Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/54—Spiro-condensed
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• This invention relates to a chemo-enzymatic industrial scale production of gabapen which is used clinically as a therapeutic agent for cerebral disorders.
• 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.
• 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).
• 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.
• 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.
• 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.
• the present invention provides an improved process for the preparation of a compound of formula (I), which comprises the steps of:
• R Alky I such as methyl, ethyl and the like
• Rl hydrogen, alkali metal or alkaline earth metal, ammonium, organic ammonium and the like
• 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.
• 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.
• 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.
• 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.
• step (a) is preferably carried out at ambient temperature to reflux temperature, more preferably at reflux temperature.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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.
• 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,
• 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.
• 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.
• 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
• 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).
• 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.
• 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.
• 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.
• 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
• 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) .
• 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 /cm 2 or equivalent unit; more preferably hydrogen pressure in the range of 10-20 kg /cm 2 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.
• 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
• 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%.
• 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 /cm 2 or equivalent unit; more preferably hydrogen pressure in the range of 10-20 kg /cm 2 or equivalent units.
• step (e) 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.
• step (e) 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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/cm 2 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.
• 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/cm 2 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.
• 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.
• 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.
• 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.
• 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.
• 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 /cm 2 . 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.
• 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 /cm 2 . 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.
• 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 /cm 2 . 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.
• 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 /cm 2 .
• 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.
• 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 /cm 2 .
• 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.
• 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 /cm 2 .
• 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.
• 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).
• 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 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).
• 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).
• 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 /cm 2 . 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).
• 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).
• 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).
• 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). ⁇
• l-Aminomethyl l-cyclohexaneacetic acid (gabapentin):
• 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).
• 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 /cm 2 . 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.
• 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 /cm 2 . 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.
• 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 /cm 2 . 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.
• 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 /cm 2 . 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.

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• 2013
  • 2013-06-18 WO PCT/IB2013/001264 patent/WO2013190357A1/fr not_active Ceased

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