Methods for preparing levetiracetam and its intermediates

Abstract

Disclosed is a method for preparing levetiracetam and intermediates from a compound of formula (I), wherein CR is selected from cyano, carboxylic acid, carboxamide, alkali metal carboxylate, alkaline earth metal carboxylate, alkyl carboxylate and mixtures thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a continuation application filed under 35 U.S.C. §120 and claims priority to U.S. application No. 17 / 166,662, filed on February 3, 2021, the contents of which are incorporated herein by reference. Field of the Invention

[0003] The present invention relates to N-(3-substituted propyl)-2-aminobutyronitrile, a preparation method thereof and use thereof in preparing levetiracetam and an intermediate thereof. Background Art

[0004] Levetiracetam is the S-enantiomer of levetiracetam in a class of anticonvulsant drugs. It is used in combination with other drugs to treat certain types of seizures in adults and children with epilepsy. Levetiracetam has the following structure:

[0005]

[0006] Although many methods for preparing levetiracetam have been developed, it is commercially produced by one of two methods first disclosed in GB 1309692 and U.S. Patent No. 4,696,943. In the first method, 2-pyrrolidone and 2-halobutyric acid alkyl ester are used as raw materials in a process according to the following reaction scheme:

[0007]

[0008] Where X is a halogen, HM is a metal hydride, R 1 It is an alkyl group.

[0009] In the second method, L-2-aminobutanamide hydrochloride and alkyl 4-halobutyrate or 4-halobutyryl halide are used as starting materials in a process according to the following reaction scheme:

[0010]

[0011] Where X is a halogen, R 1 is an alkyl group, and the base is an organic base or an inorganic base, such as triethylamine or sodium carbonate.

[0012] Both methods of producing levetiracetam have inherent disadvantages. In the process according to the first method, the metal hydride required to deprotonate 2-pyrrolidone is dangerous to handle on a large scale and presents serious safety issues for the manufacturing plant. In addition, alkyl 2-halobutyrates are not only not commercially available, but are also extremely harmful and pose environmental and occupational problems.

[0013] In the method according to the second method, just like the 2-halobutyric acid alkyl ester in the method of the first method, 4-halobutyric acid alkyl ester and 4-halobutyryl halide are also extremely harmful and cause the same environmental and occupational problems. In addition, L-2-aminobutanamide hydrochloride is produced specifically for levetiracetam and is therefore expensive. L-2-aminobutanamide hydrochloride is produced by racemic 2-aminobutanamide through optical resolution, or by L-2-aminobutyric acid, which is not a naturally occurring L-amino acid, but is produced specifically for this purpose. Although a lot of efforts have been made to improve the methods for producing L-2-aminobutanamide hydrochloride and L-2-aminobutyric acid, they are still expensive. In addition, in the cyclization process under strong alkaline conditions, the product of levetiracetam is partially racemized or hydrolyzed. In order to obtain pharmaceutical grade products, a lot of purification is required.

[0014] The object of the present invention is to overcome these inherent disadvantages in the preparation process of levetiracetam and disclose a method for preparing levetiracetam and its intermediates from readily available raw materials. The method according to the present invention is concise, builds all necessary structural elements in a one-pot synthesis, and obtains levetiracetam from commercially and economically available raw materials in far fewer steps than the prior art methods. Summary of the invention

[0015] The present invention discloses a novel intermediate having the following structural formula (II):

[0016]

[0017] wherein CR is cyano, carboxylic acid, carboxamide, alkali metal carboxylate, alkaline earth metal carboxylate, alkyl carboxylate and mixtures thereof; wherein alkali metal is lithium, sodium, potassium or mixtures thereof; wherein alkaline earth metal is magnesium, calcium, barium or mixtures thereof; and wherein alkyl refers to a C straight chain, cyclic or branched paraffin group containing 1 to 12 carbon atoms 1 -C 12 Preferably, the alkyl group is C 1 -C 4 These intermediates can be used to prepare levetiracetam.

[0018] The present invention also relates to a method for preparing an intermediate of formula (II), comprising propionaldehyde, a cyanide source and a compound of formula H 2 NCH 2 CH 2 CH 2The reaction of a primary amine of CR, wherein CR is cyano, carboxylic acid, carboxamide, alkali metal carboxylate, alkaline earth metal carboxylate, alkyl carboxylate and mixtures thereof; wherein the cyanide source is alkali metal cyanide, alkaline earth metal cyanide, zinc cyanide or hydrogen cyanide; the alkali metal is lithium, sodium, potassium or mixtures thereof; the alkaline earth metal is magnesium, calcium, barium or mixtures thereof.

[0019] The present invention further relates to various methods for preparing levetiracetam and its intermediates from the novel intermediate of formula (II), wherein the method converts the novel intermediate of formula (II) into a key precursor of levetiracetam having the following structural formula:

[0020]

[0021] Where R is hydrogen or C 1 -C 12 alkyl. DETAILED DESCRIPTION

[0022] definition

[0023] The term "alkyl" refers to a straight chain, branched chain or cyclic paraffin (hydrocarbon) group containing 1 to 12 carbon atoms. Exemplary "alkyl" includes 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, etc. The term "C 1 -C 12 "Alkyl" refers to a straight chain, cyclic or branched paraffin group containing 1 to 12 carbon atoms, for example methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, isobutyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl and octyl.

[0024] The compounds of the present invention may form salts, which are also within the scope of the present invention. Unless otherwise indicated, the compounds of formula (II) to (X) mentioned herein should be understood to include their salts. The term "salt" as used herein refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases.

[0025] The compounds of the present invention can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, alkanoic acid, alkyl sulfonic acid, aromatic sulfonic acid, isethionic acid, and the like.

[0026] The compounds of the present invention can also form salts with various organic and 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 with organic bases (such as organic amines) and salts with amino acids (such as arginine, lysine, etc.).

[0027] All stereoisomers of the compounds of the invention (e.g., those that may exist due to asymmetric carbons on various substituents), including enantiomeric and diastereomeric forms, are within the scope of the invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers having a particular activity), or may, for example, be present as a racemate or mixed with all other or other selected stereoisomers. Individual optical isomers may be obtained from the racemate by any suitable method, including, but not limited to, conventional methods, such as salt formation with an optically active acid or base followed by crystallization, or biocatalytic methods, such as selective hydrolysis with a lipase.

[0028] Description of the invention

[0029] The present invention relates to N-(3-substituted propyl)-2-aminobutyronitrile having a structure shown in formula (II), a preparation method thereof and use thereof in the preparation of levetiracetam.

[0030]

[0031] wherein CR is a substituent selected from the group consisting of cyano, carboxylic acid, carboxamide, alkali metal carboxylates, alkaline earth metal carboxylates, alkyl carboxylates, and mixtures thereof.

[0032] In the process of making propionaldehyde, a cyanide source and a 2 NCH 2 CH 2 CH 2 The compound of formula (II) is prepared economically and efficiently by the method of reacting the primary amine of CR, which reaction is described in the following scheme:

[0033]

[0034] wherein CR is cyano, carboxylic acid, carboxamide, alkali metal carboxylate, alkaline earth metal carboxylate, alkyl carboxylate and mixtures thereof, and wherein MCN represents a cyanide source such as alkali metal cyanide, alkaline earth metal cyanide, zinc cyanide or hydrogen cyanide.

[0035] Particularly useful primary amines are gamma-aminobutyric acid or its derivatives. Commercially and economically available neutral gamma-aminobutyric acid may be preferably used. Addition salts of gamma-aminobutyric acid with various acids may also be used. Alkyl esters of gamma-aminobutyric acid are also suitable for the reaction. In addition, basic salts of gamma-aminobutyric acid may be used in the reaction. Preferably, alkali metal or alkaline earth metal gamma-aminobutyrates are prepared in situ by hydrolyzing 2-pyrrolidone with an alkali metal hydroxide, or an alkaline earth metal oxide, or an alkaline earth metal hydroxide, or a mixture thereof. The alkaline reagent used to hydrolyze 2-pyrrolidone is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium oxide, magnesium hydroxide, calcium oxide, calcium hydroxide, barium oxide, barium hydroxide, and a mixture of two or more thereof.

[0036] The reaction for preparing the compound of formula (II) is carried out in aqueous solution, optionally in the presence of an organic solvent. Suitable solvents are water-soluble and are selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, methoxyethanol, ethoxyethanol and mixtures thereof.

[0037] The method for preparing the compound of formula (II) according to the present invention further comprises reacting a Schiff base of the formula:

[0038]

[0039] The Schiff base can be prepared in situ, comprising reacting propionaldehyde with a 2 NCH 2 CH 2 CH 2 The primary amine reaction of CR, wherein CR is cyano, carboxylic acid, carboxamide, alkali metal carboxylate, alkaline earth metal carboxylate, alkyl carboxylate and mixtures thereof.

[0040] The method for preparing the compound of formula (II) according to the present invention further comprises reacting a cyanohydrin of the following formula with a propionaldehyde of the following formula: 2 NCH 2 CH 2 CH 2 Primary amine reaction of CR:

[0041]

[0042] Wherein CR is cyano, carboxylic acid, carboxamide, alkali metal carboxylate, alkaline earth metal carboxylate, alkyl carboxylate and mixtures thereof. The cyanohydrin of propionaldehyde can be prepared by reacting propionaldehyde with a cyanide source (such as alkali metal cyanide, alkaline earth metal cyanide, zinc cyanide or hydrogen cyanide). The cyanohydrin can be prepared in situ and used as it is, or used after separation as a pure product.

[0043] After preparation, the compound of formula (II) can be isolated from the reaction mixture. On the other hand, according to the various methods disclosed herein, it can also be used as is to prepare levetiracetam. The method for preparing levetiracetam is described in the following reaction scheme. Solvents, temperature, pressure and other reaction conditions can be easily selected by those of ordinary skill in the art. The raw materials are commercially available or easily prepared by those of ordinary skill in the art.

[0044] In a first embodiment of the invention for the preparation of levetiracetam, the compound of formula (II) is converted to (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) in a process comprising steps according to the following reaction scheme:

[0045]

[0046] 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.

[0047] In this aspect of the first embodiment of the present invention, first by using a base the cyano group in the compound of formula (II) is hydrolyzed into a carboxylate. Suitable alkali is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium oxide, calcium oxide, barium oxide and two or more mixtures thereof. By adding acid, the resulting carboxylate is acidified to form the 2-N-(3-carboxypropyl)-aminobutyric acid of formula (III). Suitable acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, lower alkanoic acid, alkyl sulfonic acid, aromatic sulfonic acid and mixtures thereof.

[0048] By adjusting the pH to a range of 3 to 5, the compound of formula (III) can be easily isolated from the solution, and at this time, the compound is precipitated from the solution. The compound of formula (III) can be easily isolated by the method of solid-liquid separation technology, such as filtering or centrifugation. On the other hand, the compound of formula (III) can be used in the solution for further reaction without separation.

[0049] It has now been discovered that under various reaction conditions, the intermediate of formula (III) can be cyclized to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV), which is a key intermediate and well-known precursor of levetiracetam.

[0050] In a method for preparing the key intermediate of formula (IV), the intermediate of formula (III) is heated to melting while removing the water formed during the cyclization process. After no more water is released, the cyclization reaction is complete. The product can be recrystallized from water or used in the next step of the method.

[0051] In another method for preparing the key intermediate of formula (IV), the intermediate of formula (III) is suspended in a solvent having a boiling point of at least 100°C and heated to reflux to carry out the cyclization reaction while removing the water formed. Suitable solvents are selected from toluene, xylene, trimethylbenzene, cumene, cymene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, C 4 -C 10 Alcohol and C 2 -C 8 Alkanoic acid.

[0052] In another method for preparing the key intermediate of formula (IV), the intermediate of formula (III) is suspended in water and heated to 90°C to 260°C under autogenous pressure or pressure to carry out the cyclization reaction from (III) to (IV). Preferably, the 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, the product precipitates from the aqueous solution upon cooling. After separating the product of formula (IV) by solid-liquid separation, the mother liquor can be used to suspend a new batch of intermediate (III) and carry out the cyclization reaction. This cyclization method of intermediate (III) cyclization produces the key intermediate (IV) in quantitative yield without using any additional reagents.

[0053] It is particularly advantageous that all reaction steps leading to the key intermediate of formula (IV) are carried out in a one-pot synthesis without lengthy isolation of any intermediate. The one-pot approach of multiple reactions according to the present invention results in a concise method for preparing levetiracetam from basic starting materials such as 2-pyrrolidone, a cyanide source and propionaldehyde.

[0054] In this embodiment of the invention, 2-pyrrolidone is hydrolyzed to alkali metal or alkaline earth metal γ-aminobutyrate by using a base. Suitable bases are selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium oxide, calcium oxide, barium oxide and a mixture of two or more thereof. A cyanide source, i.e., alkali metal cyanide, is added to a solution of alkali metal or alkaline earth metal γ-aminobutyrate, followed by propionaldehyde. Preferably, after 2-pyrrolidone is hydrolyzed to alkali metal or alkaline earth metal γ-aminobutyrate, before adding alkali metal cyanide and propionaldehyde, a strong alkaline solution is neutralized with an acid. After the formation of the intermediate of formula (II) is completed, a base is added to the solution to hydrolyze the cyano group. Suitable bases are selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium oxide, calcium oxide, barium oxide and a mixture of two or more thereof. The strong alkaline solution is then acidified with an acid and heated to obtain a key intermediate of formula (IV). Suitable acids are selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, lower alkanoic acid, alkyl sulfonic acid, aromatic sulfonic acid and mixtures thereof.

[0055] For the hydrolysis of the cyano group in 2-pyrrolidone and the compound of formula (II), different bases may be used, but preferably the same base is used. Preferably an alkali metal hydroxide is used. Most preferably sodium hydroxide is used. For the acidification of the solution consisting of the alkali metal or alkaline earth metal salt of γ-aminobutyric acid and the compound of formula (III), different acids may be used. Preferably the same acid is used. Most preferably, sulfuric acid is used.

[0056] The temperature at which the compound of formula (III) forms the compound of formula (IV) is 90° C. to 260° C., preferably the reflux temperature of the solution composed of the compound of formula (III) to 160° C., more preferably 120° C. to 150° C., most preferably 130° C. to 140° C. The reaction pressure is autogenous pressure to pressurized pressure.

[0057] The reaction can be carried out discontinuously, semi-continuously or continuously. In the one-pot process, the total molar yield of the key intermediate of formula (IV) is at least 50%, particularly greater than 70%, more particularly greater than 80%, most particularly greater than 85%.

[0058] Then, the racemic compound of formula (IV) is subjected to optical resolution by using an optically active resolution agent. Suitable resolution agents can be selected from those listed in David Kozma, CRC Handbook of Optical Resolution via Diastereomeric Salt Formation, 2002, CRC Press, which are incorporated herein in their entirety. After the S-enantiomer is optically resolved, the R-enantiomer is racemized into a racemic form and optically resolved again. This cyclic resolution and racemization produce the S-enantiomer of formula (V) in a yield exceeding 50%, particularly exceeding 75% to almost quantitatively 100%.

[0059] The optically pure S-enantiomer of formula (V) can be easily converted into levetiracetam of formula (I) by one of the amidation methods known in the art.

[0060] In another aspect of the first embodiment of the present invention, in a process comprising steps according to Reaction Scheme 2, the key intermediate of formula (IV) is directly prepared by reacting the compound of formula (II) with an acid to hydrolyze the nitrile group and form the key intermediate of formula (IV) in situ.

[0061]

[0062] Wherein CR is cyano, carboxylic acid, carboxamide, alkali metal carboxylate, alkaline earth metal carboxylate, alkyl carboxylate and mixtures thereof.

[0063] Suitable acids are selected from sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, alkylsulfonic acids, aromatic sulfonic acids and mixtures of two or more thereof. Preferably, sulfuric acid is used to convert the compound of formula (II) into the intermediate of formula (IV).

[0064] In this embodiment of the invention, 2-pyrrolidone is hydrolyzed to alkali metal gamma-aminobutyrate or alkaline earth metal gamma-aminobutyrate with a base. Suitable bases are selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, magnesium oxide, calcium oxide, barium oxide and a mixture of two or more thereof. Preferably, after the hydrolysis of 2-pyrrolidone, the strongly alkaline solution is neutralized with an acid, and then alkali metal cyanide or alkaline earth metal cyanide and propionaldehyde are added. A cyanide source, i.e. alkali metal cyanide, is added to the solution containing alkali metal gamma-aminobutyrate or alkaline earth metal gamma-aminobutyrate, and then propionaldehyde is added. After the formation of the intermediate of formula (II) is completed, acid is then added to the solution to hydrolyze the nitrile group and cyclize the aminobutyric acid group to obtain the key intermediate of formula (IV). Suitable acids are 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. The temperature at which the compound of formula (III) forms the compound of formula (IV) is 90°C to 260°C, preferably the reflux temperature of the solution composed of the compound of formula (III) is to 160°C, more preferably 120°C to 150°C, and most preferably 130°C to 140°C. The reaction pressure is from autogenous pressure to pressurized pressure. The reaction can be carried out discontinuously, semi-continuously or continuously. In the one-pot process, the total yield of the key intermediate of formula (IV) is at least 50%, particularly greater than 70%, more particularly greater than 80%, and most particularly greater than 85%.

[0065] The one-pot method for preparing the intermediate of formula (IV) according to the present invention results in a concise method for preparing levetiracetam from a basic starting material (such as 2-pyrrolidone), a cyanide source and propionaldehyde.

[0066] In the second embodiment of the preparation of levetiracetam according to the present invention, the compound of formula (II) is converted into the key intermediate of formula (IV) according to the method described in the first embodiment of the present invention, and then the compound of formula (IV) is reacted with formula R 1 OH is converted into an ester of formula (VI), wherein R 1 C 1 -C 12 Alkyl, preferably C 1 -C 4 This racemic ester of formula (VI) is subjected to optical resolution by selective hydrolysis of the ester into an optically active ester (VII) and an optically active acid using a lipase, which is used to prepare levetiracetam in a process comprising steps according to the following reaction scheme:

[0067]

[0068] wherein CR is cyano, carboxylic acid, carboxamide, alkali metal carboxylate, alkaline earth metal carboxylate, alkyl carboxylate and mixtures thereof; R 1 C 1 -C 12 Alkyl, preferably C 1 -C 4 alkyl.

[0069] The S-enantiomer of the ester is subjected to an amidation reaction by methods known in the art to form levetiracetam of formula (I), while the R-enantiomer of the acid is subjected to a racemization reaction to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV), which can be reacted with an alcohol R 1 The OH reacts to form a starting ester of formula (VI) which is used for cleavage by lipase.

[0070] In a third embodiment of the invention, the compound of formula (II) is first converted into a diester of formula (VIII), which is then cyclized to an ester of formula (VI). The ester is then selectively hydrolyzed by lipase to an optically active ester and an acid. Levetiracetam is prepared from the S-enantiomer of the ester.

[0071]

[0072] wherein CR is cyano, carboxylic acid, carboxamide, alkali metal carboxylate, alkaline earth metal carboxylate, alkyl carboxylate and mixtures thereof; R 1 C 1 -C 12 Alkyl, preferably C 1 -C 4 alkyl.

[0073] By reacting a compound of formula (II) with an alcohol R 1 OH reacts in the presence of an acid to form a diester of formula (VIII); wherein R 1 C 1 -C 12 Alkyl, preferably C 1 -C 4Alkyl. Suitable acids are selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, alkylsulfonic acids and arylsulfonic acids. Sulfuric acid is preferably used. The diester formed can be separated or used directly for cyclization to form a compound of formula (VI). The cyclization reaction is carried out with a base and optionally in the presence of a phase transfer catalyst. Suitable bases are selected from organic bases, 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 are selected from quaternary ammonium salts and quaternary phosphonium salts. Benzyltriethylammonium chloride or tetrabutylammonium bromide is preferably used. Organic bases are also useful, particularly suitable for cyclization. Suitable organic bases are pyridine and tertiary amines. Suitable organic bases are selected from trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, pyridine, picoline, 2-methyl-5-ethylpyridine, lutidine, collidine, DABCO and mixtures thereof.

[0074] The S-enantiomer of the ester of formula (VII) is subjected to amidation reaction by methods known in the art to form levetiracetam of formula (I), while the R-enantiomer of the acid is subjected to racemization reaction to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV), which can be reacted with the alcohol R 1 The OH reacts to form a starting ester of formula (VI) which is used for cleavage by lipase.

[0075] In a fourth embodiment of the present invention, the compound of formula (II) is cyclized to an intermediate of formula (IX), wherein CR is an alkyl carboxylate, i.e., COOR 1 :

[0076]

[0077] Where R 1 C 1 -C 12 Preferably, R 1 C 1 -C 4 alkyl.

[0078] The formation of the compound of formula (IX) is carried out with a base and optionally in the presence of a phase transfer catalyst. Suitable bases are selected from organic bases, 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 are selected from quaternary ammonium salts and quaternary phosphonium salts. Preferably benzyltriethylammonium chloride or tetrabutylammonium bromide is used. Organic bases are also useful, particularly suitable for cyclization. Suitable organic bases are pyridine and tertiary amines. Suitable organic bases are selected from trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, pyridine, picoline, 2-methyl-5-ethylpyridine, lutidine, collidine, DABCO and mixtures thereof.

[0079] The nitrile group in compound (IX) can be hydrolyzed with an acid to form a carboxylic acid to obtain an intermediate of formula (IV), or reacted with an alcohol R in the presence of an acid. 1 OH reacts to form an ester to give a compound of formula (VI) wherein R 1 C 1 -C 12 Alkyl, preferably, R 1 C 1 -C 4 The suitable acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, alkyl sulfonic acid, aryl sulfonic acid and mixtures thereof. Then, according to the method described in the first and second embodiments of the present invention, the two intermediates are optically resolved and converted into levetiracetam.

[0080] Example

[0081] The following examples will illustrate the practice of the present invention but are not intended to limit the scope of the invention.

[0082] Example 1

[0083] To a 1 L flask containing a solution of 300 mL of water, 50 g of sodium cyanide and 105 g of γ-aminobutyric acid was added 58.0 g of propionaldehyde while maintaining the temperature below 25° C. After stirring at room temperature for 2 h, the solution was found to contain 2-N-(sodium carboxypropyl)-aminobutyronitrile of formula (II) in a molar yield of about 95%. LC-MS+1: 171. The solution was used without further purification.

[0084] Example 2

[0085] 58.0 g of propanal was added dropwise to a 1 L flask containing a solution of 300 mL of water, 50 g of sodium cyanide and 105 g of γ-aminobutyric acid, while maintaining the temperature below 25°C. After stirring the solution at room temperature for 2 h, 60 g of sodium hydroxide was added and the solution was heated to reflux for 2 h. Then, sulfuric acid was added until the pH value was 3-4. After cooling to room temperature, the precipitated solid material was filtered and washed with ice water to obtain 125 g of 2-N-(carboxypropyl)aminobutyric acid of formula (III). MS+1: 190.

[0086] Example 3

[0087] In a glass pressure bottle, 40.0 g of 2-N-(carboxypropyl)aminobutyric acid was suspended in 200 mL of water containing 5 g of sulfuric acid. The suspension was heated to 150° C. to obtain a clear solution and maintained at this temperature for 4 h. After cooling to room temperature, a crystalline solid was formed and filtered to give 31 g of (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) as a white substance. Melting point: 154-156. MS+1: 172.

[0088] Example 4

[0089] To a 1L flask containing a solution of 300mL water, 50g sodium cyanide and 105g γ-aminobutyric acid was added dropwise 58.0g propionaldehyde while keeping the temperature below 25°C. The solution was stirred at room temperature for 2h, and then 150g sulfuric acid was added to the solution. The solution was placed in a pressure glass bottle and stirred in a bath at 140-145°C for 1h. After stopping stirring, oil phase separation was observed. Further cooling to room temperature formed a beige crystalline solid. Recrystallization from water with a small amount of decolorizing charcoal gave (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) as a white crystalline solid. Melting point: 154-156. MS+1: 172.

[0090] Example 5

[0091] 58.0 g of propanal was added dropwise to a 1 L flask containing a solution of 300 mL of water, 50 g of sodium cyanide and 105 g of γ-aminobutyric acid, while keeping the temperature below 25 ° C. After stirring the solution at room temperature for 2 h, 60 g of sodium hydroxide was added and the solution was heated to reflux for 2 h. Then, sulfuric acid was added to a pH of 2.0. 140 g of sulfuric acid was used. The solution was then heated to 150 ° C in an autoclave under autogenous pressure for 4 h. After cooling to room temperature, the precipitated solid material was filtered and washed with water. The off-white material was dissolved in hot water and decolorized with a small amount of activated carbon to obtain (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) as a white crystalline solid. Melting point: 154-156 ° C. MS+1: 172.

[0092] Example 6

[0093] 90 g of 2-pyrrolidone was added to a solution containing 60 g of sodium hydroxide and 250 mL of water. After the solution was refluxed for 2 h, 50 g of sodium cyanide was added, followed by dropwise addition of 58 g of propionaldehyde while maintaining the temperature below 25 ° C. 40 g of sodium hydroxide was then added to the solution, and the solution was refluxed for 2 h. Then, sulfuric acid was added until the pH value was 2.0. 160 g of sulfuric acid was used. The solution was then heated to 150 ° C under autogenous pressure in an autoclave for 4 h. After cooling to room temperature, the precipitated solid material was filtered and washed with water. The off-white material was dissolved in hot water and decolorized with a small amount of activated carbon to obtain (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) as a white crystalline solid. Melting point: 154-156 ° C. MS+1: 172.

[0094] Example 7

[0095] 170 g of white recrystallized (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) and 121 g of R-(+)-α-phenylethylamine were added to 500 mL of toluene. The solution was briefly heated to 90° C. After cooling to room temperature, a crystalline salt was formed, which was filtered. The salt was purified by dissolving in 350 mL of toluene by heating. The solution was cooled and filtered to obtain the R-(+)-α-phenylethylamine salt of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V).

[0096] The salt is dissociated in 300 mL of deionized water containing 12 g of sodium hydroxide. After extracting twice with toluene to remove R-(+)-α-phenylethylamine, the aqueous solution is acidified to pH 2-3 with sulfuric acid. The mixture is cooled on ice and the crystals are filtered out to obtain (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V). Melting point: 124-126°C.

[0097] 40 g of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V) was dissolved in 200 mL of anhydrous methanol containing 0.1 g of p-toluenesulfonic acid. After the solution was refluxed for 2 h to form the methyl ester, the solution was cooled on ice and ammonia was introduced into the solution. The solution was kept at room temperature for 16 h. After removing excess ammonia and methanol under vacuum, the residual solid was recrystallized in ethyl acetate to obtain 32 g of (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide of formula (I). Melting point: 117-118°C.

[0098] It should be understood that the foregoing embodiments, explanations and drawings are for illustrative purposes only, and in view of this disclosure, various modifications of the present invention are self-evident to those skilled in the art. These modifications fall within the concept and scope of the present application and the scope of the appended claims.

Claims

1. A method for preparing (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV): include: (a) hydrolyzing the compound of formula (II) using an alkali metal hydroxide or an alkaline earth metal hydroxide, The following product is obtained: wherein CR is selected from carboxylic acids, alkali metal carboxylates, alkaline earth metal carboxylates and mixtures thereof; wherein M is an alkali metal or an alkaline earth metal; wherein the alkali metal is lithium, sodium, potassium or a mixture thereof; wherein the alkaline earth metal is magnesium, calcium, barium or a mixture thereof; (b) reacting the product of step (a) with an acid; and (c) cyclizing the product of step (b) to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV); The acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, lower alkanoic acid, alkyl sulfonic acid, aromatic sulfonic acid and mixtures thereof; The cyclization reaction of the compound of formula (III) with an acid to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) is carried out by heating.

2. The process according to claim 1, wherein the compound of formula (II) is prepared by mixing propionaldehyde, a cyanide source and a primary amine of formula H2NCH2CH2CH2CR in an aqueous solution or an aqueous solvent, wherein CR is selected from carboxylic acids, alkali metal carboxylates, alkaline earth metal carboxylates and mixtures thereof; wherein the alkali metal is lithium, sodium, potassium or mixtures thereof; wherein the alkaline earth metal is magnesium, calcium, barium or mixtures thereof; The solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, methoxyethanol, ethoxyethanol and mixtures thereof; and the cyanide source is selected from alkali metal cyanide, alkaline earth metal cyanide, zinc cyanide and hydrogen cyanide.

3. A method for preparing (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV), comprising reacting a compound of formula (II) with an acid: wherein CR is selected from carboxylic acids, alkali metal carboxylates, alkaline earth metal carboxylates, and mixtures thereof; The acid is 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.

4. The process according to claim 3, wherein the compound of formula (II) is prepared by mixing propionaldehyde, a cyanide source and a primary amine of formula H2NCH2CH2CH2CR in an aqueous solution or an aqueous solvent: wherein CR is selected from carboxylic acids, alkali metal carboxylates, alkaline earth metal carboxylates and mixtures thereof; wherein the alkali metal is lithium, sodium, potassium or mixtures thereof; wherein the alkaline earth metal is magnesium, calcium, barium or mixtures thereof; wherein the solvent is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, tetrahydrofuran, dioxane, methoxyethanol, ethoxyethanol and mixtures thereof; wherein the cyanide source is selected from alkali metal cyanides, alkaline earth metal cyanides, zinc cyanide and hydrogen cyanide.

5. A method for preparing levetiracetam of formula (I) from a compound of formula (IV): The (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) is resolved into the optically active (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V): and The (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V) is subjected to an amidation reaction to form the (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide of formula (I): The preparation method of (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV): include: (a) hydrolyzing the compound of formula (II) using an alkali metal hydroxide or an alkaline earth metal hydroxide, The following product is obtained: wherein CR is selected from carboxylic acids, alkali metal carboxylates, alkaline earth metal carboxylates and mixtures thereof; wherein M is an alkali metal or an alkaline earth metal; wherein the alkali metal is lithium, sodium, potassium or a mixture thereof; wherein the alkaline earth metal is magnesium, calcium, barium or a mixture thereof; (b) reacting the product of step (a) with an acid; and (c) cyclizing the product of step (b) to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV); The acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, lower alkanoic acid, alkyl sulfonic acid, aromatic sulfonic acid and mixtures thereof; The cyclization reaction of the compound of formula (III) with an acid to form (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) is carried out by heating.

6. The method according to claim 5, wherein the (RS)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (IV) is resolved into the optically active (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid of formula (V) using a resolving agent selected from dehydroabietylamine, (R)-(+)-1-phenylethylamine, (S)-(-)-1-phenylethylamine and D-(-)-threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol.

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