TWI308912B - Process for preparing 2-oxo-1-pyrrolidine derivatives - Google Patents

Description

1308912 V. INSTRUCTION DESCRIPTION OF THE INVENTION (1) The present invention relates to a 2-oxy-1 -pyrrolidine derivative, a process for the preparation thereof and use thereof. The present invention is also directed to a process for preparing an α-ethyl-2-oxy-pyrrolidinium derivative from an unsaturated 2-oxy-1-pyrrolidine derivative. In particular, the present invention relates to novel intermediates and methods for preparing (S)-(-)-α-ethyl-2-oxy-1-pyrrolidinium, which are named after the international non-exclusive name. Levetiracetam, its dextrorotatory enantiomer and related compounds. Levetiracetam is shown to have the following structural formula··

Levetiracetam Levetiracetam is a levorotatory compound disclosed in European Patent No. 1 62036 as a treatment and prevention of hypoxia and ischemic episodes of the central nervous system. Such compounds are also useful in the treatment of epilepsy, which has been tested for the right-handed enantiomer (R)-(+)_α-ethyl-2-oxy-1-pyrrolidine of the present invention as a therapeutic indication. Acetamide is completely inactive (A.). GOWER et al., European Journal of Pharmacology, 222, (1 992), 1 93-203). Finally, European Patent Application No. 64 5 1 3 9 shows that such compounds have an anxiolytic activity. An asymmetric carbon atom carries a hydrogen atom on the plane of the paper (not shown). The preparation of levetiracetam is described in the European Patent No. 162 036 and the British Patent No. 2 225 322, both of which are assigned to the assignee of the present invention. The preparation of the dextrorotatory enantiomer (R)-(+)-α-ethyl-2-oxo-1-pyrrolidineacetamide is disclosed in European Patent No. 165 919. Having said that, these methods cannot fully meet the requirements of 1308912 A7 V. Inventions (2) Industrial processes. Therefore, new approaches have been developed through asymmetric hydrogenation reactions of novel precursors. In a characteristic aspect, the present invention provides a compound having a compound of the formula (A) and a pharmaceutically acceptable salt thereof.

Ο (A) (Please read the notes on the back and fill out this page.) Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the consumer consortium, where X is -CONR5R6 or -COOR7 or -CO-R8 or CN; R1 is hydrogen or alkyl , aryl, heterocycloalkyl, heteroaryl, halogen atom, aryl group, nitro group, cyano group; R2 'R3, R4 are the same or different, and each is hydrogen or a halogen atom, a hydroxyl group, Amine, nitro, cyano, decyl, decyloxy, sulfonyl, sulfinyl 'alkylamino, carboxy, ester, ether, decyl, sulfonyl 'sulfonamide , alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, alkyl, alkoxy, oxyester, Oxidantamine, aryl, arylamine, aryloxy, heterocycloalkyl, heteroaryl, vinyl; R5, R6, R7 are the same or different, and each is hydrogen, hydroxy, alkyl , aryl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy; and R8 are hydrogen, thiol, sulfhydryl, halogen atom, aryl, aryl, heterocyclic, heteroaryl, Alkylthio, arylthio . The term "hospital base" is used herein to include a straight-chain 'branched or toroidal part or its -4- paper scale applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). ----I--- 1308912 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printing 5, Inventions () Combined and saturated monovalent hydrocarbon groups containing 1-20 carbon atoms and preferably 1-5 carbon atoms . The alkyl group may be optionally selected from 1 to 5, respectively, selected from a halogen atom, a hydroxyl group, a decyl group, an amine group, a nitro group, a cyano group, a decyl group, a decyloxy group, a sulfonyl group, a sulfinyl group, an alkylamino group. , carboxy, ester, ether, decyl, sulfonate, sulfonylamino, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylsulfinyl, arylsulfin Base, alkylthio, arylthio, oxyester, oxoamine, heterocycloalkyl, heteroaryl, vinyl, (Ci-Cs) alkoxy, (C6-Cic) aryloxy, ( Substituent substitution of the C6-Ci()) aryl group. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or at least one selected from halogen atoms a group of a group consisting of a hydroxyl group, a thiol group, an amine group, a nitro group, and a cyano group, such as a trifluoromethyl group, a trichloromethyl group, a 2,2,2-trichloroethyl group, and a 1,1-dimethyl group. -2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl. The term "heterocycloalkyl" is used herein to mean "(G-C6)cycloalkyl" as defined above, with at least one oxime, S and/or N atom cleavage carbocyclic ring structure such as tetrahydrofuranyl. , tetrahydropyranyl, hexahydropyridyl, hexahydropyridinyl, morpholinyl, pyrrolidinyl or by at least one selected from the group consisting of a halogen atom, a hydroxyl group, a thiol group, an amine group, a nitro group, a cyano group The base of the group is replaced. The term "alkoxy" is used herein to include -0-alkyl, wherein "alkyl" is as defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group Base, for example, trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, M-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2 , 2 · trichloroethyl. The term "alkylthio" is used herein to include -S-alkyl, of which "alkyl" (please read the phonetic note on the back? Then fill out this page), install----book-t China National Standard (CNS) A4 Specification (210 X 297 mm) 1308912 A7 B7 V. Invention Description (), as defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl '2,2,2-trimethylethyl or substituted with at least one halo group a base such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1, didimethyl-2,2-dibromoethyl, 1,1-dimethyl-2, 2,2-trichloroethyl. The term "homo-amino group" is used herein to include -NH, or -N (hospital) 2, wherein "alkyl" is as defined above. Preferred alkyl groups are methyl, ethyl, propyl, n-propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or at least one Halogen-substituted group. The term "aryl" is used herein to include an organic group derived from an aromatic hydrocarbon by removal of a hydrogen atom, such as phenyl, phenoxy, naphthyl, aralkyl 'benzyl, optionally 1 Up to 5 selected from a halogen atom, a hydroxyl group, a decyl group, an amine group, a nitro group, a cyano group, a decyl group, a decyloxy group, a sulfonyl group, a sulfinyl group, an alkylamino group, a carboxyl group, an ester group, and an ether. , amidino, sulfonate, sulfonylamino, alkylsulfonyl, alkoxycarbonyl, alkylsulfinyl, alkylthio, oxyester, oxoamine, aryl, (CVC6 Substituent substitution of a group consisting of an alkoxy group, a (c6-c1Q) aryloxy group, and a (C6-C1Q) aryl group. The aryl group is composed of 1 to 3 rings, preferably 1 ring, and 2 to 30 carbon atoms and preferably 6 to 10 carbon atoms. Preferred aryl groups are phenyl, phenyl, cyanophenyl, nitrophenyl, methoxyphenyl, naphthyl, benzyl 'halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl Base, 2-phenylethyl. The term "arylamino" is used herein to include -NH aryl or -N(aryl) 2 group, wherein "aryl" is as defined above. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, naphthyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2 _Phenylethyl. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). ** ^1 ^1 ·_1·-fn nnn _ Ministry of Economics Intellectual Property Bureau of Staff Consumer Cooperatives Printed 1308912 ^____ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed A7 B7 Invention Description () The term 'aryloxy' is used here to include -0-aryl, where "aryl" is defined As before. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxy; benzyl, nitrobenzyl, 2 - phenylethyl. The term "arylthio" is used herein to include -S-aryl, wherein "aryl" is as defined above. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxy; benzyl, nitrobenzyl, 2 - phenylethyl. The term "halogen atom" is used herein to include Cl, Br, F, I atoms. The term "hydroxy" is used herein to mean the formula -0H. The term "base" is used herein to mean the -SH group. The term "cyano" is used herein to mean the formula -CN. The term "nitro" is used herein to mean the formula -N〇2. The term "amine" is used herein to mean the formula ΝΗ2 group. The term "carboxy" is used herein to mean the formula -C00H. The term "sulfonic acid group" is used herein to mean the formula -S03H group. The term "sulfonamide" is used herein to mean the formula -so2nh2. The term "heteroaryl" is used herein unless otherwise indicated, otherwise it means that the "aryl" as defined above carries at least one ruthenium, s and/or N 岔 carbene ring structure, such as Z π 固定, furan. Base, pyridyl, thienyl, isodentate, imidazolyl, benzimidazolyl, tetrazolyl, pyridinyl, pyrimidinyl, quinolyl, isoquinolinyl, isobenzofuranyl And thienyl, pyrazolyl, fluorenyl, isodecyl, fluorenyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl, or benzoxazolyl, selective Up to 5 points - 7 - This paper scale applies to China National Standard (CNS) A4 specifications (210 X 297 mm) — i—I — Pack —! — Order --------- (Read first Note on the back page again) 1308912 A7 __B7___ V. Description of invention (6) (Please read the note on the back and fill out this page) Do not choose from hydroxyl, halogen, sulfhydryl, amine, nitro, cyanide Base, fluorenyl, decyloxy, sulfonyl, sulfinyl, alkylamino, carboxyl, ester, ether, decyl, sulfonate, sulfonamide, alkyl sulfonate Substituent substitution of a group consisting of a group, an alkoxycarbonyl group, an oxyester group, a oxonium group, an alkoxycarbonyl group, a (Q-Cs) alkoxy group, and a (c^c5)alkyl group. "Aralkyloxy" The term is used herein to denote the radical of the formula aryl-(anthracene-alkyl)-. Preferred aralkyl is benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenethyl, diphenylmethyl, (4-methoxyphenyl)diphenylmethyl. The term "mercapto" is used herein to mean a carboxylic acid group, and thus includes alkyl-CO-, aryl. a group of a base-CO-, a heteroaryl-CO-, an aralkyl-CO- group, wherein each hydroxyl group is as defined. The preferred alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Iso- or tert-butyl, 2,2,2-trimethylethyl or a group substituted with at least one halo group. Preferred aryl is phenyl, phenyl, cyanophenyl, nitro Phenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl. Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative, printing "oxygen oxime" The term "base" is used herein to mean a carboxylic acid group, and thus includes an alkyl-C0-0-, aryl-C0 group. a group of -0-, heteroaryl-CO-O-, aralkyl-C0-0-, wherein each hydroxy group is as defined herein. Preferably, the alkyl group and the aryl group are as defined for the fluorenyl group. The term "s-alkyl" or "so2-aryl" is defined as "base group" and "square group" as defined above. Preferred bases are methyl, ethyl, propyl and iso a propyl group, a butyl group, an iso- or a tri-butyl group, a 2,2,2-trimethylethyl group or a group substituted with at least one halo group. Preferably, the aryl group is a phenyl group, a halophenyl group or a cyanogen group. Phenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyan-8- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1308912 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed invention description () benzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl. The term "sub-expansion" refers to the formula -S0 - the base of the yard or the base of _s0_aryl. The definitions of "hospital base" and "aryl" are as before. Preferably, the base is methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group base. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, yl, halo; cyanobenzyl, methoxybenzyl, nitrobenzyl ' 2 - phenylethyl. The term "ester group" means the formula - C00 - or the base of -C00-aryl group, wherein "alkyl" and "aryl" are as defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group base. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, henyl, halooctyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2 - phenylethyl. The term "oxyester" means a radical of the formula -o-coo-alkyl or -O-C00-aryl, wherein "alkyl" and "aryl" are as defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group base. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, benzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2 - phenylethyl. The term "ether group" means a group of the formula alkyl 〇-alkyl or alkyl-0-aryl or aryl-fluorene-aryl, wherein "alkyl" and "aryl" are as defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group base. Preferred aryl groups are phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, -9-. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297). —*—装--------订---------AWI (please read the note on the back first? Then fill out this page) Oxygenamine-based Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printed 1308912 A7 B7 V. DESCRIPTION OF THE INVENTION () Benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl. The term "amylamine" means a radical of the formula _C0NH2_ or -C0NH or _C0N(alkyl)2 or -CHNH aryl or _C〇N(square)2, wherein "alkyl" and " "Aryl" is defined as before. Preferably, the alkyl group contains from 1 to 4 carbon atoms and the aryl group contains from 6 to 10 carbon atoms. Preferably, the base is methyl 'ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or substituted with at least one halo base. Preferred aryl groups are phenyl 'halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2 - phenylethyl. The word indicates the formula -0-CONH2- or -0-C0NH alkyl or -0-C0N(alkyl) 2 or -〇-C〇NH aryl or -0-C0N(aryl) 2, wherein "Base" and "aryl" are as defined above. Preferably, the alkyl group contains from 1 to 5 carbon atoms and the aryl group contains from 6 to 8 carbon atoms. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-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, cyanyl, methoxyoctyl, nitropropenyl, 2 - phenylethyl. Preferably R1 is methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl or substituted with at least one halo group , for example, trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2, 2,2-trichloroethyl. Preferably, R2, R3 and R4 are each independently hydrogen or a halogen atom or methyl, ethyl, propyl 'isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl Or .10. This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) I. Install 1308912 Α7 Β7 V. Invention Description () a group substituted with at least one halo group, such as trifluoromethyl, trichloromethyl, 2.2.2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-di Methyl - (Please read the notes on the back and fill out this page) 2.2.2- Trichloroethyl. Preferably R5 and R6 are methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl. Preferably R7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy , phenyl, benzyl, or a group substituted with at least one halo group such as trifluoromethyl, chlorophenyl. Preferably R8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, phenyl, benzyl, or The group substituted with at least one halo group such as trifluoromethyl, chlorobenzyl or where X is -CN. Unless otherwise stated, the compounds of formula (A) described herein, whether individually or collectively, include geometric isomers, namely Z (Zusanimen) and E (Entgegen) isomers and Its mixture (racemic mixture). The Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives, prints the Z (Simmon) and E (Anjiu) isomers of the compound of formula (A) for the asymmetric hydrogenation method described below (wherein R1 is methyl, R2 and R4) The best results are obtained for Η and X is -CONH2 or -COOME or -COOEt or -COOH. In this group, compounds in which R3 is a hydrogen, an alkyl hydrazide* (particularly a difluorovinyl group) are particularly suitable: ( — ............ . < A characteristic aspect of the invention relates to a method for preparing a compound of the formula (A), which comprises the following reaction: -11- The paper scale is applicable to the Chinese national standard (εΝέ) Α 4 specification (210 X 297 gong) PCT) 1308912 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 10, Invention Description () Compound of formula (A) where X is -CONR5R6 or -COOR7 or -CO-R8 or CK 'can be conveniently passed through the formula The α-ketocarboxylic acid derivative of (C) wherein R1 and X are as defined above, and the pyrrolidone of the formula (D) wherein R, R3, and R4 are as defined above, and are prepared according to the following reaction scheme (1). .

Reaction Scheme (1) Compound of the formula (Α) wherein X is -COOR7 is conveniently via the formula (C') α-ketocarboxylic acid derivative, where X is -COOR7 and pyrrolidine of the formula (D) The ketone was prepared according to the reaction of the reaction scheme (2) shown below.

Reaction Scheme (2) Appropriate reaction conditions involve the use of toluene under reflux. As a result, in the obtained compound (Α), R7 is conveniently converted from hydrazine to alkyl group or from alkyl group to hydrazine. The general formula (C) or (C') derivatives and the general formula (D) pyrrolidone are well known in the art and can be prepared synthetically according to the references, for example, by reference to the "Heterocyclic Chemistry Handbook" by A. Katrisky. Pergamon, 1 985 (Chapter 4) and "Understanding Heterocyclic Chemistry" by A. Katrisky and CW Rees, Pogmont, 1984 (Vol. 4, Chapters 3.03 and 3.06). -12- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) 1308912 A7 B7 11 V. Inventions () General formula (A) The compound wherein X is -CONH2 or -CONFER6 is conveniently converted to the hydrazine chloride by the corresponding acid (the compound of formula (A) where X is CO 2 H), followed by aminolysis or the first or second amine with the formula NHR5R6. Reaction preparation. This method is illustrated by the following two reaction diagrams (3 and 4).

(Please read the precautions on the back and fill out this page.) I·Installation of the Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives, Printing Reaction Chart (4) These reactions are preferably carried out using PC15 to obtain ruthenium chloride, followed by anhydrous ammonia or The first or second amine of HNR5R6 is reacted to obtain the desired olefinic amine amide. The compound of the formula (A) wherein X is -COOR7 can be conveniently converted from the corresponding acid obtained by the reaction scheme (2) (the compound (A), where X is COOH) to ruthenium chloride, followed by the compound of the formula R7-〇H (Alcohol), where R7 is defined as previously prepared by alcoholysis. (Refer to Reaction Figure 5) -13- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1308912 A7 B7

PCL

R7-OH

R3 R

Reaction Scheme (5) These reactions are preferably carried out using PC15 to obtain hydrazine chloride, followed by the use of R7-indole hydrazide to obtain a predetermined ester. The foregoing reaction conditions are well known to those skilled in the art. In another feature, the invention relates to the use of a compound of the formula (Α) as a synthetic intermediate. Compounds of the formula (Α), where X is -CONH2, are of particular interest as hydrogenation of such compounds to form levetiracetam. Z (Simmon) and E (Anjiu) of these compounds can be subjected to rapid and selective asymmetric hydrogenation to any of the desired enantiomers. The bond joining R1 to the molecule represents a Z isomer or an E isomer. As a special case, the compound (B) synthesized using the compound (A) can be explained according to the following reaction scheme (6). (Please read the precautions on the back and fill out this page) 装装# Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

IT

R

R

R N 〇

X (B) Reaction diagram (6) where R1, R2, R3, R4 and X are defined as before -14 - This paper scale applies to China National Standard (CNS) A4 specification (21G X 297 public) 1308912 A7 B7 i, invention DESCRIPTION (') Preferably, R1 is methyl, ethyl, propyl, isopropyl, butyl or isobutyl: most preferably methyl, ethyl or n-propyl. Preferably, R2 and R4 are each independently hydrogen or a halogen atom or methyl, ethyl, propyl, isopropyl, butyl, isobutyl; and most preferably hydrogen. Preferably, R 3 · CrQ alkyl, C 2 -C 5 alkynyl, cyclopropyl azide, each optionally having one or more halogen atoms, a cyano group, a thiocyano group, an azide group, an alkylthio group, a ring a propyl group, a fluorenyl group and/or a phenyl group; a phenyl group; a phenylsulfonyl group; a phenylsulfonyloxy group, a tetrazolyl group, a triazolyl group, a thienyl group, a furyl group, a pyrrolyl group, a pyridyl group, Any phenyl moiety may be substituted with one or more halogen atoms, a court base, a halogen-based group, an alkoxy group, a nitro group, an amine group, and/or a phenyl group.

Most preferred is methyl, ethyl, propyl, isopropyl, butyl or isobutyl. I ---1 Preferably X is -COOH or -COOMe or -COOEt or -CONH2 ; optimally -CONH2. The compound of formula (B) may be isolated or converted into its pharmaceutically acceptable salt in a free form in a conventional manner, or vice versa. Preferably, the individual compounds of the compound of the formula (B) have the formula (B '), (B,,) and (B,,,). (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printed Clothes

(B,)

(B-) The compound of the formula (B) is suitable for the treatment of epilepsy and related diseases. According to the other -15- This paper scale applies the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1308912 Α7 Β7 18 5, invention description () As the industry knows, depending on the substitution form, not all formulas ( Both A) and (B) compounds can form salts, so that "pharmaceutically acceptable salts" are applied only to the compounds of formula (A) or (B) which have the ability to form salts. The following examples are for illustrative purposes only and are not intended to be limiting of the invention. Those skilled in the art will appreciate that routine variations and modifications of the examples below may be made without departing from the spirit or scope of the invention. Example 1 The preparation of precursor A 1 was carried out by refluxing with a-ketobutyric acid and pyrrolidone under reflux, 70% crude yield. z: E represents the ratio of the amount of Z isomer to the amount of E isomer.

OH

Η I τ Toluene, reflux 'Ding-Stark 70% (please read the note on the back and fill out this page) I-Installation i Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed OH Recrystallized OH Γ 丫N Indoleone·16ν〇1 丫70% Z:E=80:1 Precursor A1 Z:E= 149 :1 Melting point 165 - 166pC Reaction Figure 7 Crude product recrystallized from acetone '70% yield. The double-key geometry is based on the class of 20%. This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1308912 A7 B7 19 V. Inventive Note () Structure-like compound 1 H-NMR ( The interaction of the NMR spectral data is designated as Z. Example 2 Precursor A2 was prepared from A1 using diazomethane in THF. The Z-E ratio during the distillation was observed to vary from 80:1 to 29:1 (see Reaction Scheme 8). On OMe , Ν ο Ο 1. CH2N2, THF, 100 % I. Distillation, 80% Precursor A1 Z : E = 80 : 1 Precursor A2 Z : E = 29 :; Reaction Figure 8 Precursor A2 'E The structure was obtained from the Z isomer of the precursor A1 using ethanol, dicyclohexylmethyleneimine (DCC) and dimethylaminopyridine (DMAP) as described in Reaction Scheme 9.

EtOH (3 eq.) DCC (1 eq.). 2. n - _DMAP (0.·) equivalent), Ding (plus volume) U Room temperature (r.t), 24 hours. 〇 —----^

(Please read the notes on the back and fill out this page.) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Precursor A2, E Isomers .... 100. The esterification of the precursor A 1 is also carried out on a small scale using PC15 in THF followed by methanol to obtain a predetermined methyl ester (Z: E = 5:1). Reference reaction scheme 10 ° precursor A1 Z isomer Reaction Figure-21. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 1308912 A7 B7 V. Description of invention ( Τ on ο Ν, /Ο 1. PC15 equivalent, THF, () C 2. MehH 1 equivalent, pyridinium OMe

Precursor A2 E : Z = 5 : 1 Precursor A1 Reaction Figure 10 The precursor A2 is also prepared by reacting methyl ketobutyrate with pyrrolidone in refluxing toluene in the presence of a catalytic amount of phosphonium chloride. Refer to Reaction Figure 11.

Ο (Please read the note on the back and fill out this page) Install I n I. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Agricultural Precursor Α 2 Ζ: Π = 6:1 Reaction Figure 1 1 Ketobutyric acid ester The chemical system was carried out using methanol according to the reference method or using a diazotamine. Subsequent condensation gave a precursor Α 2, 60% yield. This method compares the higher ε isomer content obtained via the route of precursor A 1 (reaction Figure 8). Other ester derivatives of the precursor A 2 can be prepared in both ways. -22- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1308912 A7 B7 V. Invention description (23) Table 1

St. Ma. Am. mg. Catalyst Cou. Loa. Solv. 112 Pres. (,.v. % % A1 100 (S,S)-Et*DUPHOS OTf(-) 5.0 EtOH 4 100 95 A1 100 (SS) -BPPM 〇Tf(-) 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 〇Tf(-) 2.0 EtOH 4 100 93.8 A2 (Z) 200 (S,S)-Et-DUPHOS ΟΤΓ(~) 0.5 EtOH 4 100 99.1 A2 (Z) 200 (S,S)-Me-DUPHOS OTf(-) 1,0 EtOH 5 100 98.9 A2 (Z) 300 (S,S)-Me-DUPHOS OTf(-) 2.0 IPA 5 100 97.9 A2, (E) 200 (SfS)-Me-DUPHOS OTf(-) 0.5 EtOH 5 100 99.4 A2,( E) 300 (SS)-Me-DUPHOS OTf(-) 0.5 IPA 5 100 94.0 A2 (E) 4000 (SS)-Me-DUPHOS BF4(-) 0.025 MeOH 5 100 97.4 A2 (Z) 4000 (SS)-Me -DUPHOS BF4(-) 0.01 MeOH 5 99 99 A2 (Z) 4000 (SS)-Me-DUPHOS BF4H 0.005 MeOH 5 25 97 A2' (E) 300 (S,S)-BPPM OTf(-) 0.5 MeOH 1 100 -99.3 A2' (E) 300 (S,S)-BPPM OTf(-) 0.5 EtOAc 1 100 -95.2 A2 (E) 300 (S,S)-BPPM OTf(-) 0.5 Toluene 1 100 -96.2 A2 (Z 200 (RR)-DIPAMP BF4H 2.0 EtOAc 5 100 94.5 A2, (E) 200 (R,R)-DIPAMP BF4(-) 0.5 EtOAc 5 92 96.5 Table, St. Ma Show starting material; Am for quantity; Cou. for relative ion; Loa. for load mol%; Solv. for solvent, H2 Pres. (Please read the back note first and then fill out this page) Pack—* ntn I - The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed indicates hydrogen pressure (atmospheric pressure); and CV indicates conversion rate. Example 6: Asymmetric hydrogenation of precursor A3 The same procedure as in Example 5 was used; various rhodium and ruthenium catalysts were screened, with reference to the representative results of Figure 13 and Table 2. -25- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1308912 A7 B7 V. Invention description (榭$ mu μ mu μ cheek § 1:1 E^rt • SOJa CSH 悬 οο Οοε •rtoq •300 A° Z6 L, s 8_ε6 ·inch 6 ε6 〇卬扪' Lm_ 001οοι 001 001001 001 §1 06-0S 001 001

Uooz-S9 - t ZI 91 0 inch 91 QL β SI SI 91 91 inch I inch inch inch inch inch inch inch inch 0 inch 0 inch 01 0Z οε οζ 03 0Ζ 03 SUQ SUQHOS Η23 χοΰ §α SOQ SOQ IO^E/HO】^ Μ 〇δ (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed brewing collar w εν _镒•s (-U10 UH s〇HdD9s-(ss) 00^ ·0 ( -UH〇uh SOHdna-s-(ss) OS ·0 [-HVLO gsdds-(s*s} 〇00Mo.l (_)sms &lt;ί&quot;ν&amp;αέ·Η) oos s Hsm § dwvdIa-HH) 00^ z 00^ 0·Ι')sms diwdia 丨(H*&amp;00^ ·0 H2S s dIATVdIa-(H*H) Cos 91 (丨).v〇CIVMISAH) 00^ •z: [-pvo PH dvMIS-(H) 001 Pack -------- Order --------- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) -2 1308912 A7 B7 26 V. Description of the invention () Inhibition of catalysis. The inhibition of the catalytic action by the coordination solvent suggests that A3 is a poor coordination matrix, especially compared to other α-mercapto methacrylic acid derivatives. (Please read the back of the note first and then fill out this page) Good coordination matrix. Despite this, excellent results were obtained at DCM. As can be seen, this solvent consistently achieves 97 to 98% e.e. enantioselectivity on a scale of 0.5 to 15 grams. Other useful prospects were obtained from the EtOAc-DCM solution mixture and toluene. Table 3: Hydrogenation of A3 using [Rh-COD -(S,S)-Et-Duffs]OTf A3 A3 mg catalyst Molar % Solvent Solvent volume reaction time (hours) CV % ee, % 500 1.0 AcOEt/DCM 30 ^ . 1 17 95 96 500 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 CV represents the conversion rate. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Staff Consumer Cooperatives. A. Preparation of precursor A1: (Z)-2-(2-oxytetrahydro-1H-1-pyrrolyl)·2-butenoic acid (precursor Α1) 2-oxobutyric acid (25 g, 245 mmol) in a 1 liter flask equipped with a magnetic stir bar and a D-Stark gas valve, benzene (500 ml, 20 volumes) -28- The paper scale applies to the Chinese National Standard (CNS) A〇ik (210 X 297 public f) 13〇8912 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7:r 27 i, invention description () and 2-pyrrolidone ( 37.2 ml, 490 mmol, 2 equivalents). The reaction mixture was stirred under reflux with azeotropic distillation via a D-Stark coagulation valve to remove water for 5.5 hours. The solution was then concentrated to about 90 mL (3.6 vol) and allowed to cool slowly to ambient temperature. An off-white solid precipitated from the solution at about 55 °C. The solid was filtered, and the filter cake was washed with toluene (2×1 volume), then washed with dichloromethane (3×1 volume) and dehydrated under vacuum for 5 minutes to obtain a crude material (28 g, 70% yield). The crude product was refluxed in acetone (450 mL, 16 vol), slowly cooled to ambient temperature and then recrystallized from -15 to -2 CTC for 12 hours. The pure product was obtained as a white crystalline solid (21 g, 50% yield). Melting point (m _ p ·) 1 6 5 _ 5 -1 6 6 °C. ;H-NMR (CDC13): (5 (chemical shift) 2·13 (5Η, bimodal (d) and multimodal), 2·51 (2Η, trimodal (t)), 3_61(2H, t), 6.27 (lH, four peaks (q)), 8 to 10 (1H, broad); E-isomer signal, δ 1.85 (3H, t), 7·18 (1Η, q). 13C NMR (MeOH-d4) : 5 14.7, 1 9.6, 32.1, 1 5.4, 1 30.8, 137.7, 166.6, 177.9. Z:E ratio 149:1, determined by 1H NMR. Thin layer chromatography (TLC): Si〇2, toluene/AcOH/ MeOH (4:1: 〇_5), UV and anisaldehyde dyeing B. Preparation of precursor A2: (Z)-2-(2-oxytetrahydro-1H-1-pyrrolyl)-2-butene Methyl enoate (precursor A2) Precursor Al (12 g, 71 mmol) was dissolved in THF (240 mL, 20 vol) at 〇-5 ° C. Diazomethane in ether solution (200 mL, ca. 78) Millol, 1 · 1 equivalent) is added to the reaction mixture in several portions, the temperature is maintained below -29- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ------- ---装--------Book--------- (Please read the note on the back and fill out this page) 1308912 A7 B7 28 V. Invention description () 5 °C. The last reaction, the reaction mixture turned yellow. Stir at low temperature for 30 minutes' then let it warm. The remaining traces of diazomethane were added dropwise to dilute acetic acid in THF and the yellow solution became colorless. The reaction mixture was concentrated in vacuo and the crude material was distilled (93-94 ° C , 0.01 mm Hg) Obtained pure product (9.44 g '%) as a colorless oil which solidified upon cooling below 1 ° C. *H NMR (CDC13): 5 2.0 (3H, d)5 2.1 (2H, m), 2.43(2H, t), 3.54(2H,t), 3.76(3H, s), 5.96(1H,q); E-isomer signal, 5 1·75(3Η,t) and 7· 05(1Η, q) 13C NMR (MeOH-d4): (5 14.4, 1 9.7, 32.5 1, 52.6, 1 30.1, 165.6, 177.4. Z:E ratio 29:1, determined by H1 NMR. C. 2 Preparation of methyl oxybutyrate 2-oxybutyric acid (15 g) was distilled under reduced pressure (84 ° C, 20 mm Hg) using a Kugelruhr apparatus to obtain 14 g of pure material. The 2-oxobutyric acid (14 g) was dissolved in methanol (anhydrous, 20 mL, 14 vol.), and dichloroethane (anhydrous, 80 mL, 5.7 vol) was taken in the presence of a few drops of ethanesulfonic acid. The reaction mixture was stirred at reflux under an inert atmosphere for 18 hours. It was then cooled, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by distillation (b.p. 76 ° C, 20 mmH) to afford the product as a colorless oil (7.53 g, 48% yield). NMR (CDC13): &lt;5 0.88 (3H, d), 2.66 (2H, q), 3.63 (3H, s) Reference biochemistry, 2670, 1 917. D. (Z)-2-(2-Oxotetrahydro-1Η-1-pyrrolyl)-2-butenoic acid methyl ester (Precursor-30- This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 mm) (Please read the note on the back and fill out this page) Binding---------· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Clothing 1308912 A7 B7 29 V. Invention Description ( Preparation of A2). Packing (please read the precautions on the back and fill out this page). Feed the methyl 2-oxobutanoate in a 10 〇 ml flask equipped with a magnetic stir bar and a D-Stark valve. (7.5 g, 73 mmol), toluene (50 ml, 7 vol) and 2-pigebium hexanone (8.4 ml, 111 mmol, 1.5 eq.) followed by dropwise addition of hydrazine chloride (1.6 mL, 20) Millions, 0.2 7 equivalents). The reaction mixture was stirred under reflux with azeotropic distillation via a D-Stark valve to remove water for 8 hours. After cooling, the solution was washed with a 10% aqueous potassium hydrogensulfate solution (2 x 3 volume). The aqueous phase was saturated with sodium chloride and back extracted with toluene-6. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to afford crude material (7.5 g) as an orange oil. The crude oil was purified by distillation (92-94t, 0.1 mmH) to yield the product (4.7 g, 60%) as a colourless oil. Z:E ratio 6:1, determined by 1H NMR. Preparation of Ε·(Ε)-2-(2-oxytetrahydro-1Η-1-pyrrolyl)-2-butenoic acid methyl ester (precursor A2) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed with Z-A1 (2 g, 11.8 mmol) of ethanol (2.2 ml, 37.3 mmol), tetrahydrofuran (THF, 40 ml, 20 volumes) and dimethylamine were fed into a 100 ml flask of a magnetic stir bar. Pyridine (DM AP, 150 mg ' 1.23 mmol), and the flask was placed under a nitrogen atmosphere. The reaction mixture was cooled to 0 °C before adding dicyclohexylmethyleneimine (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 tolud. The oil was washed with water (40 ml) using dichloromethane (Dcm, 40 ml then 2 x 20 ml). The solvent was dehydrated by sodium sulfate and concentrated in vacuo to obtain 2 g of E-A2 B-31- This paper scale applies to the Chinese National Standard (CNS). A4 size (210 X 297 mm) 1308912 V. Description of the invention (3G) Ester (100% yield). F. Preparation of the drive A3: (z)-2-(2-oxytetrahydro-1H-1-pyrrolyl)-2-butenylamine (precursor A 3 ) 20 liter flanged bottle for erection Stir under an inert atmosphere and feed a :! (222 g '1.313 Moer' 1 equivalent) and anhydrous thf (7.0 L, 30 volumes). Any reaction mixture was cooled to below 5 ° C, and phosphorus pentachloride (300 g ' 1.44 mTorr'].1 equivalent) was added in portions, and the reaction temperature was maintained below that. The reaction mixture was stirred at -5 to 0 ° C for 1 hour and allowed to warm to 5 ° to dissolve the remaining phosphorus pentachloride ' and then cooled below 0 ° C. The sealed ice/acetone condenser was fitted to the flask. Ammonia (about 200 g) slowly passed through the solution to maintain the temperature below 15 °C. The suspension was stirred for a further 15 minutes and excess ammonia was removed by nitrogen for a few minutes. Methanol (3.7 L, 17 vol) was added and the reaction mixture was refluxed for 1-5 h then cooled to <RTI ID=0.0>> </RTI> <RTIgt; The filtrate was evaporated to give a yellow solid. This material was dissolved in methanol (640 mL, ca. 3 vol.) and ethyl acetate (440 mL, 2 vol.) and purified using anhydrous flash chromatography (EtOAc, EtOAc EtOAc EtOAc :1) Elution was carried out to obtain a crude product (288 g). The crude product was recrystallized from isopropanol (1.9 L, ca. 8.5 vol) to afford white crystals (127 g). The solid was dehydrated at ambient temperature in a vacuum oven to obtain A3 (1 18 g, 54%). 'H NMR (CDCb + several drops of MeOD): (5 6.75 ()H, q), 3.5 (2H, t), 2·5 (2Η, t), 2.15 (2H, m), 1·7 (3Η, d), trace impurities. Elemental analysis C 56.90 (57.1 3% theoretical 値); η 7.19 (7.19% theoretical 値); 1^ 1 6.3 2 (1 6.66% theoretical 値). -32- 1308912 V. Description of invention (32 The sirkan test tube was purged with hydrogen (5X vacuum/hydrogen) and stirred at ambient temperature for 1.5 hours. The clear red-orange solution was transferred via syringe to another sir Frank tube (using argon purge). The catalyst solution was under argon. Stored at ° C and used directly for hydrogenation (T etrahedr ο η, 1 2 4 5, 1 9 8 4) I. [RuhCl(R)-Binap (C6H6)] + Cl - was prepared with a magnetic stir bar and Anhydrous 200 ml of sulphur in an argon atmosphere was fed in a test tube [RuC12(C6H6)]2 (0.3 g, 0.66 mmol) and (R)-Binap (0.815 g, 1.3 mmol). Degassed anhydrous benzene (20 ml, 60 volumes) and ethanol (130 ml, 340 volumes), the solution was degassed (3x vacuum / argon). The reddish orange suspension was heated to 50-55 °C through 45 A clear brown solution was obtained in minutes. The solution was passed through celite. The pad was filtered under argon into another sir Frank tube. The solvent was evaporated in vacuo to give a yellow solid (1.08 g, 86%), which was stored at 0-5 ° C under argon. J, 3064, 1994) 〇J. [RuCl(R)-Binap(C6H6)] + BF4_ was prepared with a magnetic stir bar and fed in an anhydrous tube of 100 ml sulphur in an 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 (3x vacuum / argon) And transferred to another sir Frank tube containing a suspension of AgBF4 (0.15 g, 0.77 mmol, 1.5 eq.) in dichloromethane (] 〇 ml, 22 vol). The mixture was stirred vigorously. · 5 hours, then filtered through celite under argon atmosphere. The filtrate was concentrated in vacuo to give a green solid (0.42 g, 88%), which was stored at 0-5 ° C under argon (Journal of Organic Chemistry, 3064) ,] 994). -34- 1308912 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7____ 33 ' ~ five, invention description () K-Ru (OCOCH3)2-[( The preparation of R)-BinaP] was equipped with a magnetic stir bar and fed in an anhydrous 200 ml sulphur tube under argon atmosphere [RuC12(C6H6)]2 (0.805 g, 1.60 mmol) and (R) _ Binap (1.89 g '3_03 Halo' 0.95 equivalent). Degassed anhydrous dimethylformamide (30 ml, 38 vol) was added and the solution was degassed (3 &gt;&lt; The reaction mixture was heated to 100 ° C for 10 minutes to obtain a dark red solution' and then cooled to ambient temperature. Sodium acetate (5.2 g, 63.4 mmol) was added to a reaction vessel and stirred for 5 minutes in methanol (50 mL, 60 vol.). Deaerated water (50 ml, 60 volumes) and toluene (25 ml '30 volumes) were added, and the reaction mixture was stirred vigorously for 5 minutes. The toluene layer was transferred via syringe to another sir Frank tube (using argon purge) and the aqueous phase was extracted with toluene (2 x 25 mL). The combined toluene solution was washed with water (4 χ 10 mL), and the solvent was concentrated in vacuo at 45 ° C and vacuum dried for 12 hours (0.1 mm Hg). The tan solid was dissolved in toluene (25 mL) without stirring and hexane (75 mL) was slowly added to afford a second layer. The two phase mixture was placed around for 7 hours and then placed at 0-5 ° C for 3 days. The catalyst crystallizes. The solvent was removed under a argon atmosphere by a syringe. The solid was washed with hexane (20 mL) and evaporated in vacuo for 2 hrs to give the catalyst as a tan solid (1.76 g, 70%). Tj ' 4053 , 1992) ° L. Asymmetric hydrogenation asymmetric hydrogenation of precursors A1, A2, A3 follows the same scheme for each precursor system. Therefore, only the asymmetric hydrogenation of A3 is described as follows. Asymmetric hydrogenation of precursor A3. -35- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

装 · 1308912 A7 _______B7____ 3 5 V. Description of the invention (') The aqueous phase was evaporated to give 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 one hour. The solution was slowly cooled to 〇 ° C at a rate of 5-lOt / hour. The crystals were filtered, washed with acetone (1.6 mL, 0.4 vol.) and dried to give a white solid (3.23 g, 81% &gt;&gt; 9 9 · 8 % e. e., 5 4 p p m R h). Purification of (S)-a-ethyl-2-oxy-1-pyrrolidineacetamide (Littiracetam): Levetiracetam obtained by the aforementioned asymmetric hydrogenation (5 g, 9 8 % ee A white crystalline solid (3.94 g, 81%, &gt; 99.8% ee, 52 ppm Rh) was obtained from acetone (30 ml, 6 vol.). This material (3 g) was recrystallized as above to give a white crystalline solid (2.31 g, 77%, &gt;99.80 / 〇e.e., 23 ppm Rh). Melting point 118.4-119.9 ° C. (Please read the notes on the back and fill in this page) i—Installation ^1 .^1 ^1-,· n I . f Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed -37- This paper scale applies to Chinese national standards (CNS) A4 specification (210 X 297 public f ) 1308912 ;98, 2. 0 2

FP11556C Application for the case number category A4|female 4丨羃 patent specification (2Q_2 month amendment} Invention-, new name Chinese 2-oxy-1-pyrrolidine derivative method English PROCESS FOR PREPARING 2-OXO- 1-PYRROLIDINE 1 DERIVATIVES Last name. Famous country invention &creation; 1. John SURTEES 2. VIOLETA MARMON 3. EDMOND DIFFERDING 4 · Wensheng Qi VINCENT ZIMMERMANN 1.UK 2.Bulgaria 3.Luxembourg 4.Belgian accommodation, residence 1. W. Merced Pittsburgh, Belgium B-1170 Klaus Diss, 52. 2. UK 0X14 1XZ Oxfordshire No. 26, Gaither Road, Upington, Belgium 3_ Belgium Otignis-Laofen-La-Norwey B-1348 Buchenkele Road No. 55 4. Switzerland, Lausanne, Convisin CH-1093, Conviny Road, 87

Ubi Fachim SA UCB Farchim SA Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printing Line Switzerland Switzerland Boer CH-1630 CP411 Chimi Di Croix Aix - Bailangxi No. 10 ZI Plachihan Henriette Van Caenegem This paper scale applies to China's national rate (CNS>A4 specification (210 X297 嫠1308912 A7 B7 year f month^!修(^)王换页14 V. Invention description ( DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of a compound of formula (B)

Wherein R1, R2, R3, R4 and X are as defined above, the process is obtained via a catalytic asymmetric hydrogenation reaction as exemplified above and defining a compound of formula (A) as before. Catalytic hydrogenation is described in various publications or books such as "catalytic asymmetric synthesis and auxiliary. Pair of ligands" 3〇91^1丨1^867(1611-Penne(1 994)-Savoirs actuel, interEdition/CNRS Edition -7.1 "Hydrogenation Catalysts", pp. 287-300. Unless otherwise stated, the compounds of formula (B) described herein are intended to include geometric isomers, ie, Z (Salmon) and E (individually or collectively). Isomers, as well as enantiomers, diastereomers and individual mixtures (racemic mixtures). Preferably, the process of the invention relates to the preparation of compounds of formula (B) wherein R2 and R4 Is hydrogen and X is -COOH or -COOMe or -COOEt or -CONH2, and R1 is methyl; in particular wherein R3 is hydrogen, alkyl (special propyl) or haloalkenyl (particularly difluorovinyl). The best results are obtained by the method of dirasacetam wherein R1 is methyl, R2 and R4 are hydrogen, R3 is hydrogen, propyl or difluorovinyl, and X is -conh2. Including the catalytic hydrogenation reaction of the compound of the above formula (A). The preferred compound of the formula (A) is based on rhodium (Rh). Or asymmetric hydrogenation of the ruthenium (Ru) chelating agent. The asymmetric hydrogenation method is described in many publications-16- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read first) Note on the back side of this page) --------tT----------0 Ministry of Economic Affairs Intellectual Property Bureau employee fee cooperative cooperative printing 1308912 = replacement page ^ 15, five, invention Description () Documents or books such as "Asymmetric Synthesis" RA Aitken and SN Kilenyi (l 992) - Blackie Academic and Professional Publications or "Synthesis of Optically Active Amino Acids" Robert Μ· willimas (1 989) - Bocamon Press. The Rh(I) and Ru(II) complexes of the ruthenium ligands are generally diphosphines for the asymmetric hydrogenation of olefins. Many pairs of ruthenium ligands such as Diphosphinates, hydrazines (aminophosphines) and amine phosphine phosphinates or palm catalyst conjugates are described in the literature and are commercially available. The catalysts can also be combined with counterions and/or olefins. Although many information has been accumulated on the catalytic activity and stereoselectivity of the catalyst, for individual groups In general, the choice of ligands, catalysts and reaction conditions is still experimental. Typically, Rh(I)-based systems are mostly used to prepare amino acid derivatives, and Ru(n) catalysts for broad olefinic substrates. Excellent results are obtained. The catalyst chelating agents used in the present invention are DUPHOS, BPPM, BICP 'BINAP, DIPAMP, SKEWPHOS, BPPEA, DIOP, NORPHOS, PROPHOS, PENNPHOS, QUPHOS, BPPMC, BPPFA. Supported or otherwise braked catalysts prepared from the foregoing chelating agents can also be used in the present invention to achieve improved conversion rates or selectivities in addition to improved catalyst recovery and recycling. Preferably used in the method of the invention. The catalyst chelating agent is selected from the group consisting of Dufus or methyl, diethyl, diisopropyl-dufus (1,2-贰2,5-dimethylphosphine). Phosphono) benzene - U.S. Patent No. 5,171,892) 'DIPAMP (phosphine' 1,2-ethanediyl fluorene ((2-methoxyphenyl)phenyl) - US Patent No. 4,008,28 1 and 4 , No. 1, 42,992), BPPM (1-pyrrolidine carboxylic acid-17- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) n — » n ·1 &gt;1 nn 1 . Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Clothing

Replacement I Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1308912 Heart 16 V. Invention Note (), 4-(Diphenylphosphino)-2-((diphenylphosphino)methyl)-1,1- Dimethylethyl ester - Japanese Patent No. 8704523 8) and BIN AP (phosphine, (1,1'-binaphthyl)-2,2'-diylindole (diphenyl-European Patent No. 366 390 No.) The structural formula of these chelating agents is shown below.

(R)-BINAP The solvent preferred for use in the process of the 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 group consisting of halogen anions (halogen (-)), BPh4(-)CI04(-), BF4(-), PF6(-), PC16(-), OAc(-), trifluoromethanesulfonate ( 〇Τ£(-)) 'Methanesulfonate or methane sulfonate. Preferably, the relative ion system for the palm catalyst is transported from OTf(-), BF4(-) or OAc(-). The olefin is selected from the group consisting of ethylene, 1,3-butadiene, benzene, cyclohexadiene, and raw borneol-18-. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -nn ί I nnnnnn 0 I nnnna^i __ , it 1 I n I nl I (Please read the note on the back and fill out this page)

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives ^ Ϊ 308912 V. Invention Description () Diene or cyclooctane-1,5-diene (COD). The compounds of formula (A) can be converted to a high percentage enantiomer using a combination of such a pair of catalysts to a range of relative ions and a catalyst-matrix ratio ranging from 1:20 to 1:20,000 in the range of commercial solvents. An excess of the structure (ee) and a left-handed or right-handed enantiomer of the compound of formula (B) in excellent yield and high purity. In addition, this approach uses standard industry plants and equipment and therefore has a cost advantage. Such asymmetric synthesis methods can also reduce costs by avoiding the problem of recovery or disposal of the undesired enantiomers obtained by conventional synthetic methods. The most preferred method is to prepare (S)-a-ethyl-2-oxy-1-pyrrolidinium or (R)-a-ethyl-2-oxy-1-pyrrolidinium. The result, which comprises a compound of formula A' in the form of a Z isomer or an E isomer, is subjected to an asymmetric hydrogenation reaction using a palm catalyst according to the following reaction scheme.

Reference will now be made in detail to the four compounds of formula (A) wherein Ri is methyl, R2, R3 and R4 are hydrogen, and for compounds which are hereinafter referred to as precursor A1, X is -CO〇H; In the case of the compound labeled as precursor A2, X is _C00Me; for the compound labeled as precursor A2', X is _C00Et; and for the compound labeled as precursor A3, X is _C0NH2. -19- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)~ (Please read the note on the back and fill out this page)

1308912

(#正换页页五,发明说明(2ι) Example 4 Synthesis of precursor A3 can be carried out by reacting linoleic acid with phosphorus pentachloride to obtain enzyme chlorine' and then reacting with gaseous ammonia to obtain a predetermined olefin amidoxime A3. The product was confirmed to be a Z-isomer. The crude olefin amidoxime A3 was isolated from the reaction mixture by distillation in THF-MeOH and filtered to remove inorganic residue. After evaporation of solvent, a yellow solid was obtained. Purification by anhydrous flash chromatography followed by recrystallization from isopropanol to obtain a pure material. This procedure was successfully applied to the manufacture of a single batch of A3 (18 g, 54%, &gt; 99% peak area) and is summarized in the reaction scheme. 12.

Precursor A3

OH

1. PCl5, THF,: 2O; 0M, (n 2 · NH; gas 3. anhydrous rapid, Si〇2-llwt 4. recrystallization · isopropanol ~ precursor A 1 Μ% button yield reaction Figure 12 In the asymmetric hydrogenation of a portion of the precursor, the precursor is prepared in situ by reacting [Rh(CDO)2] + 〇Tr with the individual palm ligands in the preferred solvent, followed by the addition of the matrix. Several catalysts are commercially available, And used without further purification.Example 5 The results of asymmetric hydrogenation of precursors A 1 and A 2 using a variety of money-based catalyst systems are summarized in Table 1 below. The reaction system uses 0.00 5 mol% to 5 mol% catalyst and 100 mg or 200 mg substrate were subjected to ambient temperature (room temperature) for 24 hours. The reaction conditions such as hydrogen pressure, solvent type, and precursor amount were modified to obtain the most ideal conditions. All products were reacted by -23-

1308912 τ- 22 ι, description of the invention () The solvent was removed by evaporation in the mixture and was analyzed by EtOAc-NMR spectrum without further purification. The HPLC (High Performance Liquid Chromatography) method was used for the %e.e. determination of the hydrogenated product of the precursor A1. Therefore, the inventors converted the crude product to a methyl ester using diazomethane in a THF solution. The ester derivative is then used to analyze the hydrogenation of the olefinic amine ester A2 using a HPLC method. For the HPLC method, the inventors used a 4.6 x 25 mm column for the outer diameter of the palm and isopropanol/n-hexane (95:05) as the eluent. For the hydrogenated product of precursor A2, the ee results were obtained by the following HPLC method: Chiralcel outer diameter 4.6 x 250 mm, isopropanol-hexane (5:95 v/v), 2 Θ 5 nm, 1 ML/min at ambient temperature (rt), sample 1 mg/ml, 13 min (S-enantiomer), 16 min (R-enantiomer). Initially, the screening was carried out using a 5 mol% catalyst on a 100 mg scale. The percentage of enantiomeric excess (e.e.) is positive for the percentage of L-S enantiomers and negative for the % R-enantiomer. (Please read the phonetic transcription on the back? Please fill out this page again) 襄--------Book--------- Weng. Ministry of Economic Affairs Intellectual Property Bureau employee cooperation cooperation Du printing system 24-- Ben Paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1308912 A7 B7 Month 7Vi: @读换页 25 V. Invention description () Cou. indicates relative ion; Loa. indicates load mol% ; H2 Pres. means hydrogen pressure; and rt means room temperature. As described above, the rhodium catalyst has been prepared or purchased in situ and used without further purification. Ruthenium catalysts were prepared according to known reference procedures. Most of the experiments were carried out using a catalyst ranging from 0.001 mol% to 5 mol% on a 100 mg to 15 mg scale. The crude product was analyzed by iH, 13 C-NMR spectroscopy, and analyzed by HPLC.

100- 500 mg (Please read the notes on the back and fill out this page) Reaction Figure 1 3 * Manufacture of the opposite enantiomer. Example 7: Hydrogenation results using a Rh-(Et, Et)-Doufs asymmetric hydrogenation precursor A3 A3 using a Rh-Dufs catalyst are shown in Table 3. These reactions were carried out in the same manner as in Examples 5 and 6 using a hydrogen pressure of 4 atm. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumption Cooperative Printing, Generally, the enantioselectivity of the hydrogenation reaction of Rh-Doffers catalyzed α-mercapto-acrylic acid derivatives shows a minimal solvent effect. However, it is still not possible to predict in advance the effect of the selectivity and the effect on the rate of reaction of the specified substrate. It is observed that the hydrogenation reaction of A3 is highly correlated with the solvent. The non-coordinating protic solvent DCM was found to be excellent. Hydrogenation of the protic alcohol solvent results in a slower reaction and a lower selectivity. Similarly, the conversion is observed in a polar aprotic solvent such as ethyl acetate and THF. Both are expected to be coordinated with the metal and can be used in the Chinese National Standard (CNS) A4 specification (210 X 297). Mm) A7 B7

1308912 V. INSTRUCTIONS (31) A3 (10 gram) is recrystallized from isopropanol (1 liter, 9.3 vol) to obtain the final batch for hydrogenation (100 g, 93%) ° melting point 172.0 ° C - 174.2 ° C. Elemental analysis (%m/m): C 56.95 (57.1 3% theoretical 値); Η 7.10 (7.19% theoretical 値); Ν 1 6.38 (1 6.66% theoretical 値). TLC: SiO 2 , toluene / AcOH / MeOH (4: 1 : 0.5), UV and anisaldehyde dyed. G. Preparation of combined ruthenium and ruthenium catalysts - Preparation of [Rh(I)L*COD] + OTr (0.15M solution) [Rh(I)L*COD2] + OTr (35 mg, 0.075 mmol) and The palm ligand (L*, 0.. 83 mmol, 1.1 equivalent) was quickly weighed in air and fed to the flask. The flask was sealed with a rubber diaphragm and purged with argon. A water-free and degassed solvent (5 mL, 143 vol) was added via a septum. The reaction mixture was degassed (3x vacuum / argon) and stirred for 30 minutes or until all solids were dissolved. Preparation of H. Rh(I)(MeOH)2[(R)-Binap] Anhydrous 200 ml of Schlenk in vitro fed with a magnetic stir bar [Rh(I)(nbd)2]C104 ( 251 mg, 0.649 mmol, and (R)-Binap (4〇5 mg, 0.6 5 mmol) and placed under an argon atmosphere. Dichloromethane (no water, degassing, 5 ml '20 vol) was added via syringe and the reaction mixture was degassed (3x vacuum / argon). Tetrahydrofuran (anhydrous, degassing, 10 mL, 4 Torr volume) was added slowly followed by hexane (anhydrous, degassing, 2 mL, 8 〇 volume). The resulting suspension was maintained at 0-51 for 16 hours. The solvent was removed by decantation under argon and methanol (anhydrous, degassing, 5 ml, 20 volumes) was added. -33- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) T. -n -I- nnn ^ ^ · n If nni^ In II - i Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed

Replacement page 1308912 V. INSTRUCTIONS (34) Hydrogenated 1000 ml irlancoin in-feed matrix (500 mg, 3 mmol) equipped with a magnetic stir bar under atmospheric pressure of hydrogen and purged with argon . The degassed solvent was added via a syringe followed by a catalyst solution (〇.5 to 2.5 mol%). The reaction mixture was degassed (3x vacuum/argon) and then purged with hydrogen (5x vacuum/hydrogen) using a hydrogen balloon. The reaction was stirred at ambient temperature for 16-65 hours. The atmosphere of hydrogen argon was exchanged with nitrogen, and the solvent was removed by evaporation in vacuo to give a crude material. The crude product was analyzed by NMR spectral analysis and HPLC analysis. The hydrogenation at 4 atm pressure was carried out in an atmosphere zone (Zhongjia 05:83 §) (Arlich (6 1 (11^11) Chemical Company) under an argon atmosphere. Substrate (500- 1 000 mg) placed in a stainless steel high pressure vessel (Vince Technologies, France), a high pressure vessel fitted Teflon mouth (or glass dish) and a Teflon coated magnetic stir bar. Degassed solvent and catalyst Or a catalyst solution (0.25 to 2.5 mol%) is added thereto. The container is sealed, and is purged with hydrogen by a pressurized container to 4.5-5.5 atm, and then depressurized (5 times). Finally, the pressure is adjusted to a predetermined level. The temperature of the reaction mixture is stirred for 16-65 hours. Upon completion, the hydrogen pressure is exchanged with nitrogen, and the solvent is removed by real hair to obtain a crude product. The crude product is analyzed by NMR spectroscopy and analyzed by PLC. The final material is purified: (S Purification of ct-ethyl-2-oxo-l-pyrrolidineacetamide (left ferracetam) by the aforementioned asymmetric hydrogenation of levetiracetam (5 g, 98% ee) In water (20 ml, 4 volumes) and using ethyl acetate (3 X 〗 0 ml , 3 x 2 volume) extraction, then the organic phase is extracted back with water (10 ml, 2 volumes), and -36-

Claims (1)

1308912 98.. 2. ο 2 VI. Patent Application No. 90107984 "Method for the preparation of 2-oxy-l-pyrrolidine derivatives" (amended in February 2009) VI. Patent application scope 1. Preparation Method of compound of formula (B) Wherein X is -CONR5R6 or -COOR7; R1 is hydrogen, halogen or (^_6 alkyl; R2 and R4 are the same or different, and each is hydrogen, halogen or C,. 6 yards; R3 is hydrogen, halogen , (^.5 alkyl or C2_5 alkenyl, wherein the alkyl and alkenyl groups may be via one or more halogen, cyano, thiocyano, azide, alkylthio, cyclopropyl, decyl, phenyl Substituting; R5, R6 and R7 are the same or different and each are respectively hydrogen or Cl.6 alkyl; which comprises a compound of the formula (A) wherein R1, R2, R3, R4 and X have the same definitions as above The) according to the following process (6) reaction 1308912 Process (6). 2. The method of claim 1, which comprises catalytic hydrogenation. 3. The method of claim 1, wherein the compound of formula (A) is subjected to asymmetric hydrogenation using a palm catalyst. 4_ The method of claim 1, wherein R is methyl, and R 2 and R 4 are Η ' R 3 is hydrogen, alkyl or c 2 5 alkenyl substituted by one or more halogens, and X is - C〇NH2 or -COOMe or -COOEt or -COOH. 5. The method of claim 4, wherein R3 is hydrogen, n-propyl or 2,2-difluorovinyl. 6. The method of claim 1, wherein the compound of formula (A) is a Z isomer or an E isomer. 7. The method of claim 1, wherein the compound of formula (B) is (S)-α-ethyl-2-oxy-1-strong o-acetic acid amine or (R)-a-ethyl- 2-oxy-1-pyrrolidineacetamidine, which comprises the use of a compound of formula A' in the form of a Z isomer or an E isomer, using a palm catalyst, according to the following scheme: non-1308912