」一詞用於此處包括C1、B r、F 「羥基」一詞用於此處表示式-Ο Η基。「锍基」一詞用於此處表示式-S Η基。「氰基」一詞用於此處表不式-CN基。「硝基」一詞用於此處表示式-Ν02基。「胺基」一詞用於此處表示式-ΝΗ2基。「殘基」一詞用於此處表示式-COOH基。「磺酸基」一詞用於此處表示式-S03H基鹵苯基、氰、鹵平基、気〇或-N(芳基）2 基、鹵苯基、苄基、氰基苄 [中「芳基」苯基、硝基苯甲氧苄基、硝 :中「芳基」苯基、硝基苯甲氧苄基、硝、I原子。 200536828 「磺醯胺基」一詞用於此處表示式_so2nh2基。「雜芳基」一詞用於此處除另行指示，否則表示如前定義之「芳基」帶有至少一個0、S及/或N岔斷碳環系環結構，例如吡啶基，呋喃基，吡咯基，噻吩基，異噻唑基，味唑基，苯并咪唑基，四唑基，吡哄基，嘧啶基，喹_基，異喹啉基，異苯并呋喃基，苯并噻吩基，吡唑基，吲哚基，異吲哚基，嘌呤基，卡巴唑基，異噚唑基，噻唑基，_ 唑基，苯并噻唑基，或苯并噚唑基，選擇性經以至5個分別選自經基、鹵原子、疏基、胺基、硝基、氰基、醯基、醯氧基、磺醯基、亞磺醯基、烷基胺基、羧基、酯基、_ 基、醯胺基、磺酸基、磺醯胺基、烷基磺醯基、烷氧_基、氧酯基、氧醯胺基、烷氧羰基、（cvc5)烷氧基、及（cv c5)烷基組成的組群之取代基取代。「芳烷氧」一詞用於此處表示式芳基烷基卜之s 。較佳芳烷基爲苄基、鹵苄基、氰基苄基、甲氧苄基、5肖基苄基、2-苯乙基、二苯曱基、（4 -甲氧苯基）二苯甲基。「醯基」一詞用於此處表示羧酸基團，如此包括式烷基-CO-、芳基-CO-、雜芳基-CO-、芳烷基- CO -之基，其中各個羥基團定義如此節。較佳烷基爲甲基、乙基、丙基、異丙基、丁基、異-或第三-丁基、2，2,2-三甲基乙基或經以至少一個鹵基取代之基。較佳芳基爲苯基、鹵苯基、氰基苯基、硝基苯基、甲氧苯基、苄基、鹵苄基、氰基苄基、甲氧苄基、硝基苄基、2-苯基乙基。 -10- 200536828 「氧醯基」一詞用於此處表示羧酸基團’如此包括式烷基- C0-0-、芳基-C0-0-、雜芳基- C0-0-、芳烷基-C0-0- 之基，其中各個羥基定義如此處。較佳烷基及芳基係如同對醯基之定義。「磺醯基」一詞表示式-S02-烷基或-so2-芳基之基’其中「烷基」及「芳基」定義如前。較佳烷基爲甲基、乙基、丙基、異丙基、丁基、異-或第三-丁基、2，2,2-三甲基乙基或經以至少一個鹵基取代之基。較佳芳基爲苯基、鹵 b 苯基、氰基苯基、硝基苯基、甲氧苯基、苄基、鹵苄基、氰基苄基、甲氧苄基、硝基苄基、2-苯基乙基。「亞磺醯基」一詞表示式- SO-烷基或- SO-芳基之基，其中「烷基」及「芳基」定義如前。較佳烷基爲甲基、乙基、丙基、異丙基、丁基、異-或第三-丁基、2,2,2-三甲基乙基或經以至少一個鹵基取代之基。較佳芳基爲苯基、鹵苯基、氰基苯基、硝基苯基、甲氧苯基、苄基、鹵苄基 | 、氰基苄基、甲氧苄基、硝基苄基、2 -苯基乙基。「酯基」一詞表示式-C00 -烷基或- C00 -芳基之基，其中「烷基」及「芳基」定義如前。較佳烷基爲甲基、乙基、丙基、異丙基、丁基、異-或第三-丁基、2，2,2-三甲基乙基或經以至少一個鹵基取代之基。較佳芳基爲苯基、鹵苯基、氰基苯基、硝基苯基、甲氧苯基、苄基、鹵苄基、氰基苄基、甲氧苄基、硝基苄基、2 -苯基乙基。「氧酯基」一詞表示式-0-C00 -烷基或- 0- C00 -芳基 -11- 200536828 之基，其中「烷基」及「芳基」定義如前。較佳烷基爲甲基、乙基、丙基、異丙基、丁基、異-或第三-丁基、2，2,2-三甲基乙基或經以至少一個鹵基取代之基。較佳芳基爲苯基、鹵苯基、氰基苯基、硝基苯基、甲氧苯基、苄基、鹵苄基、氰基苄基、甲氧苄基、硝基苄基、2 -苯基乙基。「_基」一*詞表不式院基-〇-院基或院基芳基或芳基 -〇-芳基之基，其中「烷基」及「芳基」定義如前。較佳烷基爲甲基、乙基、丙基、異丙基、丁基、異-或第三-丁基、2,2,2 -三曱基乙基或經以至少一個鹵基取代之基。較佳芳基爲苯基、鹵苯基、氰基苯基、硝基苯基、甲氧苯基、苄基、鹵苄基、氰基苄基、甲氧苄基、硝基苄基、2-苯基乙基。「醯胺基」一詞表示式-C〇NH2-或-CONH烷基或-CON (烷基）2或-CHNH芳基或- CON (芳基）2之基，其中「烷基」及「芳基」定義如前。較佳烷基含1-4個碳原子，及芳基含6-10個碳原子。較佳烷基爲甲基、乙基、丙基、異丙基、丁基、異-或第三-丁基、2,2，2-三甲基乙基或經以至少一個鹵基取代之基。較佳芳基爲苯基、鹵苯基、氰基苯基、硝基苯基、甲氧苯基、苄基、鹵苄基、氰基苄基、甲氧苄基、硝基苄基、2-苯基乙基。「氧醯胺基」一詞表示式-〇_c〇NH2-或-0 一 C0NH烷基或- 0-C0N(烷基）2或- 0-C0NH芳基或- 0-C0N (芳基）2之基，其中「烷基」及「芳基」定義如前。較佳烷基含1-5個 -12- 200536828 碳原子及芳棊含6-8個碳原子。較佳烷基爲甲基、乙基、丙基、異两基、丁基、異-或第三-丁基、2,2,2_三甲基乙基或,經以娶少一個鹵基取代之基。較佳芳基爲苯基、鹵苯基、氨基苯_、硝基苯基、甲氧苯基、苄基、鹵苄基、氰基平基、甲氡苄基、硝基苄基、2 -苯基乙基。The term "halogen atom" is used herein to include C1, Br, F. The term "hydroxyl" is used herein to represent the formula -OH. The term "fluorenyl" is used herein to represent the formula -S fluorenyl. The term "cyano" is used herein to denote -CN. The term "nitro" is used herein to represent the radical of formula -N02. The term "amine group" is used herein to represent a group of formula -NQ2. The term "residue" is used herein to represent the formula -COOH group. The term "sulfonate" is used herein to represent a formula -S03H-based halophenyl, cyano, halophenyl, 気 or -N (aryl) 2, halophenyl, benzyl, cyanobenzyl [Chinese "Aryl" phenyl, nitrobenzylbenzyl, nitrate: "aryl" phenyl, nitrobenzylbenzyl, nitrate, I atom. 200536828 The term "sulfoamido" is used herein to represent the radical of formula _so2nh2. The term "heteroaryl" is used herein unless otherwise indicated, meaning "aryl" as defined above bears at least one 0, S, and / or N-branched carbocyclic ring structure, such as pyridyl, furyl , Pyrrolyl, thienyl, isothiazolyl, mizolyl, benzimidazolyl, tetrazolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolinyl, isobenzofuranyl, benzothienyl , Pyrazolyl, indolyl, isoindolyl, purine, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl, or benzoxazolyl, with selectivity up to 5 Each is selected from the group consisting of a hydroxyl group, a halogen atom, a thiol group, an amine group, a nitro group, a cyano group, a fluorenyl group, a fluorenyl group, a sulfonyl group, a sulfinyl group, an alkylamino group, a carboxyl group, an ester group, and a radical , Amido, sulfonic, sulfoamido, alkylsulfoamido, alkoxy-, oxyester, oxamido, alkoxycarbonyl, (cvc5) alkoxy, and (cv c5) A group consisting of an alkyl group is substituted with a substituent. The term "aralkoxy" is used herein to denote s of the formula arylalkyl. Preferred aralkyls are benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, 5-shocosylbenzyl, 2-phenethyl, diphenylfluorenyl, (4-methoxyphenyl) diphenyl methyl. The term "fluorenyl" is used herein to denote a carboxylic acid group, and thus includes groups of the formula alkyl-CO-, aryl-CO-, heteroaryl-CO-, aralkyl-CO-, where each hydroxyl group Mission definition is such a section. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group. base. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2 -Phenylethyl. -10- 200536828 The term "oxofluorenyl" is used herein to indicate a carboxylic acid group 'so includes the formula alkyl-C0-0-, aryl-C0-0-, heteroaryl-C0-0-, aromatic Alkyl-C0-0-, wherein each hydroxyl group is as defined herein. Preferred alkyl and aryl groups are as defined for fluorenyl. The term "sulfofluorenyl" represents a group of the formula -S02-alkyl or -so2-aryl, wherein "alkyl" and "aryl" are as defined above. Preferred alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group base. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl. The term "sulfinyl" refers to a radical of the formula -SO-alkyl or -SO-aryl, where "alkyl" and "aryl" are as defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group. base. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl. The term "ester group" refers to a group of the formula -C00-alkyl or -C00-aryl, wherein "alkyl" and "aryl" are as defined above. Preferred alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group base. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2 -Phenylethyl. The term "oxyester" refers to a radical of the formula -0-C00-alkyl or -0-C00-aryl-11-200536828, where "alkyl" and "aryl" are as defined above. Preferred alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group base. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2 -Phenylethyl. The term "_ 基" means a radical of the radical -0-yuan or a radical of aryl or aryl-0-aryl, wherein "alkyl" and "aryl" are as defined above. Preferred alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group base. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2 -Phenylethyl. The term "amido" represents a radical of the formula -CONH2- or -CONHalkyl or -CON (alkyl) 2 or -CHNHaryl or -CON (aryl) 2, where "alkyl" and " "Aryl" is as defined above. Preferred alkyl groups contain 1-4 carbon atoms, and aryl groups contain 6-10 carbon atoms. Preferred alkyl is methyl, ethyl, propyl, isopropyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group base. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2 -Phenylethyl. The term "oxoamino" represents the formula -0_c〇NH2- or -0-CONH alkyl or -0-COON (alkyl) 2 or -0-CONH aryl or -0-COON (aryl) The base of 2 in which "alkyl" and "aryl" are as defined above. Preferred alkyl groups contain 1-5 -12-200536828 carbon atoms and arylfluorenes contain 6-8 carbon atoms. Preferred alkyl group is methyl, ethyl, propyl, isodiyl, butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl or Substitute the base. Preferred aryl groups are phenyl, halophenyl, aminobenzene, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanopinyl, formamylbenzyl, nitrobenzyl, 2- Phenylethyl.

車父佳R1爲甲基，乙基，丙基，異丙基，丁基，異-或第 H _T ^ ’ 2,2,2_三甲基乙基或經以至少一個鹵基取代之基 ’例如二氟甲基，三氯甲基，2，2,2 -三氯乙基，1，1-二甲基-2,2_ 一填乙基，1,1-二甲基-2,2,2·三氯乙基。 _ @ R2 ' R3及R4分別爲氫或鹵原子或甲基，乙基，丙基’異丙裏’丁基，異-或第三-丁基，2,2,2_三甲基乙基 $ '經U Μ少〜個鹵基取代之基，例如三氟甲基，三氯甲基 ’ 2,2,2-二氡乙基，1，1_二甲基_2,2_二溴乙基，1，1-二甲基 -2,2,2-二氯乙基。較佳R5^R6爲甲基，乙基，丙基，異丙基，丁基，異-或第二_丁義，2,2,2-三甲基乙基。較佳R7馬氮，甲基，乙基，丙基，異丙基，丁基，異_ 或弟二-丁基，2,2,2_三甲基乙基，甲氧基，乙氧基，苯基 ’ I 或經以至少一個鹵基取代之基例如三氟甲基，氯苯基。Chevroja R1 is methyl, ethyl, propyl, isopropyl, butyl, iso- or H_T ^ '2,2,2-trimethylethyl or a group substituted with at least one halo group 'E.g. difluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2_ one-filled ethyl, 1,1-dimethyl-2,2 , 2 · trichloroethyl. _ @ R2 'R3 and R4 are hydrogen or halogen atom or methyl, ethyl, propyl'isopropyl'butyl, iso- or tertiary-butyl, 2,2,2-trimethylethyl $ 'U ~ M ~~ halogen-substituted groups, such as trifluoromethyl, trichloromethyl' 2,2,2-difluorethyl, 1,1-dimethyl-2, 2-dibromo Ethyl, 1,1-dimethyl-2,2,2-dichloroethyl. Preferably R5 ^ R6 is methyl, ethyl, propyl, isopropyl, butyl, iso- or di-butyi, 2,2,2-trimethylethyl. Preferred R7 is nitrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or di-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy , Phenyl 'I or a group substituted with at least one halo group such as trifluoromethyl, chlorophenyl.

較佳R8爲氫，甲基，乙基，丙基，異丙基，丁基，異_ 或第三-丁基，2,2,2-三甲基乙基，苯基，苄基，或經以至少一個鹵基取代之基例如三氟甲基，氯苄基或此處X爲-CN -13-Preferably R8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, phenyl, benzyl, or Substituted with at least one halo group such as trifluoromethyl, chlorobenzyl or where X is -CN -13-

200536828 除非另行陳述，否則此處述及通式（A)化合物無論個別表示或集合表示意圖包括幾何異構物亦即Z(住沙門 (Zusammen))及E(安久占（Entgegen))異構物及其混合物 (外消旋混合物）。就後述非對稱氫化方法而言，對式（A)化合物之Z(住沙門）及E(安久占）異構物（其中R1爲甲基，R2及R4爲Η及 X爲- CONH2或- COOMe或- COOEt或- COOH)獲得最佳結果。於此組群，以其中R3爲氫，烷基（特別丙基）或鹵烯基 (特別二氟乙烯基）之化合物特別適宜。本發明之一特徵方面係有關一種製備具有通式（A)化合物之方法，此種方法包括下列反應：通式（A)化合物此處X爲-CONR5R6或-COOR7或 -C0-R8或CN，可方便地經由通式（C)之α -酮基羧酸衍生物此處R1及X定義如前，與通式（D)之吡咯啶酮‘此處R2 、R3、R4定義如前根據如下反應圖（1)反應製備。200536828 Unless otherwise stated, the compounds of general formula (A) mentioned herein, whether represented individually or collectively, are schematic diagrams including geometric isomers, that is, Z (Zusammen) and E (Entgegen) isomers And mixtures thereof (racemic mixtures). For the asymmetric hydrogenation method described below, for the compounds of formula (A), the Z (Suzumana) and E (Anjiuzhan) isomers (where R1 is methyl, R2 and R4 are hydrazones, and X is -CONH2 or-COOMe Or-COOEt or-COOH) for best results. Of this group, compounds in which R3 is hydrogen, alkyl (especially propyl) or haloenyl (especially difluorovinyl) are particularly suitable. A characteristic aspect of the present invention relates to a method for preparing a compound having the general formula (A), which method comprises the following reaction: A compound of the general formula (A) where X is -CONR5R6 or -COOR7 or -C0-R8 or CN, Conveniently via the α-ketocarboxylic acid derivative of the general formula (C) Here R1 and X are defined as before, and pyrrolidone of the general formula (D) is defined here as R2, R3, R4 as before according to the following Reaction diagram (1) Reaction preparation.

R3 R4R3 R4

反應圖（1)Reaction diagram (1)

通式（Α)化合物此處X爲- CO OR7可方便地經由通式（C，） α -酮基羧酸衍生物此處X爲-COOR7與通式（D)之吡咯啶酮根據如下反應圖（2)反應製備。 -14- 200536828Compounds of general formula (A) where X is -CO OR7 can be conveniently via the general formula (C,) α-ketocarboxylic acid derivatives where X is -COOR7 and pyrrolidone of general formula (D) is reacted according to the following Figure (2) Reaction preparation. -14- 200536828

反應圖（2) 適當反應條件涉及回流使用甲苯。結果所得化合物（A) 中，R7方便由Η轉成烷基或由烷基轉成Η。Reaction Diagram (2) Suitable reaction conditions involve the use of toluene at reflux. In the compound (A) obtained as a result, R7 is conveniently converted from fluorene to alkyl or from alkyl to fluorene.

通式（C)或（C’）衍生物及通式（D)吡咯啶酮爲業界人士眾所周知，且可根據參考文件所述合成製備，例如參考「雜環族化學手冊」作者A· Katrisky，波加蒙（Pergamon)，1985( 第4章）以及「理解雜環族化學」作者A. Katrisky及C.w. Rees，波加蒙，1984(第4卷，第3.03及3.06章）。Derivatives of general formula (C) or (C ') and pyrrolidone of general formula (D) are well known in the industry and can be prepared synthetically according to reference documents, for example, refer to the author of "Handbook of Heterocyclic Chemistry" A. Katrisky, Pergamon, 1985 (Chapter 4) and A. Katrisky and Cw Rees, authors of "Understanding Heterocyclic Chemistry", Pergamon, 1984 (Vol. 4, Chapters 3.03 and 3.06).

通式（A)化合物此處X爲-CONH2或-CONR5R6可方便地經由將對應酸（式（A)化合物此處X爲C02H)轉成醯氯，隨後接著氨解或與通式NHR5R6之第一或第二胺反應製備。如下二反應圖（3及4)說明此種方法。Compounds of general formula (A) where X is -CONH2 or -CONR5R6 can be conveniently converted to phosphonium chloride by converting the corresponding acid (compound of formula (A) where X is C02H), followed by ammonolysis or the first step with the general formula NHR5R6 Preparation of one or second amines. The following two reaction diagrams (3 and 4) illustrate this method.

反應圖（3) 200536828Reaction Diagram (3) 200536828

反應圖（4) 此等反應較佳係使用PC15進行獲得醯氯，接著爲無水氨或式HNR 5 R6之第一或第二胺反應獲得所需烯醯胺醯胺。通式（A)化合物此處X爲- COOR7可方便地由將反應圖（2) 所得對應酸（化合物（A)，此處X爲COOH)轉成醯氯，隨後使用式R7-〇H化合物（醇），此處R7定義如前進行醇解製備。（參考反應圖5)Reaction Scheme (4) These reactions are preferably carried out using PC15 to obtain ammonium chloride, followed by reaction with anhydrous ammonia or a first or second amine of the formula HNR 5 R6 to obtain the desired amidineamine. Compounds of general formula (A) where X is -COOR7 can be conveniently converted from the corresponding acid (compound (A), where X is COOH) obtained in the reaction diagram (2) into chloro chloride, and then using the compound of formula R7-OH (Alcohol), here R7 is defined as previously prepared by alcoholysis. (Refer to reaction diagram 5)

R3 R4 R3 R4R3 R4 R3 R4

反應圖（5) 此等反應較佳係使用P C 15進行獲得醯氯，接著使用 R、〇H醇解獲得預定酯。前述反應條件爲業界人士眾所周知。於另一特徵方面，本發明係有關使用式（A)化合物作爲合成中間物。式（A)化合物’此處X爲-C0NH2作爲將此種化合物氫化結果形成左堤拉西坦特別令人感興趣。此等化合物之z ( 住沙門）及E(安久占）可進行快速及選擇性之非對稱氫化反 -16- 200536828 應成爲預定產物之任一種對映異構物。接合R !至分子之鍵結表不Z異構物或E異構物。至於特例，使用化合物（A)合成的化合物（B)可根據如下反應圖（6)說明。 D3 ι-λ4Reaction Scheme (5) These reactions are preferably carried out using P C 15 to obtain ammonium chloride, followed by R, 0H alcoholysis to obtain a predetermined ester. The aforementioned reaction conditions are well known to those skilled in the art. In another characteristic aspect, the invention relates to the use of a compound of formula (A) as a synthetic intermediate. Compounds of formula (A) 'where X is -C0NH2 are of particular interest as a result of the hydrogenation of such compounds to form levetiracetam. These compounds, z (Zhushamen) and E (Anjiuzhan), can undergo fast and selective asymmetric hydrogenation. -16-200536828 should be any enantiomer of the intended product. The bond between R! And the molecule represents either the Z isomer or the E isomer. As for a specific example, the compound (B) synthesized using the compound (A) can be explained based on the following reaction scheme (6). D3 ι-λ4

反應圖（6) 其中R1、R2、R3、R4及X定義如前。較佳R1爲甲基、乙基、丙基、異丙基、丁基或異丁基 ;最佳爲甲基、乙基或正丙基。較佳R2及R4分別爲氫或鹵原子或甲基、乙基、丙基、異丙基、丁基、異丁基；及最佳各別爲氫。較佳R3爲CVC5烷基、C2-C5炔基、環丙基疊氮基，各自選擇性經以一或多個鹵原子、氰基、硫氰基、疊氮基、烷硫基、環丙基、醯基及/或苯基取代；苯基；苯基磺醯基；苯基磺醯氧基，四唑基，***基，噻吩基，呋喃基，吡咯基，吡啶基，藉此任何苯基部分可經以一或多個鹵原子、烷基、鹵烷基、烷氧基、硝基、胺基及/或苯基取代 :最佳爲甲基、乙基、丙基、異丙基、丁基或異丁基。較佳 X 爲-COOH 或-COOMe 或-COOEt 或-CONH2;最佳爲-C0NH2。式（B)化合物可以習知方式呈自由態形式單離或轉變成 -17- 200536828 其醫藥可接受性鹽，或反之亦然。較佳藉由通式（B)之化合物中個別化合物具有式（B’）、 (B，，）及（B，，，）。Reaction diagram (6) where R1, R2, R3, R4 and X are as defined above. Preferably R1 is methyl, ethyl, propyl, isopropyl, butyl or isobutyl; most preferably methyl, ethyl or n-propyl. Preferably, R2 and R4 are hydrogen or a halogen atom or methyl, ethyl, propyl, isopropyl, butyl, isobutyl, respectively; and most preferably hydrogen. Preferably, R3 is a CVC5 alkyl group, a C2-C5 alkynyl group, or a cyclopropyl azide group, each of which is optionally Phenyl, sulfenyl and / or phenyl substitution; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazolyl, triazolyl, thienyl, furyl, pyrrolyl, pyridyl, thereby any The phenyl moiety can be substituted with one or more halogen atoms, alkyl, haloalkyl, alkoxy, nitro, amine, and / or phenyl groups: most preferably methyl, ethyl, propyl, isopropyl Base, butyl or isobutyl. Preferably, X is -COOH or -COOMe or -COOEt or -CONH2; more preferably -C0NH2. The compound of formula (B) can be isolated or transformed in a free form in a conventional manner into a pharmaceutically acceptable salt of -17-200536828, or vice versa. It is preferred that the individual compounds of the compound of the general formula (B) have the formula (B '), (B ,,) and (B ,,,).

式（B)化合物適合用於治療癲癇及相關疾病。根據另— 具體實施例，本發明係有關一種製備式（B)化合物之方法Compounds of formula (B) are suitable for the treatment of epilepsy and related diseases. According to another embodiment, the present invention relates to a method for preparing a compound of formula (B)

其中R1、R2、R3、R4及X定義如前，該方法係經由如前舉例說明且定義如前之對應式（A)化合物之催化非對稱性氫化反應獲得。催化氫化說明於多種公開文獻或書籍例如「催化非對稱合成-輔助之對掌配體」Jacqueline Seyden-Penne( 1 994)-S avoirs actuel，interEdition/CNRS Edition-7.1章「氫化催化劑」28 7-3 00頁。除非另行陳述，否則於此處述及通式（B)化合物無論個別或集合皆意圖包括幾何異構物，亦即Z (住沙門）及E (安久占）異構物，以及對映異構物、非對映異構物及各別混 -18- 200536828 合物（外消旋混合物）。較佳本發明方法係有關製備式（B)化合物，其中R2及R4 爲氫及X爲- COOH或- COOMe或- COOEt或- CONH2，以及 R1爲甲基；特別其中r3爲氫、院基（特別丙基）或鹵燒基 (特別二氟乙烯基）。使用左堤拉西坦之製法獲得最佳結果，式（B)化合物其中R1爲甲基，R2及R4爲氫，R3爲氫、丙基或二氟乙烯基，及X爲- CONH2。通常此種方法包括前將述式（A)化合物進行催化氫化反應。較佳式（A)化合物係使用基於铑（Rh)或釕（Ru)蟄合劑之對掌催化進行非對稱氫化。非對稱氫化方法述於許多公開文獻或書籍例如「非對稱合成」R.A. Aitken以及S.N. Kilenyi(1992)-布來奇（Blackie)學術及專業出版或「光學活性胺基酸之合成」Robert Μ · Willi mas( 1 9 8 9)-波加蒙出版社。對掌螫合配體之Rh( I )及Ru( Π )複合體通常爲二膦類用於烯烴的非對稱氫化極爲成功。許多對掌二螫合基配體例如二亞膦酸鹽、貳（胺基膦）及胺基膦亞膦酸鹽或對掌催化劑錯合物述於參考文獻且爲市面可得。對掌催化劑也可結合相對離子及/或烯烴。雖然已經累積許多對掌催化劑之催化活性及立體選擇性之資訊’但對個別基質而言，配體、對掌催化劑及反應條件的選擇仍然係靠實驗進行。通常以Rh( I )爲主的系統大半用於製備胺基酸衍生物，Ru( Π )催化劑對寬廣烯屬基質可獲得絕佳結果。用於本發明之對掌催化劑螫合劑有杜 -19- 2-00536828 弗斯（DUPHOS)，BPPM，BICP，BINAP，DIPAMP，SKEWPHOS ，BPPEA，DIOP，NORPHOS，PROPHOS，PENNPHOS， QUPHOS，BPPMC，BPPFA。由前述螫合劑製備的經支載或以其它方式制動催化劑也可用於本發明，俾除了改良催化劑的回收以及循環利用之外也獲得改良轉換率或選擇性。較佳用於本發明方法之對掌催化劑螫合劑係選自杜弗斯或甲基、二乙基、二異丙基-杜弗斯（1，2-貳2,5-二甲基磷諾基（phospholano))苯-美國專利第 5，171，892 號），DIPAMP( 膦，1，2-乙二基貳（（2-甲氧苯基）苯基-美國專利第4,008，281 及4，142,992號），：8??1^(1-吡咯啶羧酸，4-(二苯基膦基）-2-((二苯基膦基）甲基）-1，1-二甲基乙基酯-日本專利第 8 704 5 2 3 8 號）及 BINAP(膦，（1，1’-聯萘）-2,2’-二基貳（二苯基-歐洲專利案第〇 3 6 6 3 9 0號）。此等螫合劑之結構式顯示如下。R1, R2, R3, R4 and X are as defined above, and the method is obtained through the catalytic asymmetric hydrogenation of the corresponding compound of formula (A) as exemplified and defined as above. Catalytic hydrogenation is described in various published documents or books such as "Catalyzed Asymmetric Synthesis-Aided Ligand" Jacqueline Seyden-Penne (1 994)-Savois actuel, interEdition / CNRS Edition-Chapter 7.1 "Hydrogenation Catalysts" 28 7- 3 00 pages. Unless otherwise stated, the compounds of general formula (B) mentioned herein are intended to include geometrical isomers, individually or collectively, that is, the Z (Summon Gate) and E (Anjiu) isomers, and the enantiomers Compounds, diastereoisomers and individual mixed -18-200536828 compounds (racemic mixtures). Preferably, the method of the present invention relates to the preparation of a compound of formula (B), wherein R2 and R4 are hydrogen and X is -COOH or -COOMe or -COOEt or -CONH2, and R1 is methyl; in particular, r3 is hydrogen, Especially propyl) or haloalkyl (especially difluorovinyl). The best results were obtained using the method of Levetiracetam. The compound of formula (B) wherein R1 is methyl, R2 and R4 are hydrogen, R3 is hydrogen, propyl or difluorovinyl, and X is -CONH2. Generally, this method involves the aforementioned catalytic hydrogenation of a compound of formula (A). Preferably, the compound of formula (A) is asymmetrically hydrogenated using a palm catalyst based on a rhodium (Rh) or ruthenium (Ru) coupler. Asymmetric hydrogenation methods are described in many public literature or books such as "Asymmetric Synthesis" RA Aitken and SN Kilenyi (1992) -Blackie Academic and Professional Publications or "Synthesis of Optically Active Amino Acids" Robert M. Willi mas (1 9 8 9)-Pergamon Press. Rh (I) and Ru (Π) complexes of palmitate ligands are usually diphosphines, which are very successful for asymmetric hydrogenation of olefins. Many of the palmitinyl ligands such as bisphosphonates, amidines (aminophosphines) and aminophosphinophosphonates or palmitate catalyst complexes are described in the references and are commercially available. The palm catalyst may also incorporate counter ions and / or olefins. Although a lot of information on the catalytic activity and stereoselectivity of the palm catalyst has been accumulated ', for individual substrates, the choice of ligand, palm catalyst and reaction conditions is still carried out experimentally. Rh (I) -based systems are mostly used for the preparation of amino acid derivatives, and Ru (Π) catalysts achieve excellent results for a wide range of olefinic substrates. The palm catalyst couplers used in the present invention are Du-19-2-2-00536828 Fuchs (DUPHOS), BPPM, BICP, BINAP, DIPAMP, SKEWPHOS, BPPEA, DIOP, NORPHOS, PROPHOS, PENNPHOS, QUPHOS, BPPMC, BPPFA. Supported or otherwise braked catalysts prepared from the aforementioned coupling agents can also be used in the present invention. In addition to improving the recovery and recycling of catalysts, they also achieve improved conversion or selectivity. The palm catalyst coupler which is preferably used in the method of the present invention is selected from the group consisting of Duffers or methyl, diethyl, diisopropyl-Duffers (1,2-, 2,5-dimethylphosphono (Phospholano) benzene-U.S. Patent No. 5,171,892), DIPAMP (Phosphine, 1,2-Ethylenedifluorene ((2-methoxyphenyl) phenyl)-U.S. Patent Nos. 4,008,281 and 4 No. 142,992), 8 ?? 1 ^ (1-pyrrolidinecarboxylic acid, 4- (diphenylphosphino) -2-((diphenylphosphino) methyl) -1,1-dimethyl Ethyl Ester-Japanese Patent No. 8 704 5 2 3 8) and BINAP (Phosphine, (1,1'-Binaphthalene) -2,2'-Diylfluorene (Diphenyl-European Patent Case No. 03 6 6 3 9 0). The structural formulas of these admixtures are shown below.

(R,R)-DIPAMP (S’S)-BPPM (S，S)-Et-杜弗斯(R, R) -DIPAMP (S ’S) -BPPM (S, S) -Et-Duvers

(R)-BINAP -20- 200536828 較佳用於本發明方法之溶劑係選自四氫呋喃（THF)，二甲基甲醯胺（DMF)，乙醇，甲醇，二氯甲烷（DCM)，異丙醇（IPA)，甲苯，乙酸乙酯（AcOEt)。相對離子係選自鹵陰離子（鹵（-))，BPh4(-)C104(-)，BF4(-) ，PF6(-)，PC16(-)，OAc(-)，三氟甲院磺酸基（〇Tf(-))，甲烷磺酸基或甲烷磺酸酯。較佳用於對掌催化劑之相對離子係選自〇Tf(-)、BF4(-)或〇Ac(-)。儲烴係選自乙燃，1，3 - 丁二稀，苯，環己二；(:希，原冰片 1 二烯或環辛-1，5-二烯（COD)。使用此等對掌催化劑組合一定範圍之相對離子且催化劑-基質比係於1:20至1:20,000之範圍於商用溶劑之範圍內，可將式（A)化合物轉成具有高度百分比對映異構物過量（e.e.)以及絕佳產率及高純度之式（B)化合物之左旋或右旋對映異構物。此外，此種辦法係使用標準產業工廠業及設備，因此具有成本上的優勢。此種非對稱合成方法由於可避免習知合成方法所得非 •期望對映異構物之回收或拋棄問題，故也可降低成本。使用製備（S) - α -乙基-2-氧基-1-吡咯啶乙醯胺或（R) - α -乙基-2-氧基-1-吡咯啶乙醯胺之方法可獲得最佳結果，其中包含呈Ζ異構物或Ε異構物形式之式A ’化合物根據如下反應圖使用對掌催化劑接受非對稱氫化反應。 -21 - 200536828(R) -BINAP -20- 200536828 The solvent preferably used in the method of the present invention is selected from the group consisting of tetrahydrofuran (THF), dimethylformamide (DMF), ethanol, methanol, dichloromethane (DCM), isopropanol (IPA), toluene, ethyl acetate (AcOEt). The relative ion system is selected from the halide anion (halogen (-)), BPh4 (-) C104 (-), BF4 (-), PF6 (-), PC16 (-), OAc (-), trifluoromethane sulfonic group (〇Tf (-)), methanesulfonate or methanesulfonate. The relative ion system preferably used for the palm catalyst is selected from the group consisting of Otf (-), BF4 (-) or OAc (-). The hydrocarbon storage system is selected from the group consisting of ethane, 1,3-butadiene, benzene, and cyclohexane; (: Greek, probornol 1 diene or cyclooctane-1,5-diene (COD). Use these palms A certain range of relative ions in the catalyst combination and a catalyst-to-substrate ratio in the range of 1:20 to 1: 20,000 are in the range of commercial solvents. The compounds of formula (A) can be converted into compounds with a high percentage of enantiomeric excess (ee ) And the left- or right-handed enantiomers of the compound of formula (B) with excellent yields and high purity. In addition, this method uses standard industrial plants and equipment, so it has a cost advantage. The symmetric synthesis method can also reduce the cost because it can avoid the problem of recovering or discarding the undesired enantiomers obtained by the conventional synthesis method. Preparation (S)-α-ethyl-2-oxy-1-pyrrole Best results are obtained with pyridoxamine or (R) -α-ethyl-2-oxy-1-pyrrolidinacetamide, which includes formula A in the form of the Z isomer or E isomer. 'The compound is subjected to an asymmetric hydrogenation reaction using a palm catalyst according to the following reaction diagram. -21-200536828

A，A,

後文將特別參照四種式（A)化合物說明，其中R1爲甲基、R2、R3及R4爲氫，以及對後文標示爲前驅物A1之化合物而言，X爲-COOH ; 對後文標示爲前驅物A2之化合物而言，X爲-COOMe 對後文標示爲前驅物A2’之化合物而言，X爲_C00Et :以及對後文標示爲前驅物A3之化合物而言，X爲-C0Nh2。如業界人士已知，視取代形式決定，並非全部通式（A) 及（B)化合物皆可形成鹽，故述及「醫藥可接受性鹽」僅應用至具有形成鹽熊力之通式（A)或（B)化合物。【實施方式】下列實例僅供舉例說明之用，而非意圖也非解釋爲限制本發明。業界人士了解可未超出本發明之精髓或範圍對下列實例之例行變化及修改。實例1 前驅物A 1之製備係參照反應圖7，經由α -酮基丁酸與吡咯啶酮於回流加熱進行，70%粗產率。Ζ:Ε表示Ζ異構物量對Ε異構物量之比。 -22- 200536828In the following, particular reference will be made to four compounds of formula (A), in which R1 is methyl, R2, R3, and R4 are hydrogen, and for compounds labeled as precursor A1 later, X is -COOH; For compounds labeled as precursor A2, X is -COOMe For compounds labeled as precursor A2 ', X is _C00Et: and for compounds labeled as precursor A3, X is- C0Nh2. As known to those in the industry, depending on the substitution form, not all compounds of the general formulae (A) and (B) can form salts, so the reference to "pharmaceutically acceptable salts" applies only to the general formula (A) that has the ability to form salts. Or (B) a compound. [Embodiments] The following examples are for illustrative purposes only, and are not intended to be interpreted as limiting the present invention. Those skilled in the art understand that routine changes and modifications to the following examples can be made without departing from the spirit or scope of the present invention. Example 1 Precursor A 1 was prepared by referring to Reaction Figure 7 by heating α-ketobutyric acid and pyrrolidone under reflux at 70% crude yield. Z: E represents the ratio of the amount of the Z isomer to the amount of the E isomer. -22- 200536828

OHOH

ΗΗ

ΟΟ

甲苯，回流，丁·史塔克 70% Υ ΟΗToluene, reflux, Ding Stark 70% Υ ΟΗ

〇 Ο ΟΗ〇 Ο ΟΗ

Ζ:Ε= 149 :1 熔點 165 - 166 反應圖7 粗產物由丙酮再結晶，7 0 %產率。雙鍵幾何係基於與類似結構之已知化合物1H-NMR(核磁共振）光譜資料之交互關係被指定爲Z。實例2 前驅物A2係使用重氮甲烷於THF製自A1。觀察得蒸餾期間Z-E比由80:1變化至29: 1(參考反應圖8)。Z: E = 149: 1 Melting point 165-166 Reaction Figure 7 The crude product was recrystallized from acetone, 70% yield. The double bond geometry is designated as Z based on the interaction with 1H-NMR (nuclear magnetic resonance) spectral data of known compounds of similar structure. Example 2 The precursor A2 was prepared from A1 using diazomethane in THF. It was observed that the Z-E ratio during the distillation changed from 80: 1 to 29: 1 (refer to Reaction Figure 8).

OHOH

1. CH2N2，THF，100% 2. _蒸餾，80% OMe1. CH2N2, THF, 100% 2. _distillation, 80% OMe

〇〇

〇前驅物A1 Z : E = 80 : 1 前驅物A2 Z : E = 29 : 1 反應圖8 -23- 200536828 前驅物A 2 ’之E異構物如反應圖9所述係使用乙醇、二環己基甲二醯亞胺（DC C)以及二甲基胺基吡啶（D MAP)而得自前驅物A1之Z異構物。〇 Precursor A1 Z: E = 80: 1 Precursor A2 Z: E = 29: 1 Reaction Figure 8 -23- 200536828 The E isomer of precursor A 2 'as described in reaction Figure 9 uses ethanol, bicyclic Hexylformamide (DC C) and dimethylaminopyridine (D MAP) were obtained from the Z isomer of precursor A1.

EtOH(3 當量） DCC(1 當量）、、DMAP(CU 當量)，TiiF(20 容積) 室溫(r.t)，24小時前驅物A1 Z異構物EtOH (3 equivalents), DCC (1 equivalent), DMAP (CU equivalents), TiiF (20 volumes), room temperature (r.t), 24 hours precursor A1 Z isomer

〇Et 前驅物A2, 反應圖9 E異構物. 100°/。產率〇Et precursor A2, reaction Figure 9 E isomer. 100 ° /. Yield

前驅物A1之酯化也以小規模使用PC15於THF然後使用甲醇進行，獲得預定甲酯（Z:E = 5:1)，參考反應圖10。The esterification of the precursor A1 was also performed on a small scale using PC15 in THF and then methanol to obtain a predetermined methyl ester (Z: E = 5: 1). Refer to Reaction Figure 10 for reference.

OHOH

前驅物A1 1. PC15 當量，THF，0〇C 2. MeOH Γ當量，吡啶Precursor A1 1. PC15 equivalent, THF, 0 ° C 2. MeOH Γ equivalent, pyridine

則驅物A2 E : Z = 5 : 1 反應圖10 實例3 前驅物A2亦係經由酮基丁酸甲酯與吡咯啶酮於回流甲苯於催化量之磷醯氯存在下反應製備，參考反應圖11。 -24- 200536828The precursor A2 E: Z = 5: 1 is shown in Figure 10. Example 3 The precursor A2 is also prepared by reacting methyl ketobutyrate with pyrrolidone in refluxing toluene in the presence of a catalytic amount of phosphorous chloride. Refer to the reaction diagram. 11. -24- 200536828

POCh '催化劑甲苯，回流，丁-史塔克 60% OMePOCh 'catalyst toluene, reflux, D-Stark 60% OMe

前驅物A2 7.:R = 6:1 反應圖11Precursor A2 7.:R = 6: 1 Reaction Figure 11

酮基丁酸之酯化係使用甲醇遵照參考文獻方法或使用重氮甲烷進行。隨後縮合反應獲得前驅物A2，60%產率。此種方法比較經由前驅物A1之途徑（反應圖8)獲得較高E 異構物含董。兩種途徑皆可製備前驅物A2之其它酯衍生物〇實例4 前驅物A3之合成可經由烯醯胺酸與五氯化磷反應獲得醯氯，及然後與氣態氨反應獲得預定烯醯胺醯胺A3進行產物證實爲Z-異構物。粗烯醯胺醯胺A3係經由於THF-Me OH蒸餾，及過濾去除無機殘餘物而由反應混合物中分離。蒸發去除溶劑後’ 獲得黃色固體。粗料係藉無水急速層析純化，接著由異丙醇再結晶獲得純物料。此種程序可成功地應用於製造單批 -25- 200536828 A 3 ( 1 1 8克，5 4 %，〉9 9 %尖峰面積）且摘述於反應圖1 2。 NH,The esterification of ketobutyric acid is carried out using methanol following the reference method or using diazomethane. Subsequent condensation reaction gave precursor A2 in 60% yield. This method compares the way to obtain higher E isomers via the precursor A1 pathway (Figure 8). Both esters can be used to prepare other ester derivatives of precursor A2. Example 4 Synthesis of precursor A3 can be obtained by the reaction of melamine acid and phosphorus pentachloride to obtain ammonium chloride, and then reacted with gaseous ammonia to obtain a predetermined melamine. The amine A3 product was confirmed to be the Z-isomer. The crude amidamide A3 was separated from the reaction mixture by distillation with THF-Me OH and removal of the inorganic residue by filtration. After removing the solvent by evaporation ', a yellow solid was obtained. The crude material was purified by anhydrous flash chromatography, followed by recrystallization from isopropanol to obtain pure material. This procedure can be successfully applied to make a single batch of -25- 200536828 A 3 (118 grams, 54%,> 99% peak area) and is summarized in the reaction diagram 12. NH,

OHOH

I. PCl5,THF；2〇5M»0°Cr：人/0 2竭氣體 / · 3.無水急速，si〇rllwtI. PCl5, THF; 2〇5M »0 ° Cr: Human / 0 2 exhaust gas / · 3. Anhydrous rapid, si〇rllwt

_ 4.再結晶-異丙P 前驅物A1 54%溆產率前驅物A3 反應圖12_ 4. Recrystallization-Isopropyl P Precursor A1 54% Yield Precursor A3 Reaction Figure 12

大部分前驅物之非對稱氫化反應中，前驅物係經由 [Rh(CDO)2] + OTf·與個別對掌配體於首選溶劑反應，接著加入基質而原位製備。若干催化劑爲市面可得’且未經進一步純化即供使用。實例5 使用多種以铑爲主的催化劑系統對前驅物A 1及A2進行非對稱氫化所得結果摘述於下表1。反應係使用0.005 莫耳％至5莫耳％催化劑以及100毫克或200毫克基質於周圍溫度（室溫）進行24小時。反應條件如氫壓、溶劑種類、前驅物量經修改俾獲得最理想條件。全部產物係由反應混合物中蒸發去除溶劑分離，且未經進一步純化藉1 H-NMR光譜術分析。 HP LC (高效液相層析術）方法用於前驅物A1氫化產物之 %e.e.測定。因此，發明人使用重氮甲烷於THF溶液將粗產物轉成甲酯。然後酯衍生物使用對掌HPLC方法分析監視烯醯胺酯A2之氫化反應。用於HPLC方法，發明人使用對掌外徑4·6 X 2 5 0毫米管柱及異丙醇/正己烷（9 5:05 )作爲溶析液。對前驅物A2之氫化產物，經由下述對掌HP LC方法獲 -26- 200536828 得e.e.結果：開洛塞（Chii.alcel)外徑4.6 X 2 5 0毫米，異丙醇-己院（5 : 9 5 v / v )，2 0 5毫微米’ 1毫升/分鐘於周圍溫度（r 1) ，樣本1毫克/毫升，1 3分鐘（S -對映異構物1 6分鐘（R -對映異構物）。最初，餘選係於1 0 0毫克規模使用5莫耳％催化劑進行。對映異構物過量（e · e .)百分比結果爲正表示左旋S -對映異構物百分比，以及負表示右旋R _對映異構物百分比。表1In most asymmetric hydrogenation reactions of precursors, the precursors are prepared in situ by reacting with individual ligands in the preferred solvent via [Rh (CDO) 2] + OTf ·, and then adding the matrix. Several catalysts are commercially available 'and are ready for use without further purification. Example 5 The results of asymmetric hydrogenation of precursors A1 and A2 using various rhodium-based catalyst systems are summarized in Table 1 below. The reaction was carried out using 0.005 mole% to 5 mole% catalyst and 100 mg or 200 mg of substrate at ambient temperature (room temperature) for 24 hours. The reaction conditions such as hydrogen pressure, solvent type, and amount of precursors are modified to obtain the optimal conditions. All products were isolated by evaporation of the reaction mixture to remove the solvent, and were analyzed by 1 H-NMR spectroscopy without further purification. The HP LC (High Performance Liquid Chromatography) method was used to determine the% e.e. Of the hydrogenated product of precursor A1. Therefore, the inventors used diazomethane in THF to convert the crude product to methyl ester. The ester derivative was then analyzed using a para-HPLC method to monitor the hydrogenation reaction of melamine ester A2. For the HPLC method, the inventors used a column with an outer diameter of 4 · 6 × 250 mm and an isopropanol / n-hexane (9 5:05) as the eluent. For the hydrogenated product of precursor A2, -26- 200536828 was obtained via the following HP HP method: ee results: Chii.alcel outer diameter 4.6 X 2.5 mm, isopropanol-Hexion (5 : 9 5 v / v), 205 nm '1 ml / min at ambient temperature (r 1), sample 1 mg / ml, 1 3 min (S-enantiomer 16 min (R-pair Enantiomers). Initially, the co-selection was performed on a 100 mg scale using 5 mole% catalyst. Enantiomeric excess (e.e.) percentage results are positive for L-S-enantiomer. Percentages, and negative indicates the percentage of d-R_ enantiomers. Table 1

St. Am. 催化齊(1 . · G〇u* L〇a. S(〕！v. C'.V. r.rSt. Am. Catalytic Qi (1. · G〇u * L〇a. S ()! V. C'.V. R.r

Ma. 毫克 Pres. % % A1 100 (S,S)-Et-DUPHOS 0Tf(-) 5.0 EtOH 4 100 95 A1 100 (S.S)-BPPM OTf㈠ 5.0 EtOH 1 68 -64 A1 100 (R,R)-DIPAMP BF4(>) 5.0 DCM 4 100 92 A2 (Z) 200 (S,S)-Et-DUPHOS ΟΎΪ(-) 2,0 EtOH 4 100 98.8 A2 (Z) 200 (S,S)-Et-DUPHOS ΟΤΓ(-) 0.5 EtOH 4 100 99.1 A2 (Z) 200 (S,S)-Me-DUPHOS OTf㈠ 1.0 EtOH 5 100 98.9 A2(Z) 300 (S.S)-Me-DUPHOS OTf㈠ 2.0 IPA 5 100 97.9 A2，(E) 200 (S.S)-Me-DUPHOS 0Tf(-) 0.5 EtOH 5 100 99.4 Α2’·(Ε) 300 (S.S)-Me-DUPHOS OTf㈠ 0,5 IPA 5 100 94.0 Α2 (Ε) 4000 (S,S)-Me-DUPHOS BF4㈠ 0.025 MeOH 5 100 97.4 Α2 (Ζ) 4000 (StS)-Me-DUPHOS BF4(-) 0.01 MeOH 5 99 99 Α2 (Ζ) 4000 (S,S)-Me-DUPHOS BF4H 0.005 MeOH 5 25 97 Α2· (Ε) 300 {S,S)-BPPM OTf㈠ 0.5 MeOH 1 100 -99.3 ΝΣ (Ε) 300 (S,S)-BPPM 0Tf(-) 0.5 EtOAc 1 100 -95.2 Α2 (Ε) 300 (S,S)-BPPM OTf(-) 0.5 甲苯 1 100 -96.2 Α2 (Ζ) 200 (RR)-DIPAMP BMH 2.0 EtOAc 5 100 94.5 Α2,（Ε) 200 (R，R)-DIPAMP BF4㈠ 0,5 EtOAc 5 92 96.5 表 :中， St. Ma表示起始物料；Am 表示量； C 〇 u .表示相對離子； L o a .表示載荷莫耳％ ; Solv. .表示溶劑，H2 P res.Ma. Mg Pres.%% A1 100 (S, S) -Et-DUPHOS 0Tf (-) 5.0 EtOH 4 100 95 A1 100 (SS) -BPPM OTf㈠ 5.0 EtOH 1 68 -64 A1 100 (R, R) -DIPAMP BF4 (>) 5.0 DCM 4 100 92 A2 (Z) 200 (S, S) -Et-DUPHOS ΟΎΪ (-) 2,0 EtOH 4 100 98.8 A2 (Z) 200 (S, S) -Et-DUPHOS ΟΤΓ (-) 0.5 EtOH 4 100 99.1 A2 (Z) 200 (S, S) -Me-DUPHOS OTf㈠ 1.0 EtOH 5 100 98.9 A2 (Z) 300 (SS) -Me-DUPHOS OTf㈠ 2.0 IPA 5 100 97.9 A2, (E ) 200 (SS) -Me-DUPHOS 0Tf (-) 0.5 EtOH 5 100 99.4 Α2 '· (Ε) 300 (SS) -Me-DUPHOS OTf㈠ 0,5 IPA 5 100 94.0 Α2 (E) 4000 (S, S) -Me-DUPHOS BF4㈠ 0.025 MeOH 5 100 97.4 Α2 (Z) 4000 (StS) -Me-DUPHOS BF4 (-) 0.01 MeOH 5 99 99 Α2 (Z) 4000 (S, S) -Me-DUPHOS BF4H 0.005 MeOH 5 25 97 Α2 · (Ε) 300 (S, S) -BPPM OTf㈠ 0.5 MeOH 1 100 -99.3 ΝΣ (Ε) 300 (S, S) -BPPM 0Tf (-) 0.5 EtOAc 1 100 -95.2 Α2 (E) 300 (S , S) -BPPM OTf (-) 0.5 toluene 1 100 -96.2 Α2 (Z) 200 (RR) -DIPAMP BMH 2.0 EtOAc 5 100 94.5 Α2, (Ε) 200 (R, R) -DIPAMP BF4㈠ 0,5 EtOAc 5 92 96.5 In the table: St. Ma represents the starting material; Am represents ; C u is square relative ion;. L o a load represented mole%;... Solv represents solvents, H2 P res.

表不氣壓（大氣壓），以及c.v.表不轉化率。實例6 :前驅物A 3之非對稱氫化 -27- 200536828 使用如實例5之相同方法；多種铑及釕催化劑經過篩選，參考反應圖1 3及表2之代表性結果。Table indicates atmospheric pressure (atmospheric pressure), and c.v. indicates conversion. Example 6: Asymmetric hydrogenation of precursor A 3 -27- 200536828 The same method as in Example 5 was used; a variety of rhodium and ruthenium catalysts were screened. Refer to Figure 13 and Table 2 for representative results.

-28- 200536828-28- 200536828

寧「/ . 职w % % s .1 —εcov s ss s s ^ 1 1 .Doo 1 s cs嗽. 卜 6 ΟΟΙΐ;ΖΙ 寸 0寸 sop s HJ10 s SOHdn9s-{sco} 0010 Z6 02*c9T 寸 0寸 sp100(丨一JHO SOHdn9s.{s.s} ooln L— 001〇。0卜丨1〇9 0 寸 I Kos so5X0 s sdds's) 0002 looo02tCDr—l寸ocslKoso; zsg s dsdICHHpi} § 8CO6 001 t q 卜寸 OCNH23 s (，)2g s dsia 丨(H«) 00S K寸6 001 t ON 寸 OS 8q s (丨)scqs JwvdlcHHs0010 CO6 001 t 81 寸 OS §a 0」 qy dMvdI9{H‘H} oolo 06 06-ocowuooi 寸ossoa s2sa s CMVfcCHirH) ooln Iln Inco丨 001 t 91 寸 OS OCSJK/KOS 91 Havo dH dvNIa-{H) ooln nzoo丨 001 t 91lo.17ln<NH〇s s (丨ovo s JVNS—S001 -29- 200536828 表中Cou·表示相對離子；Loa.表示載荷莫耳％;H2PreS· 表示氫壓；以及rt表示室溫。如前述，铑催化劑已經於原位製備或購買且未經進一步純化即供使用。釕催化劑係根據已知參考文獻程序製備。大部分實驗係於100毫克至15毫克規模使用0.001莫耳％至5莫耳％催化劑進行。粗產物係藉，13C-NMR光譜術分析，以及藉對掌HP LC分析。Ning "/. W w%% s .1 —εcov s ss ss ^ 1 1 .Doo 1 s cs cough. Bu 6 ΟΟΙΐ; ZΙ inch 0 inch sop s HJ10 s SOHdn9s- {sco} 0010 Z6 02 * c9T inch 0 Inch sp100 (丨 a JHO SOHdn9s. {Ss} ooln L— 001〇. 0 卜丨 1〇9 0 inch I Kos so5X0 s sdds's) 0002 looo02tCDr—l inch ocslKoso; zsg s dsdICHHpi} § 8CO6 001 tq bu inchOC (,) 2g s dsia 丨 (H «) 00S K inch 6 001 t ON inch OS 8q s (丨) scqs JwvdlcHHs0010 CO6 001 t 81 inch OS §a 0 ″ qy dMvdI9 {H'H} oolo 06 06-ocowuooi inch ossoa s2sa s CMVfcCHirH) ooln Iln Inco 丨 001 t 91 inch OS OCSJK / KOS 91 Havo dH dvNIa- (H) ooln nzoo 丨 001 t 91lo.17ln < NH〇ss (丨 ovo s JVNS-S001 -29- 200536828 in the table Cou · represents relative ions; Loa. Represents load mole%; H2PreS · represents hydrogen pressure; and rt represents room temperature. As mentioned above, rhodium catalysts have been prepared or purchased in situ and are available without further purification. Ruthenium catalysts Prepared according to known reference procedures. Most experiments were performed on a 100 mg to 15 mg scale using 0.001 mole% to 5 mole% catalyst. The crude product was borrowed , 13C-NMR spectroscopic analysis, and HP LC analysis by counterpart.

100-500 mg 左堤拉西坦反應圖13 *製造相反對映異構物。實例7 :使用Rh-(Et，Et)-杜弗斯非對稱氫化前驅物A3 A3使用Rh-杜弗斯催化劑氫化結果示於表3。此等反應係以如實例5及6之相同方式使用氫壓4大氣壓進行。通常，Rh-杜弗斯催化α -醯基胺基丙烯酸衍生物之氫化反應之對映選擇性顯示極小溶劑效應。但仍然無法事先預測對應選擇性的影響，以及對指定基質反應速率的影響。觀察A3之氫化反應與溶劑有高度關聯。發現非配位質子惰性溶劑DCM優異。於質子醇系溶劑氫化導致反應較緩慢且選擇性降低。同理，於極性質子惰性溶劑如乙酸乙酯及THF觀察得轉化率減低，二者預期皆與金屬配位且可抑制催化作用。藉配位溶劑抑制催化作用提示A3爲不良 -30- 200536828 配位基質，特別比較其它α -醯基胺基丙烯酸衍生物爲不良配位基質。雖言如此，於DCM獲得絕佳結果。如所見，於此溶劑於0 · 5至1 5克規模可一致地達成9 7至9 8 % e . e .對映選擇性。於E t Ο A c - D C Μ溶液混合物及甲苯可獲得其它有用展望的結果。表3:使用[尺11-(：00-(3,3)*^1-杜弗斯]〇丁£氫化八3 數量催化劑溶劑溶劑反應 c.v. e. e A3 莫耳％容積時間％ % 毫克 (小時） 500 1.0 AcOEt/DCM ^ . 1 30 17 95 ! ?6 500 1.0 DCM 20 17 100 97 500 0.5 DCM 30 16 99 98 500 0.5 DCM 40 16 100 97 500 2.5 DCM 40 17 100 97 10000 1.0 甲苯 30 65 93 92 500 1.0 甲苯 30 16 95 95 表中C.V.表示轉化率。 Α·前驅物A 1 之製備： (ζμ 2^(2- •氧基四氫-1H-1 -吡咯基）-2 丁烯酸（前驅物A1) 配 !備有磁攪棒及丁- 史塔克凝氣瓣之 1升燒瓶內進給2 - 氧基丁酸（25 克，245 : 毫莫耳），甲苯（5 00毫升，20容積）及2 -吡咯啶酮（3 7.2毫升， 49〇毫莫耳，2當量 )。反應混 ' 31 - 200536828 合物於回流下攪拌伴以經由丁 -史塔克凝氣瓣共沸蒸餾去除水歷經5 · 5小時。然後溶液濃縮至約9 〇毫升（3.6容積）且任其緩慢冷卻至周圍溫度。灰白色固體於約5 5 t開始由溶液中沉澱出。固體經過濾，濾餅以甲苯（2 X 1容積）洗滌，接著以二氯甲烷（3 X 1容積）洗滌，及於過濾器真空脫水5分鐘獲得粗物料（2 8克，7 0 %產率）。粗產物回流溶解於丙酮（4 5 0毫升，1 6容積），緩慢冷卻至周圍溫度及任其於-1 5至-2 0 °C再結晶1 2小時時間。獲得純產物呈白色結 1 晶固體（21克，50%總產率）。熔點（m · p ·) 1 6 5 · 5 - 1 6 6 °C。 j-NMR (CDC13):5 (化學位移）2·13(5Η，雙峰（d)及多峰 )，2.51(211，三峰（〇)，3.61(211，〇，6.27(111，四峰（9))，8 至10 (1H，寬）；E-異構物信號，5 1.85(3H, t)，7.18(1H，q)。 13C NMR(MeOH-d4): 5 1 4.7, 1 9.6, 3 2.1, 1 5.4, 1 3 0.8, 137.7, 166.6, 177.9 ° . Z:E 比 149:1，藉1H NMR 測定。薄層層析（丁1^)^02，甲苯/八〇011/%6〇11(4:1:0.5)，11¥ 及茴香醛染色。 Β·前驅物A2之製備：（Z)-2-(2-氧基四氫-丨^-吡咯基）-2-丁烯酸甲酯（前驅物A2) 前驅物A 1 (1 2克，7 1毫莫耳）於〇 - 5 °C溶解於T H F (2 4 0 毫升，20容積）。重氮甲烷於醚溶液（200毫升，約78毫莫耳，1 · 1當量）分成數份添加至反應混合物，溫度維持低於 -32- 200536828 5 °c。藉最後一份反應劑，反應混合物轉 x 一巴。又於低溫攪拌3 0分鐘，然後任其溫熱。剩餘微量重氮甲产’豕100-500 mg Levetiracetam Reaction Figure 13 * The opposite enantiomer is made. Example 7: Hydrogenation using Rh- (Et, Et) -Duffers asymmetric hydrogenation precursor A3 A3 Hydrogenation using Rh-Duffers catalyst is shown in Table 3. These reactions were performed in the same manner as in Examples 5 and 6 using a hydrogen pressure of 4 atmospheres. In general, the enantioselectivity of Rh-Dovers-catalyzed hydrogenation of α-fluorenylaminoacrylic acid derivatives shows minimal solvent effects. However, it is still not possible to predict in advance the effect of corresponding selectivity and the effect on the reaction rate of a given matrix. Observe that the hydrogenation of A3 is highly correlated with the solvent. The non-coordinated proton inert solvent DCM was found to be excellent. The hydrogenation of aprotic alcohol solvents results in slower reactions and reduced selectivity. In the same way, the reduction in conversion is observed in polar aprotic solvents such as ethyl acetate and THF, both of which are expected to coordinate with the metal and inhibit the catalysis. The inhibition of catalysis by the coordination solvent suggests that A3 is a poor coordination matrix. Especially compared to other α-amidoaminoacrylic acid derivatives, it is a poor coordination matrix. Having said that, great results were obtained in DCM. As can be seen, 97 to 98% e.e. enantioselectivity can be consistently achieved here on a scale of 0.5 to 15 grams. Other useful and promising results can be obtained with E t O A c-D C M solution mixtures and toluene. Table 3: Using [feet 11- (: 00- (3,3) * ^ 1-Duffers] 〇丁 £ hydrogenation 8 3 quantity catalyst solvent solvent reaction cve e A3 mole% volume time %% mg (hour) 500 1.0 AcOEt / DCM ^. 1 30 17 95!? 6 500 1.0 DCM 20 17 100 97 500 0.5 DCM 30 16 99 98 500 0.5 DCM 40 16 100 97 500 2.5 DCM 40 17 100 97 10000 1.0 toluene 30 65 93 92 500 1.0 Toluene 30 16 95 95 In the table, CV indicates the conversion rate. Preparation of A. Precursor A 1: (ζμ 2 ^ (2- • oxytetrahydro-1H-1 -pyrrolyl) -2 butenoic acid (precursor A1) Equipped with 2-oxybutyric acid (25 g, 245: millimolar), toluene (500 ml, 20 vol.) In a 1 liter flask equipped with a magnetic stir bar and Ding-Stark condensate flap ) And 2-pyrrolidone (3 7.2 ml, 49.0 mmol, 2 equivalents). The reaction mixture '31-200536828 was stirred at reflux with water removed by azeotropic distillation with butane-Stark condensate valve. Over 5.5 hours. The solution was then concentrated to about 90 ml (3.6 vol) and allowed to cool slowly to ambient temperature. The off-white solid was opened at about 5 5 t. Precipitated from the solution. The solid was filtered, the filter cake was washed with toluene (2 X 1 volume), then with dichloromethane (3 X 1 volume), and vacuum dehydrated in the filter for 5 minutes to obtain a crude material (28 g , 70% yield). The crude product was dissolved under reflux in acetone (450 ml, 16 vol), slowly cooled to ambient temperature and allowed to recrystallize at -15 to -20 ° C for 12 hours. The pure product was obtained as a white crystalline solid (21 g, 50% total yield). Melting point (m · p ·) 1 6 5 · 5-16 ° C. J-NMR (CDC13): 5 (chemical shift ) 2.13 (5Η, doublet (d) and multimodal), 2.51 (211, three peaks (0), 3.61 (211, 0, 6.27 (111, four peaks (9)), 8 to 10 (1H, broad ); E-isomer signals, 5 1.85 (3H, t), 7.18 (1H, q). 13C NMR (MeOH-d4): 5 1 4.7, 1 9.6, 3 2.1, 1 5.4, 1 3 0.8, 137.7 , 166.6, 177.9 °. Z: E ratio 149: 1, measured by 1H NMR. Thin layer chromatography (Ding 1 ^) ^ 02, toluene / 80011 /% 6101 (4: 1: 0.5), 11 ¥ and anisaldehyde staining. B. Preparation of precursor A2: (Z) -2- (2-oxytetrahydro- 丨 ^ -pyrrolyl) -2-butenoic acid methyl ester (precursor A2) precursor A 1 (12 g, 7 1 mmol) was dissolved in THF (240 ml, 20 volumes) at 0-5 ° C. Diazomethane in ether solution (200 ml, about 78 mM, 1.1 equivalents) was added to the reaction mixture in portions, and the temperature was maintained below -32-200536828 5 ° c. To borrow the last reactant, the reaction mixture turns x 1 bar. Stir again at low temperature for 30 minutes, then allow to warm. Residual traces of diazomethyl production ’豕

滴添加極稀乙酸於THF破壞至黃色溶液旧I 一灸…、B。反應混合物經真空濃縮’粗物料經蒸|留（9 3 - 9 4n m \ 〇·01毫米汞柱）其於i〇°c以下冷卻 NMR(CDC13): δ 2.0(3H，d)，2·1(2Η 2 4., ，m)，2·43(2Η，t)，Add very dilute acetic acid in THF to destroy the yellow solution. The reaction mixture was concentrated in vacuo. The crude material was distilled and retained (9 3-9 4n m \ 〇 · 01 mm Hg). It was cooled below 10 ° C. NMR (CDC13): δ 2.0 (3H, d), 2 · 1 (2Η 2 4.,, m), 2.43 (2Η, t),

獲得純產物（9 · 4 4克，7 3 % )呈無色油時固化。 3·54(2Η’ t)’ 3·76(3Η’ s)’ 5·96(1Η，q) ; E-異構物信號，占 1.75(3H，t)及 7·05(1Η，q)。 13C NMR(MeOH-d4):(5 14.4, 19.7, 32.51，52.6, 13〇 u 165.6， 177.4〇 Z:E 比 29:1，藉 H1 NMR 測定。 C. 2-氧基丁酸甲酯之製備 2 -氧基丁酸（15克）使用庫久路（Kugelruhr)裝置於減壓下蒸餾（8 4 °C，20毫米汞柱）獲得14克純物料。經蒸鶴的2-氧基丁酸（1 4克）溶解於甲醇（無水，2 0毫升，1.4容積），及二氯乙烷（無水，8 0毫升，5 · 7容積）於數滴乙烷磺酸存在下進行。反應混合物於惰性氣氛下回流攪拌1 8小時。然後任冷卻，以硫酸鎂脫水，過濾及真空濃縮。粗料藉蒸餾純化（沸點7 6°C，20毫米汞柱）獲得純產物呈無色油 (7.5 3 克，4 8 °/。產率）。 4 NMR (CDC13):5 0·88(3Η，d)，2·66(2Η，q)，3.63(3H，s) 參考生物化學，2670，1917。 D. (Z)-2-(2 -氧基四氫-1Η-1-吡咯基）-2 -丁烯酸甲酯（前驅物 -33- 200536828 A2)之製備配備有磁攪棒及丁-史塔克凝氣瓣之100毫升燒瓶內進給2-氧基丁酸甲酯（7.5克，73毫莫耳），甲苯（50毫升，7 容積）及2 -吡咯啶酮（8 · 4毫升，1 1 1毫莫耳，1 . 5當量）接著逐滴添加磷醯氯（1.6毫升，20毫莫耳，0.27當量）。反應混合物於回流下攪拌伴以經由丁-史塔克凝氣瓣共沸蒸餾去除水歷經8小時。冷卻後溶液以1 0%硫酸氫鉀水溶液（2 X 3容積）洗滌。水相以氯化鈉飽和，及以甲苯（1 X 6容積） | 回萃取。合倂有機相以硫酸鎂脫水，過濾及真空濃縮獲得粗物料（7.5克）呈橙色動相油。粗油經蒸餾（9 2-94 °C，0.1 毫米汞柱）獲得純產物（4.7克，60%)呈無色油。 Z:E 比 6: 1，藉1H NMR 測定。 Ε.(Ε)-2-(2-氧基四氫-1Η-1-吡咯基）-2-丁烯酸甲酯（前驅物 A2)之製備配備有磁攪棒之無水100毫升燒瓶內進給Z-A1(2克， 11_8毫莫耳），乙醇（2.2毫升，37.3毫莫耳），四氫呋喃（丁1^ >，40毫升，20容積）及二甲基胺基吡啶（D MAP，1 50毫克 ’ 1 ·23毫莫耳），燒瓶係置於氮氣氣氛下。反應混合物於加入二環己基甲二醯亞胺（DCC，2.46克，11.9毫莫耳）前冷卻至〇°C，然後加熱至周圍溫度。反應混合物激烈攪拌 21小時。隨後加入己烷（40毫升）至沉澱固體。沉澱經過濾出及濾液經真空濃縮獲得3.03克無色液體油。油於水（40 毫升）使用二氯甲烷（D CM，40毫升然後2 X 20毫升）洗滌，溶劑藉硫酸鈉脫水及真空濃縮獲得2克E-A2乙酯（100% -34- 200536828 產率）。 F.前驅物A 3之製備：（z)- 2 - ( 2 -氧基四氫-1 Η - 1 -13比略基）-2 - 丁烯醯胺（前驅物Α3) 架設2 〇升凸緣瓶供於惰性氣氛下攪拌且進給A 1 (2 2 2克，1.313莫耳，1當量）及無水THF(7.0升，30容積）。任反應混合物冷卻至5°C以下’分成數份添加五氯化磷（3 00 克，1.44莫耳，1.1當量）’反應溫度維持低於l〇°C。反應混合物於-5至〇 °C攪拌1小時’任其溫熱至1 5 °C而溶解丨剩餘五氯化磷，然後冷卻〇°C以下。塡裝乾冰/丙酮之冷凝器嵌合至燒瓶上，氨氣（約200克）緩慢通過溶液，維持溫度低於1 5 °C。懸浮液又攪拌1 5分鐘，藉通過氮氣數分鐘去除過量氨氣。加入甲醇（3.7升’ 1 7容積），反應混合物回流1.5小時，然後冷卻至30°C以下過濾，以THF/甲醇（2:1 ，600毫升，約3容積）洗滌。濾液經蒸發獲得黃色固體。此物質溶解於甲醇（640毫升，約3容積）及乙酸乙酯（440 毫升，2容積）及使用無水急速層析術純化（矽膠，11重量 >，3.4千克）使用乙酸乙酯/甲醇（6:1)洗提獲得粗產物（288 克）。粗產物由異丙醇（1 . 9升，約8 · 5容積）再結晶獲得白色晶體（1 2 7克）。固體於真空烘箱於周圍溫度脫水2曰獲得 A 3 (1 1 8 克，5 4 % )。 NMR(CDC13 +數滴 MeOD):(5 6.75(1H，q)，3.5(2H，t)， 2·5(2Η，t)，2.15(2H，m)，1·7(3Η，d)，微量雜質。元素分析C 5 6.90(5 7· 13%理論値）；Η 7.19 (7. 19%理論値）；ν 1 6.3 2( 1 6.6 6 %理論値）。 -35- 200536828 A3( 108克）再度由異丙醇（1升，9·3容積）再結晶獲得最後批料用於氫化硏究（100克，93%)。熔點 1 7 2 · 0 °C - 1 7 4.2 °C。元素分析（％111/111):€ 5 6.9 5 (5 7.1 3 %理論値）；117.10 (7 . 1 9 % 理論値）；N 1 6 · 3 8 ( 1 6.6 6 % 理論値）。 TLC:Si02，甲苯 /AcOH/MeOH(4: 1 :〇_5)，UV 及茴香醛染色。 G·對掌铑及釕催化劑之製備-[Rh(I)L*COD] + 〇Tr(0.15M溶液）之製備 [Rh(I)L*COD2] + OTf(35毫克，0.075毫莫耳）以及對掌配體（L*，0.. 83毫莫耳，1.1當量）快速於空氣中稱重以及進給至燒瓶。燒瓶使用橡皮隔膜密封以及以氬氣掃除。無水且經過除氣的溶劑（5毫升，143容積）經隔膜添加。反應混合物經除氣（3 X真空/氬氣）及攪拌30分鐘或至全部固體溶解爲止。 H.Rh(I)(MeOH)2[(R)-Binap]之製備配備有磁攪棒之無水200毫升西蘭克（Schlenk)試管內進給[Rh(I)(nbd)2]C104(25 1 毫克，0.649 毫莫耳）及（R)-Binap (405毫克，〇.65笔莫耳）且置於氬氣氣氛下。二氯甲烷（無水，除氣，5毫升，20容積）經注射器添加且反應混合物經除氣（3 X真空/氬氣）。緩慢加入四氫呋喃（無水，除氣，10毫升，40容積）接著加入己烷（無水，除氣，20 毫升，8 0容積）。所得懸浮液於〇 - 5 °C維持1 6小時。於氬下傾析去除溶劑，及加入甲醇（無水，除氣，5毫升，2 0 -36- 200536828 容積）。西蘭克試管使用氫氣（5 X真空/氫）掃除及於周圍溫度攪拌1 · 5小時。澄淸紅橙色溶液經注射器移轉至另一西蘭克試管（使用氬氣掃除）。催化劑溶液於氬下儲存於0-5 °C 及直接用於氫化（Tetrahedron，1245，1984)。 I. [RuhCl(R)-Binap(C6H6)] + Cl-之製備配備有磁攪棒且於氬氣氣氛下之無水200毫升西蘭克試管內進給[RuC12(C6H6)]2(0.3 克，0.66 毫莫耳）及（R)-Binap (0.8 1 5克，1 . 3毫莫耳）。加入經除氣的無水苯（2 0毫升，6 0 I 容積）及乙醇（1 3 〇毫升，3 3 0容積），溶液經除氣（3 X真空/ 氬氣）。紅橙色懸浮液加熱至5 0- 5 5 °C經45分鐘獲得澄淸褐色溶液。溶液經西來特（c elite)襯墊於氬下過濾入另一西蘭克試管內。溶劑經真空蒸發獲得催化劑呈黃色固體 (1.08克，86%)，於氬下儲存於0-5°C (有機化學期刊，3〇64 ，1 994)° J. [RuCl(R)-Binap(C6H6)]+BF4·之製備配備有磁攪棒且於氬氣氣氛下之無水100毫升西蘭克試 I 管內進給[RuCl(R)-Binap(C6H6)] + Cl-(0_45 克，0.52 毫莫耳）以及經過除氣之無水二氯甲烷（2〇毫升，44容積）。所得溶液經除氣（3 X真空/氬氣），且經注射器移轉至另一個西蘭克試管其中含有AgBF4(0.15克，〇.77毫莫耳，1.5當量）於二氯甲烷（10毫升，22容積）之懸浮液。混合物經激烈攪拌0.5小時，然後於氬氣氣氛下經西來特過濾。濾液經真空濃縮獲得催化劑呈綠色固體（〇·42克，88%)，其係於氬下儲存0-5 °C (有機化學期刊，3 064，1 994)。 -37- 200536828 K. Ru(〇COCH3)2-[(R)-Binap]之製備配備有磁攪棒且於氬氣氣氛下之無水2 0 0毫升西蘭克g式管內進給[RuC12(C6H6)] 2 ( 0.8 0 5克，uo毫莫耳）以及（R)_ Binap(1.89克’ 3.03笔吴耳，0.95當量）。加入經除氣之無水二甲基甲醯胺（3 0毫升’ 3 8容積），溶液經除氣（3 X真空/氬氣）。反應混合物加熱至10(TC歷10分鐘，獲得暗紅色溶液，然後冷卻至周圍溫度。乙酸鈉（5.2克，6 3 · 4毫莫耳’ 20當量）於甲醇（50毫升，60容積）之除氣溶液進給至反應谷益及擾泮5分纟里。加入除氣水（50毫升，60容積）及甲苯（2 5毫升，3 0容積），及反應混合物激烈攪拌5分鐘。甲苯層經注射器移至另一個西蘭克試管（使用氬氣掃除），及水相以甲苯（2 X 2 5毫升）萃取。合倂甲苯溶液以水（4 X 1 〇毫升）洗滌，溶劑經於4 5 °C真空濃縮及真空脫水1 2小時（〇 . 1 毫米汞柱）。黃褐色固體未經攪拌即溶解於甲苯（2 5毫升），緩慢添加己烷（7 5毫升）而生成第二層於頂上。二相混合物於周圍放置7小時，然後於〇 - 5 °C放置3日。催化劑結 > 晶出。溶劑於氬氣氣氛下經注射器去除，固體由己烷（2 0 毫升）洗滌，及真空脫水2小時獲得催化劑呈黃褐色固體 (1 . 7 6克，7 0 % )儲存於氬下於0 - 5 t：(有機化學期刊，4 0 5 3 ，1992) 〇 L. 前驅物Al、A2、A3之非對稱氫化非對稱氫化反應對各前驅物係遵循相同方案。因此，僅說明A3之非對稱氫化如後。前驅物A 3之非對稱氫化。 -38- 200536828 於大氣壓氫氣壓力下氫化配備有磁攪棒之無水1 00毫升西蘭克試管內進給基質 (5 0 0毫克’ 3毫莫耳）且以氬氣掃除。經注射器加入經除氣的溶劑，接著加入催化劑溶液（0.5至2.5莫耳％)。反應混合物經除氣（3 X真空/氬氣），然後使用氫氣汽球以氫氣掃除（5 X真空/氫）。反應於周圍溫度攪拌1 6 _ 6 5小時。氫氬氣氛與氮氣交換，真空蒸發去除溶劑獲得粗產物，粗產物藉NMR光譜分析及對掌HPLC分析分析。丨於4大氣壓壓力下進行氫化全部操作皆係於氣氛帶（AtmosBag)(亞利希（Aldrich)化學公司）於氬氣氣氛下下進行。基質（500-1000毫克）置於不鏽鋼高壓容器（法國文希（Vince)技術公司），高壓容器嵌合鐵弗龍嘴（或玻璃皿）以及鐵弗龍塗層磁攪棒。經除氣的溶劑及催化劑或催化劑溶液（0.2 5至2.5莫耳％)加入其中。容器經密封，及藉加壓容器至4.5-5.5大氣壓而以氫氣掃除，然後解除加壓（5次）。最後，壓力調整至預定程度 > ’反應混合物周圍溫度攪拌16-65小時。完成時，氫壓與氮氣交換，溶劑經真發去除獲得粗產物，粗產物藉NMR 光譜分析及對掌HP LC分析分析。終物料之純化：（S) - α -乙基-2-氧基-1-吡咯啶乙醯胺（左堤拉西坦）之純化藉前述非對稱氫化所得左堤拉西坦（5克，98%e.e.)溶解於水（20毫升，4容積）及使用乙酸乙酯（3X10毫升，3X2 容積）萃取，然後有機相以水（10毫升，2容積）回萃取，及 -39- 200536828 水相經蒸發獲得淡黃色固體（4.83克，80%)。固體（4克）溶解於丙酮（24毫升，6容積）’及回流加熱1小時。溶液以 5-l〇°C /小時速率緩慢冷卻至〇°C。晶體經過濾出，使用丙酮（1.6毫升，0.4容積）洗滌及脫水獲得白色固體（3.23克 ’ 81%，> 9 9.8 % e . e . j 54ppm Rh) 〇 (S)-a -乙基-2 -氧基-l-卩比咯卩定乙醯胺（左堤拉西坦）之純化：經由前述非對稱氫化所得左堤拉西坦（5克，9 8 % e . e .)由丙_ (3 0毫升，6容積）如前述再結晶獲得白色結晶固體 I (3.94 克，81%，〉99.8%e.e.，52ppmRh)。此物料（3 克）再度如前述再結晶獲得白色結晶固體（2 · 3 1克，7 7 %，〉99.8%e.e·，23ppm Rh) 〇熔點 1 1 8.4 -1 1 9.9。(：。【圖式簡單說明】無【主要元件符號說明】無 .The pure product obtained (9.44 g, 73%) solidified as a colorless oil. 3 · 54 (2Η 't)' 3.76 (3Η 's)' 5.96 (1Η, q); E-isomer signals, accounting for 1.75 (3H, t) and 7.05 (1Η, q) . 13C NMR (MeOH-d4): (5 14.4, 19.7, 32.51, 52.6, 13〇u 165.6, 177.4〇Z: E ratio 29: 1, measured by H1 NMR. C. Preparation of methyl 2-oxybutyrate 2-Oxybutyric acid (15 g) was distilled under reduced pressure (8 4 ° C, 20 mmHg) using a Kugelruhr unit to obtain 14 g of pure material. 2-Oxybutyric acid steamed by crane (14 g) was dissolved in methanol (anhydrous, 20 ml, 1.4 vol.) And dichloroethane (anhydrous, 80 ml, 5.7 vol.) In the presence of a few drops of ethanesulfonic acid. The reaction mixture was Stir at reflux under an inert atmosphere for 18 hours. Then cool down, dehydrate with magnesium sulfate, filter, and concentrate in vacuo. Purify the crude material by distillation (boiling point 76 ° C, 20 mm Hg) to obtain the pure product as a colorless oil (7.5 3 g , 4 8 ° /. Yield). 4 NMR (CDC13): 50.88 (3Η, d), 2.66 (2Η, q), 3.63 (3H, s) Reference Biochemistry, 2670, 1917. D . Preparation of (Z) -2- (2-oxytetrahydro-1Η-1-pyrrolidinyl) -2-butenoic acid methyl ester (precursor-33- 200536828 A2) equipped with magnetic stir bar and T-history In a 100 ml flask with a Tucker condensate valve, methyl 2-oxybutyrate (7 .5 g, 73 mmoles), toluene (50 ml, 7 volumes) and 2-pyrrolidone (8.4 ml, 1.1 mmoles, 1.5 equivalents) followed by the dropwise addition of phosphonium chloride ( 1.6 ml, 20 mmol, 0.27 equivalent). The reaction mixture was stirred at reflux with water removed by azeotropic distillation via Ding-Stark condensate flap over 8 hours. After cooling, the solution was taken with a 10% aqueous potassium hydrogen sulfate solution ( 2 X 3 volume). The aqueous phase was saturated with sodium chloride and extracted with toluene (1 X 6 volume). Back extraction. The combined organic phase was dehydrated with magnesium sulfate, filtered and concentrated in vacuo to obtain a crude material (7.5 g) with an orange color. Mobile phase oil. Crude oil was distilled (9 2-94 ° C, 0.1 mm Hg) to obtain pure product (4.7 g, 60%) as a colorless oil. Z: E ratio 6: 1, determined by 1H NMR. Ε. Preparation of (E) -2- (2-oxytetrahydro-1Η-1-pyrrolidinyl) -2-butenoic acid methyl ester (precursor A2). Feed Z into a 100 ml anhydrous anhydrous flask equipped with a magnetic stir bar. -A1 (2 g, 11-8 mol), ethanol (2.2 ml, 37.3 mol), tetrahydrofuran (butane 1 >, 40 ml, 20 vol) and dimethylaminopyridine (D MAP, 1 50 Mg '1.23 milligrams The flask was placed under a nitrogen atmosphere. The reaction mixture was cooled to 0 ° C before adding dicyclohexylformamide (DCC, 2.46 g, 11.9 mmol), and then heated to ambient temperature. The reaction mixture was stirred vigorously for 21 hours. Hexane (40 mL) was then added to precipitate a solid. The precipitate was filtered off and the filtrate was concentrated in vacuo to obtain 3.03 g of a colorless liquid oil. Oil in water (40 ml) was washed with dichloromethane (D CM, 40 ml and then 2 X 20 ml). The solvent was dehydrated with sodium sulfate and concentrated in vacuo to obtain 2 g of E-A2 ethyl ester (100% -34- 200536828 yield). ). F. Preparation of precursor A 3: (z)-2-(2 -oxytetrahydro-1 fluorene-1 -13 pyridyl)-2-butenylamine (precursor A3) erection of 2 liters The edge bottle was stirred under an inert atmosphere and fed with A 1 (2 2 2 g, 1.313 mol, 1 equivalent) and anhydrous THF (7.0 liter, 30 volume). Allow the reaction mixture to cool to below 5 ° C and add phosphorus pentachloride (300 g, 1.44 moles, 1.1 equivalents) in several portions. The reaction temperature is maintained below 10 ° C. The reaction mixture was stirred at -5 to 0 ° C for 1 hour 'and allowed to warm to 15 ° C to dissolve the remaining phosphorus pentachloride, and then cooled below 0 ° C. A dry ice / acetone condenser was fitted into the flask, and ammonia gas (about 200 g) slowly passed through the solution, maintaining the temperature below 15 ° C. The suspension was stirred for an additional 15 minutes, and excess ammonia was removed by passing through nitrogen for several minutes. Methanol (3.7 liters' 17 volumes) was added, and the reaction mixture was refluxed for 1.5 hours, then cooled to 30 ° C and filtered, and washed with THF / methanol (2: 1, 600 ml, about 3 volumes). The filtrate was evaporated to give a yellow solid. This material was dissolved in methanol (640 ml, about 3 volumes) and ethyl acetate (440 ml, 2 volumes) and purified using anhydrous flash chromatography (silica gel, 11 weight >, 3.4 kg) using ethyl acetate / methanol ( 6: 1) Elution gave crude product (288 g). The crude product was recrystallized from isopropanol (1.9 liters, approximately 8.5 vol.) To obtain white crystals (127 g). The solid was dehydrated in a vacuum oven at ambient temperature to obtain A 3 (118 g, 54%). NMR (CDC13 + several drops of MeOD): (5 6.75 (1H, q), 3.5 (2H, t), 2.5 (2Η, t), 2.15 (2H, m), 1.7 (3Η, d), Trace impurities. Elemental analysis C 5 6.90 (5 7 · 13% theoretical 値); Η 7.19 (7. 19% theoretical 値); ν 1 6.3 2 (1 6.6 6% theoretical 値). -35- 200536828 A3 (108 g ) Again recrystallized from isopropanol (1 liter, 9 · 3 volume) to obtain the final batch for hydrogenation research (100 g, 93%). Melting point 1 72 · 0 ° C-1 7 4.2 ° C. Element Analysis (% 111/111): € 5 6.9 5 (5 7.1 3% of theoretical 値); 117.10 (7.1 9% of theoretical 値); N 1 6 · 3 8 (1 6.6 6% of theoretical 値). TLC: Si02 , Toluene / AcOH / MeOH (4: 1: 〇_5), UV and anisaldehyde staining G. Preparation of para-rhodium and ruthenium catalyst-[Rh (I) L * COD] + 〇Tr (0.15M solution) The preparation of [Rh (I) L * COD2] + OTf (35 mg, 0.075 millimoles) and the palmate ligand (L *, 0 .. 83 millimoles, 1.1 equivalents) were quickly weighed in the air and charged. The flask was sealed with a rubber septum and purged with argon. An anhydrous and degassed solvent (5 ml, 143 vol) was added through the septum. The reaction mixture was passed through Gas (3 X vacuum / argon) and stirring for 30 minutes or until all solids are dissolved. Preparation of H.Rh (I) (MeOH) 2 [(R) -Binap] Anhydrous 200 ml of Zeeland equipped with a magnetic stir bar [Rh (I) (nbd) 2] C104 (25 1 mg, 0.649 mmol) and (R) -Binap (405 mg, 0.65 Mol) in a Schlenk tube and placed in argon Gas atmosphere. Dichloromethane (anhydrous, degassed, 5 ml, 20 vol.) Was added via syringe and the reaction mixture was degassed (3 X vacuum / argon). Tetrahydrofuran (anhydrous, degassed, 10 ml, 40 ml) was added slowly. Volume) followed by addition of hexane (anhydrous, degassed, 20 ml, 80 volumes). The resulting suspension was maintained at 0-5 ° C for 16 hours. The solvent was removed by decantation under argon, and methanol (anhydrous, degassed) was added. , 5 ml, 20-36- 200536828 volume). The Silenk test tube was swept with hydrogen (5 X vacuum / hydrogen) and stirred at ambient temperature for 1.5 hours. The clear red-orange solution was transferred via syringe to another west. Rank test tube (purged with argon). The catalyst solution was stored at 0-5 ° C under argon and used directly for hydrogenation (Tetrahedron, 1245, 1984). I. Preparation of [RuhCl (R) -Binap (C6H6)] + Cl- Anhydrous 200 mL Silk test tube equipped with a magnetic stir bar and under an argon atmosphere [RuC12 (C6H6)] 2 (0.3 g , 0.66 millimoles) and (R) -Binap (0.8 15 grams, 1.3 millimoles). Degassed anhydrous benzene (20 mL, 60 I volume) and ethanol (130 mL, 330 volume) were added, and the solution was degassed (3 X vacuum / argon). The red-orange suspension was heated to 50-55 ° C for 45 minutes to obtain a clear brown solution. The solution was filtered through a c elite pad under argon into another Cylon test tube. The solvent was evaporated in vacuo to obtain the catalyst as a yellow solid (1.08 g, 86%), and stored at 0-5 ° C under argon (Journal of Organic Chemistry, 3064, 1 994) ° J. [RuCl (R) -Binap ( Preparation of C6H6)] + BF4 · Anhydrous 100 ml of Cylon test I equipped with a magnetic stir bar and argon atmosphere [RuCl (R) -Binap (C6H6)] + Cl- (0_45 g, 0.52 mmol) and degassed anhydrous dichloromethane (20 ml, 44 vol). The resulting solution was degassed (3 X vacuum / argon) and transferred via a syringe to another Westland test tube containing AgBF4 (0.15 g, 0.77 mmol, 1.5 equivalents) in dichloromethane (10 mL , 22 volumes) of suspension. The mixture was stirred vigorously for 0.5 hours and then filtered through Celite under an argon atmosphere. The filtrate was concentrated in vacuo to obtain a catalyst as a green solid (0.42 g, 88%), which was stored at 0-5 ° C under argon (Journal of Organic Chemistry, 3 064, 1 994). -37- 200536828 Preparation of K. Ru (〇COCH3) 2-[(R) -Binap] Anhydrous 2000 ml Cylon g-type tube equipped with a magnetic stir bar in an argon atmosphere [RuC12 (C6H6)] 2 (0.8 0 5 g, uo millimoles) and (R) _ Binap (1.89 g '3.03 pen Wuer, 0.95 equivalents). Degassed anhydrous dimethylformamide (30 ml ' 38 volumes) was added and the solution was degassed (3 X vacuum / argon). The reaction mixture was heated to 10 (TC for 10 minutes to obtain a dark red solution, and then cooled to ambient temperature. Sodium acetate (5.2 g, 63. 4 millimoles' 20 equivalents) in methanol (50 ml, 60 volumes) was divided The gas solution was fed into the reaction valley and disturbed for 5 minutes. Degassed water (50 ml, 60 vol) and toluene (25 ml, 30 vol) were added, and the reaction mixture was stirred vigorously for 5 minutes. The toluene layer was passed through The syringe was moved to another Cylon test tube (purged with argon), and the aqueous phase was extracted with toluene (2 X 2 5 ml). The toluene solution was washed with water (4 X 10 ml), and the solvent was passed through 4 5 Concentrated in vacuum and dehydrated under vacuum for 12 hours (0.1 mm Hg). The yellow-brown solid was dissolved in toluene (25 ml) without stirring, and hexane (75 ml) was slowly added to form a second layer on Overhead. The two-phase mixture was left for 7 hours and then at 0-5 ° C for 3 days. The catalyst crystallized. The solvent was removed via a syringe under an argon atmosphere, and the solid was washed with hexane (20 ml), and Dehydration under vacuum for 2 hours gave the catalyst as a yellow-brown solid ( 1.76 g, 70%) stored under argon at 0-5 t: (Journal of Organic Chemistry, 40 5 3, 1992) 〇L. Asymmetric hydrogenation of precursors Al, A2, A3 Asymmetric hydrogenation reaction The same scheme is followed for each precursor. Therefore, only the asymmetric hydrogenation of A3 is described as follows. Asymmetric hydrogenation of precursor A 3. -38- 200536828 Hydrogenated 100 ml of anhydrous water equipped with a magnetic stir bar at atmospheric pressure. The substrate (500 mg '3 mmol) was fed into a Cylon tube and swept with argon. The degassed solvent was added via a syringe, followed by the catalyst solution (0.5 to 2.5 mole%). The reaction mixture was passed through Degas (3 X vacuum / argon), then use a hydrogen balloon to sweep off with hydrogen (5 X vacuum / hydrogen). Stir at ambient temperature for 16 -6 5 hours. Exchange the hydrogen argon atmosphere with nitrogen, remove the solvent by vacuum evaporation The crude product was obtained. The crude product was analyzed by NMR spectroscopy and palm HPLC analysis. 丨 Hydrogenation at 4 atmospheres. All operations are performed in the AtmosBag (Aldrich Chemical Company) under an argon atmosphere. The matrix (500-1000 mg) was placed Stainless steel high pressure vessel (Vince Technology Company, France), high pressure vessel fitted with Teflon nozzle (or glass dish) and Teflon coated magnetic stir bar. Degassed solvent and catalyst or catalyst solution (0.2 5 To 2.5 mol%) was added thereto. The vessel was sealed, and the vessel was purged with hydrogen by pressurizing the vessel to 4.5-5.5 atmospheres, and then depressurized (5 times). Finally, the pressure was adjusted to a predetermined level > 'Reaction mixture around The temperature was stirred for 16-65 hours. Upon completion, the hydrogen pressure was exchanged with nitrogen, and the solvent was removed by real hair to obtain a crude product. The crude product was analyzed by NMR spectrum analysis and HP HP analysis. Purification of the final material: purification of (S) -α-ethyl-2-oxy-1-pyrrolidinacetamidine (leviracetam). Levoiracetam (5 g, 98% ee) dissolved in water (20 ml, 4 volumes) and extracted with ethyl acetate (3X10 ml, 3X2 volumes), then the organic phase was extracted back with water (10 ml, 2 volumes), and -39- 200536828 aqueous phase Evaporation gave a pale yellow solid (4.83 g, 80%). The solid (4 g) was dissolved in acetone (24 ml, 6 vol) and heated at reflux for 1 hour. The solution was slowly cooled to 0 ° C at a rate of 5-10 ° C / hour. The crystals were filtered, washed with acetone (1.6 ml, 0.4 volume) and dehydrated to obtain a white solid (3.23 g '81%, > 9 9.8% e. E. J 54 ppm Rh) 〇 (S) -a -ethyl- Purification of 2-oxo-l-pyrrolidine acetamidin (levetiracetam): Levetiracetam (5 g, 98% e.e.) obtained from the aforementioned asymmetric hydrogenation was obtained from propyl (30 ml, 6 volumes) was recrystallized as before to obtain white crystalline solid I (3.94 g, 81%,> 99.8% ee, 52 ppmRh). This material (3 g) was recrystallized as described above to obtain a white crystalline solid (2.31 g, 77%,> 99.8% e.e., 23 ppm Rh). Melting point 1 1 8.4 -1 1 9.9. (:. [Schematic description of the diagram] None [Description of the main component symbols] None.

-40--40-

Claims

200536828 十、申請專利範圍： 1·一種具有通式（B)之化合物， R3 R4200536828 10. Scope of patent application: 1. A compound with general formula (B), R3 R4

其中 R1爲甲基， R2及R4爲氫， R3爲（CVC5)烷基或（C2-C5)鹵烯基，以及 X 爲—COOH，-COOMe 或-COOEt ;. 及其幾何異構物，對映異構物，非鏡像異構物，彼等混合物及其醫藥可接受鹽。 2. 如申請專利範圍第1項之具有通式（B)之化合物，其中R3 爲丙基。 · 3. 如申請專利範圍第1項之具有通式（B)之化合物，其中R3 爲二氟乙烯基。 4. 如申請專利範圍第1項之具有通式（B)之化合物，其中X 爲-COOH。 5. 如申請專利範圍第1項之具有通式（B)之化合物，其中X 爲 COOMe。 6 .如申請專利範圍第1項之具有通式（B )之化合物，其中X 爲-COOEt。 7.如申請專利範圍第1至6項中任一項之具有通式（B)之 -41 - 200536828 化合物，其爲左旋對映異構物。 8.如申請專利範圍第1至6項中任一項之具有通式（B)之化合物，其爲右旋對映異構物。 9 . 一種製備具有通式（B)化合物之左旋或右旋對映異構物及其醫藥可接受鹽之方法，Where R1 is methyl, R2 and R4 are hydrogen, R3 is (CVC5) alkyl or (C2-C5) haloalkenyl, and X is -COOH, -COOMe, or -COOEt; and its geometric isomers, Enantiomers, non-image isomers, their mixtures and their pharmaceutically acceptable salts. 2. For example, a compound having the general formula (B) in item 1 of the scope of patent application, wherein R3 is propyl. · 3. For example, the compound having the general formula (B) in item 1 of the patent application scope, wherein R3 is a difluorovinyl group. 4. The compound having the general formula (B), as in item 1 of the patent application scope, wherein X is -COOH. 5. For example, a compound having the general formula (B) in item 1 of the patent application scope, wherein X is COOMe. 6. The compound having the general formula (B) according to item 1 of the scope of patent application, wherein X is -COOEt. 7. The compound of the formula -41-200536828 having the general formula (B) according to any one of claims 1 to 6, which is a L-enantiomer. 8. The compound having the general formula (B) according to any one of claims 1 to 6, which is a dextro enantiomer. 9. A method for preparing a L- or D-enantiomer of a compound having the general formula (B) and a pharmaceutically acceptable salt thereof,

其中R1爲甲基以及X爲- COOH，該方法包括則驅物A1 之非對稱氫化反應Where R1 is methyl and X is -COOH, the method includes an asymmetric hydrogenation reaction of A1

前驅物A1 1 〇. —種製備具有通式（B)化合物之左旋或右旋對映異構物及其醫藥可接受鹽之方法，Precursor A1 1 〇.-A method for preparing a left- or right-handed enantiomer of a compound having the general formula (B) and a pharmaceutically acceptable salt thereof,

其中R爲甲基以及X爲-COOMe，該方法包括前驅物A2 的Z異構物或E異構物之非對稱氫化反應 -42- 200536828Where R is methyl and X is -COOMe, this method includes asymmetric hydrogenation of the Z isomer or E isomer of precursor A2 -42- 200536828

OMe 前驅物A2 ° 11. 一種製備具有通式（B)化合物之左旋或右旋對映異構物及其醫藥可接受鹽之方法，OMe precursor A2 ° 11. A method for preparing a left- or right-handed enantiomer of a compound having the general formula (B) and a pharmaceutically acceptable salt thereof,

(B)(B)

其中R1爲甲基以及X爲- COOEt’該方法包括前驅物A2, 之非對稱氫化反應Where R1 is methyl and X is -COOEt '. The method includes asymmetric hydrogenation of precursor A2.

〇Et 前驅物A2’ 其中X爲-C00R7，其中該方法包括如下反應圖（5)所示，將酸〔該酸爲式（a)〇Et precursor A2 ’where X is -C00R7, where the method includes the following reaction scheme (5), the acid [the acid is the formula (a)

㈧ R2㈧ R2

-43- 1 2.—種製備具有通式（A)化合物之方法， 200536828 化合物，其中X爲-co2h〕轉成醯氯’隨後使用式r7-oh 化合物進行醇解反應，-43- 1 2. A method for preparing a compound having the general formula (A), a compound of 200536828, in which X is -co2h] is converted into chloro chloride 'followed by alcoholysis reaction using a compound of formula r7-oh,

PCI, -5-1 r7-〇hPCI, -5-1 r7-〇h

R4R4

〇〇

㈧ co〇r7㈧ co〇r7

反應圖(5) 其中 R1爲氫或烷基，芳基，雜環烷基，雜芳基’鹵原子’羥基，胺基，硝基，氰基；Reaction scheme (5) wherein R1 is hydrogen or alkyl, aryl, heterocycloalkyl, heteroaryl'halogen'hydroxy, amino, nitro, cyano;

R2及R4爲相同或相異’且各自分別爲氫或鹵原子’羥基，胺基，硝基’氰基，醯基，醯氧基，_s〇2 -烷基，_ S02-芳基，-SO-烷基，-SO-芳基’烷基胺基’羧基’酯基，醚基，醯胺基，磺酸基，磺醯胺基’烷氧羰基’烷硫基’芳硫基’院基’垸氧基’執醋基’氧釀肢基’方基，芳基胺基，芳氧基，雜環烷基’雜芳基’乙燏基； R3爲氫，鹵原子，羥基，胺基，硝基，氰基，醯基’醯氧基，-S02-烷基，-S02-芳基，-SO-烷基，-SO-芳基，烷基胺基，羧基，酯基，醚基，醯胺基，磺酸基，磺醯胺基，院氧羰基，院硫基’芳硫基’院基’院氧基’氧酯基，氧醯胺基，芳基’芳基胺基’芳氧基’雜環烷基，雜芳基，（c2-c5)烯基，（C2-C5)炔基’疊氮基’苯基磺醯氧基；其中各（C2-C5)烯基、（c2-c5)炔基可經一個 -44- 200536828 或多個鹵原子，氰基，硫氰基，疊氮基’院硫基’環丙基，醯基及/或苯基取代，以及 R7爲氫，羥基，烷基，芳基，雜環烷基’雜芳基，院氧基，或芳氧基；其中各烷基爲具有直鏈、分支或環狀部分或其組合且含有1-20個碳原子，以及可經1至5個分別選自鹵原子、羥基、锍基、胺基、硝基、氰基、醯基、醯氧基、-S〇2-院基、-S02 -芳基、-SO-院基、-SO -方基、丨兀基fe基、羧基、酯基、醚基、醯胺基、磺酸基、磺醯胺基、烷氧羰基、烷硫基、芳硫基、氧酯基、氧醯胺基、雜環烷基、雜芳基、乙烯基、（CVC5)烷氧基、（C6-C1G)芳氧基、 (c6-c1C))芳基所組成的組群之取代基取代；其中各芳基可經1至5個分別選自鹵原子、羥基、锍基、胺基、硝基、氰基、醯基、醯氧基、-S02-烷基、-so2-芳基、-so-烷基、-so-芳基、烷基胺基、羧基、酯基、醚基、醯胺基、磺酸基、磺醯胺基、烷氧羰基、烷硫基、氧酯基、氧醯胺基、芳基、（cvc6)烷氧基、（c6-c10) 芳氧基、（c^-c,)烷基所組成的組群之取代基取代。 13.如申請專利範圍第12項之方法，其中R2，R3，R4爲氫 ;R1爲甲基以及R7爲甲基。 -45- 200536828 七、指定代表圖： (一）本案指定代表圖為：無 (二) 本代表圖之元件符號簡單說明: 無R2 and R4 are the same or different 'and each is a hydrogen or halogen atom' hydroxyl, amine, nitro 'cyano, fluorenyl, fluorenyl, _s02-alkyl, _S02-aryl,- SO-alkyl, -SO-aryl ', alkylamino, carboxy' ester, ether, sulfonyl, sulfonyl, sulfonamido ', alkoxycarbonyl, alkylthio, and arylthio. "Methoxy", ethoxy, "oxo", "aryl", arylamino, aryloxy, heterocycloalkyl, "heteroaryl", ethyl "; R3 is hydrogen, halogen atom, hydroxyl, amine Group, nitro, cyano, fluorenyl'fluorenyloxy, -S02-alkyl, -S02-aryl, -SO-alkyl, -SO-aryl, alkylamino, carboxyl, ester, ether Group, sulfonyl group, sulfonyl group, sulfonylamino group, oxocarbonyl group, oxo group 'arylthio group, oxo group, oxo group', oxyester group, oxo group, aryl 'arylamino group 'Aryloxy' heterocycloalkyl, heteroaryl, (c2-c5) alkenyl, (C2-C5) alkynyl'azido'phenylsulfonyloxy; each of (C2-C5) alkenyl The (c2-c5) alkynyl group can pass one -44- 200536828 or more halogen atoms, cyano, thiocyano, and azide. 'Cyclopropyl, fluorenyl and / or phenyl substituted, and R7 is hydrogen, hydroxy, alkyl, aryl, heterocycloalkyl' heteroaryl, oxo, or aryloxy; wherein each alkyl It has a linear, branched or cyclic moiety or a combination thereof and contains 1-20 carbon atoms, and can be selected from halogen atoms, hydroxyl groups, fluorenyl groups, amine groups, nitro groups, cyano groups, and fluorene groups through 1 to 5 respectively. Group, fluorenyloxy group, -S02-single group, -S02-aryl group, -SO-single group, -SO-squaryl group, carbonyl group, carboxyl group, ester group, ether group, fluorenylamino group, Sulfonyl, sulfonamido, alkoxycarbonyl, alkylthio, arylthio, oxyester, oxamido, heterocycloalkyl, heteroaryl, vinyl, (CVC5) alkoxy, ( C6-C1G) aryloxy, (c6-c1C)) aryl group is substituted by a substituent; wherein each aryl group may be selected from 1 to 5 respectively selected from a halogen atom, a hydroxyl group, a fluorenyl group, an amine group, Nitro, cyano, fluorenyl, fluorenyl, -S02-alkyl, -so2-aryl, -so-alkyl, -so-aryl, alkylamino, carboxyl, ester, ether, Sulfonylamino, sulfonyl, sulfonamido, alkoxycarbonyl, alkylthio, oxyester The substituent group consisting of oxygen acyl group, an aryl group, (cvc6) alkoxy, (c6-c10) aryloxy, (c ^ -c,) alkyl. 13. The method according to item 12 of the patent application, wherein R2, R3, and R4 are hydrogen; R1 is a methyl group and R7 is a methyl group. -45- 200536828 VII. Designated Representative Map: (I) The designated representative map in this case is: None (II) The component symbols of this representative map are simply explained: None

八、本案若有化學式時，請揭示最能顯示發明特徵的化學式:8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: