Preparation method of brivaracetam and intermediate thereof

Abstract

The invention discloses a method for preparing brivaracetam by converting an intermediate shown in # imgabs0 # into an intermediate shown in # imgabs1 #. Wherein R1 and R2 are independently selected from hydrogen, alkali metal, alkaline earth metal, alkyl or a mixture thereof.

Description

[0001] This application claims priority to U.S. patent application No. 18 / 368,754, filed September 15, 2023, which claims the benefit of U.S. Provisional Application No. 63 / 441,890, filed January 30, 2023, filed under 35 U.S.C. 119(e), each of which is incorporated herein by reference in its entirety. Technical Field

[0002] The present invention relates to a preparation method of brivaracetam and an intermediate thereof. Background Art

[0003] Brivaracetam belongs to the acetamide class of drugs used to treat epilepsy and related central nervous system disorders. The chemical name of Brivaracetam is (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide, and its structure is as follows:

[0004]

[0005] There are various methods for synthesizing brivaracetam. The synthesis of brivaracetam has been extensively reviewed by Gayke et al. in "A Review of Synthetic Pathways to Brivaracetam: An Antiepileptic Drug" (M. Gayke, H. Narode, G. Eppa, RS Bhosale, and JS Yadav, published in ACS Omega, Vol. 7, 2022, pp. 2486-2503), the entire contents of which are incorporated herein by reference.

[0006] Brivaracetam contains two chiral centers, which presents unique challenges for its industrial production. If the (2S) chiral carbon is derived from commercially available L-2-aminobutyramide, the second (4R) chiral carbon must be constructed using enantiomerically pure (4R)-propyl-butyrolactone derivatives, which are not readily available and difficult to prepare. On the other hand, if the (4R) chiral carbon is derived from (4R)-propyl-2-oxopyrrolidine, a (2R)-halobutyric acid derivative must be used to form the second chiral carbon.

[0007] However, (2R)-halobutyric acid derivatives are not only commercially unavailable but also extremely hazardous, potentially posing environmental and occupational safety concerns. Furthermore, even when using two optically pure chiral starting materials to synthesize brivaracetam, obtaining optically pure brivaracetam remains difficult due to the chiral centers in L-2-aminobutyramide or (2R)-halobutyric acid being susceptible to racemization during the reaction.

[0008] It is known that when one of two chiral centers is used to induce the other chiral center, the resulting product inevitably contains impurities. To obtain optically pure brivaracetam, extensive purification, including liquid chromatography, is required. The unwanted optical isomers separated after purification are wasted because there is currently no feasible method for optically resolving and enriching brivaracetam (especially the inactive (4R)-carbon of the 2-oxopyrrolidine moiety) followed by racemization.

[0009] The present invention aims to overcome the shortcomings inherent in existing brivaracetam preparation processes by providing a method for preparing brivaracetam and its intermediates from readily available and easily prepared starting materials. The method is simple and efficient, constructing all required building blocks in a single step through a cascade reaction, significantly reducing the number of steps compared to existing techniques. Furthermore, the process allows for the convenient racemization and recycling of all unwanted optical isomers. Summary of the Invention

[0010] The present invention relates to a method for preparing brivaracetam from the following novel intermediate (II):

[0011]

[0012] Among them, R 1 is hydrogen, an alkyl group, an alkali metal or an alkaline earth metal; wherein the alkali metal is lithium, sodium, potassium or a mixture thereof, and the alkaline earth metal is magnesium, calcium, barium or a mixture thereof; the alkyl group refers to a straight-chain, cyclic or branched alkane group containing 1 to 12 carbon atoms, preferably a C1-C4 alkyl group.

[0013] The present invention is achieved by converting the intermediate represented by formula (II) into the intermediate represented by formula (V):

[0014]

[0015] And optical resolution is performed to obtain the intermediate shown in formula (VI):

[0016]

[0017] Brivaracetam was then prepared. DETAILED DESCRIPTION

[0018] Definition of terms

[0019] The term "alkyl" refers to a straight chain, branched chain, or cyclic alkane (hydrocarbon) group containing 1 to 12 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term "C1-C8 alkyl" refers to a straight chain, branched chain, or cyclic alkane group containing 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, and octyl.

[0020] The compounds of the present invention may form salts, and the salts formed are also within the scope of protection of the present invention. Unless otherwise indicated, the compounds of formula (II) to formula (XII) mentioned herein also include their salt forms. The term "salt" herein refers to acidic and / or basic salts formed from inorganic and / or organic acids or bases.

[0021] The compounds of the present invention can form salts with a variety of organic or inorganic acids. Exemplary acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, alkanoic acid, alkylsulfonic acid, aromatic sulfonic acid, isethionic acid and other similar acids. The compounds of the present invention can also form salts with a variety of organic or inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts (such as lithium salts, sodium salts, potassium salts), alkaline earth metal salts (such as calcium salts and magnesium salts), salts formed with organic bases (such as organic amines), and salts formed with amino acids (such as arginine, lysine, etc.).

[0022] All stereoisomers of the compounds involved in the present invention (e.g., isomers due to asymmetric carbons on different substituents), including enantiomers and diastereomers, are included within the scope of the present invention. A single stereoisomer of the compound of the present invention may be in a form substantially free of other isomers (e.g., a pure or substantially pure optical isomer with a specific activity), or in the form of a mixture, such as a racemate or a mixture with all or part of other stereoisomers. A single optical isomer may be obtained by separation from a racemate by any appropriate method, including but not limited to conventional methods, such as crystallization after forming a salt with an optically active acid or base, or by biocatalytic methods, such as selective hydrolysis by lipase.

[0023] Description of the Invention

[0024] The present invention relates to a process for preparing brivaracetam using N-[(2R)-propyl-3-carboxyl]-2-aminobutyronitrile represented by formula (II) as a starting material:

[0025]

[0026] Among them, R 1 It is hydrogen, an alkyl group, an alkali metal or an alkaline earth metal; wherein the alkali metal includes lithium, sodium, potassium or a mixture thereof, and the alkaline earth metal includes magnesium, calcium, barium or a mixture thereof; the alkyl group refers to a straight chain, branched chain or cyclic alkane group containing 1 to 12 carbon atoms, preferably a C1-C4 alkyl group.

[0027] The first embodiment of the present invention is to prepare brivaracetam represented by formula (I) by the following reaction scheme:

[0028]

[0029] In this preferred embodiment, the intermediate of formula (II) reacts with a base (denoted as MOH) to produce the intermediate of formula (III), wherein M is an alkali metal or alkaline earth metal, or a mixture thereof. The alkali metal may be lithium, sodium, potassium, or a mixture thereof; the alkaline earth metal may be magnesium, calcium, barium, or a mixture thereof.

[0030] Preferably, the intermediate of formula (II) is first hydrated in the presence of a catalyst to obtain the amide of formula (IIIa). Suitable catalysts may be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium oxide, calcium oxide, barium oxide, and mixtures of two or more thereof. The catalyst is preferably the same catalyst used to subsequently hydrolyze formula (IIIa) to produce the carboxylate of formula (III). It is further preferred to use an alkali metal hydroxide, and most preferably sodium hydroxide.

[0031] The reaction temperature for hydration of the nitrile group may be 0° C. to 60° C., preferably 5° C. to 40° C., more preferably 10° C. to 35° C., and most preferably 15° C. to 30° C. Studies have found that when the reaction temperature is higher than 60° C., the yield decreases significantly.

[0032] In this stage of the first embodiment of the invention, the amide group in the intermediate of formula (IIIa) is subsequently hydrolyzed to the carboxylate of formula (III) using an alkali metal hydroxide, alkaline earth metal hydroxide or alkaline earth metal oxide.

[0033] Suitable hydroxides can be selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium oxide, calcium oxide, barium oxide, and mixtures thereof of two or more. The resulting carboxylate is acidified by adding acid to generate the intermediate shown in formula (IV). The acid used can be selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, lower alkanoic acid, alkyl sulfonic acid, aromatic sulfonic acid, and mixtures thereof.

[0034] The intermediate represented by formula (IV) then undergoes a cyclization reaction to generate (2RS)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butyric acid represented by formula (V), which is a key novel intermediate for preparing brivaracetam in the process of the present invention.

[0035] In one method for preparing the key intermediate represented by formula (V), the intermediate represented by formula (IV) is heated and melted while continuously removing water generated during the cyclization process. When no more water is released, the cyclization reaction is complete. The resulting product can be obtained by recrystallization from water or used directly in the next reaction.

[0036] In another method for preparing the key intermediate of formula (V), the intermediate of formula (IV) is suspended in a solvent having a boiling point of at least 100°C and heated under reflux to carry out the cyclization reaction while simultaneously removing the generated water. Suitable solvents include toluene, xylene, trimethylbenzene, isopropylbenzene, 4-isopropyltoluene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, C4-C 10 Alcohols and C2-C5 fatty acids.

[0037] In a further method for preparing the key intermediate of formula (V), the intermediate of formula (IV) is suspended in water and heated to 100°C to 200°C under autogenous pressure to cause cyclization to produce formula (V). The preferred reaction temperature is 110°C to 180°C, more preferably 120°C to 160°C, and most preferably 130°C to 150°C. After the reaction is completed, the product precipitates from the aqueous phase during the cooling process. After obtaining the product of formula (V) by solid-liquid separation, the mother liquor can be directly used to suspend the next batch of intermediates of formula (IV) and carry out cyclization reaction. This cyclic cyclization process can achieve a quantitative yield of the key intermediate of formula (V) without the need for additional reagents.

[0038] The steps for producing the key intermediate of formula (V) are sequentially connected in series without requiring tedious isolation of any intermediate, significantly simplifying the process. This method is particularly advantageous. The multi-step cascade reaction process of the present invention provides a simple and efficient route for preparing brivaracetam.

[0039] The compound of formula (II) can be efficiently prepared by reacting propionaldehyde, a cyanide source and a (3R)-propyl γ-aminobutyric acid derivative represented by formula (VIII), as shown in the following scheme:

[0040]

[0041] Wherein, MCN represents a cyanide source, which may be alkali metal cyanide, alkaline earth metal cyanide, zinc cyanide or hydrocyanic acid; R 1It is hydrogen, an alkyl group, an alkali metal or an alkaline earth metal; the alkali metal includes lithium, sodium, potassium or a mixture thereof; the alkaline earth metal includes magnesium, calcium, barium or a mixture thereof; the alkyl group refers to a straight chain, cyclic or branched alkane group containing 1 to 12 carbon atoms, preferably a C1-C4 alkyl group.

[0042] The (3R)-propyl γ-aminobutyric acid derivative represented by formula (VIII) can be prepared using conventional methods and can be used directly as a pure product or as the product of the previous reaction without further isolation or purification. The optical purity of the derivative is at least 90%, preferably at least 95%, more preferably at least 97%, and most preferably at least 99%.

[0043] The reaction to prepare the intermediate of formula (II) is carried out in aqueous solution, optionally in the presence of an organic solvent. The organic solvent should be water-soluble and may be selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, methoxyethanol, ethoxyethanol, and mixtures thereof. The reaction is preferably carried out in pure aqueous solution.

[0044] The method of preparing the intermediate of formula (II) of the present invention further comprises reacting a Schiff base represented by the following formula:

[0045]

[0046] The method comprises reacting a cyanide source, wherein the Schiff base can be generated in situ, comprising reacting propionaldehyde with an intermediate represented by formula (VIII).

[0047] The method for preparing the compound of formula (II) of the present invention further comprises using propionaldehyde cyanohydrin shown in the following formula to carry out the reaction:

[0048]

[0049] React with the compound represented by formula (VIII). Propionaldehyde cyanohydrin can be prepared by reacting propionaldehyde with a cyanide source (e.g., alkali metal cyanide, alkaline earth metal cyanide, zinc cyanide, or hydrocyanic acid). The cyanohydrin can be generated in situ and used directly, or it can be separated into a pure form for use.

[0050] After being prepared, the compound of formula (II) can be isolated from the reaction mixture or directly used as a crude product in subsequent reactions.

[0051] In a first embodiment of the present invention, a base is used to hydrolyze the cyano group in the compound of formula (II). The base is selected from alkali metal hydroxides, alkali metal carbonates, alkaline earth metal hydroxides, and mixtures thereof. The alkaline solution is then acidified with an acid to produce the compound of formula (IV), and further cyclized to obtain the key compound of formula (V). Suitable acids may be selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, lower alkanoic acids, alkylsulfonic acids, aromatic sulfonic acids, and mixtures thereof.

[0052] The compounds of formula (III) and formula (IV) can be separated and purified, but preferably are not separated, but directly converted into the key intermediate formula (V) in the cascade reaction. In the cascade reaction process, the overall molar yield of the key intermediate of formula (V) is at least 50%, preferably higher than 70%, more preferably higher than 80%, and most preferably higher than 85%.

[0053] In another embodiment of the present invention, the key intermediate of formula (IV) is directly prepared by reacting the compound of formula (II) with an acid to hydrolyze its nitrile group. The acid used can be selected from sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, alkyl sulfonic acid, aromatic sulfonic acid and a mixture of two or more thereof. Preferably, sulfuric acid is used to convert the compound of formula (II) into the intermediate of formula (IV).

[0054] The racemic compound represented by formula (V) is optically resolved by an optically active resolving agent. Suitable resolving agents can be selected from the various compounds listed in David Kozma's CRC Handbook of Optical Resolution via Diastereomeric Salt Formation (2002, CRC Press), the entire contents of which are incorporated herein by reference.

[0055] Among chiral amine resolving agents, dehydroabietylamine was found to form a crystalline salt with the compound of formula (V) and was used to resolve it into the compound of formula (VI). The structure of the salt is as follows:

[0056]

[0057] After optical resolution of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butyric acid represented by formula (VI), (2R)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butyric acid represented by formula (VII) is racemized to (2RS)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butyric acid represented by formula (V), and optical resolution is again performed. The racemization of (2R)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butyric acid in formula (VII) can be accomplished in an alkali metal hydroxide solution.

[0058] This resolution-racemization cycle method can achieve a yield of the (2S)(4R) enantiomer exceeding 50%, and even exceeding 75%, reaching near-quantitative yield. Therefore, the process of the present invention is extremely efficient and does not lose any valuable late-stage materials, which is a significant advantage over existing technologies.

[0059] Optically pure (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butyric acid of formula (VI) can be easily converted into brivaracetam of formula (I) by a carboxylic acid transamidation method well known to those skilled in the art.

[0060] In the second embodiment of the present invention for preparing Brivaracetam, the intermediate of formula (II) is first converted into the intermediate of formula (IV) according to the method of the first embodiment, and then the intermediate of formula (IV) is reacted with R 1 OH (where R 1 C1-C 12 The racemic ester of formula (IX) is then selectively optically hydrolyzed by a hydrolase to obtain the optically active acid of formula (VI), which is then further prepared by the following reaction scheme.

[0061]

[0062] where R 2 C1-C 12 Alkyl group, preferably C1-C4 alkyl group.

[0063] Suitable enzymes are alkaline proteases, such as the commercially available Alcalase enzyme preparation. This enzyme selectively hydrolyzes the ester of formula (IX) to produce the compound of formula (VI). The compound of formula (IV) has an optical purity greater than 90%. The impure product can be purified by recrystallization from a solvent. Preferably, purification is performed by salt formation with dehydroabietylamine. After purification, the purity of the intermediate of formula (IV) can be increased to at least 98%, preferably greater than 99%.

[0064] After enzymatic hydrolysis, the compound represented by formula (X) can be racemized under alkaline conditions. Suitable bases include alkali metal alkoxides, alkali metal hydrides, alkali metal amides, and mixtures thereof, with methanolic sodium hydroxide being particularly preferred. Alternatively, the compound represented by formula (X) can be first hydrolyzed to the compound represented by formula (VII), followed by racemization in an alkali metal hydroxide solution.

[0065] In a third embodiment of the present invention, the compound represented by formula (II) is first converted to a diester represented by formula (VIII), which is then subjected to a cyclization reaction to produce an ester compound represented by formula (VI). The ester is then selectively hydrolyzed by a hydrolase to produce an optically active acid. Ultimately, brivaracetam is prepared from this pure acid.

[0066]

[0067] where R 1 C1-C 12 Alkyl group, preferably C1-C4 alkyl group.

[0068] The diester of formula (XI) is prepared by reacting a compound of formula (II) with an alcohol R 1 OH is generated by reaction in the presence of acid, where R 1 C1-C 12 Alkyl, preferably C1-C4 alkyl. Suitable acid can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, alkyl sulfonic acid and aromatic sulfonic acid, preferably sulfuric acid. The diester generated can be separated and purified, and can also be directly used in the subsequent cyclization reaction to generate the intermediate shown in formula (IX). The cyclization reaction is carried out under the action of a base, and a phase transfer catalyst can be optionally added. The base used can be selected from alkali metal hydroxides, alkali metal carbonates, alkali metal phosphates, alkali metal sulfites, alkaline earth metal hydroxides, alkaline earth metal oxides or mixtures thereof. Suitable phase transfer catalysts can be selected from quaternary ammonium salts or quaternary phosphonium salts. Preferably, benzyltriethylammonium chloride or tetrabutylammonium bromide is used.

[0069] In a fourth embodiment of the present invention, the intermediate represented by formula (II) is cyclized to generate the intermediate represented by formula (XII):

[0070]

[0071] where R 1 C1-C 12 Alkyl group, preferably C1-C4 alkyl group.

[0072] The preparation of the intermediate shown in formula (XII) is carried out under the action of a base, and a phase-transfer catalyst can be optionally added. Applicable alkali can be selected from alkali metal hydroxides, alkali metal carbonates, alkali metal phosphates, alkali metal sulfites, alkaline earth metal hydroxides, alkaline earth metal oxides or their mixtures. Applicable phase-transfer catalysts can be selected from quaternary ammonium salts and quaternary phosphonium salts. Preferably, benzyltriethylammonium chloride or tetrabutylammonium bromide are used.

[0073] The nitrile group in the compound of formula (XII) can be hydrolyzed to a carboxylic acid to yield an intermediate of formula (IV), or to an ester to yield an intermediate of formula (IX). These two intermediates can then be optically resolved according to the methods described in the first and second embodiments of the present invention and further converted to brivaracetam.

[0074] Example

[0075] The following examples are used to illustrate the embodiments of the present invention, but should not be considered as limiting the scope of protection thereof.

[0076] Example 1

[0077] In a 1L reaction flask, 200mL of water, 10g of sodium cyanide, and 29g of (3R)-propyl γ-aminobutyric acid were added, and 12g of propionaldehyde was added dropwise at below 25°C. After stirring at room temperature for 2 hours, the reaction solution produced 2-(RS)-N-(2R-propyl-carboxypropyl)-aminobutyronitrile represented by formula (II). LC-MS +1 The reaction solution was used directly without further purification.

[0078] Example 2

[0079] In a 1L reaction flask, add 50mL of water, 10g of sodium cyanide, and 29g of (3R)-propyl γ-aminobutyric acid. Add 12g of propionaldehyde dropwise below 25°C. After stirring at room temperature for 2 hours, add 25g of 30% sodium hydroxide and raise the temperature to 30°C to produce 2-(RS)-N-(2R-propyl-carboxypropyl)-aminobutyramide represented by formula (IIIa). LC-MS +1 It is 231.

[0080] Example 3

[0081] In a 1L reaction flask, add 200mL of water, 10g of sodium cyanide, and 29g of (3R)-propyl γ-aminobutyric acid. Add 12g of propionaldehyde dropwise below 25°C. After stirring at room temperature for 2 hours, add 24g of 50% sodium hydroxide all at once. Continue stirring for 4 hours, then heat under reflux for 4 hours. After cooling the reaction solution to room temperature, add 50mL of 30% hydrochloric acid to produce the intermediate represented by formula (VI). LC-MS +1 It is 232.

[0082] Example 4

[0083] 23 g of the intermediate of formula (VI) was suspended in 100 mL of water and heated to 130°C in a high-pressure reaction flask for 8 hours. After cooling to room temperature, crystals precipitated and were filtered to obtain 17 g of (2RS)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanoic acid of formula (V). LC-MS +1 It is 214.

[0084] Example 5

[0085] To 30 mL of acetonitrile were added 4.2 g of white recrystallized (2RS)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butyric acid (Formula (V)) and 6.1 g of dehydroabietinamine. The solution was heated to 60°C to obtain a clear solution. After cooling to room temperature, a crystalline salt precipitated. The crystals were filtered and recrystallized twice from 15 mL of ethyl acetate to obtain the product, dehydroabietinamine salt of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butyric acid (Formula (VI)). The optical purity of the compound represented by Formula (VT) was 99%.

[0086] The salt was dissolved in 20 mL of deionized water containing 1 g of sodium hydroxide, extracted twice with toluene to remove dehydroabietylamine, and the aqueous phase was adjusted to pH 2-3 with sulfuric acid. After cooling in an ice bath, crystals were precipitated and filtered to obtain (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butyric acid represented by formula (VI).

[0087] 1 g of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butyric acid represented by formula (VI) was dissolved in 30 mL of anhydrous methanol to which 0.1 g of p-toluenesulfonic acid had been added, and the mixture was heated under reflux for 2 hours to obtain the methyl ester. The reaction solution was concentrated under vacuum to obtain an oily residue, to which 20 mL of 25% aqueous ammonia was added, and the mixture was allowed to stand at room temperature for 16 hours. Excess ammonia and methanol were then removed under vacuum, and the product was extracted by adding 50 mL of dichloromethane. After removing the dichloromethane, 0.7 g of a white solid product, namely (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butyramide represented by formula (I), was obtained. LC-MS +1 It is 213.

[0088] Example 6

[0089] To a flask, 30 mL of methanol, 2 g of (2RS)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanoic acid (Formula (V)), and 0.1 g of p-toluenesulfonic acid monohydrate were added. The mixture was heated under reflux for 2 hours to produce the methyl ester (2RS)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanoic acid (Formula (IX)). The methanol was then removed under vacuum to yield an oily residue. To this mixture, 20 mL of water containing 1.0 g of sodium bicarbonate and 0.6 g of Alcalase enzyme were added, and the mixture was stirred vigorously at room temperature for 8 hours.

[0090] 10 mL of dichloromethane was added to the mixture to remove unreacted methyl ester. The aqueous phase was then adjusted to pH 1 with hydrochloric acid to obtain 0.7 g of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanoic acid of formula (VI) with an optical purity of 91%.

[0091] It should be understood that the above embodiments and descriptions are for illustrative purposes only. It will be apparent to those skilled in the art that various modifications and variations of the present invention may be made. Such modifications are intended to be included within the spirit and scope of this application and to be protected by the appended claims.

Claims

1. A method for preparing brivaracetam represented by formula (I): The following steps are involved: (a) converting the intermediate represented by formula (II) into the intermediate represented by formula (IX); where R 1 and R 2 Each independently represents hydrogen, an alkyl group, an alkali metal or an alkaline earth metal; wherein the alkali metal is lithium, sodium, potassium or a mixture thereof; the alkaline earth metal is magnesium, calcium, barium or a mixture thereof; the alkyl group refers to a straight chain, cyclic or branched alkane group containing 1 to 12 carbon atoms; (b) splitting the intermediate represented by formula (IX) to obtain the intermediate represented by formula (X); as well as (c) converting the intermediate represented by formula (X) into brivaracetam represented by formula (I).

2. The method according to claim 1, wherein the preparation of the intermediate represented by formula (II) comprises: reacting propionaldehyde, a cyanide source and a primary amine having the following structure in an aqueous solution in the presence of an optionally added solvent: where R 1 is selected from hydrogen, alkali metal, alkaline earth metal, alkyl and mixtures thereof; the cyanide source is alkali metal cyanide, alkaline earth metal cyanide, zinc cyanide or hydrocyanic acid; the alkali metal is lithium, sodium, potassium or mixtures thereof; the alkaline earth metal is magnesium, calcium, barium or mixtures thereof; the alkyl is C1-C 12 ; The solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, methoxyethanol, ethoxyethanol and mixtures thereof.

3. The method according to claim 1, wherein the intermediate represented by formula (II) is prepared by reacting a Schiff base represented by the following formula with a cyanide source in an aqueous solution by optionally adding a solvent: wherein the cyanide source is alkali metal cyanide, alkaline earth metal cyanide, zinc cyanide or hydrocyanic acid; and R 1 is selected from hydrogen, alkali metal, alkaline earth metal, alkyl and mixtures thereof; the cyanide source is alkali metal cyanide, alkaline earth metal cyanide, zinc cyanide or hydrocyanic acid; the alkali metal is lithium, sodium, potassium or mixtures thereof; the alkaline earth metal is magnesium, calcium, barium or mixtures thereof; the alkyl is C1-C 12 ; The solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, methoxyethanol, ethoxyethanol and mixtures thereof.

4. The method according to claim 1, wherein the intermediate represented by formula (II) is prepared by reacting propionaldehyde cyanohydrin represented by the following formula with a primary amine represented by the following formula by selectively adding a solvent to an aqueous solution: where R 1 is selected from hydrogen, alkali metal, alkaline earth metal, alkyl and mixtures thereof; the cyanide source is alkali metal cyanide, alkaline earth metal cyanide, zinc cyanide or hydrocyanic acid; the alkali metal is lithium, sodium, potassium or mixtures thereof; the alkaline earth metal is magnesium, calcium, barium or mixtures thereof; the alkyl is C1-C 12 ; The solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, methoxyethanol, ethoxyethanol and mixtures thereof.

5. The method according to claim 1, wherein the process of converting the intermediate represented by formula (II) into the intermediate represented by formula (IX) further comprises the following steps: (1) hydrolyzing the intermediate represented by formula (II) to form the intermediate represented by formula (III); wherein M is an alkali metal or an alkaline earth metal or a mixture thereof; the alkali metal is lithium, sodium, potassium or a mixture thereof; the alkaline earth metal is magnesium, calcium, barium or a mixture thereof, (2) reacting the intermediate represented by formula (III) with an acid to generate the intermediate represented by formula (IV): as well as (3) converting the intermediate represented by formula (IV) into the intermediate represented by formula (IX).

6. The method according to claim 1, wherein the compound represented by formula (IX) is resolved using dehydroabietylamine.

7. The method according to claim 1, wherein alkaline protease is used to resolve the compound represented by formula (IX).

8. A compound having the following molecular formula:

9. A salt having the following molecular formula:

10. A compound having the following molecular formula: where R 1 is hydrogen, an alkyl group, an alkali metal or an alkaline earth metal; the alkali metal is lithium, sodium, potassium or a mixture thereof; the alkaline earth metal is magnesium, calcium, barium or a mixture thereof.

11. A compound having the following molecular formula: Wherein M is an alkali metal or an alkaline earth metal; the alkali metal is lithium, sodium, potassium or a mixture thereof; the alkaline earth metal is magnesium, calcium, barium or a mixture thereof.

12. A compound having the following molecular formula: Wherein M is an alkali metal or an alkaline earth metal; the alkali metal is lithium, sodium, potassium or a mixture thereof; the alkaline earth metal is magnesium, calcium, barium or a mixture thereof.

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