DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“ONE-POT PROCESS FOR THE PREPARATION OF GABAPENTIN INTERMEDIATE”

GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block, Madhapur, Hyderabad,
Telangana, INDIA - 500 081

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION:
The present invention relates to a one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, which is a key intermediate for the preparation of gabapentin. Particularly, the present invention relates to a one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, which is simple, economical, user-friendly, safer and commercially viable.

BACKGROUND OF THE INVENTION:
1-(Cyanomethyl) cyclohexane-1-carbonitrile serves as a key precursor for the preparation of gabapentin and having the structure shown below:

Gabapentin, chemically also known as 1-(aminomethyl)-1-cyclohexaneacetic acid, and having the structure shown below:

Gabapentin was disclosed first in US 4,024,175 by Warner-Lambert Co. It is a well-recognized drug used for treatment of epilepsy and other cerebral disorders.

Bioorganic & Medicinal Chemistry Letters (2006), 16(9), 2333-2336 discloses the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile by reflux condensation of cyclohexanone and ethyl cyanoacetate in toluene, subsequent desolvation, exchange of the solvent for ethanol-water and reaction with potassium cyanide. The method has low yield and complex operation, and is not suitable for industrial production.

Advanced Synthesis & Catalysis (2007), 349(10), 1667-1670 discloses condensation of ethyl cyanoacetate and cyclohexanone in anhydrous benzene containing ammonium acetate and glacial acetic acid. The reaction mixture was refluxed and remove water to give crude product, which was purified by column chromatography, and then the condensate is reacted with sodium cyanide in 90% ethanol to obtain 1-(cyanomethyl) cyclohexane-1-carbonitrile. The method has low yield, requires column chromatography for purifying an intermediate, and is not suitable for industrial production.

Although several routes have been developed for the synthesis of 1-(cyanomethyl) cyclohexane-1-carbonitrile, most of them are not commercially viable and not industrially applicable. Hence, the inventors of the present invention provide a one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, which is simple, economical, user-friendly, safer and commercially viable.

OBJECTIVES OF THE INVENTION:
It is an objective of the present invention to overcome the shortcomings of the prior art.
It is an objective of the present invention to provide a one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, which is simple, economical, user-friendly, safer and commercially viable.

It is another objective of the present invention to provide a one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, which avoids multiple work up procedures for preparation of alkyl 2-cyano-2-cyclohexylideneacetate.

It is another objective of the present invention to provide a one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, which avoids the use of additional solvent for purification of alkyl 2-cyano-2-cyclohexylideneacetate.

It is another objective of the present invention to provide a one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, which avoids the use of column chromatographic technique for purification of alkyl 2-cyano-2-cyclohexylideneacetate.

It is yet another objective of the present invention to provide a process for the preparation of gabapentin.

SUMMARY OF THE INVENTION:

According to an aspect of the present invention, there is provided a one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, comprising the steps of:
a) treating cyclohexanone with alkyl cyanoacetate in the presence of an alkaline reacting compound optionally in the presence of a suitable solvent to provide alkyl 2-cyano-2-cyclohexylideneacetate in-situ; and
b) reacting in-situ alkyl 2-cyano-2-cyclohexylideneacetate with a suitable nitrile source in the presence of a suitable solvent to provide 1-(cyanomethyl) cyclohexane-1-carbonitrile.

According to another aspect of the present invention, there is provided a process for the preparation of gabapentin, comprising the steps of:
a) reacting cyclohexanone with alkyl cyanoacetate in the presence of an alkaline reacting compound optionally in the presence of a suitable solvent to provide alkyl 2-cyano-2-cyclohexylideneacetate in-situ;
b) reacting in-situ alkyl 2-cyano-2-cyclohexylideneacetate with a suitable nitrile source in the presence of a suitable solvent to provide 1-(cyanomethyl) cyclohexane-1-carbonitrile; and
c) converting 1-(cyanomethyl) cyclohexane-1-carbonitrile into gabapentin.

DETAILED DESCRIPTION:
The following description is provided to assist in a comprehensive understanding of exemplary embodiments of the invention. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary.
Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness.
The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purpose only and not for the purpose of limiting the scope of the invention as defined by the appended claims and their equivalents.
It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
Features that are described and/or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and/or in combination with or instead of the features of the other embodiments.
It should be emphasized that the term “comprises/comprising” when used in this specification is taken to specify the presence of stated features, steps or components but does not preclude the presence or addition of one or more other features, steps, components or groups thereof.

The term “solvent/ suitable solvent” used in the present invention is selected from the
group comprising of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons; wherein alcohol is selected from
the group consisting of methanol, ethanol, iso-propanol, n-butanol, iso-butanol and the like; ester is selected from the group consisting of ethyl acetate, isopropyl acetate; ketone is selected from the group consisting of acetone, methyl isobutyl ketone, methyl
ethyl ketone; ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, dioxane and the like; halogenated solvent is selected from the group consisting of dichloromethane, chloroform, chlorobenzene, bromobenzene and the like; hydrocarbons is selected from the group consisting of heptane, hexane, cyclohexane, cycloheptane, toluene, xylene, cyclohexane and the like; nitrile is selected from the group consisting of acetonitrile, propionitrile and the like; amide is selected from the group consisting of N,N-dimethylformamide, N,N-dimethyl acetamide and the like; sulfoxide such as dimethyl sulfoxide; sulfone; or mixtures thereof.

Accordingly, the present invention provides a one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, which is simple, economical, user-friendly, safer and commercially viable.

In one embodiment, the present invention provides a process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, comprising the steps of:
a) treating cyclohexanone with alkyl cyanoacetate in the presence of an alkaline reacting compound optionally in the presence of a suitable solvent to provide alkyl 2-cyano-2-cyclohexylideneacetate in-situ; and
b) reacting in-situ alkyl 2-cyano-2-cyclohexylideneacetate with a suitable nitrile source in the presence of a suitable solvent to provide 1-(cyanomethyl) cyclohexane-1-carbonitrile.

The step a) of above process involves the reaction of cyclohexanone with alkyl cyanoacetate in the presence of an alkaline reacting compound optionally in the presence of a suitable solvent and can be carried out at a suitable temperature under appropriate reaction conditions to provide alkyl 2-cyano-2-cyclohexylideneacetate in-situ.

The alkyl cyanoacetate is used in step a) selected from methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, isopropyl cyanoacetate, butyl cyanoacetate and the like; preferably methyl cyanoacetate or ethyl cyanoacetate.

The alkaline reacting compound used in step a) is selected from organic or inorganic base selected from triethylamine, methylamine, ethylamine, isopropyl amine, diisopropylamine, diisopropylethyl amine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethyl amino pyridine, morpholine, pyridine, 2,6-lutidine, sodium acetate, ammonium acetate, potassium acetate, lithium acetate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; preferably, piperidine, sodium acetate or ammonium acetate.

The suitable solvent used in step a) is selected from alcohol such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol and the like; preferably methanol.

The suitable temperature used in step a) is at about 20oC to about 70oC; preferably at about 25oC to about 65oC.

In step a) of above process, water produced in the reaction is optionally removed concomitantly from the reaction mixture.

The step b) of above process involves the reaction of in-situ alkyl 2-cyano-2-cyclohexylideneacetate with a suitable nitrile source in the presence of a suitable solvent under appropriate reaction conditions to provide 1-(cyanomethyl) cyclohexane-1-carbonitrile.

The suitable nitrile source used in step b) is selected from sodium cyanide, potassium cyanide, cuprous cyanide and the like; preferably sodium cyanide or potassium cyanide.

The suitable solvent used in step b) is selected from alcohol such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol, water and the like or mixture thereof; preferably methanol, water or mixture thereof.

The step b) of above process further comprises reacting the in-situ alkyl 2-cyano-2-cyclohexylideneacetate with a suitable nitrile source, wherein the reaction is carried out by the addition of suitable nitrile source in a single lot or lot-wise manner.

In the prior known processes, the process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile involved multiple work up procedures, additional solvent for purification and column chromatography to prepare alkyl 2-cyano-2-cyclohexylideneacetate, which leads to low yields and low purity at high temperatures, cost-ineffective process not suitable for large scale industrial operations.

However, the present invention provides a one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, which avoids multiple work up procedures, additional solvent for purification and column chromatography to prepare alkyl 2-cyano-2-cyclohexylideneacetate and leads to formation of high yields and high purity at lower temperatures, which is cost-effective and suitable for large scale industrial operations.

The above process is illustrated in the following synthetic scheme I:

In an embodiment, the present invention also provides a one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile which can also be practiced in a continuous flow manner.

In another embodiment, the present invention provides a process for the preparation of gabapentin, comprising the steps of:
a) treating cyclohexanone with alkyl cyanoacetate in the presence of an alkaline reacting compound optionally in the presence of a suitable solvent to provide alkyl 2-cyano-2-cyclohexylideneacetate in-situ;
b) reacting in-situ alkyl 2-cyano-2-cyclohexylideneacetate with a suitable nitrile source in the presence of a suitable solvent to provide 1-(cyanomethyl) cyclohexane-1-carbonitrile; and
c) converting 1-(cyanomethyl) cyclohexane-1-carbonitrile into gabapentin.

The step a) of above process involves the reaction of cyclohexanone with alkyl cyanoacetate in the presence of an alkaline reacting compound optionally in the presence of a suitable solvent and can be carried out at a suitable temperature under appropriate reaction conditions to provide alkyl 2-cyano-2-cyclohexylideneacetate in-situ.

The alkyl cyanoacetate used in step a) is selected from methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, isopropyl cyanoacetate, butyl cyanoacetate and the like; preferably methyl cyanoacetate or ethyl cyanoacetate.

The alkaline reacting compound used in step a) is selected from organic or inorganic base selected from triethylamine, methylamine, ethylamine, isopropyl amine, diisopropylamine, diisopropylethyl amine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethyl amino pyridine, morpholine, pyridine, 2,6-lutidine, sodium acetate, ammonium acetate, potassium acetate, lithium acetate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; preferably, piperidine, sodium acetate or ammonium acetate.

The suitable solvent used in step a) is selected from alcohol such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol and the like; preferably methanol.

The suitable temperature used in step a) is at about 20oC to about 70oC; preferably at about 25oC to about 65oC.

In step a) of above process, water produced in the reaction is optionally removed concomitantly from the reaction mixture.

The step b) of above process involves the reaction of in-situ alkyl 2-cyano-2-cyclohexylideneacetate with a suitable nitrile source in the presence of a suitable solvent under appropriate reaction conditions to provide 1-(cyanomethyl) cyclohexane-1-carbonitrile.

The suitable nitrile source used in step b) is selected from sodium cyanide, potassium cyanide, cuprous cyanide and the like; preferably sodium cyanide or potassium cyanide.

The suitable solvent used in step b) is selected from alcohol such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol, water and the like or a mixture thereof; preferably methanol, water or a mixture thereof.

The step b) of above process further comprises reacting the in-situ alkyl 2-cyano-2-cyclohexylideneacetate with a suitable nitrile source, wherein the reaction is carried out by the addition of suitable nitrile source in a single lot or lot-wise manner.

The step c) of above process involves the conversion 1-(cyanomethyl) cyclohexane-1-carbonitrile into gabapentin, which can be carried out by the methods known in the art or as per the process described herein by the present invention.

The above process is illustrated in the following synthetic scheme II:

In another embodiment, the present invention provides the use of one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, in the preparation of gabapentin with high purity and high yield.

In the foregoing section, embodiments are described by way of examples to illustrate the processes of invention. However, these are not intended in any way to limit the scope of the present invention. Variants of the examples that would be evident to a person ordinarily skilled in the art are within the scope of the present invention.

EXAMPLES:
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1:
Preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile
Cyclohexanone (99.04 g), ammonium acetate (4.29 g) and methanol (50 mL) were taken into a clean and dry RBF at 25-35°C. The reaction mass was cooled to 0-5°C, methyl cyanoacetate (100 g) was added and stirred for 4 hrs±15 min at the same temperature. The reaction mass temperature was raised to 45-50°C and the solvent was distilled-off completely under vacuum at below 50°C. Cyclohexanone (5 g) and methanol (50 mL) were added into the reaction mass at 40-50°C and stirred for 2 h ± 15 at the same temperature. The solvent was distilled-off completely at below 50°C. Cyclohexanone (5 g) and methanol (50 mL) were added into the reaction mass at 45-50°C and stirred for 2 h ± 15 at the same temperature. The solvent was distilled-off completely under vacuum at below 50°C. The reaction mass was cooled to 20-30°C, methanol (150 mL) was added, and followed by aqueous sodium cyanide (49.45g of sodium cyanide in 200.0 mL of water) addition into the reaction mass through addition funnel at below 75 °C, rinsed the addition funnel with water (100 mL) and charged the rinse into the reaction mass. The reaction mass was heated to vigorous reflux temperature and stirred under vigorous reflux for 8 to 10 hrs. The reaction mass was cooled to 20-30°C, water (1000 mL) was added and stirred for 2-3 hours at same temperature. The reaction mass was cooled to 0-5°C and stirred 2-3 hours at same temperature. Filtered the slurry mass, washed the material with chilled water (2x200 mL) and dried the wet material under vacuum at 50-55°C to get the title compound. Yield: 84%

Example 2:
Preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile
Cyclohexanone (99.04 g), piperidine (4.29 g) were taken into a clean and dry RBF at 25-35°C. The reaction mass was cooled to 0-5°C, ethyl cyanoacetate (100 g) was added and stirred for 4 hrs±15 min at same temperature. The reaction mass temperature was raised to 45-50°C and the volatile liquids distilled-off the completely under vacuum at below 50°C. Cyclohexanone (5 g) and methanol (50 mL) were added into the reaction mass at 40-50°C and stirred for 2 h ± 15 at the same temperature. The solvent was distilled-off completely at below 50°C. Cyclohexanone (5 g) and methanol (50 mL) were added into the reaction mass at 45-50°C and stirred for 2 h ± 15 at the same temperature. The solvent was distilled-off completely under vacuum at below 50°C. The reaction mass was cooled to 20-30°C, methanol (150 mL) was added, and followed by aqueous potassium cyanide (49.45g of potassium cyanide in 200.0 mL of water) added into the reaction mass through addition funnel at below 75°C, rinsed the addition funnel with water (100 mL) and charged the rinse into the reaction mass. The reaction mass was heated to vigorous reflux temperature and stirred under vigorous reflux for 8 to 10 hrs. The reaction mass was cooled to 20-30°C, water (1000 mL) was added and stirred for 2-3 hours at same temperature. The reaction mass was cooled to 0-5°C and stirred 2-3 hours at same temperature. Filtered the slurry mass, washed the material with chilled water (2x200 mL) and dried the wet material under vacuum at 50-55°C to get the title compound. Yield: 80%

Example 3:
Preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile
Cyclohexanone (208 g) and sodium acetate (4.96 g) were taken into a clean and dry RBF at 25-35°C, then methyl cyanoacetate (200 g) was added into the reaction mass at below 65°C and stirred for 3 to 4 hours at same temperature. The reaction mass temperature was cooled to 25-35oC, water (60 ml) was added and stirred for 15 to 20 mins at same temperature then stopped the stirring and separated the layers. Aqueous sodium cyanide solution (98.92 g of sodium cyanide in 300 ml of water) was added to the reaction mass over a period of 1 hour through addition funnel at below 60oC, rinsed with water (50 ml) and stirred for 30 to 40 min at below 60oC. Heat the reaction mass to vigorous reflux and stirred for 8-10 hours. The reaction mass temperature was cooled to 40-50oC, water (800 ml) was added, stirred for 2-3 hours at 25-35°C, then cooled to 2-8oC and stirred for 2-3 hours at same temperature. The slurry mass was filtered, washed with water and dried at 50-55oC for 12-13 hours to get the title compound.
Yield: 78%

Example 4:
Preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile
Cyclohexanone (208 g) and ammonium acetate (15.16 g) were taken into a clean and dry RBF at 25-35°C, then ethyl cyanoacetate (200 g) was added into the reaction mass at below 65°C and stirred for 3 to 4 hours at same temperature. The reaction mass temperature was cooled to 25-35oC, water (60 ml) was added and stirred for 15 to 20 mins at same temperature then stopped the stirring and separated the layers. Methanol (80 ml) and potassium cyanide (98.92 g) were added to a separate RBF at 25-35oC and stirred for 30 to 45 mins at same temperature. The reaction mass temperature was cooled to 5-15oC, then the above separated organic layer was added to the reaction mass through addition funnel at below 25oC and the funnel rinsed with methanol (20 ml), raise the reaction mass temperature to 25-35oC and stirred for 3 to 4 hours at same temperature. Water (800 ml) was added to the reaction mass, stirred for 2-3 hours at 25-35°C, then cooled to 2-8oC and stirred for 2-3 hours at same temperature. The slurry mass was filtered, washed with water and dried at 50-55oC for 12-13 hours to get the title compound.
Yield: ~81%.

Example 5:
Preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile
Cyclohexanone (208 g) and piperidine (5.14 g) were taken into a clean and dry RBF at 25-35°C, then ethyl cyanoacetate (200 g) was added into the reaction mass at below 65°C and stirred for 3 to 4 hours at same temperature. The reaction mass temperature was cooled to 25-35oC, water (60 ml) was added and stirred for 15 to 20 mins at same temperature then stopped the stirring and separated the layers. Aqueous sodium cyanide solution (98.92 g of sodium cyanide in 300 ml of water) was added to the reaction mass over a period of 1 hour through addition funnel at below 60oC, rinsed with water (50 ml) and stirred for 30 to 40 min at below 60oC. Heat the reaction mass to vigorous reflux and stirred for 8-10 hours. The reaction mass temperature was cooled to 40-50oC, water (800 ml) was added, stirred for 2-3 hours at 25-35°C, then cooled to 2-8oC and stirred for 2-3 hours at same temperature. The slurry mass was filtered, washed with water and dried at 50-55oC for 12-13 hours to get the title compound. Yield: 80%

Example 6:
Preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile
Cyclohexanone (208 g) and ammonium acetate (15.15 g) were taken into a clean and dry RBF at 25-35°C, then ethyl cyanoacetate (200 g) was added into the reaction mass at below 65°C and stirred for 3 to 4 hours while water produced by the reaction was separated. Methanol (80 ml) and sodium cyanide (29.68 g) were added to a separate RBF at 25-35oC and stirred for 30 to 45 mins at same temperature. The reaction mass temperature was cooled to 5-15oC, then the above separated organic layer added to the reaction mass through addition funnel at below 25oC and the funnel rinsed with methanol (20 ml), raise the reaction mass temperature to 25-35oC and stirred for 3 to 4 hours at same temperature. Aqueous sodium cyanide solution (69.24 g of sodium cyanide in 250 ml of water) was added to the reaction mass through addition funnel at below 60oC, rinsed with water (50 ml) and stirred for 30 to 40 min at below 60oC. Heat the reaction mass to vigorous reflux and stirred for 8-10 hours. The reaction mass temperature was cooled to 40-50oC, water (800 ml) was added, stirred for 2-3 hours at 25-35°C, then cooled to 2-8oC and stirred for 2-3 hours at same temperature. The slurry mass was filtered, washed with water and dried at 50-55oC for 12-13 hours to get the title compound. Yield: 80%

Example 7:
Preparation of 1-cyanocyclohexaneacetic acid
To a clean and dry RBF, 1-cyanocyclohexaneacetonitrile (242 g), ethanol (150 g), toluene (536 mL) and anhydrous hydrogen chloride (159 g) were added into the reaction mass at RT. The mixture is held cold for three days, at which point an additional 40 g of hydrogen chloride gas is added. The mixture is stirred cold for an additional four days, at which point the solvent and excess hydrogen chloride are removed by distillation under vacuum, maintaining the flask at below 25°C. The mixture is cooled in an ice bath and water (1500 ml) was added, pH of the reaction mass adjusts to 4-4.5 with aqueous sodium hydroxide and stirred for 24 hours. Toluene (300 mL) was added to the reaction mass, the aqueous and toluene layers separated. Methanol (100 ml) and sodium hydroxide (600 ml) were added to the toluene layer, heated up to 40°C and stirred for four hours. The aqueous layer cooled to 0-5°C, then the pH of the aqueous phase is adjusted to 3 with concentrated hydrochloric acid. The reaction mass filtered and dried to get the title compound. Yield: 78%

Example 8:
Preparation of gabapentin
To a clean and dry RBF, water (600 mL), 1-cyanocyclohexaneacetic acid (100 g), 25% aqueous ammonia (45 g) and ammonium acetate (23 g) were added and stirred for 10 to 20 min at 15-20°C. Degas the reaction mass with nitrogen, transferred to an autoclave, then Raney nickel (15 g) was added and hydrogenated under 15 kg/cm2 pressure at 60-70oC. The reaction mass temperature cooled to RT and pH of the reaction mass adjust to 7-7.5 using acetic acid (23 mL). The reaction mass was filtered through celite, the aqueous layer was evaporated under high vacuum at less than 45°C. The slurry obtained was strip off under high vacuum at less than 45°C with 3 times using toluene. IPA (500 mL) in toluene (600 mL) were added to the reaction mass, stirred for 30 min at 30-40°C, filter, washed with IPA in toluene and dried to get crude compound. IPA (400 mL) was added to the above wet crude compound and stirred for 20 to 30 min at 15-25°C. The reaction mass filtered, washed with IPA and dried to get crude compound. Water (30 mL), methanol (150 mL) and IPA (350 mL) were added to the above crude compound, heated to 50-60°C and stirred for 30min. The reaction mass cooled to 0-10°, stirred for an hour, filter the solid, washed with IPA, suck dry and dried the material under vacuum at below 40°C to get the title compound.
Yield: 75%

Dated this: 18th day of September, 2024.
Signature:
Name: Mr. Rama Rao Javvaji
Patent Agent Reg. No.: IN/PA-1669
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana, INDIA-500 081 ,CLAIMS:We Claim:
1. A one-pot process for the preparation of 1-(cyanomethyl) cyclohexane-1-carbonitrile, comprising the steps of:
a) treating cyclohexanone with alkyl cyanoacetate in the presence of an alkaline reacting compound without any solvent to provide alkyl 2-cyano-2-cyclohexylideneacetate in-situ; and
b) reacting in-situ alkyl 2-cyano-2-cyclohexylideneacetate of step a) with a suitable nitrile source in the presence of a suitable solvent to provide 1-(cyanomethyl) cyclohexane-1-carbonitrile.

2. The process as claimed in claim 1, wherein in step a) the alkyl cyanoacetate is selected from methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, isopropyl cyanoacetate and butyl cyanoacetate; and the alkaline reacting compound is selected from organic or inorganic base.

3. The process as claimed in claim 1, wherein in step a) water produced in the reaction is optionally removed concomitantly from the reaction mixture.

4. The process as claimed in claim 1, wherein in step a) the reaction is carried out at a suitable temperature of about 20oC to about 70oC.

5. The process as claimed in claim 1, wherein in step b) the suitable nitrile source is selected from sodium cyanide, potassium cyanide and cuprous cyanide; and the suitable solvent is selected from alcohol such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol, water or mixtures thereof.

6. The process as claimed in claim 1, wherein in step b) the nitrile source is added either in one or multiple lots.

7. A process for the preparation of gabapentin, comprising the steps of:
a) treating cyclohexanone with alkyl cyanoacetate in the presence of an alkaline reacting compound without any solvent to provide alkyl 2-cyano-2-cyclohexylideneacetate in-situ;
b) reacting in-situ alkyl 2-cyano-2-cyclohexylideneacetate with a suitable nitrile source in the presence of a suitable solvent to provide 1-(cyanomethyl) cyclohexane-1-carbonitrile; and
c) converting 1-(cyanomethyl) cyclohexane-1-carbonitrile into gabapentin.

8. The process as claimed in claim 7, wherein in step a) the alkyl cyanoacetate is selected from methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, isopropyl cyanoacetate and butyl cyanoacetate; and the alkaline reacting compound is selected from organic or inorganic base.

9. The process as claimed in claim 7, wherein in step a) water produced in the reaction is optionally removed concomitantly from the reaction mixture.

10. The process as claimed in claim 7, wherein in step b) the suitable nitrile source is selected from sodium cyanide, potassium cyanide and cuprous cyanide; and the suitable solvent is selected from alcohol such as methanol, ethanol, iso-propanol, n-butanol, iso-butanol, water or mixtures thereof.

Dated this: 18th day of September, 2024.
Signature:
Name: Mr. Rama Rao Javvaji
Patent Agent Reg. No.: IN/PA-1669
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana, INDIA-500 081