WO2013190357A1

WO2013190357A1 - A process for the preparation of gabapentin

Info

Publication number: WO2013190357A1
Application number: PCT/IB2013/001264
Authority: WO
Inventors: Swapnil Gulabrao YERANDE; Rajesh Mataprasad THAKUR; Sundarakrishna S. SHARMA; Ashok Kumar Gangopadhyay; Helmut Rupp; Hitesh KUBAVAT; Kuppuswamy Nagarajan; Arul Selvan; Rambabu Nunna; Vivekananda Induharappa JALAJAKSHI
Original assignee: Hikal Limited
Priority date: 2012-06-18
Filing date: 2013-06-18
Publication date: 2013-12-27
Also published as: WO2013190357A8

Abstract

The present invention provides an improved process for the preparation of a compound of formula (I),

Description

"A PROCESS FOR THE PREPARATION OF GABAPENTIN"

Field of the Invention

This invention relates to a chemo-enzymatic industrial scale production of gabapen which is used clinically as a therapeutic agent for cerebral disorders.

O)

Background of the Tnvention

Gabapentin, the generic name for 1-aminomethyl-l-cyclohexaneacetic acid having the structure shown in formula (I) is a well recognized drug used for treatment of epilepsy and other cerebral disorders.

(I)

The discovery of this compound and its process of preparation are first claimed in US Patents US 4,024, 175 and US 4,087,544 respectively. A number of manufacturing processes are available in prior art for this compound out of these a few are summarized in schemes 1 and 2.

Warner- Lambert's US Patents nos. 4,024, 175 and 4,087,544 described the process (shown in the general scheme 1) consisting of transforming monomethyl ester of a compound of formula (2) to a compound of formula (3) i.e. acyl azide followed by rearrangement to isocyanate and further followed by hydrolysis with aqueous hydrochloric acid to obtain gabapentin hydrochloride. The gabapentin was obtained by treatment of its hydrochloride with anion exchange resin (OH form). The handling of acyl azide can be hazardous and the use of anion exchanger makes the process unattractive.

In US 5068413 the process described includes first the hydrolysis of a compound of formula (12) (general scheme 2) to a compound of formula (13), decarboxylation of a compound of formula (13) to a compound of formula (10) followed by catalytic hydrogenation using 5% Rhodium on carbon to give gabapentin which was purified by crystallization. Alternatively gabapentin hydrochloride was isolated and free gabapentin was obtained by anion exchanger (OH form).

An improved process by Warner Lambart is described in US 5,319, 135. The process involve synthesis of intermediate 2-azaspiro[4.5]decane-3-one (gabalactam) by converting 1 -cyanocyclohexaneacetonitrile a compound of formula (1 1) to ethyl 1-cyanocyclohexane acetate a compound of formula (9) selectively followed by hydrogenation in isopropyl alcohol over Raney Nickel at 300 psi and 130°C (general scheme 2) to afford gabalactam of formula (VII). Subsequently the gabalactam of formula (VII) was hydrolyzed in aqueous hydrochloric acid and neutralized by anion exchanger (OH form). The selective conversion of a compound of formula ( 1 1) to a compound of formula (9) is quite tedious and the use of anion exchanger makes the process unattractive.

A high yielding process for gabapentin is disclosed in US 5,091 ,567 which involve Wittig- Horner reaction on cyclohexanone followed by Michael addition of nitromethane to get a compound of formula (8) mentioned in general scheme (2). In subsequent steps a compound of formula (8) was hydrogenated to a mixture of gabalactam (7) and gabapentin (I) followed by acidic hydrolysis to gabapentin hydrochloride and finally free gabapentin was obtained by passing through a column of anion exchanger (OH form). The overall yield was found to be 44%. Although overall yield is quite impressive, the use of potentially hazardous nitromethane makes the process unfavorable for manufacturing.

A significant process improvement for converting gabapentin hydrochloride to gabapentin is described in US 6,518,456, wherein the process involve conversion of gabalactam to gabapentin hydrochloride by acidic hydrolysis followed by neutralization with a base such as sodium hydroxide to its isoelectric point (pH = 7.1 to 7.2) and filtration thus avoiding the use of large excess of solvent required in ion exchange chromatography. It was further purified

Formula (4) Gabapentin (I)

In another improved process for gabalactam, a compound of formula (7) as mentioned in general scheme 2 is disclosed in WO 2004046108 by Hoffmann degradation using bromine and NaOH, followed by extraction of lactam in toluene. The yield is as high as 81 % and purity >99%.

Another innovative approach is described in US 2005/0148792 that involves alkylation of imine derived from cyclohexane carboxaldehyde followed by reductive amination of resulting intermediate to lactam followed by acidic hydrolysis to give gabapentin in three steps. Due to the high cost and very poor overall yield this process can not be commercialized.

In US patent application 2007/0287861 another process was claimed that involves Hoffman reaction on 1 , 1-diacetic acid monoamide of formula (4) as mentioned in general scheme 2 using alkali and sodium hypochlorite followed by thermal cyclization. to gabalactam (7). Finally . gabalactam (7) was hydrolyzed by heating in hydrochloric acid followed by purification by crystallization. The overall yield is 74% based on a compound of formula (4).

Formula (11) Scheme (2)

Pfizer in its patent WO 2007/ 129286 described a short process involving hydrolysis of 1-cyanocyclohexaneacetic acid ethyl ester of formula (9) in (scheme 2) with alkali followed by hydrogenation of the corresponding alkali metal salt of formula ( 10) (general scheme 2) solution in water at 3.5 bar, and 30°C for 14 to 16 hrs followed by isoelectric focusing at pH 7.1 to isolate gabapentin. This was further purified by crystallization in overall 60 to 67% yield based on 1-cyanocyclohexaneacetic acid ethyl ester. The process involves preparation of a compound of formula (9) from a compound of formula (1 1) mentioned in scheme (2) following tedious procedure described by Warner- Lambart in their patent US 5,693,845. Therefore this method does not provide superiority over prior art.

Accordingly therefore, there is an urgent need to develop a process for the preparation of gabapentin of formula (I), which is readily amenable to scale-up. Hence, we focused our research to simplify the process for the preparation of (I) with greater yield and higher chemical purity by using a genetically modified nitralase enzyme as a biocatalyst for the conversion of the dinitrile (1 1) to its cyano acid or its salts (10) in a substantially cost effective and eco-friendly manner and to obviate the problems associated with the prior art process(s). Objectives of the Invention

The main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is simple, economical, user- friendly and commercially viable.

Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s), which makes the present invention eco-friendly as well.

Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a greater yield with higher chemical purity.

Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the byproduct formed during the reaction can be reusable and thereby recyclable, which makes the process industrially more suitable.

Summary of the Invention

Accordingly, the present invention provides an improved process for the preparation of a compound of formula (I), which comprises the steps of:

(I)

(a) reacting cyclohexanone of formula (II) and alkyl cyanoacetate of formula (III) in presence of a weak base salt with or without an weak organic acid in an organic solvent to get cyano-cyclohexyllidene-acetic acid alkyl ester of formula (IV);

(b) reacting 2-cyano-2-cyclohexyllidene-acetic acid alkyl ester of formula (IV) with a suitable cyanide source in suitable solvent to get 1 -cyanomethyl-cyclohexanecarbonitrile of formula (V); (c) converting 1-cyanomethyl-cyclohexanecarbonitrile of formula (V) to 1-cyano- cyclohexyl-acetic acid or salts thereof, of formula (VI) with a genetically modified nitrilase enzyme in water at appropriate pH and temperature;

(d) reducing 1 -cyano-cyclohexyl-acetic acid or salts thereof, of formula (VI) optionally to gabalactam of formula (VII) or gabapentin of formula (I) by catalytic hydrogenation at a suitable pH and elevated temperature in water or in organic solvent or mixture thereof; and

(e) hydrolysing gabalactam of formula (VII) to gabapentin of formula (I) via acidic hydrolysis by conventional means.

The above process is illustrated in the following synthetic scheme (3):

Wherein

R = Alky I such as methyl, ethyl and the like

Rl = hydrogen, alkali metal or alkaline earth metal, ammonium, organic ammonium and the like

Detailed description of the Invention

The present invention now will be described more fully hereinafter. Indeed, the invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms "a", "an", "the", include plural referents unless the context clearly dictates otherwise.

In accordance with the objectives wherein the present invention provides an improved process for the preparation of a compound of formula (I) from a precursor which is obtained with surprising selectivity by having new enzymatic step wherein the genetically modified nitralase enzyme as a biocatalyst is applied.

Accordingly in an embodiment of the present invention, the said weak organic acid used in step (a) is preferably selected from the group consisting of benzoic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, acetic acid and the like.

In another embodiment of the present invention, the said weak base salt used in step (a) is preferably selected from the group consisting of ammonium acetate, ammonium benzoate, ammonium succinate, alkyl ammonium acetate and the like, more preferably ammonium acetate.

In another embodiment of the present invention, the said organic solvent in step (a) is selected from the group consisting of chloroform, cyclohexane, toluene, dichloromethane, ethyl acetate, methyl tertiary butyl ether and the mixture thereof.

In another embodiment of the present invention, the reaction of step (a) is preferably carried out at ambient temperature to reflux temperature, more preferably at reflux temperature.

In another embodiment of the present invention, the crude compound of formula (IV) of the said step (a) can be used as such or can be purified by distillation by different techniques well understood by those skilled in the art.

In another embodiment of the present invention, the said suitable cyanide source of step (b) is preferably selected from the group consisting of lithium cyanide, potassium cyanide, sodium cyanide and the like, more preferably sodium cyanide and potassium cyanide and most preferably sodium cyanide. In another embodiment of the present invention, the said suitable solvent in step (b) is preferably selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, cyclohexane and the like or mixture thereof, more preferably water or methyl alcohol or mixture thereof.

In another embodiment of the present invention, the reaction of step (b) is preferably carried out at a temperature range between 45°C.to 120°C, more preferably 45°C to 1 10°C and most preferably at reflux temperature of the solvent used.

In another embodiment of the present invention, the mode of preparation of a compound of formula (VI) of step (c) can be defined as; preparing a dispersion of required amount of finely powdered compound of formula (V) that can optionally be achieved by sieving through 50 to 300 mesh and suspended in water or optionally micronized in water for required period of time and contacting this suspension with the said genetically modified nitrilase enzyme 2-30 U/g of substrate at appropriate pH preferably in the range between 6.5 to 8.0, more preferably at 7.5+ 0.2 under stirring at 25°C to 50°C till the complete consumption of compound of formula (V); usually it requires 12 to 48 hrs.

In another embodiment of the present invention, the loading of a compound of formula (V) in reaction of step (c) preferably can be chosen from 50 to 100 g per liter of water; more preferably 65 to 85 g per liter of water.

In another embodiment of the present invention, the loading of the said genetically modified nitrilase enzyme for the preparation of formula (VI) in reaction of step (c) is preferably used and selected from 4 to 25 U per g of a compound formula (V), more preferably 6 to 20 U per gram of a compound formula (V).

In another embodiment of the present invention, during the preparation of compound of formula (VI), the pH of the solution can be maintained in the range of 7.5 + 0.2 by a suitable buffer by methods well known in the art; one of the most preferred way to achieve is to use a phosphate or acetate buffer or maintain the pH with the addition of suitable acid, which is selected from the group consisting of acetic acid, citric acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like, the most preferred acid is hydrochloric acid and or a base which is selected from the group consisting of ammonia, mono, di and tri alkyl amine, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, the most preferred base is sodium bicarbonate.

In another embodiment of the present invention, the said reaction of step (c) is preferably carried out at a temperature range between 25 °C to 40°C, more preferably 28°C to 38°C and most preferably a temperature range between 30°C to 37°C.

In another embodiment of the present invention, the reaction mixture after the preparation of compound (VI) in step (c) can be used directly for the subsequent step after removal of protein matter and optionally the solution can be concentrated by the removal of 50 to 75% of water or optionally compound of formula (VI) can be isolated by acidification.

In another embodiment of the present invention, the preparation of compound of formula (VI) in step (c) comprises: isolation of a compound of formula (VI) after acidification followed by extraction of a compound of formula (VI) into an organic solvent which is selected from the group consisting of ethyl acetate, chloroform, dichloromethane, methyl tertiary butyl ether, methyl isobutyl ketone, cyclohexane, toluene, butanols and the like; and subsequently extracting it as its salt in water by using a base which is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, barium hydroxide, ammonium hydroxide, quaternary ammonium hydroxide, primary C |-C ₁₀ alkyl amine, secondary Ci-Cio alkyl amine or tertiary C|-Cio alkyl amine, wherein the alkyl group can be straight chain, branched chain or cyclic in nature.

In another embodiment of the present invention, the said genetically modified nitrilase enzymes are mentioned in PCT application WO2012048865 of c-LEcta and more specifically as Sequence ID No. 08. The present inventors were motivated to pursue the conversion of 1-cyanomethyl-cyclohexanecarbonitrile of formula (V) to 1 -cyano-cyclohexyl-acetic acid or salts thereof, of formula (VI) with the said enzyme and achieved successfully with surprising selectivity, improved conditions, higher yields, minimum waste; therefore as a result promoting the green chemistry of preparation of a compound of formula (I).

In another embodiment of the present invention, the preparation of gabapentin of formula (I) or gabalactam of formula (VII) or mixture of gabapentin and gabalactam comprises catalytic hydrogenation of compound (VI) under elevated temperature and hydrogen pressure with particular pH in solvent. The wet gabapentin can be isolated by simple evaporation after removing the catalyst followed by solvent wash to the reaction mass or solvent wash after evaporation to reduce the gabalactam content while gabalactam can be isolated as such or saturated with salts followed by solvent extraction in batch process or continuous process at elevated temperature. In case of conversion of 1-cyano-cyclohexyl-acetic acid (VI) to gabalactam of formula (VII) the said catalytic hydrogenation is preferred at pH >10, while in case of the conversion of salts of 1 -cyano-cyclohexyl-acetic acid (VI) to gabapentin of formula (I), the preferred pH is < 10.

In another embodiment of the present invention, the preparation of gabalactam of formula (VII) in step (d) is achieved by catalytic hydrogenation of alkali metal or alkaline earth metal salt of 1-cyano cyclohexane-1 -acetic acid of formula (VI) under elevated temperature and hydrogen pressure with particular pH followed by isolation of the gabalactam by extractions by batch process or continuous process with solvents.

In another embodiment of the present invention, the preparation of gabalactam of formula (VII) of step (d) is by catalytic hydrogenation of alkali metal or alkaline earth metal salt of 1 - cyano-cyclohexane- 1 -acetic acid of formula (VI) wherein the alkali or alkaline earth metal salts can be obtained as follows: from the isolated 1 -cyano-cyclohexane-l -acetic acid and converting it into its salt or extracting the 1-cyano-cyclohexane- l -acetic acidwith methyl isobutyl ketone, dichloromethane, methyl tertiary butyl ether, butanols and the like followed by extraction with alkali metal or alkaline metal hydroxide or carbonates in water or water containing water miscible solvent like ethanol, methanol, tetrahydrofuran and the like; isolated alkali or alkaline earth metal salt of 1 -cyano-cyclohexane-l -acetic acid; in situ conversion of the ammonium salt of 1-cyano-cyclohexane- l -acetic acid in enzymatic reaction mass as such or partially concentrated, into other alkali and alkaline earth salts.

In another embodiment of the present invention, the preparation of gabalactam of formula (VII) of step (d) is done by catalytic hydrogenation of alkali metal or alkaline earth metal salt of 1 -cyano cyclohexane-1 -acetic acid of formula (VI) wherein the earth metal salts can be made by using of alkaline earth metal base, which is preferably selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like, more preferably sodium hydroxide.

Another embodiment of the present invention describes a process for the preparation of gabalactam of formula (VII) of step (d) by catalytic hydrogenation of alkali metal or alkaline earth metal salt of 1-cyano-cyclohexane-l -acetic acid of formula (VI) wherein preferably ammonium salt of 1-cyano-cyclohexane- l -acetic acid from enzymatic reaction mass can be converted in situ into other alkali and alkaline earth salts as such with the total volume or after partial concentration; wherein the preferable concentration can be between 25 to 50%.

Another embodiment of the present invention describes a process for the preparation of gabalactam of formula (VII) of step (d) by catalytic hydrogenation of alkali metal or alkaline earth metal salt of I -cyano-cyclohexane-1 -acetic acid of formula (VI) wherein the catalyst is preferably selected from the group consisting of nickel, palladium, ruthenium, rhodium and their different chemical forms and grades optionally fresh or recovered or mixture of fresh and recovered catalyst while the most preferred catalyst is Nickel.

Another embodiment of the present invention describes a process for the preparation of gabalactam of formula (VII) of step (d) by catalytic hydrogenation of alkali metal or alkaline earth metal salt of 1 -cyano-cyclohexane- l -acetic acid of formula (VI) wherein the reaction temperature preferably can be in the range between 30° to 150°C; more preferably in the range between 80 to 90°C.

Another embodiment of the present invention describes a process for the preparation of gabalactam of formula (VII) of step (d) . by catalytic hydrogenation of alkali metal or alkaline earth metal salt of 1 -cyano-cyclohexane-l -acetic acid of formula (VI), wherein the solvent preferably can be selected from the group consisting of water, methanol, ethanol, isopropanol, butanolss, tetrahydrofuran or a mixture thereof; more preferably water.

Another embodiment of the present invention describes a process for the preparation of gabalactam of formula (VII) of step (d) by catalytic hydrogenation of alkali metal or alkaline earth metal salt of 1 -cyano-cyclohexane-l -acetic acid of formula (VI), wherein preferably hydrogen pressure can be minimum >2.0 kg /cm² or equivalent unit; more preferably hydrogen pressure in the range of 10-20 kg /cm² or equivalent units. Another embodiment of the present invention describes a process for the preparation of gabalactam of formula (VII) of step (d) by catalytic hydrogenation of alkali metal or alkaline earth metal salt of 1 -cyano-cyclohexane-l -acetic acid of formula (VI), wherein the pH range of the hydrogenation mixture can be maintained preferably in the range of 8 to 14; more preferably between 10 to 13.

In another embodiment of the present invention describes a process for the preparation of gabalactam of formula (VII) of step (d) by catalytic hydrogenation of alkali metal or alkaline earth metal salt of 1-cyano-cyclohexane-l -acetic acid of formula (VI) wherein the solvent for the extraction of gabalactam can be preferably selected from the group consisting of toluene, cyclohexane, dichloromethane, chloroform, methyl tertiary butyl ether, methyl isobutyl ketone, butanols and the like; wherein the more preferable solvent is toluene; optionally alkali or alkaline earth metal salts can be used for the saturation of reaction mass during extraction process; wherein the most preferred salt can be chosen from sodium chloride or potassium chloride or calcium chloride.

Another embodiment of the present process for the preparation of gabapentin of formula (I) of step (e) comprises the catalytic hydrogenation of compound (VI) wherein the organic base salt can be obtained as follows: from the isolated 1 -cyano-cyclohexane- l -acetic acid and converting it into its salt or extracting the 1 -cyano-cyclohexane-l -acetic acid with a solvent which is selected from the group consisting of methyl isobutyl ketone, dichloromethane, methyl tertiary butyl ether, butanols and the like followed by extraction with ammonia or an organic amine in water or water^ containing water miscible solvent like methanol, ethanol, tetrahydrofuran and the like; isolated ammonium / organic amine salt of 1-cyano cyclohexane- 1 -acetic acid; treatment of the enzymatic reaction mass containing ammonium salt of 1-cyano-cyclohexane-l -acetic acid with an organic amine; enzymatic reaction mass as such or partially concentrated ammonium salt of 1 -cyano cylohexane- 1 -acetic acid; ;enzymatic reaction mass as such or partially concentrated containing ammonium salt of 1- cyano cyclohexane- 1 -acetic acid after charcoal treatment.

Another embodiment of the present invention describes a process for the preparation of gabapentin of formula (I) comprised of catalytic hydrogenation of a solution of a compound (VI) as an ammomium salt wherein the concentration of the salt preferably can be between 5 to 60%, more preferably between 15 to 30%. In another embodiment of the present invention a process is described for the preparation of gabapentin of formula (I) by the catalytic hydrogenation of compound (VI) in step (e), wherein the catalyst is preferably selected from the group consisting of Nickel, palladium, ruthenium, rhodium and their different chemical forms and grades optionally fresh or recovered or mixture of fresh and recovered catalyst while the most preferred catalyst is Nickel.

Another embodiment of the present invention describes a process for the preparation of gabapentin of formula (I) by the catalytic hydrogenation of compound (VI) in step (e), wherein the reaction temperature preferably can be in the range between 30° to 150°C, more preferably at in the range between 50° to 60°C.

Another embodiment of the present invention describes a process for the preparation of gabapentin of formula (I) by the catalytic hydrogenation of compound (VI) in step (e), wherein the said organic solvent is water miscible solvent, which is preferably selected from the group consisting of methanol, ethanol, isopropanol, butanolss, tetrahydrofuran and the like.

Another embodiment of the present invention describes a process for the preparation of gabapentin of formula (I) by the catalytic hydrogenation of compound (VI) in step (e), wherein the hydrogen pressure preferably can be minimum >2.0 kg /cm² or equivalent unit; more preferably hydrogen pressure in the range of 10-20 kg /cm² or equivalent units.

In yet another embodiment of the present invention describes a process for the preparation of gabapentin of formula (I) by the catalytic hydrogenation of compound (VI) in step (e), wherein the pH range of the hydrogenation mixture can be maintained preferably between 5 to 1 1 , more preferably between 7.5 to 1 1.

In still another embodiment of the present invention describes a process for the preparation of gabapentin of formula (I) by the catalytic hydrogenation of compound (VI) in step (e), wherein the solvent for reducing the gabalactam content in gabapentin can be preferably selected from the group consisting of toluene, dichloromethane, chloroform, methyl tertiary butyl ether, methyl isobutyl ketone, butanols and the like; more preferably dichloromethane and toluene.

Examples : The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

Example 1.1

Cyano-cyclohexyllidene-acetic acid methyl ester:

To a 250 mL round bottom flask fitted with condenser, thermometer pocket, Dean Stark and overhead mechanical stirrer in an oil bath was charged methyl tertiary butyl ether (125 mL), cyclohexanone (25.0 g; 255 mmol) and methyl cyanoacetate (25.23 g; 255 mmol). To the resulting solution acetic acid (1.98 g; 33 mmol) and ammonium acetate (1.92 g; 249 mmol) was added and e" fluxed for 16 hrs with concomitant removal of water azeotropically using Dean Stark. The reaction mixture was cooled to room temperature and the organic layer was washed with water (20 mL). The solvent was recovered by distillation. The crude product was obtained as a brown oil in 43.3g (94%) yield; 93.7 % GC purity; Ή NMR (CDCI3) δ 1.67 (m, 2H), 1.74 (m, 2H), 1.83 (m, 2H), 2.67 (t, 2H), 2.99 (t, 2H), 3.83 (s, 3H).

Example 1.2

Cyano-cyclohexyllidene-acetic acid methyl ester:

To a 100 mL round bottom flask fitted with condenser, thermometer pocket, Dean Stark and overhead mechanical stirrer in an oil bath was charged toluene (50 mL), cyclohexanone (10.0 g; 102 mmol) and methyl cyanoacetate (10.1 g; 102 mmol). To the resulting solution benzoic acid (1.7 g; 14 mmol) and ammonium acetate (0.77 g; 10 mmol) was added and refluxed for 7.5 hours with concomitant removal of water azeotropically using Dean Stark. The reaction mixture was cooled to room temperature and the organic layer was washed with water (10 mL). The solvent was recovered by distillation. The crude product was obtained in 17.5 g (95.3%) yield as light brown oil with 92.3 % GC purity.

Example 1.3

Cyano-cyclohexylidene-acetic acid methyl ester:

To a 4 litre round bottom flask fitted with condenser, thermometer pocket, Dean Stark and overhead mechanical stirrer in an oil bath was charged cyclohexane (700 mL), cyclohexanone (100.0 g; 1.02 mol) and methyl cyanoacetate (101.0 g; 1.02 mol). To the resulting solution ammonium acetate (7.38 g; 0.096 mol) was added and refluxed for 4 to 8 hours at 75 to 80°C with concomitant removal of water azeotropically using Dean Stark. The reaction mixture was cooled to room temperature and the organic layer was washed with water (100 mL). The solvent was recovered by distillation. The crude product was obtained in 180 g (98.5%) with purity 95% by GC and was further purified by vacuum distillation. The pure product was obtained in 159.0 g (87.36%) as clear oil with purity 98.9% by GC.

Example 2.1

1-Cyanomethyl-cyclohexanecarbonitrile:

To a 1 litre 4 neck round bottom flask fitted with condenser, thermometer pocket and overhead mechanical stirrer in an oil bath was charged water (37.5 mL) and methanol (300 mL). To the solvent mixture charged sodium cyanide (8.205 g; 167 mmol) followed by methyl-2-cyano-2-cyclohexylidene acetate (25 g; 139.7 mol) slowly with the help of addition funnel. Additional amount of methanol (37.5 mL) was added to the charge vessel to transfer the remaining methyl-2-cyano-2-cyclohexylidene acetate on the addition funnel and wall of the flask. The reaction mixture was refluxed till the completion of the reaction (4 hours). Approximately 85 % methanol from the reaction mass was distilled at 80-85°C. To the residue water (75 mL) was added. The reaction mixture was gradually cooled to room temperature and subsequently at 0 to 5°C and stir for 1 hrs. The separated solid was filtered. And washed with water, suck dried the cake for 4 hours. It was further dried in a vacuum oven at dried to get 17.7 g (85.9%) of the title compound with GC purity 99.59%.

Example 2.2

1-Cyanomethyl-cyclohexanecarbonitrile:

To a 1 litre 4 neck round bottom flask fitted with condenser, thermometer pocket and overhead mechanical stirrer in an oil bath was charged water (75 mL) and methanol (575.0 mL). To the solvent mixture charged sodium cyanide (90.26 g; 1.84 mol) followed by methyl-2-cyano-2-cyclohexylidene acetate (300 g; 1.676 mol) slowly with the help of addition funnel. Additional amount of methanol ( 100 mL) was added to the charge vessel to transfer the remaining methyl-2-cyano-2-cyclohexylidene acetate on the addition funnel and wall of the flask. The reaction mixture was refluxed till the completion of the reaction (4 hours). Approximately 85 % methanol from the reaction mass was distilled at 80 to 85°C. To the residue water ( 150 mL) was added. The reaction mixture was gradually cooled to room temperature and subsequently at 0 to 5°C and stir for 1 hour. The separated solid was filtered and washed with water, suck dried the cake for 4 hours. It was further dried in a vacuum oven at dried to get 225.8 g (90.47%) of the title compound with GC purity 99.69%.

Example 2.3

1-Cyanomethyl-cyclohexanecarbonitrile:

To a 2 litre 4 neck round bottom flask fitted with condenser, thermometer pocket and overhead mechanical stirrer in an oil bath was charged water (1 15 mL) and methanol (935 mL). To the solvent mixture charged sodium cyanide (150.4 g; 3.07 mol) followed by methyl-2-cyano-2-cyclohexylidene acetate (500 g; 2.79 mol) slowly with the help of addition funnel. Additional amount of methanol (100 mL) was added to the charge vessel to transfer the remaining methyl-2-cyano-2-cyclohexylidene acetate on the addition funnel and wall of the flask. The reaction mixture was refluxed till the completion of the reaction (7.5 hours). Approximately 85 % methanol from the reaction mass was distilled at 80 to 85°C. To the residue water (300 mL) was added. The reaction mixture was gradually tooled to room temperature and subsequently at 0 to 5°C and stir for 1 hour. The separated solid was filtered and washed with water, suck dried the cake for 4 hours. It was further .dried in a vacuum oven to get 371.7 g (89%) of the title compound with GC purity 98.6%.

Example 2.4

1-Cyanomethyl-cyclohexanecarbonitrile:

To a 5 litre 4 neck round bottom flask fitted with condenser, thermometer pocket and overhead mechanical stirrer in an oil bath was charged water (210 mL) and methanol ( 1790 mL). To the solvent mixture charged sodium cyanide (208.0 g; 4.213 mol) followed by methyl-2-cyano-2-cyclohexylidene acetate (700 g; 3.857mol) slowly with the help of addition funnel. Additional amount of methanol (lOOmL) was added to the charge vessel to transfer the remaining mefhyl-2-cyano-2-cyclohexylidene acetate on the addition funnel and wall of the flask. The reaction mixture was refluxed till the completion of the reaction. Approximately 85 % methanol from the reaction mass was distilled at 80 to 85 °C. To the residue water (2100 mL) was added and distilled out the remaining methanol from the reaction mass at 85 to 90°C. The reaction mixture was gradually cooled to room temperature and subsequently at 0 to 5°C and stir for 1 hour. The separated solid was filtered and the wash the wet cake with water (700 mL x 2); suck dried the cake for 4 hours to get a wet cake of 646.0 g of 1-cyanomethyl-cyclohexanecarbonitrile. It can be used as such for the next step or can be dried to get 569.5 g (98.95%) of the title compound with GC purity 99.3%. AH the aqueous layers were collected and quenched with freshly prepared 10 to 30 % aqueous Ferric chloride (FeCl₃) solution stored overnight and checked for cyanide before disposal;

Ή NMR (CDC1₃)

δ 1.49, 1.61 (2xm, 4H), 1.67 (m, 1H), 1 68 (m, 2H), 1.85 (m, 1H), 2.11 (m, 2H), 2.69 (s, 2H).

Example 2.5

1-Cyanomethyl-cyclohexanecarbonitrile:

In a 2 litre 4 neck round bottom flask fitted with condenser, thermometer pocket and overhead mechanical stirrer in an oil bath was charged methyl-2-cyano-2-cyclohexylidene acetate (250 g; 1.397mol). A solution of sodium cyanide (75.28 g; 1.54 mol) in water (1200 mL) was added slowly in above reaction mass with help of addition funnel (exotherm observed ~ 25 to 30°C). After the addition was over additional water (50 mL) was added to the charge vessel to wash the remaining sodium cyanide and wall of the flask. The reaction mixture was heated at 105 to 1 10°C and start down ward distillation to remove methanol from the reaction mass till the temperature of the reaction mass reach 95°C (-95 mL methanol and water was removed). The reaction was maintained at this temperature till the starting material and the intermediate almost disappeared. Usually it takes 4 to 8 hrs. The reaction mixture was gradually cooled to the room temperature. The separated solid was filtered on sintered funnel and the cake was washed with water till neutral pH. The wet cake was suck dried for 1 hour and dried to get 192 g (94.1 %) of 1 -cyanomethyl- cyclohexanecarbonitrile with purity 99.10 by GC.

Example 2.6

1-Cyanomethyl-cyclohexanecarbonitrile:

In a 1 litre 4 neck round bottom flask fitted with condenser, thermometer pocket and overhead mechanical stirrer in an oil bath was charged methyl-2-cyano-2-cyclohexylidene acetate (200 g; 1.1 17 mol). A solution of sodium cyanide (55.6 g; 1.13 mol) in water (350 mL) was added slowly in above reaction mass with help of addition funnel (exotherm observed ~ 25 to 30°C). After the addition was over additional water (50 mL) was added'to the charge vessel to wash the remaining sodium cyanide and wall of the flask. The reaction mixture was heated at_. 105 to 1 10°C and start down ward distillation to remove methanol from the reaction mass till the temperature of the reaction mass reach 95°C (1.5 hours). The reaction was maintained at this temperature till the starting material and the intermediate almost disappeared in 3 hours. The reaction mixture was gradually cooled to the room temperature. The separated solid was filtered on sintered funnel and the cake was washed with water till neutral pH. The wet cake was suck dried for 1 hour and dried to get 160.5 g (97.2%) of 1 -cyanomethyl-cyclohexanecarbonitrile with purity 99.99 by GC.

Example 2.7

1-Cyanomethyl-cyclohexanecarbonitrile (from cyclohexanone in one pot):

To a 250 mL round bottom flask fitted with condenser, thermometer pocket, and overhead mechanical stirrer and thermo jacket were charged methanol (50 mL), cyclohexanone (25 g; 255 mmol) and methyl cyanoacetate (25.5 g; 257 mmol). To the resulting solution ammonium acetate (20 g; 259 mmol) and sodium cyanide ( 12.5 g; 255 mmol) were added and heated at 65 to 70°C for 4-5 hrs. The methanol was distilled till the vapor temperature reached to 95°C. The reaction mixture was maintained at this temperature for 9 hours. The reaction mixture was cooled to room temperature. The separated solid was filtered on sintered funnel and the cake was washed with water till neutral pH. The wet cake was suck dried for 1 hour and dried further in a vacuum oven to get 28.68 g (76.0%) of 1 - cyanomethyl-cyclohexanecarbonitrile with purity 94.4% by GC.

Example 3.1

(l-Cyano÷cyclohexyl)-acetic acid:

A 2 litre 4 neck round bottom flask was fitted with, pH meter and, overhead mechanical stirrer and temperature probe. A solution of sodium carbonate (0.40 g, 0.004 mmol) was prepared in demineralised water (550 mL, 30.55 mol) and pH was adjusted to 7.5 by adding IN hydrochloric acid (- 1.0 mL) or a pinch of sodium bicarbonate. The total volume made up to 666 mL using demineralised water. Finely powderd 1-cyanomethyl- cyclohexanecarbonitrile (50 g, 0.33 mmol) was added into the buffer solution under stirring (140 to 150 Rotation Per Minute) at room temperature for 10 minutes. Again the pH was adjusted to 7.5 using IN hydrochloric acid or sodium bicarbonate and stirred for 10 minutes. The enzyme (0.315 g having 1.27 KU specific activity; enzyme load of 8.01 U / g of substrate) was added to the reaction mixture and stirred at 25°C for 24 h. The pH of the reaction was maintained at 7.4 + 0.2 by adding IN hydrochloric acid or solid sodium bicarbonate. After 24 hours the reaction mixture was cooled to room temperature and filtered to recover unreacted dinitrile (15 g). The filtrate was taken into 2 litre 4 necked round bottom flask and chilled at 0 to 2°C and equipped with pH meter and acidified with concentrated hydrochloric acid (~ 35.0 ml) to pH 1 to 2. A white solid product precipitated out which was filtered and washed with water (100 mL) and suck dried to get a wet 1 -cyano-cyclohexyl- acetic acid in 66 % yield with a purity of 86.9% by GC.

Example 3.2

(l-Cyano-cyclohexyl)-acetic acid:

A 2 lit 4 neck round bottom flask was fitted with, pH meter and overhead mechanical stirrer and temperature probe. A solution of sodium bicarbonate (0.40 g, 0.004 mmol) was prepared in demineralised water (550 mL, 30.55 mol) and pH was adjusted to 7.5 by adding IN hydrochloric acid (- 1.0 mL) or a pinch of sodium bicarbonate. The total volume made up to 666 mL using demineralised water. Finely powdered 1-cyanomethyl- cyclohexanecarbonitrile (50 g, 0.33 mmol) was added into the buffer solution under stirring (140 to 150 Rotation Per Minute) at room temperature for 10 minutes. Again the pH was adjusted to 7.5 using IN hydrochloric acid or sodium bicarbonate and stirred for 10 minutes. The enzyme (0.547 g having 1.1 KU specific activity; enzyme load of 12.02 U / g of substrate) was added in the reaction mixture and stirred at 25°C for 24 hours. The pH of the reaction was maintained at 7.4 + 0.2 by adding IN hydrochloric acid or solid sodium bicarbonate. After 24 hours the reaction mixture was cooled to room temperature and filtered to remove unreacted dinitrile (3.2 g). The filtrate was taken into 2 litre 4 necked round bottom flask and chilled at 0 to 2°C and equipped with pH meter and acidified with concentrated hydrochloric acid (~ 35.0 mL) to pH 1 to 2. A white solid product precipitated out which was filtered and washed with water (100 mL) and suck dried to get a wet 1-cyano-cyclohexyl)- acetic acid in 91 % yield with a purity of 92.8% by GC.

Example 3.3

(l-Cyano-cyclohexyl)-acetic acid:

A 2 lit 4 neck round bottom flask was fitted with, pH meter and overhead mechanical stirrer and temperature probe. A solution of sodium bicarbonate (0.40 g, 0.004 mmol) was prepared in demineralised water (550 ml, 30.55 mol) and pH was adjusted to 7.5 by adding IN hydrochloric acid (- 1.0 ml) or a pinch of sodium bicarbonate. The total volume made up to 666 mL using demineralised water. Finely powdered 1 -cyanomethyl- cyclohexanecarbonitrile (50.0 g, 0.33 mmol) was added into the buffer solution under stirring (140 to 150 Rotation Per Minute) at room temperature for 10 minutes. Again the pH was adjusted to 7.5 using IN hydrochloric acid or sodium bicarbonate and stirred for 10 minutes. The enzyme (0.73 g having 1.1 KU specific activity; enzyme load of 16.02 U / g of substrate) was added in the reaction mixture and stirred at 25°C for 24 hours. The pH of the reaction was maintained at 7.4 + 0.2 by adding IN hydrochloric acid or solid sodium bicarbonate. After 24 hours the reaction mixture was cooled to room temperature and filtered to remove trace amount of dinitrile. The filtrate was taken into 2 litre 4 necked round bottom flask and chilled at 0 to 2°C and equipped with pH meter and acidified with concentrated hydrochloric acid (~ 35.0 mL) to pH 1 to 2. A white solid product precipitated out which was filtered and washed with water (100 mL) and suck dried to get a wet l -cyano-cyclohexyl)-acetic acid in 94 yield with a purity of 92.3% by GC.

Example 3.4

(1 -Cyano-cy clohexyl)-acetic acid :

A 2 litre 4 neck round bottom flask was fitted with, pH meter and overhead mechanical stirrer and temperature probe. A solution of sodium bicarbonate (0.40 g, 0.004 mmol) was prepared in demineralised water (550 mL, 30.55 mol) and pH was adjusted to 7.5 by adding IN hydrochloric acid (- 1.0 mL) or a pinch of sodium bicarbonate. The total volume made up to 666 mL using demineralised water. Finely powdered 1-cyanomethyl- cyclohexanecarbonitrile (50.0 g, 0.33 mmol) was added into the buffer solution under stirring (140 to 150 Rotation Per Minute) at room temperature for 10 minutes. Again the pH was adjusted to 7.5 using IN hydrochloric acid or sodium bicarbonate and stirred for 10 minutes. The enzyme (0.365 gm having 1.1 KU specific activity; enzyme load of 8.01 U / g of substrate) was added in the reaction mixture and stirred at 25°C for 24 hours. The pH of the reaction was maintained at 7.4 + 0.2 by adding IN hydrochloric acid or solid sodium bicarbonate. After 24 hours the reaction mixture was cooled to room temperature and filtered to remove unreacted dinitrile (1.2 g). The filtrate was taken into 2 litre 4 necked_. round bottom flask and chilled at 0 to 2^HC and equipped with pH meter and acidified with concentrated hydrochloric acid (~ 35.0 ml) to pH 1 to 2. A white solid product precipitated out which was filtered and washed with water (100 mL) and suck dried to get a wet 1 -cyano-cyclohexyl)- acetic acid in 94% yield with a purity of 93.35% by GC. Example 3.5

(l-Cyano-cyclohexyl)-acetic acid:

A 2 litre 4 neck round bottom flask was fitted with, pH meter and overhead mechanical stirrer and temperature probe. A solution of sodium bicarbonate (0.40 g, 0.004 mmol) was prepared in demineralised water (550 mL, 30.55 mol) and pH was adjusted to 7.5 by adding IN hydrochloric acid (-1.0 mL) or a pinch of sodium bicarbonate. The total volume made up to 666 mL using DM water. Finely powdered 1-cyanomethyl- cyclohexanecarbonitrile (50.0 g, 0.33 mmol) was added into the buffer solution under stirring (140 to 150 Rotation Per Minute) at room temperature for 10 minutes. Again the pH was adjusted to 7.5 using IN hydrochloric acid or sodium bicarbonate and stirred for 10 minutes. The enzyme (0.73 g having 1.1 KU specific activity; enzyme load of 16.02 U / g of substrate) was added in the reaction mixture and stirred at 25°C for 24 hours. The pH of the reaction was maintained at 7.4 + 0.2 by adding IN hydrochloric acid or solid sodium bicarbonate. After 24 hours the reaction mixture was cooled to room temperature and filtered to remove unreacted dinitrile if any. The filtrate was taken into 2 lit 4 necked round bottom flask and chilled at 0 to 2°C and equipped with pH meter and acidified with concentrated hydrochloric acid (~ 35.0 mL) to pH I to 2. A white solid product precipitated out which was filtered and washed with water (100 mL) and suck dried to get a wet l-cyano-cyclohexyl)-acetic acid in 98.5% yield with a purity of 93.8% by GC.

Example 3.6

(l-Cyano-cyclohexyl)-acetic acid:

A 2 litre 4 neck round bottom flask was fitted with, pH meter and overhead mechanical stirrer and temperature probe. A solution of sodium bicarbonate (0.40 g, 0.004 mmol) was prepared in demineralised water (550 mL, 30.55 mol) and pH was adjusted to 7.5 by adding IN hydrochloric acid (-1.0 mL) or a pinch of sodium bicarbonate. The total volume made up to 666 mL using demineralised water. Fine powder of 1-cyanomethyl- cyclohexanecarbonitrile (50.0 g, 0.33 mmol) was added into the buffer solution under stirring (140 to 150 Rotation Per Minute) at room temperature for 10 minutes. Again the pH was adjusted to 7.5 using IN hydrochloric acid or sodium bicarbonate and stirred for 10 minutes. The enzyme (0.365 g having 1.1 KU specific activity; enzyme load of 8.01 U / g of substrate) was added in the reaction mixture and stirred at 35°C for 24 hours. The pH of the reaction was maintained at 7.4 + 0.2 by adding IN hydrochloric acid or solid sodium bicarbonate. After 24 hours the reaction mixture was cooled to room temperature and filtered to recover unreacted dinitrile ( 1.0 g). The filtrate was taken into 2 litre 4 necked round bottom flask and chilled at 0 to 2°C and equipped with pH meter and acidified with concentrated hydrochloric acid (~ 35.0 mL) to pH 1 to 2. A white solid product precipitated out which was filtered and washed with water (100 mL) and suck dried to get a wet l -cyano-cyclohexyl)-acetic acid (69.8 g ; MC 26.6% w/w) in 93% yield based on dry weight with a purity of 95.5% by GC.

Example 3.7

(l-Cyano-cyclohexyl)-acetic acid:

A 2 lit 4 neck round bottom flask was fitted with, pH meter and overhead mechanical stirrer and temperature probe. A solution of sodium bicarbonate (0.40 g, 0.004 mmol) was prepared in demineralised water (550 mL, 30.55 mol) and pH was adjusted to 7.5 by adding IN hydrochloric acid (-1.0 mL) or a pinch of sodium bicarbonate. The total volume made up to 666 ml using demineralised water. Finely powdered 1 -cyanomethyl- cyclohexanecarbonitrile (50.0 g, 0.33 mmol) was added into the buffer solution under stirring ( 140 to 150 Rotation Per Minute) at room temperature for 10 minutes. Again the pH was adjusted to 7.5 using IN hydrochloric acid or sodium bicarbonate and stirred for 10 minutes! The enzyme (0.73 g having 1.1 KU specific activity; enzyme load of 16.02 U / g of substrate) was added in the reaction mixture and stirred at 35°C for 24 hours. The pH of the reaction was maintained at 7.4 + 0.2 by adding IN hydrochloric acid or solid sodium bicarbonate. After 24 hours the reaction mixture was cooled to room temperature and filtered to remove any unreacted dinitrile. The filtrate was taken into 2 litre 4 necked round bottom flask and chilled at 0 to 2°C and equipped with pH meter and acidified with concentrated hydrochloric acid (~ 35.0 ml) to pH 1 to 2. A white solid product precipitated out which was filtered and washed with water (100 mL) .and suck dried to get l-cyano-cyclohexyl)-acetic acid in 98.6% yield based on dry weight with a purity of 97.22% by GC.

Example 3.8

(l-Cyano-cyclohexyl)-acetic acid:

A 2 litre 4 neck round bottom flask was fitted with, pH meter and overhead mechanical stirrer and temperature probe. A solution of sodium bicarbonate (0.40 g, 0.004 mmol) was prepared in demineralised water (550 mL, 30.55 mol) and pH was adjusted to 7.5 by adding IN hydrochloric acid (71.0 mL) or a pinch of sodium bicarbonate. The total volume made up to 666 mL using demineralised water. Finely powdered 1 -cyanomethyl- cyclohexanecarbonitrile (50.0 g, 0.33 mmol) was added into the buffer solution under stirring (140 to 150 Rotation Per Minute) at room temperature for 10 minutes. Again the pH was adjusted to 7.5 using IN hydrochloric acid or sodium bicarbonate and stirred for 10 minutes. The enzyme (0.315 g having 1.27 KU specific activity; enzyme load of 8.01 U / g of substrate) was added in the reaction mixture and stirred at 35°C for 24 hours. The pH of the reaction was maintained at 7.4 + 0.2 by adding IN hydrochloric acid or solid sodium bicarbonate. After 24 hours the reaction mixture was cooled to room temperature and filtered , to remove unreacted dinitrile (15 g). The filtrate was taken into 2 litre 4 necked round bottom flask and chilled at 0 to 2°C and equipped with pH meter and acidified with concentrated hydrochloric acid (~ 35.0 mL) to pH 1 to 2. A white solid product precipitated out which was filtered and washed with water ( 100 mL) and suck dried to get l -cyano-cyclohexyl)-acetic acid in 67.9% yield based on dry weight with a purity of 93.8% by GC.

Example 4.1

2-Aza-spiro[4.5]decane-3-one (Gabalactam):

A sodium salt solution of ( 1 -cyano-cyclohexyl)-acetic (45 g; 0.269 mol) was prepared by dissolving in water (405 mL) and sodium hydroxide ( 12.92 g; 0.32 mol). The resulting solution at pH 12 + 2 was transferred into a one liter autoclave and Raney Nickel 1.25 g (2.5 % WAV) was added. The reaction mass was flushed two times with 5.0 Kg/cm² pressure of nitrogen and then by hydrogen. The reaction mass was heated to ~80°C and subjected to 8.0 Kg/cm hydrogen pressure under stirring. After 8 hours additional quantity of Raney Nickel ( 1.25 g; 2.5% WAV) was added and maintained the reaction at the same temperature and pressure till the starting material disappeared. The heating was stopped and the autoclave was allowed to come to room temperature. The reaction mass was filtered to recover catalyst. The recovered catalyst was washed and separately stored it in water. To the filtrate toluene ( 1000 mL) was added and heated to 80 to 85°C for 2.0 hours. The organic layer was separated and the aqueous layer was transferred to the reaction flask and the extraction repeated with toluene at 80°C under stirring. This extraction operation was carried out for 5 times. Combined toluene layer was distilled and the solid obtained was dried at 45 to 50°C in a vacuum oven to give 36 g (87.8%) 2-aza-spiro[4.5]decane-3-one (Gabalactam) with HPLC purity of 99.5%; mp. 90 to 91°C; Ή NMR (CDC1₃) δ 1.53 (m, 10H), 2.18 (s, 2H), 3.15 (s, 2H), 6.49 (br, NH). Example 4.2

2- Aza-spiro[4.5]decane-3-one (Gabalactam) :

A sodium salt solution of (l-cyano-cyclohexyl)-acetic (308.45 g; 1.84 moles) was prepared by dissolving in 3.0 v water and 1.1 eq. of sodium hydroxide. The resulting solution at pH 12 + was transferred into a two litre autoclave and Raney Nickel 17.5 g (5 % WAV) was added. The reaction mass was flushed two times with 5.0 Kg/cm pressure of nitrogen and then by hydrogen. The reaction mass was heated to ~80°C and subjected to 10.0 Kg/cm² hydrogen pressure under stirring. The reaction was maintained at the same temperature and pressure till the starting material disappeared. The heating was stopped and the autoclave was allowed to come to room temperature. The reaction mass was filtered to recover catalyst. Wash recovered catalyst and separately stored it in water. To the filtrate toluene (1400 mL) was added and heat to 80 to 85°C for 2 hour. The organic layer was separated and the aqueous layer was transferred to the reaction flask and repeated the extraction with toluene at 80°C under stirring. This extraction operation was carried out for 5 to 7 times. Toluene layer was distilled and the solid obtained was dried at 45 to 50°C under vacuum in vacuum oven to give 275 g (97.3%) 2-aza-spiro[4.5]decane-3-one (Gabalactam); mp. 90 to 91 °C; Ή NMR (CDC1₃) δ 1.53 (m, 1 OH), 2.18 (s, 2H), 3.15 (s, 2H), 6.49 (br, NH)

Example 4.3

2-Aza-spiro[4.5]decane-3-one (Gabalactam) from 1-Cyanomethyl- cyclohexanecarbonitrile:

(a) To a 30 litre reactor fitted with, pH meter and overhead mechanical stirrer and temperature probe, a solution of sodium bicarbonate (32 g, 0.38 mmol) was prepared in demineralised water (15.98 L) and pH was adjusted to 7.5 by adding IN hydrochloric acid or sodium bicarbonate as required. The total volume made up to 19.98 L using demineralised water. Finely powdered 1 -cyanomethyl-cyclohexanecarbonitrile (1.5 kg, 10.12 mol) was added into the buffer solution under stirring ( 140 to 150 Rotation Per Minute) at room temperature for 10 minutes. Again the pH was adjusted to 7.5 using IN hydrochloric acid or sodium bicarbonate and the mixture stirred for 10 minutes. The enzyme ( 1 1.0 g having 1.1 KU specific activity; enzyme load of 8.01 U / g of substrate) was added in the reaction mixture and stirred at 25°C for 28 hours. The pH of the reaction was maintained at 7.4 ± 0.2 by adding IN hydrochloric acid (-1.2 kg) or solid sodium bicarbonate. After 24 hours the reaction mixture was cooled to room temperature and filtered to remove any undissolved material. The filtrate was taken into 30 L reactor and chilled at 0 to 2°C and equipped with pH meter and acidified with concentrated hydrochloric acid (~ 1.23 kg) to pH 1 to 2. A white solid product precipitated out which was filtered and washed with water (2 L) and suck dried to get wet l-cyano-cyclohexyl)-acetic acid weighing 2.84 kg (moisture content 43.5%); 97% yield based on dry weight with a purity of 88.2% by GC. The wet cake was dissolved in water containing sodium hydroxide (486 g; 1215 mol) and the total solution was made up to 10.18 kg. The solution was kept at room temperature for several hours (4 to 8 hours) and filtered. The resulting solution showed HPLC assay of monoacid as 12.88%.

(b) The above solution (5590 mL = 720 g of monoacid; 4.31 mol) was charged in a 10 L autoclave and Raney Nickel (43.2 g; 6% w/w) was added. The reaction mass was flushed two times with 5.0 Kg/cm pressure of nitrogen and then by hydrogen. The reaction mass was heated to -80 °C and applied 10.0 Kg/cm² hydrogen pressure under stirring. Maintained the reaction at the same temperature and pressure till the starting material disappeared ( 10 hours). The heating was stopped and the autoclave was allowed to come to room temperature. The reaction mass was filtered to recover catalyst. Wash recovered catalyst and separately stored it in water. To the filtrate toluene (1500 mL) was added and heat to 80 to 85°C for 2 hours. The organic layer was separated and the aqueous layer was transferred to the reaction flask and repeated the extraction with toluene at 80°C under stirring. This extraction operation was carried out for 5 to 7 times. Toluene layer was distilled and the solid obtained was dried at 45 to 50°C under vacuum in vacuum oven to give 515 g (93.63%) 2-aza-spiro[4.5]decane-3-one (Gabalactam) with > 99.5% purity by GC.

Example 4.4

2-Aza-spiro[4.5]decane-3-one (Gabalactam) from 1-Cyanomethyl- cyclohexanecarbonitrile :

The aq. solution obtained in 5.1 (a) (1941 mL = 250 g of monoacid; 1.49 mol) was charged in a 5 litre autoclave and Raney Nickel (25g; 10% w/w) was added. The reaction mass was flushed two times with 5.0 Kg/cm² pressure of nitrogen and then by hydrogen. The reaction mass was heated to -80 °C and applied 10.0 Kg/cm² hydrogen pressure under stirring. Maintained the reaction at the same temperature and pressure for 4 hours. The heating was stopped and the autoclave was allowed to come to room temperature. The reaction mass was filtered to recover catalyst. Wash recovered catalyst and separately stored it in water. To the filtrate sodium chloride (550 g) was added followed by toluene (500 mL) and heated to 80 to 85°C for 2 hours. The organic layer was separated and the aqueous layer was transferred to the reaction flask and repeated the extraction with toluene at 80"C under stirring. This extraction operation was carried out for 3 times. Toluene layer was distilled and the solid obtained was dried at 45-50°C under vacuum in vacuum oven to give 157.5 g (81.9%) 2-aza-spiro[4.5]decane-3-one (Gabalactam) with > 99.5% purity by GC.

Example 4.5

The aq. solution obtained in 5.1 (a) (1630 mL = 210 g of monoacid; 1.257 mol) was charged in a 5 lit autoclave and recovered Raney Nickel (21g; 10% w/w) from 5.2 was added. The reaction mass was flushed two times with 5.0 Kg/cm² pressure of nitrogen and then by hydrogen. The reaction mass was heated to -80 °C and applied 10.0 Kg/cm² hydrogen pressure under stirring. Maintained the reaction at the same temperature and pressure for 4.5 hours. The heating was stopped and the autoclave was allowed to come to room temperature. The reaction mass was filtered to recover catalyst. Wash recovered catalyst and separately stored it in water. To the filtrate. toluene (500 mL) was and heated to 80 to 85°C for 2 hours. The organic layer was separated and the aqueous layer was transferred to the reaction flask and repeated the extraction with toluene at 80°C under stirring. This extraction operation was carried out for 3 times. Toluene layer was distilled and the solid obtained was dried at 45 to 50°C under vacuum in vacuum oven to give 153.9 g (80.0%) 2-aza-spiro[4.5]decane-3-one (Gabalactam) with > 99.5% purity by GC.

Example 4.6

The aq. solution obtained in 5.1 (a) ( 1630 mL = 210 g of monoacid; 1.257 mol) was charged in a 5 litre autoclave and recovered Raney Nickel (21g; 10% w/w) from 5.3 was added. The reaction mass was flushed two times with 5.0 Kg/cm² pressure of nitrogen and then by hydrogen. The reaction mass was heated to -80 °C and applied 10.0 Kg/cm² hydrogen pressure under stirring. Maintain the reaction at the same temperature and pressure for 5.5 hours. The heating was stopped and the autoclave was allowed to come to room temperature. The reaction mass was filtered to recover catalyst. Wash recovered catalyst and separately stored it in water. To the filtrate sodium chloride (480 g) was added followed by toluene (500 mL) was and heated to 80 to 85°C for 2 hours. The organic layer was separated and the aqueous layer was transferred to the reaction flask and repeated the extraction with toluene at 80°C under stirring. This extraction operation was carried out for 4 times. Toluene layer was distilled and the solid obtained was dried at 45 to 50°C under vacuum in vacuum oven to give 160.6 g (87.7%) 2-aza-spiro[4.5]decane-3-one (Gabalactam) with > 99.5% purity by GC.

Example 4.7

(a) To a 30 liter reactor fitted with, pH meter and overhead mechanical stirrer and temperature probe, a solution of sodium bicarbonate (32 g, 0.38 mmol) was prepared in demineralised water (15.98 L) and pH was adjusted to 7.5 by adding IN hydrochloric acid or sodium bicarbonate as required. The total volume made up to 19.98 L using demineralised water. Finely powdered 1 -cyanomethyl-cyclohexanecarbonitrile ( 1.5 kg, 10.12 mol) was added into the buffer solution under stirring (140 to 150 Rotation Per Minute) at room temperature for 10 minutes. Again the pH was adjusted to 7.5 using IN hydrochloric acid or sodium bicarbonate and stirred for 10 minutes. The enzyme ( 1 1.0 g having 1.1 KU specific activity; enzyme load of 8.01 U / g of substrate) was added in the reaction mixture and stirred at 25°C for 28 hours. The pH of the reaction was maintained at 7.4 + 0.2 by adding IN hydrochloric acid (-1.2 kg) or solid sodium bicarbonate. After 24 hours the reaction mixture, was cooled to room temperature and filtered to remove any undissolved material. The filtrate was taken into 30 L reactor and chilled at 0 to 2°C and equipped with pH meter and acidified with concentrated hydrochloric acid (~ 1.23 kg) to pH 1 to 2. A white solid product precipitated out which was filtered and washed with water (2 L) and suck dried to get a wet l -cyano-cyclohexyl)-acetic acid in 3.25 kg (moisture content 53.8%); 88% yield based on dry weight with a purity of 96.02% by GC. The wet cake was dissolved in water containing sodium hydroxide (486 g; 1215 mol) and the total solution was made up to 10.49 kg. The solution was kept at room temperature for several hours (4 to 8 hours) and filtered. The resulting solution showed HPLC assay of monoacid as 1 1.18%.

(b) The solution (1788.9 mL = 200 g of monoacid; 1.198 mol) obtained above was charged in a 5 litre autoclave and recovered Raney Nickel (43.2 g; 6% w/w) from batch 5.4 was added. The reaction mass was flushed two times with 5.0 Kg/cm² pressure of nitrogen and then by hydrogen. The reaction mass was heated to ~80°C and applied 10.0 Kg/cm² hydrogen pressure under stirring. Maintain the reaction at the same temperature and pressure till the starting material disappeared (7 hours). The heating was stopped and the autoclave was allowed to come to room temperature. The reaction mass was filtered to recover catalyst. Wash recovered catalyst and separately stored it in water. To the filtrate sodium chloride (530 g) was added followed by toluene (500.0 mL) was added and heat to 80 to 85°C for 2 hours. The organic layer was separated and the aqueous layer was transferred to the reaction flask and repeated the extraction with toluene at 80°C under stirring. This extraction operation was carried out for 4 times. Toluene layer was distilled and the solid obtained was dried at 45 to 50°C under vacuum in vacuum oven to give 157.38 g (86.15%) 2-aza-spiro[4.5]decane-3-one (Gabalactam) with > 99.5% purity by GC.

Example 4.8

(b) The aqueous solution (1788.9 mL = 200 g of monoacid; 1.198 mol) obtained in batch 5.5 (a) was charged in a 5 L autoclave and recovered Raney Nickel (43.2 g; 6% w/w) from batch 5.5 was added. The reaction mass was flushed two times with 5-0 Kg/cm pressure of nitrogen and then by hydrogen. The reaction mass was heated to -80 °C and applied 10.0 Kg/cm² hydrogen pressure under stirring. Maintain the reaction at the same temperature and pressure till the starting material disappeared (8 hours). The heating was stopped and the autoclave was allowed to come to room temperature. The reaction mass was filtered to recover catalyst. Wash recovered catalyst and separately stored it in water. To the filtrate sodium chloride (530 g) was added followed by toluene (500 mL) was added and heat to 80 to 85°C for 2 hours. The organic layer was separated and the aqueous layer was transferred to the reaction flask and repeated the extraction with toluene at 80°C under stirring. This extraction operation was carried out for 4 times. Toluene layer was distilled and the solid obtained was dried at 45 to 50°C under vacuum in vacuum oven to give 155.6 g (86.45%) 2-aza-spiro[4.5]decane-3-one (Gabalactam) with > 99.5% purity by GC.

Example 4.9

2-Aza-spiro[4.5]decane-3-one (Gabalactam) from cyano cyclohexane-l-acetic acid or its salt:

Cyano cyclohexane- l -acetic acid wet (129 g of 58.51 % solution≡ 75g as 100% basis) in water (5 vol) and sodium hydroxide (1.1 eq) is charged to pre-cleaned autoclave (pH of solution 13.5). Then 10% (7.5 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 19.5 hours at 80°C with a hydrogen pressure of 10 kg /cm². The reaction mass filtered after the completion of reaction to remove Raney Nickel. Gabalactam is isolated by toluene extraction. The aqueous layer saturated with sodium chloride (18 g). Lactam is isolated by toluene extractions (3x 150 mL) at 50 to 60°C. The molar yield is 90.5% with purity of > 99%.

Example 4.10

Sodium salt of cyano cyclohexane-1 -acetic acid solution (1500 g of 16% solution≡ 240g as 100% basis) in water (pH of solution 13.5) and is charged to pre-cleaned autoclave. Then 10% (24 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated at 80°C for 18 hours with a hydrogen pressure of 10 kg /cm^2' The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The aqueous layer saturated with sodium chloride (245 g). Gabalactam is isolated by toluene extractions (3x 150 mL) at 50 to 70°C. The molar yield is 91.9% with purity of >99%.

Example 4.11

Barium salt of cyano cyclohexane- 1 -acetic acid (645 g of 15.5% solution≡ 100 g as 100% basis) in water (pH of solution 13.5) and is charged to pre-cleaned autoclave. Then 10% (10 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated at 80°C for 20 hours with a hydrogen pressure of 10 kg /cm . The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The aqueous layer saturated with sodium chloride (125 g). Gabalactam is isolated by toluene extraction (3 x300 mL) at 50°C. The molar yield of gabalactam is 90% with purity of >99%.

Example 5.1

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin):

Ammonium salt of 1 -cyano cyclohexane-1 -acetic acid (641.84 g of 7.79% content≡ 50g as 100% basis) in water (enzymatic hydrolysis mass as such, pH -7.5) is charged to pre- cleaned autoclave. Then 15% (7.5 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 4 hours at 60°C and 1 hour at 50°C with a hydrogen pressure of 15.0 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dicholoromethane (2x25 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 62 g having moisture content 28.59%; the molar yield is 86.3% on dry basis. The purity of gabapentin is 93.2 % a/a with gabalactam of 3.45 % a/a, 1 -carboxy cyclohexane-acetic acid of 0.02% a/a and 1-cyano cyclohexane- 1 -acetic acid of 0.94% a/a. The dichloromethane layer upon evaporation gave additionally about 4.5% (molar yield) of gabalactam.

Ή NMR 300 MHz (D₂0): δ 1.3 - 1.6 (m, 10H), δ 2.3 - 2.4 (s, 2H), δ 2.8 - 2.9 (s, 2H). Example 5.2

(l-Aminomethyl-cyclohexane)-acetic acid (gabapentin)

Ammonium salt of 1-cyano-cyclohexyl-acetic acid (516.8 g of 7.74% content≡ 40g as 100% basis) in water (enzymatic hydrolyzed mass as such, pH 7.4) is charged to pre-cleaned autoclave. Then 15% (6 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 4 hours at 60°C and 2 hours at 50°C with a hydrogen pressure of 10 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dichloromethane (2 x 20 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 59 g having moisture 25.5%; the molar yield is 85.68%. The purity of gabapentin 94.43% a/a , 1 - carboxy cyclohexyl-acetic acid 0.02% a/a, gabalactam of 1.62% a/a and 1-cyano-cyclohexyl- acetic acid of 0.9% a/a. The dichloromethane layer upon evaporation gave additionally about 3% (molar yield) of gabalactam.

Example 5.3

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin)

Ammonium salt of 1-cyano cyclohexane- 1 -acetic acid (512.82 g of 19.5% content≡ lOOg as 100% basis) in water (enzymatic hydrolyzed mass after partial concentration, pH 7.52) is charged to pre-cleaned autoclave. Then 15% (15 g, on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 4 hours at 60°C with a hydrogen pressure of 15 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is extracted with dicholoro methane (2x50mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 1 16.5 g having moisture 26%; the molar yield is 84.3%. The purity of gabapentin is 93% a/a with gabalactam of 0.95% a/a. The dichloromethane layer upon evaporation gave additionally about 6% (molar yield) of gabalactam.

Example 5.4

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin)

Isolated wet 1-cyano cyclohexane-1 -acetic acid (689.5 g of 65.26% content≡ 450 g as 100% basis) in methanolic ammonia in five volumes is charged to pre-cleaned autoclave. Then 45.0 g of dry or active basis ( 15% based on input) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 16 hours at 60°C with a hydrogen pressure of 10 kg/cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 388.8 g, the molar yield is 84.3%.

Example 5.5

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin)

Ammonium salt of 1 -cyano cyclohexane-1 -acetic acid (493.6 g of 15.60% content≡ 77g as 100% basis) in water (obtained by extractive acidification of enzyme reaction output to 1 -cyano cyclohexane- 1 -acetic acid which was extracted in methyl isobutyl ketone followed by extraction with aqueous ammonia - pH -7.6) is charged to pre-cleaned autoclave. Then 15% (1 1.55 gram, on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 4 hours at 60°C and 2 hours at 50°C with a hydrogen pressure of 15 kg /cm². The reaction mass is filtered over hyflo bed or equivalent after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dicholoro methane (2x38.5mL).The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 78 g having moisture 7.49%, the molar yield is 91.33%. The purity of gabapentin is 96% a/a with gabalactam 0.9% a/a. The dichloromethane layer upon evaporation gave additionally about 6% (molar yield) of gabalactam.

Example 5.6

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin)

Ammonium salt of 1 -cyanocyclohexane- l -acetic acid (277.5 g of 18.02% content≡ 50g as 100% basis) in water (obtained by acidification of enzyme reaction output to 1-cyano cyclohexane-1 -acetic acid which was extracted in methyl isobutyl ketone followed by extraction with aqueous ammonia - pH -7.6) is charged to pre-cleaned autoclave. Then 15% recovered (from example 5.10) and 2% fresh (7.5 g + lg, on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 4 hours at 60°C and 4 hours at 50°C with a hydrogen pressure of 15 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate washed with dicholoromethane (2x50mL). The aqueous layer upon evaporation under vacuum at less than 45°C. gave wet gabapentin of 58.68g having moisture 20.03%; the molar yield is 89%. The purity of gabapentin is 91.47% a/a with gabalactam 0.84% a/a, 1 - cyano cyclohexane-l-acetic acid of 1.2% a a and 1-carboxy cyclohexane-l -acetic acid 0.03% a/a. The dichloromethane layer upon evaporation gave additionally about 5.5% (molar yield) of gabalactam.

Example 5.7

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin)

Ammonium salt of 1 -cyano cyclohexane- l-acetic acid (277.5 g of 18.02% content≡ 50g as 100% basis) in water (obtained by acidification of enzyme reaction output to 1 -cyano cyclohexane-l-acetic acid which was extracted in methyl isobutyl ketone followed by extraction with aqueous ammonia at pH -7.6) is charged to pre-cleaned autoclave. Then 15% recovered (from example 5.12) and 6% fresh ( 10.5g + 3 g on dry or active basis ) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 4 hours at 60°C and 2 hours at 50°C with a hydrogen pressure . of 15 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dicholoromethane (2x50 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 55.42 g having moisture 21.65%; the molar yield is 85%. The purity of gabapentin is 91.94% a/a with gabalactam 2.18% a a, 1 - cyano cyclohexane -1- acetic acid of 0.41 % a/a and 1-carboxy cyclohexane-l-acetic acid 0.05% a/a. The dichloromethane layer up on evaporation gave additionally about 5% (molar yield) of gabalactam.

Example 5.8

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin)

Cyano cyclohexane - 1- acetic acid wet (171 g of 58.51 % content≡ lOOg as 100% basis) in water (5 vol) and aqueous ammonia ( 1.12 eq) are charged to pre-cleaned autoclave. Then 10% (10 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 8 hours at 60°C with a hydrogen pressure of 10 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The aqueous layer upon evaporation under vacuum at less than 45°C gave 96 g (84.7%) of wet gabapentin (moisture content 9.5%); (purity of gabapentin 84%, gabalactam 12% , 1 -cyano cyclohexane-1 -acetic acid of 1.0% a/a and 1-carboxy cyclohexane-1 -acetic acid 0.5% a/a respectively).

Example 5.9

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin)

Cyano cyclohexane- 1 -acetic acid (1 10 g) in water (1 vol), methanol (4 vol) and methanolic ammonia is charged to pre-cleaned autoclave. Then 10% (1 1 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 26 hours at 60°C with a hydrogen pressure of 10 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The aqueous layer upon evaporation under vacuum at less than 45°C gave 95.0 g (83.1 %) wet gabapentin (moisture content 10.3%). Purity of gabapentin 81 %, along with gabalactam 12%, 1-cyano cyclohexane- 1 -acetic acid of 1.0% a/a and 1-carboxy cyclohexane-1 -acetic acid 0.5% a/a.

Example 5.10

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin)

Ammonium salt 1- cyano cyclohexane-1 -acetic acid (250 g of 20% content≡ 50g as 100% basis) in water (obtained by acidification of enzyme reaction output to 1 -cyano cyclohexane-1 -acetic acid which was extracted in methyl isobutyl ketone followed by extraction with aqueous ammonia at pH ~ 7.5) is charged to pre-cleaned autoclave. Then 15% (7.5 g on dry or active basis) of 10% palladium on carbon is charged to the autoclave and this suspension is hydrogenated for 5 hours at 60°C with a hydrogen pressure of 15.0 kg /cm . The reaction mass is filtered after the completion of reaction to remove palladium. The clear filtrate is washed with dicholoromethane (2x25 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 52.6 g having moisture 22.6%; the molar yield is 80%. The purity of gabapentin is 96.9% a/a with gabalactam of 0.9% a/a 1-carboxy cyclohexane- 1 -acetic acid of 0.03% and 1-cyano cyclohexane- -acetic acid of 0.45% a/a. The dichloromethane layer upon evaporation gave additionally about 6.5% of gabalactam (molar yield). Example 5.11

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin)

Cyano cyclohexane-1 -acetic acid dry (50g) in tetrahydrofuran (50 mL) and water (4200 mL) is charged to pre-cleaned autoclave, pH of the solution 7.6. Then 15% (7.5 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 10 hours at 60°C with a hydrogen pressure of 15 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dicholoromethane (2x25 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 54 g having moisture of 23.5%; the molar yield is 80.52%. The purity of gabapentin is 96.6% a/a with gabalactam of 1 % a/a, 1 -carboxy cyclohexane- 1 -acetic acid of 0.1 1 % a/a and 1 -cyano cyclohexane- 1 -acetic acid of 0.5% a/a. The dichloromethane layer upon evaporation gave additionally about 7.5% of gabalactam (molar yield).

Example 5.12

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin)

Pure solid ammonium salt of 1 -cyanocyclohexane- 1 -acetic acid (50g as 100% basis) in water (5 vol) is charged to pre-cleaned autoclave. Then 15% (7.5 g on dry or active basis) of 15% Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 4 hours at 60°C with a hydrogen pressure of 15.0 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dicholoromethane (2x25 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 58 g having moisture content 20%; the molar yield is 90%. The purity of gabapentin is 98.5% a/a with gabalactam of 0.35% a/a, 1-carboxy cyclohexane-1 -acetic acid of 0.05% and 1-cyano cyclohexane-1 -acetic acid of 0.12% a/a. The dichloromethane layer upon evaporation gave additionally about 2.5% of gabalactam (molar yield).

Example 5.13

1-AminomethyI-l-cyciohexaneacetic acid (gabapentin):

Ammonium salt 1-cyano cyclohexane-1 -acetic acid (250 g of 20% content≡ 50g as 100% basis) in water (Obtained by acidification of enzyme reaction output to 1 -cyano cyclohexane-1- acetic acid which was extracted in methyl isobutyl ketone followed by extraction with aqueous ammonia at pH -7.55) is charged to pre-cleaned autoclave. Then 15% (7.5 g, on dry or active basis) of Rhodium on carbon is charged to the autoclave and this suspension is hydrogenated for 5 hours at 60°C with a hydrogen pressure of 15.0 kg /cm². The reaction mass is filtered after the completion of reaction to remove Rhodium on carbon. The clear filtrate is washed with dicholoromethane (2x25mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 58 g having moisture content 25.5%; the molar yield is 84.2%. The purity of gabapentin is 96.5% a/a with gabalactam of 1.1 % a a, and 1-cyano cyclohexane- 1 -acetic acid of 0.1 % a/a. The dichloromethane layer upon evaporation gave additionally about 6% of gabalactam (molar yield).

Example 5.14

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin):

Ammonium salt 1-cyano cyclohexane- 1 -acetic acid (250 g of 20% content≡ 50g as 100% basis) in water (obtained by acidification of enzyme reaction output to 1 -cyano cyclohexane-1 -acetic acid which was extracted in methyl isobutyl ketone followed by extraction with aqueous ammonia at pH -7.6) is charged to pre-cleaned autoclave. Then 15% (7.5 g on dry or active basis) of platinum metal or platinum oxide is charged to the autoclave and this suspension is hydrogenated for 5 hours at 60°C with a hydrogen pressure of 15.0 kg /cm . The reaction mass is filtered after the completion of reaction to remove platinum metal or platinum oxide. The clear filtrate is washed with dichloromethane (2x25mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 53.5 g having moisture content 25%; the molar yield is 78.2%. The purity of gabapentin is 94.7% a a with gabalactam of 1.4% a/a, 1-cyano cyclohexane- 1 -acetic acid of 0.22% a/a. The dichloromethane layer upon evaporation gave additionally about 9% of gabalactam (molar yield).

Example 5.15

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin):

Cyano cyclohexane- 1 -acetic acid (50g) in water (5 vol) and triethylamine ( 1 , 12 eq, pH of the solution 7.6) is charged to pre-cleaned autoclave. Then 15% (7.5 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 8 hours at 60°C with a hydrogen pressure of 15 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dicholoromethane (2x25 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 59 g having moisture between 28%; the molar yield is 82.8%. The purity of gabapentin is 93% a/a with gabalactam of 2% a a, 1-carboxy cyclohexane-1 -acetic acid of 0.03% and 1-cyano cyclohexane-1 -acetic acid of 0.15% a/a. The dichloromethane layer upon evaporation gave additionally about 6% of gabalactam (molar yield).

Example 5.16

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin):

Ammonium salt 1-cyano cyclohexane-1 -acetic acid (50 g) in isopropyl alcohol (1 vol) and water (4 vol) is charged to pre-cleaned autoclave, pH of the solution 7.5. Then 15% (7.5 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 8 hours at 60°C with a hydrogen pressure of 15 kg /cm . The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dicholoromethane (2x25 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 58 g having moisture content 26%; the molar yield is 83.6%. The purity of gabapentin is 96.1 % a/a with gabalactam of 0.7% a/a, 1 -carboxy cyclohexane-1 -acetic acid of 0.02% and 1-cyano cyclohexane- 1 -acetic acid of 0.01 % a/a. The dichloromethane layer upon evaporation gave additionally about 7% of gabalactam (molar yield). _ί

Example 5.17

l-Aminomethyl=l-cyclohexaneacetic acid (gabapentin):

Ammonium salt of 1- cyano cyclohexane -1- acetic acid (50g), in water (5 volumes, pH of the solution 10.5) and triethylamine (1.12 eq) is charged to pre-cleaned autoclave. Then 15% (7.5 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 6 hours at 60°C with a hydrogen pressure of 15 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dicholoromethane (2x25 mL).The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 49 g having moisture content of 21.7%; the molar yield is 75%. The purity of gabapentin is 95.3% a/a with gabalactam of 1 % a/a, 1-carboxy cyclohexane-1 -acetic acid of 0.05% and 1-cyano cyclohexane-1 -acetic acid of 0.43% a/a. The dichloromethane layer upon evaporation gave additionally about 10% of gabalactam (molar yield). Example 5.18

1-Aminomethyl-l-cycIohexaneacetic acid (gabapentin):

Ammonium salt of 1 -cyano cyclohexane-1 -acetic acid (50g), in water (5 volumes) and diethyl amine (1.02 eq, pH of the solution 1 1) is charged to pre-cleaned autoclave. Then 15% (7.5 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 5 hours at 60°C with a hydrogen pressure of 15 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dicholoromethane (2x25 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 55.9 g having moisture content of 25.9%; the molar yield is 80.7%. The purity of gabapentin is 94.7% a/a with gabalactam of 1.3% a/a, 1 -carboxy cyclohexane- 1 -acetic acid of 0.04% and 1-cyano cyclohexane- 1 -acetic acid of 1.04% a/a. The dichloromethane layer upon evaporation gave additionally about 7% of gabalactam (molar yield).

Example 5.19

1-Aminpmethyl-l-cyclohexaneacetic acid (gabapentin):

Ammonium salt of 1 -cyano cyclohexane- 1 -acetic acid (641.8 g of 7.79% content≡ 50g as 100% basis) in water, (obtained by acidification of enzyme reaction output to 1-cyano cyclohexane-1 -acetic acid which was extracted in methyl isobutyl ketone followed by extraction with aqueous ammonia at pH -7.6) is charged to pre-cleaned autoclave. Then 15% (7.5 g, on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 10 hours at 40°C with a hydrogen pressure of 15.0 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dicholoromethane (2x25 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 61g having moisture 28.33%; the molar yield is 85%. The purity of gabapentin is 96.2% a/a with gabalactam of 0.8% a/a, and 1 - cyano cyclohexane- 1 -acetic acid of 0.13% a/a. The dichloromethane layer upon evaporation gave additionally about 4.5% (molar yield) of gabalactam.

Example 5.20

1-Aminomethyl-l-cyclohexaneacetic acid (gabapentin):

Ammonium salt of 1-cyano cyclohexane- 1 -acetic acid (250 g of 20% content≡ 50g as 100% basis) in water (obtained by acidification of enzyme reaction output to 1 -cyano cyclohexane-1 -acetic acid which was extracted in methyl isobutyl ketone followed by extraction with aqueous ammonia at pH -7.56) is charged to pre-cleaned autoclave. Then 15% (7.5 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 4 hours at 60°C and 4 hours at 50°C with a hydrogen pressure of 10 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with methyl isobutyl ketone (2x25 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 61.35 g having moisture content of 26.66%; the molar yield is 87.7%. The purity of 'gabapentin is 95% a/a with gabalactam of 1.5% a/a. The methyl isobutyl ketone layer upon evaporation gave additionally about 6% (molar yield) of gabalactam.

Example 5.21

1-AminomethyI-l-cyclohexaneacetic acid (gabapentin) :

Ammonium salt of 1 - cyano cyclohexane -1- acetic acid (222.2 g of 22.5% content≡ 50g as 100% basis) in water (obtained by acidification of enzyme reaction output to 1-cyano cyclohexane- 1 -acetic acid which was extracted in methyl isobutyl ketone followed by extraction with aqueous ammonia at pH -7.6) is charged to pre-cleaned autoclave. Then 15% (7.5 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 4 hours at 60°C and 4 hours at 50°C with a hydrogen pressure of 10 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with toluene (2x25 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 62 g having moisture content of 25.5%; the molar yield is 90%. The purity of gabapentin is 95% a/a with gabalactam of 1 .5% a/a. The toluene layer upon evaporation gave additionally about 6% (molar yield) of gabalactam.

Example 5.22

1-Aminoniethyl-l-cyclohexaneacetic acid (gabapentin):

Ammonium salt of 1 -cyano cyclohexane- 1 -acetic acid (285.7 g of 17.5% content≡ 50g as 100% basis) in water (obtained by acidification of enzyme reaction output to 1-cyano cyclohexane- 1 -acetic acid which was extracted in methyl tertiary butyl ether followed by extraction with aqueous ammonia at pH -7.6) is charged to pre-cleaned autoclave. Then 15% (7.5 g on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 4 hours at 60°C and 4 hours at 50°C with a hydrogen pressure of 10 kg /cm². The reaction mass is filtered after the completion of reaction to remove Raney Nickel. The clear filtrate is washed with dicholoromethane (2x25 mL). The aqueous layer upon evaporation under vacuum at less than 45°C gave wet gabapentin of 59 g having moisture content of 23.5%; the molar yield is 88%. The purity of gabapentin is 95% a/a with gabalactam of 1.5% a/a. The dichloromethane layer upon evaporation gave additionally about 6% (molar yield) of gabalactam.

Example 5.23

1-AminomethyI-l-cyclohexaneacetic acid (Gabapentin in one pot from 1-Cyanomethyl- cyclohexanecarbonitrile):

A 2 litre 4 neck round bottom flask fitted with, pH meter and overhead mechanical stirrer and temperature probe. 1-cyanomethyl-cyclohexanecarbonitrile (50.0 g, 0.33 mmol) was charged in water (665 mL) into micronizer and micronized for 30 minutes (observed particle size is 90% less than 175μπι). Charged 3.42 g (specific activity: 0.175 kU/g, enzyme load of 12.15 U / gm of substrate) in one portion at 35 ± 1 °C and adjusted the pH by using dilute ammonia [prepared by mixing 1.0 g (concentrated ammonia) and demineralised water (9 mL)] and N hydrochloric acid (- 1.0 ml) to 7.4 + 0.2. Maintained at 7.4 + 0.2 by adding dilute ammonia solution or hydrochloric acid for 24 hours. The reaction mixture was cooled to 25 to 35°C and filtered to remove trace amount of protein matter. The filtrate was concentrated to about 250 g (~ 22% solution) at less than 45°C under vacuum (650 mm-Hg) and charcoalized the reaction mixture at 40 to 45°C with 15% charcoal with respect to dinitrile (1 -cyanomethyl-cyclohexanecarbonitrile). The said charcoalized reaction mixture was charged to pre-cleaned autoclave. Then 1 1.3 g (on dry or active basis) of Raney Nickel is charged to the autoclave and this suspension is hydrogenated for 5 hours at 60°C and 3 hours at 50°C with a hydrogen pressure of 10 kg /cm². The reaction mass filtered after the completion of reaction to remove catalyst Raney Nickel. The clear filtrate is washed with dichloromethane (2x25mL) at 25 to 30°C. The aqueous layer is treated with dimethyl glyoxime (another option is to use metal scavenger) to reduce the nickel content. Upon evaporation the aqueous layer is concentrated under vacuum at less than 45°C gave wet gabapentin of 66 g having moisture 26.3%; the molar yield is 85.5% on dry basis based on 1- cyanomethyl-cyclohexanecarbonitrile. The purity of gabapentin is 95.16% a/a with gabalactam of 1.28% a/a. The dichloromethane layer upon evaporation gave additionally about 6% (molar yield) of gabalactam.

The following list of abbreviations is used in this invention: a/a : area/area

cm² : Square centimeter

GC : gas chromatography

g : gram

HPLC : high pressure liquid chromatography

Kg : kilogram

KU : kilo unit

L : litre

niL : milliliter

mmol : milimole

mol : mole

NMR : nuclear magnetic resonance spectroscopy

U : unit

Claims

Claims:

(1) An improved process for the preparation of a compound of formula (I),

(I)

which comprises the steps of:

(a) reacting cyclohexanone of formula (II) and alkyl cyanoacetate offormula (III) in presence of a weak base salt with or without an weak organic acid in an organic solvent to get cyano-cyclohexyllidene-acetic acid alkyl ester of formula (IV);

(//) (///) (IV)

wherein R = Alkyl such as methyl, ethyl and the like

(b) reacting 2-cyano-2-cyclohexyllidene-acetic acid alkyl ester of formula (IV) with a suitable cyanide source in suitable solvent to get 1-cyanomethyl-cyclohexanecarbonitrile of formula (V);

(V) (c) converting l-cyanomethyl-cyclohexanecarbonitrile of formula (V) to 1-cyano- cyclohexyl-acetic acid or salts thereof, of formula (VI) with a genetically modified nitrilase enzyme in water at appropriate pH and temperature;

(VI)

wherein

R.2 = hydrogen, alkali metal, alkaline earth metal, ammonium, organic ammonium and the like

(d) reducing 1-cyano-cyclohexyl-acetic acid or salts thereof, of formula (VI) optionally to gabalactam of formula (VII) or gabapentin of formula (I) by catalytic hydrogenation at a suitable pH and elevated temperature in water or in organic solvent or mixture thereof; and

(VII) (I)

(e) hydrolysing gabalactam of formula (VII) to gabapentin of formula (I) via acidic

hydrolysis.

(VII) (!)

(2) The process according to claim 1 , wherein the said weak organic acid used in step (a) is preferably selected from the group consisting of benzoic acid, succinic acid maleic acid, fumaric acid, phthalic acid, acetic acid and the like.

(3) The process according to claim 1 , wherein the said weak base salt used in step (a) is preferably selected, from the group consisting of ammonium acetate, ammonium benzoate, ammonium succinate, alkyl ammonium acetate and the like, more preferably ammonium acetate.

(4) The process according to claim 1 , wherein the said organic solvent in step (a) is selected from the group consisting of chloroform, cyclohexane, toluene, dichloromethane, ethyl acetate, methyl tertiary butyl ether and the mixture thereof.

(5) The process according to claim 1 , wherein the reaction of step (a) is preferably carried out at ambient temperature to reflux temperature, more preferably at reflux temperature.

(6) The process according to claim 1, wherein the crude compound of formula (IV) of the said step (a) can be used as such or can be purified by distillation by different techniques well understood by those skilled in the art.

(7) The process according to claim 1 , wherein the said suitable cyanide source of step (b) is preferably selected from the group consisting of lithium cyanide, potassium cyanide, sodium cyanide and the like, more preferably sodium cyanide and potassium cyanide and most preferably sodium cyanide.

(8) The process according to claim 1 , wherein the said solvent in step (b) is preferably selected from the group consisting of water, methyl alcohol, ethyl alcohol, isopropyl alcohol, cyclohexane and the like or mixture thereof, more preferably water or methyl alcohol or mixture thereof.

(9) The process according to claim 1, wherein the reaction of step (b) preferably carried out at a temperature range between 45°C to 120°C, more preferably 45°C to 1 10°C and most preferably at reflux temperature of the solvent used.

(10) The process according to claim 1 , wherein the mode of preparation of a compound of formula (VI) of step (c) can be defined as; preparing a dispersion of required amount of finely powdered compound of formula (V) that can optionally be achieved by sieving through 50 to 300 mesh and suspended in water or optionally micronzed in water for required period of time and contacting this suspension with the said genetically modified nitrilase enzyme 2-30 U/g of substrate at appropriate pH preferably in the range between 6.5 to 8.0, more preferably at 7.5+ 0.2 under stirring at 25°C to 50°C till the complete consumption of compound of formula (V).

(1 1) The process according to claim 1 , wherein the loading of a compound of formula (V) in reaction of step (c) preferably can be chosen from 50 to 100 g per liter of water; more preferably 65 to 85 g per liter of water.

(12) The process according to claim 1 , wherein the loading of the said genetically modified nitrilase enzyme for the preparation of formula (VI). in reaction used of step (c) preferably used and selected from 4 to 25 U per g of a compound formula (V), more preferably 6 to 20 U per gram of a compound formula (V).

(13) The process according to claim 10, wherein the said pH is maintained by a suitable buffer such as phosphate or acetate buffer or with the addition of suitable acid or base.

(14) The process according to claim 13, wherein the said acid is preferably selected from the group consisting of acetic acid, citric acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like, more preferably hydrochloric acid.

(15) The process according to claim 13, wherein the said base is selected from the group consisting of ammonia, mono, di and tri alkyl amine, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, more preferably sodium bicarbonate.

(16) The process according to claim 1 , wherein the reaction of step (c) is preferably carried out at a temperature range between 25°C to 40°C, more preferably between 28°C to 38°C and most preferably between 30°C to 37°C.

( 17) The process according to claim 1 , wherein the the reaction mixture after the preparation of compound (VI) in step (c) can be used directly for the subsequent step after removal of protein matter and optionally the solution can be concentrated by the removal of 50 to 75% of water or optionally compound of formula (VI) can be isolated by acidification.

(18) The process according to claim 1, wherein the preparation of compound of formula (VI) in step (c) comprises: isolation of a compound of formula (VI) after acidification followed by extraction of a compound of formula (VI) into an organic solvent and subsequently extracting it as its salt in water by using a base.

(19) The process according to claim 18, wherein the said organic solvent is selected from the group consisting of ethyl acetate, chloroform, dichloromethane, methyl tertiary butyl ether, methyl isobutyl ketone, cyclohexane, toluene, butanols and the like.

(20) The process according to claim 18, wherein the said base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, barium hydroxide, ammonium hydroxide, quaternary ammonium hydroxide, primary Ci-Cio alkyl amine, secondary Ci-Cio alkyl amine or tertiary Ci-Cio alkyl amine, wherein the alkyl group can be straight chain, branched chain or cyclic in nature.

(21) The process according to claim 1 , wherein the said reduction of 1-cyano-cyclohexyl- acetic acid (VI) to gabalactam of formula (VII) by the catalytic hydrogenation in step (d) is preferred at pH >10, while in case of the reduction of salts of 1-cyano-cyclohexyl-acetic acid (VI) to gabapentin of formula (I) is preferred at pH < 10.

(22) The process for the preparation of gabalactam of formula (VII) by catalytic hydrogenation of alkali metal or alkaline earth metal salt of 1-cyano cyclohexane-1 -acetic acid of formula (VI) under elevated temperature and hydrogen pressure at particular pH followed by isolation of the gabalactam, which can be isolated as such or saturated with salts followed by extraction by batch process or continuous process with solvents.

(23) The process according to claim 22, wherein the preparation of alkali or alkaline earth metal salts can be as follows: from the isolated 1 -cyano cylohexane- 1 -acetic acid and converting it into its salt or extracting the 1-cyano cylohexane- 1 -acetic acid with an organic solvent followed by extraction with alkali metal or alkaline metal hydroxide or carbonates in water or water contain water miscible solvent; isolated alkali or alkaline earth metal salt of 1- cyano cyclohexane- 1 -acetic acid; or in situ conversion of the ammonium salt of 1-cyano cyclohexane-1 -acetic acid in enzymatic reaction mass as such or partially concentrated, into other alkali and alkaline earth metal salts.

(24) The process according to claim 23, wherein the said organic solvent is selected from the group consisting of methyl isobutyl ketone, dichloromethane, methyl tertiary butyl ether, butanols and the like.

(25) The process according to claim 23, wherein the said water miscible solvent is selected from the group consisting of ethanol, methanol, tetrahydrofuran and the like.

(26) The process according to claim 22, wherein the said alkali metal and alkaline earth metal salts can be made by using of alkali metal base and alkaline earth metal base, which is preferably selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like, more preferably sodium hydroxide.

(27) The process according to claim 22, wherein preferably ammonium salt of 1-cyano cyclohexane-1 -acetic acid from enzymatic reaction mass can be converted in situ into other alkali and alkaline earth salts as such with the total volume or after partial concentration; wherein the preferable concentration can be between 25 to 50%.

(28) The process according to claim 22, wherein the said catalyst is preferably selected from the group consisting of nickel, palladium, ruthenium, rhodium and their different chemical forms and grades optionally fresh or recovered or mixture of fresh and recovered catalyst, more preferably Nickel.

(29) The process according to claim 22, wherein the said reaction temperature preferably can be in the range between 30° to 150°C; more preferably at in the range between 80 to 90°C.

(30) The process according to claim 23, wherein the said solvent preferably can be selected from the group consisting of water, methanol, ethanol, isopropanol, butanolss, tetrahydrofuran or a mixture thereof; more preferably water.

(31) The process according to claim 22, wherein the said hydrogen pressure preferably can be minimum >2.0 kg /cm² or equivalent unit; more preferably hydrogen pressure in the range of 10-20 kg /cm² or equivalent units.

(32) The process according to claim 22, wherein the said pH range of the hydrogenation mixture can be maintained preferably is in the range of 8 to 14; more preferably between 10 to 13.

(33) The process according to claim 22, wherein the said solvent for extraction is preferably selected from the group consisting of toluene, cyclohexane, dichloromethane, chloroform, methyl tertiary butyl ether, methyl isobutyl ketone, butanols and the like, more preferably toluene.

(34) The process according to claim 22 and 23, wherein the most alkali metal or alkaline earth metal can be selected from sodium, potassium or calcium.

(35) An improved process for the preparation of gabapentin of formula (I) or mixture of gabapentin and gabalactam of formula (VII) comprising catalytic hydrogenation of compound (VI) under elevated temperature and hydrogen pressure with particular pH in solvent; the wet gabapentin can be isolated by simple evaporation after removing the catalyst followed by solvent wash to the reaction mass or solvent wash after evaporation to reduce the gabalactam content.

(36) The process according to claim 35, wherein the organic base salt can be obtained as follows:

from the isolated 1 -cyano cylohexane -1- acetic acid and converting it into its salt with appropriate base or extracting the 1-cyano cylohexane-1- acetic acid with a solvent followed by extraction with ammonia or an organic amine in water or water containing water miscible solvent; isolated ammonium or organic amine salt of 1-cyano cyclohexane-1 -acetic acid; treatment of the enzymatic reaction mass containing ammonium salt of 1-cyano cylohexane- 1 - acetic acid with an organic amine; enzymatic reaction mass as such or partially concentrated ammonium salt of 1-cyano cylohexane-1 -acetic acid; enzymatic reaction mass as such or partially concentrated containing ammonium salt of 1-cyano cyclohexane- 1 -acetic acid after charcoal treatment.

(37) The process according to claim 36, wherein the said solvent is preferably selected from the group consisting of methyl isobutyl ketone, dichloromethane, methyl tertiary butyl ether, butanols and the like.

(38) The process according to claim 36, wherein the said water miscible solvent is preferably selected from the group consisting of methanol, ethanol, tetrahydrofuran and the like.

(39) The process according to claim 36, wherein the said ammonium salt of 1-cyano cyclohexane -1- acetic acid concentration preferably can be between 5 to 60%, more preferably between 15 to 30%.

/

(40) The process according to claim 35, wherein the said catalyst is preferably selected from the group consisting of nickel, palladium, ruthenium, rhodium and their different chemical forms and grades optionally fresh or recovered or mixture of fresh and recovered catalyst while the most preferred catalyst is nickel.

(41 ) The process according to claim 35, wherein the said reaction temperature preferably can be in the range between 30° to 150°C, more preferably at in the range between 50° to 60°C.

(42) The process according to claim 36, wherein the said organic solvent is water miscible solvent, which is preferably selected from the group consisting of methanol, ethanol, isopropanol, butanolss, tetrahydrofuran and the like.

(43) The process according to claim 35, wherein the said hydrogen pressure preferably can be minimum >2.0 kg /cm² or equivalent unit; more preferably in the range of 10-20 kg /cm² or equivalent units.

(44) The process according to claim 35, wherein the said pH range of the hydrogenation mixture can be maintained preferably between 5 to 1 1 , more preferably between 7.5 to 1 1.

(45) A process substantially hereinbefore described with reference to the cited embodiments and examples.