DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of vigabatrin having desired purity. Specifically, the invention relates to the synthesis of a novel dione intermediate (5), starting with suitable amino acids such as methionine, aspartic acid etc. wherein Meldrum’s acid is used for two-carbon homologation. The intermediate (5) is further converted to vinyl ? lactam (8), which after hydrolysis, provides the amino alkanoic acid, vigabatrin (1) having desired purity.

BACKGROUND OF THE INVENTION
Vigabatrin (1), chemically known as (±) 4-amino-5-hexenoic acid is an anti-epileptic agent and also the first intention treatment for West syndrome, mainly in Europe and Canada. It is used as an adjunctive treatment in epilepsy and related syndromes, but as monotherapy for the treatment and/or prophylaxis of West syndrome. It is commercially available as Sabril® in USA, UK, Switzerland, Mexico etc. and Sabrilex® in Denmark.

Vigabtrin (1)

Vigabatrin, indicated for the treatment of refractory complex partial seizures in adults, acts as an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the catabolism of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. Vigabatrin is a racemic compound, and its (S)-enantiomer is pharmacologically active.
The oral tablet for racemic vigabatrin, with proprietary name Sabril® based on an NDA application filed by Lundbeck Pharmaceuticals, was approved by USFDA on August 21, 2009 as an anti-epileptic drug.
Vigabatrin was first disclosed in US 3,960,927 and various other references published thereafter reported different methods for synthesizing the same.
The synthetic method disclosed in US 3,960,927 comprises selective hydrogenation of 4-acetamido-5-yne-hexanoic acid methyl ester using Lindlar catalyst and gaseous hydrogen for around 12 hours to give 4-acetamido-5-ene-hexanoic acid methyl ester, followed by hydrolysis using 6N hydrochloric acid to give the desired compound, 4-amino-5-hexenoic acid. This process, necessitating selective hydrogenation utilizes very specific catalysts, involves lengthy reaction times as well as column chromatographic separations at intermediate and final step, which is not industrially viable.

The later processes, as disclosed in US 4,178,463, US 4,235,778 comprises reaction of 1,4-dichloro-2-butene with diethyl malonate under basic conditions to produce 2-vinyl cyclopropane-1,1-diethyldicarboxylate which, after reaction with ammonia under pressure gives 3-carboxamido-5-vinyl-2-pyrrolidone. Further hydrolysis of the pyrrolidone intermediate under acidic conditions provides 4-amino-5-hexenoic acid. Several drawbacks such as, a) high cost and known carcinogenicity of the reagent 1,4-dichloro-2-butene, b) significant formation of impurities and c) low overall yield make these processes commercially unviable.
EP 0546906 discloses a process for preparation of vigabatrin wherein erythritol is used as a starting material. The process comprises thermal rearrangement of erythritol in presence of formic acid to give 4-formyloxy-3-hydroxy-1-butene, followed by another thermal rearrangement in presence of propionic acid, excess triethyl orthoacetate and hydrolysis to furnish ethyl 6-formyloxy-4-hexenoate. The formate derivative is converted to the corresponding alcohol using ethanol and alcoholic HCl gas, followed by treatment with trichloroacetonitrile in presence of sodium hydride to provide ethyl 6-formyloxy-4-hexenoate, which on reaction with 6N HCl yields vigabatrin. The process is lengthy, involves expensive reactants in low-yielding thermal rearrangements and column chromatographic separations at different stages, resulting in low overall yield and hence inapplicable on industrial scale.
Synthetic processes for vigabatrin using amino acids such as L-glutamic acid or methionine as starting materials have also been reported in literature. Journal of Organic Chemistry 1993, 58, p. 1586-1588 discloses a process comprising a) selective protection of L-glutamic acid as ? -monoethyl ester, b) protection of amino group using methyl chloroformate, c) reduction of the carboxyl group employing isobutyl chloroformate and NaBH4 to provide alcohol, d) Swern oxidation using oxalyl chloride to provide the aldehyde, e) Wittig reaction and f) N-deprotection, followed by ester hydrolysis to furnish vigabatrin.

The synthetic sequence as disclosed in Tetrahedron (1994), Vol. 50(19), p. 5569-5578, comprises conversion of (R)-methionine to its methyl ester hydrochloride using thionyl chloride, N-protection using methyl chloroformate, reduction- homologation using trialkylphosphonoacetate, t-butyl lithium, DIBAL-H, followed by reduction, cyclization using magnesium, methanol, oxidation of the ? –lactam and elimination to provide vigabatrin.

Both the methods exhibit lengthy reaction sequences utilizing hazardous reagents like butyl lithium, hydrides, magnesium etc. which demand stringent control on experimental conditions such as moisture content, thus making them industrially inapplicable.

Thus, there still exists a need for an economical, industrially viable process for synthesis of vigabatrin (1), which avoids use of hazardous reagents and circumvents stringent controls on experimental conditions.

The present inventors have developed an economical and convenient process for synthesis of vigabatrin (1) which provides the desired molecule in good yield and is capable of overcoming the problems faced in prior art.

OBJECT OF THE INVENTION
An objective of the present invention is to provide a short, convenient and industrially applicable process for synthesis of vigabatrin (1).

Another object of the invention relates to preparation of a suitably protected dioxo-dioxane intermediate (4), which, when subjected to facile reactions such as reduction, deprotection, cyclization provided the desired ? lactam (7).

Yet another object of the invention relates to the conversion of the ? lactam (7) to the key intermediate 5-vinyl-2-pyrrolidinone (8) and hydrolysis thereof to provide vigabatrin in good yield, possessing purity conforming to regulatory specifications.

SUMMARY OF THE INVENTION
An aspect of the invention relates to the synthetic process for vigabatrin (1) comprising synthesis of dione intermediate (5) and further reactions thereof.

Yet another aspect of the invention relates to the synthesis of vigabatrin (1) comprising, reacting the amino acid (2) with an amine protecting reagent to provide the N-protected amino acid (3), further reaction with 2,2-dimethyl-1,3-dioxane-4,6-dione to give the dioxo-dioxane intermediate (4), which on reduction followed by deacetalization, cyclization of resultant compound (5) gives pyrrolidone intermediate (6), subsequent deprotection to give ?-lactam (7), vinylation of (7) followed by treatment with potassium hydroxide in isopropanol gave vigabatrin (1).

The objectives of the present invention will become apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors, during their quest for designing a short and convenient synthetic strategy for vigabatrin, carried out extensive experimentation aimed at an easy, industrially applicable synthesis of the substituted lactam intermediate (7).

Surprisingly, it was found that coupling of N-protected amino acids (3) with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid) provided a dioxo-dioxane intermediate (4), which after reduction, gave the reduced dione intermediate (5) as a suitable precursor for the 5-substituted ?-lactam (7). Accordingly, deacetalization of (5) and intramolecular cyclization provided the pyrrolidone intermediate (6), which, after facile amine-deprotection gave compound (7).

The substituents on the lactam ring, which originated from the amino acid, were subjected to further conversions such as oxidative-elimination, reduction-hydrolysis to afford the vinyl intermediate (8), which, when subjected to hydrolytic-ring opening provided vigabatrin (1), (Scheme-1).

Scheme-1: Synthetic scheme for vigabatrin starting with an amino acid

The instant strategy for vigabatrin synthesis, while avoiding highly specific, cumbersome Wittig-type reactions for homologation, involves use of amino acids along with a versatile reagent like Meldrum’s acid and an appropriate selective reduction method for the acid complex (4) to obtain the dione precursor (5). Various amino acids such as aspartic acid, methionine etc. are used to obtain the desired API, vigabatrin.
The reagents as well as protecting groups used in the instant sequence do not adversely affect the chirality of the intermediates, provide control on associated impurities and furnish the final product, vigabatrin in good yield.
Starting with racemic amino acids, the sequence provided racemic vigabatrin whereas optically pure S and R- vigabatrin was obtained using enantiomerically pure amino acids. For example, (R)-methionine and (S)-methionine respectively provided S- vigabatrin and R-vigabatrin. When aspartic acid was used as the starting material, D-aspartic acid, (also known as R-(-) 2-amino succinic acid or R-(-) aspartic acid), gave S- vigabatrin and L-aspartic acid furnished R-vigabatrin.
In an embodiment, Scheme-2 provides the synthetic route for vigabatrin (1), starting with the amino acid, methionine (2-a).



Scheme-2: Synthetic scheme for vigabatrin starting with methionine (2-a)

Compound (2-a) was subjected to amino group protection using a suitable protecting reagent to furnish N-protected methionine. In case of Boc protection using ditertiarybutyl dicarbonate (Boc-anhydride), the reaction was carried out in presence of an alkali metal hydroxide like sodium hydroxide and solvent tetrahydrofuran (THF) to give N-boc methionine (3-a).
Compound (3-a) was treated with 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid) in presence of a coupling agent and a catalyst to give the Meldrum’s acid complex, N-Boc methionine dioxo-dioxane intermediate (4-a). The reaction was carried out in an organic solvent selected from halogenated hydrocarbons such as methylene dichloride (MDC), ethylene dichloride (EDC), chloroform etc. in the temperature range of -15 to -5°C. The coupling agent was selected from reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), N,N’ dicyclohexyl carbodiimide (DCC), N,N’-diisopropyl carbodiimide (DIC) etc. whereas 4-dimethylamino pyridine (DMAP) was used as a catalyst.
Compound (4-a), which existed in keto-enol tautomeric forms was either isolated or used directly for subsequent reaction. Reduction of (4-a), using transfer hydrogenation reagents like sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, tetrabutyl ammonium borohydride etc. provided a novel dione intermediate (5-a). In case of borohydride reduction, the reaction was carried out in presence of acetic acid, in the temperature range of -15 to -5°C.
In a further embodiment, compound (5-a) was heated in the temperature range of 100-130°C in presence of an organic solvent selected from aromatic hydrocarbons such as toluene, xylene etc. till completion of the reaction.. After completion, as monitored by TLC and HPLC, the reaction mixture was cooled, concentrated to furnish N-boc-5-(2-methylthioethyl)-2-pyrrolidone, (6-a) which was further treated with an acid to give the ? lactam intermediate, 5-(2-methylthioethyl)-2-pyrrolidone (7-a). The acid was selected from mineral acids such as hydrochloric acid, nitric acid or organic acids like trifluoroacetic acid (TFA).
In another embodiment, compound (7-a) was oxidized using sodium periodate in water at 0-5°C. The reaction was carried out using polar protic solvents like methanol, ethanol etc.
After completion, the reaction mixture was concentrated and the residue was refluxed using halogenated aromatic solvents like ortho-dichlorobenzene. After completion of the reaction as monitored by HPLC, the reaction mass was concentrated and the residue was optionally purified to obtain the key intermediate, 5-vinyl-2-pyrrolidinone (8), having desired purity. Subjecting (8) to alkali hydrolysis using solvent such as isopropanol at reflux temperature, till completion of reaction as monitored by HPLC, followed by neutralization with acid and concentration provided the residue containing vigabatrin. Optionally, the residue was subjected to chromatographic separation to afford vigabatrin (1) having desired purity.
In yet another embodiment, Scheme-3 provides the synthetic route for vigabatrin (1) starting with the monoester of an amino acid, aspartic acid (2-b); using reaction sequence similar to the one described above. Compound (2-b) was obtained by subjecting aspartic acid to selective monoesterification using methanol and concentrated hydrochloric acid at room temperature.

Scheme-3: Synthetic scheme for vigabatrin starting from aspartic acid

Compound (2-b), when subjected to amino group protection using a suitable protecting reagent furnished the protected monoester (3). In case of Boc protection, using ditertiarybutyl dicarbonate (Boc-anhydride), the reaction was carried out in presence of an alkali metal hydroxide like sodium hydroxide and 1,4-dioxane as a solvent to give N-Boc-aspartic acid monomethyl ester (3-b). Alternatively, aspartic acid was refluxed with thionyl chloride and methanol to give the diester, which, when treated with boc anhydride, followed by reaction with lithium hydroxide provided N-Boc aspartic acid monomethyl ester (3-b).

Compound (3-b) was treated with Meldrum’s acid in presence of a coupling agent and a catalyst to give the N-Boc-aspartic acid dioxo-dioxane intermediate (4-b). The reaction was carried out in an organic solvent selected from halogenated hydrocarbons such as methylene dichloride (MDC), ethylene dichloride (EDC), chloroform, or solvents like acetonitrile, dimethylformamide (DMF), ethyl acetate etc. in the temperature range of -15 to -5°C. The coupling agent was selected from reagents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), N,N’-dicyclohexyl carbodiimide (DCC), N,N’-diisopropyl carbodiimide (DIC) etc. whereas the catalyst was selected from 4-dimethylamino pyridine (DMAP), triethyl amine (TEA), N,N’diisopropylamine (DIPA) etc.

Compound (4-b), which existed in keto-enol tautomeric forms, was either isolated or used directly for the subsequent reactions.

Further reduction of the novel intermediate (4-b), either using transfer hydrogenation reagents like sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, tetrabutyl ammonium borohydride etc. or under catalytic hydrogenation conditions using Palladium or Platinum catalysts provided yet another novel intermediate (5-b). In case of sodium borohydride reduction, the reaction was carried out in presence of acetic acid, in the temperature range of -15 to -5°C. After completion of the reaction as monitored by HPLC, water was gradually added to the stirred reaction mixture; organic layer was separated and concentrated to provide compound (5-b).

Compound (5-b) was heated in the temperature range of 100-130°C in presence of an organic solvent selected from aromatic hydrocarbons such as toluene, xylene, till completion of the reaction. After completion, as monitored by TLC and HPLC, the reaction mixture was cooled, concentrated to give N-Boc-methyl-(5-oxo-2-pyrrolidine)acetate (6-b). Further treatment with acid selected from mineral acids such as hydrochloric acid, nitric acid or organic acids like trifluoroacetic acid (TFA) gave the ? lactam intermediate (7-b).

Reduction of (7-b) using lithium borohydride (LiBH4) in tetrahydrofuran (THF) provided the 2-hydroxyethyl-pyrrolidone intermediate (7-b'). Further treatment of (7-b') with phosphorous tribromide gave the 2-bromoethyl-pyrrolidone intermediate (7-b’’), which after reaction with alkali alkoxide such as potassium tertiary butoxide provided the penultimate intermediate, 5-vinyl-2-pyrrolidone (8).

Subjecting (8) to alkali hydrolysis using solvent such as isopropanol at reflux temperature till completion, as monitored by HPLC, followed by neutralization with acid and concentration provided the residue containing vigabatrin. Optionally, the residue was subjected to chromatographic separation to afford vigabatrin (1) having desired purity.

The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

EXAMPLES

Example 1: Synthesis of N-Boc methionine (3-a)

A mixture of methionine (2-a, 10.0 g) in THF was stirred in a round bottom flask at room temperature and aqueous solution of sodium hydroxide (4.0 g in 20 ml water) was gradually added to it. Boc-anhydride (15.5 g) was then added to the mixture and stirring was continued at the same temperature till completion of the reaction as monitored by TLC. After completion, the reaction mixture was diluted with water, acidified to pH around 4 to 5 using mineral acid or organic acid like citric acid. Extraction with dichloromethane, followed by separation and concentration of the organic layer furnished N-Boc methionine (3-a) as oil.
Yield: 12.52 g

Example 2: Synthesis of (4-a)

A mixture of N-boc methionine (3-a, 8.5 g) in methylene dichloride (MDC) was stirred in a round bottom flask at room temperature. Meldrum’s acid (5.41 g) was added to it, followed by addition of DMAP (6.23 g). The stirred mixture was cooled to -10° C and a solution of N,N’ dicyclohexyl carbodiimide (DCC, 7.74 g) in MDC (70 ml) was slowly added to it at the same temperature. The stirring was continued till completion of the reaction as monitored by TLC. After completion, temperature of the reaction mixture was raised to 25° C and the mass was filtered. The filtrate was washed with 5% aqueous solution of sodium bisulfate, followed by separation and partial concentration of the organic layer under vacuum to provide a residue containing compound (4-a).

Example 3: Synthesis of (5-a)

Acetic acid (20 ml) was added to the concentrate containing compound (4-a), obtained in example 2, in methylene dichloride and the stirred mass was cooled to -10° C. Sodium borohydride (3.16 g) was slowly added to the stirred mixture at -5 to -10° C and the reaction was continued till completion, as monitored by HPLC. After completion, water was carefully added to the stirred reaction mixture and the organic layer was separated. Concentration of the organic layer provided compound (5-a) in the form of an oil.
Yield: 5.5 g

Example 4: Synthesis of 5-(2-methylthioethyl)-2-pyrrolidone (7-a)

Toluene (15 ml) was added to compound (5-a, 0.8 g) in a round bottom flask and the stirred mixture was refluxed at around 110-120°C till completion of the reaction, as monitored by HPLC. After completion of the reaction, the mixture containing the Boc-protected intermediate (6-a) was cooled to 0°C and trifluoroacetic acid (TFA, 5 ml) was added to it. Temperature of the reaction was raised to 20-30°C and stirring was continued till completion, as monitored by TLC and HPLC. After completion, the reaction mass was distilled under vacuum, along with optional treatment with toluene to provide compound (7-a) as an oil.

Example 5: Synthesis of 5-vinyl-2-pyrrolidone (8)

A solution of sodium periodate (1.0 g) in water (8 ml) was added drop-wise to a vigorously stirred ice-cold solution of the ? lactam (7-a, 0.6 g) in methanol (20 ml). The reaction mixture was stirred till completion of the oxidation reaction as monitored by HPLC. After completion, the reaction mixture was filtered, concentrated under vacuum and the residue was dissolved in chloroform. Concentration of the chloroform solution afforded the sulfoxide intermediate, which was dissolved in o-dichlorobenzene (20 ml). The resulting solution was heated at reflux temperature till completion of the elimination reaction as monitored by HPLC. After completion, the reaction mass was concentrated and the residue was optionally purified using column chromatography to give 5-vinyl-2-pyrrolidone (8).

Example 6: Synthesis of vigabatrin (1)

A mixture of (8, 0.5 g.), potassium hydroxide (0.40 g), water (0.5 ml), and isopropanol (5 ml) was heated at reflux temperature till completion of the hydrolysis reaction as monitored by HPLC. After completion, the reaction mass was cooled, neutralized by adding acid (0.45 g), and concentrated in vacuum to provide a residue.
Column chromatographic separation of the residue afforded vigabatrin (1).

Example 7: Synthesis of (S)-(+) vigabatrin ((S)-1)

(S)-(+) vigabatrin was prepared starting with (R)-methionine, following the procedures disclosed in examples 1 to 6.

Example 8: Synthesis of N-boc-aspartic acid monomethyl ester (3-b)

Sodium hydroxide (4.0 g) and 1, 4 dioxane (50 ml) were added to the stirred mixture of aspartic acid monomethyl ester, (2-b, 16.0 g), water (50 ml) at 0 to 5°C and stirring was continued at the same temperature. Boc anhydride (26.0 g) was further added to the mixture with continued stirring, initially at 0-5°C and later at ambient temperature. After completion, as monitored by HPLC, the reaction mass was quenched using sodium bisulphate solution, followed by extraction with ethyl acetate. Separation and concentration of the organic layer provided the desired compound which was optionally purified by column chromatography to give (3-b) as a colorless thick oil.
Yield: 19.08 g (70%)

Compound (2-b) in the above example was prepared as follows : Aspartic acid (15.0 g), methanol (300 ml) and concentrated hydrochloric acid (34ml) were stirred in a round bottom flask at ambient temperature till completion of the reaction as monitored by HPLC. After completion, the reaction mixture was neutralized using sodium bicarbonate, filtered and filtrate was concentrated to provide compound (2-b) as a residue.

Example 9: Synthesis of methyl–[4-(tert-butoxycarbonyl)-5-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)] pentonoate (5-b)

EDAC.HCl (15.5 g) was gradually added to the mixture of (3-b, 8.05 g), Meldrum’s acid (5.07 g), and DMAP (5.93 g) in MDC (200 ml), stirred at -10 to -5°C and stirring was continued at around -5 to 00C till complete consumption of the starting material, as monitored by TLC. The reaction mixture was stirred further at ambient temperature till completion of the formation of acid-complex (4-b), as monitored by HPLC. After completion, additional MDC (200 ml) was added to the reaction mass, followed by washing with 0.1 N hydrochloric acid. The organic layer was separated, concentrated to give a residue containing compound (4-b).

MDC (200 ml) and acetic acid (25 ml) were added to the residue and the stirred mass was cooled to -10 to -5°C, followed by gradual addition of sodium borohydride (2.6 g). Stirring was continued initially at around -5 to 00C and later at ambient temperature till completion of the reaction, as monitored by HPLC. After completion, the reaction mixture was quenched with water, the organic layer was separated and concentrated to give compound (5-b), which was optionally purified by flash chromatography.
Yield: 8.2 g (69.8%)

Example 10: Synthesis of Methyl-(5-oxo-2-pyrrolidine)acetate (7-b)

A mixture of (5-b, 1.0 g) and toluene (25 ml) was heated at 110 to 120°C till completion of the reaction as monitored by TLC and HPLC, to give compound (6-b). The reaction mixture containing compound (6-b) was cooled to 0°C and trifluoroacetic acid (5 ml) was slowly added to it, with continued stirring. The mass was allowed to warm to room temperature and stirred further till completion of reaction as monitored by HPLC.
After completion, the reaction mixture was concentrated; the residue was cooled to room temperature, followed by addition of dichloromethane. Separation and concentration of the organic layer gave compound (7-b) as light brown oil.
Yield: 0.35 g (81%)

Example 11: Synthesis of 5-vinyl-2-pyrrolidone (8), from (7-b)

LiBH4 in THF (2.5 ml of a 2 M solution) was added to a solution of (7-b, 0.38 g) in THF (12 ml), stirred at 4°C. After the initial stirring at 4°C, the reaction mixture was brought to 20-25°C and stirred further at the same temperature till completion of the reaction, as monitored by HPLC. After completion, the reaction mass was quenched using ammonium chloride solution and concentrated to furnish the residue containing the 2-hydroxyethyl-pyrrolidinone intermediate (7-b’), which was optionally purified by column chromatography.
Yield: 0.29 g (92%).
Phosphorous tribromide (PBr3 0.30 ml) was added to the mixture of compound (7-b’, 0.27 g) in THF (7 ml), stirred at -15 to -20°C till completion of the formation of bromoethyl pyrrolidone intermediate, as monitored by TLC, HPLC. After completion, chloroform was added to the reaction mixture, organic layer is separated, washed with bicarbonate and concentrated to provide the bromo-intermediate (7-b’’), which was optionally purified by column chromatography.
Yield: 0.23 g
Potassium tertiary butoxide (0.18 g) was added to the solution of (7-b’’, 0.15 g) in THF (6 ml) and the reaction mixture was refluxed till completion of the reaction as monitored by TLC, HPLC. After completion, the mass was quenched using aqueous sodium chloride solution, and extracted with ethyl acetate. Separation and concentration of the organic layer gave a residue containing compound (8).
Yield: 0.07 g (81%).

Example 12: Synthesis of vigabatrin (1)

Compound (8), as obtained in Example 11 was further converted to vigabatrin following the procedures provided in example 6.

Example 13: Synthesis of (S)-(+) vigabatrin (1)
(S)-(+) vigabatrin was prepared starting with D-aspartic acid (also known as R-(-) 2-amino succinic acid), following the procedures provided in examples 8 to 12.
,CLAIMS:We claim,
1. A process for the preparation of vigabatrin (1) and its pharmaceutically acceptable salts comprising, reacting the amino acid (2) with an amine protecting reagent to provide the N-protected amino acid (3) which on further reaction with 2,2-dimethyl-1,3-dioxane-4,6-dione gave dioxo-dioxane intermediate (4), further reduction followed by deacetalization, cyclization of resultant compound (5) gave pyrrolidone intermediate (6), subsequent deprotection gave ?-lactam (7), vinylation of (7) followed by treatment with potassium hydroxide in isopropanol gave vigabatrin (1).

2. The process as claimed in claim 1 wherein the amino acid (2) is selected from methionine (2-a, R= CH2-SCH3), aspartic acid (2-b, R = COOCH3) and wherein P is tertiarybutyloxycarbonyl.
3. The process as claimed in claim 1, comprising treatment of N-boc methionine (3-a) with 2,2-dimethyl-1,3-dioxane-4,6-dione in presence of a coupling agent and a catalyst in an organic solvent to give N-Boc methionine dioxo-dioxane intermediate (4-a), reducing (4-a) using transfer hydrogenation reagent to provide (5-a), heating (5-a) using an organic solvent selected from toluene and xylene to give (6-a), treating (6-a) with an acid to give (7-a), followed by conversion of (7-a) to vigabatrin (1).


4. The process as claimed in claim 1 comprising treatment of N-Boc-aspartic acid monomethyl ester (3-b) with 2,2-dimethyl-1,3-dioxane-4,6-dione in presence of a coupling agent and a catalyst in an organic solvent to give N-Boc-aspartic acid dioxo-dioxane intermediate (4-b), reducing (4-b) using transfer hydrogenation reagent to provide (5-b), heating (5-b) using an organic solvent selected from toluene and xylene to give (6-b), treating (6-b) with an acid selected from hydrochloric acid, nitric acid and trifluoroacetic acid to give (7-b), followed by conversion of (7-b) to vigabatrin (1).


5. The process as claimed in claims 1 to 4 wherein the coupling agent is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), N,N’-dicyclohexyl carbodiimide (DCC), N,N’-diisopropyl carbodiimide (DIC), and the catalyst is selected from 4-dimethylamino pyridine (DMAP), triethyl amine (TEA), and N,N’diisopropylamine (DIPA).
6. The process as claimed in claims 1 to 4 wherein the organic solvent is selected from acetonitrile, dimethylformamide (DMF), ethyl acetate, halogenated hydrocarbons consisting of methylene dichloride (MDC), ethylene dichloride (EDC), chloroform, and mixtures thereof.
7. The process as claimed in claim 3 wherein compound (7-a) is treated with sodium periodate in water, methanol, the resultant residue is refluxed in ortho-dichlorobenzene to give compound (8), followed by reaction of (8) with potassium hydroxide in isopropanol to provide vigabatrin (1).

8. The process as claimed in claim 4 wherein compound (7-b) is treated with lithium borohydride (LiBH4) in tetrahydrofuran, followed by treatment with phosphorous tribromide and subsequent reaction with potassium tertiary butoxide to give compound (8), followed by reaction of (8) with potassium hydroxide in isopropanol to provide vigabatrin (1).

9. The process as claimed in claims 1, 2, 3 and 7 wherein (S)-(+) vigabatrin is prepared starting with (R)-methionine.
10. The process as claimed in claims 1, 2, 4 and 8 wherein (S)-(+) vigabatrin is prepared starting with D-aspartic acid.