FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A NOVEL PROCESS FOR THE PREPARATION OF GABAPENTIN AND INTERMEDIATES THEREOF"
2. APPLICANT:
(a) NAME: Wanbury Limited
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: B-Wing, 10th Floor, BSEL Tech Park, Sector 30 A, Plot No.39/5
& 39/5A, Opp. Vashi Railway Station, Navi- Mumbai- 400 703, Maharashtra, India

FIELD OF THE INVENTION
The present invention relates to an improved process for the manufacture of gabapentin, a compound of formula l,or its ethyl ester. In particular, the process of the present invention discloses novel intermediates that serve as functional groups which on catalytic hydrogenation yields gabapentin, compound of Formula 1, or its ethyl ester in good yield and purity.
BACKGROUND OF THE INVENTION
Gabapentin, l-{aminomethyl)-cycIohexaneaceticacid is a known drug with anti-epileptic and anticonvulsant activity described for the first time in US Patent No 4024175.
WO 2008/004115 and references therein report several methods for the preparation of gabapentin. Several methods are also reported for the purification of gabapentin.
Further, most of the above methods foresee a final step of gabapentin purification that consists in the treatment of an aqueous solution of a gabapentin salt (generally hydrochloride) through a weak basic ionic exchange resin, the complete evaporation of water from the aqueous gabapentin solution eluted from the resin and the crystallization from an alcoholic solvent, generally methanol or methanol/isopropanol or ethanol/ether mixtureswhich may be converted to the Corresponding acid by treatment with a basic ion exchanger.
The inventors have now found an advantageous, efficient and economical alternative process for the preparation of gabapentin of formula 1, by employing novel intermediateswhich can be hydrogenated with lower catalyst loading and with minimum side reactions.
OBJECT OF THE INVENTION
It is therefore the object of the present invention to provide a new process for the preparation of gabapentin.

Another object of this invention, is to prepare novel imidine/iminoether intermediates and calcium salts/ammonium salts of the acid intermediates and their subsequent catalytic hydrogenation to obtain gabapentin in high yield.
SUMMARY OF THE INVENTION
In accordance with the objective, the present invention provides a novel method for the manufacture of gabapentin, compound of Formula l,or its ester in high yield,

Formula 1 obtained via catalytic hydrogenation of imidine /imino ether of formula 3,8 and 9.The novel imidine /imino ether intermediates of Formula 3,8 and 9 are obtained by reacting nitrile of Formula 2or its eater of Formula 7 with an amine of Formula 4 or alcohols respectively.
In another aspect, the present invention discloses the preparation of calcium or ammonium salts of 1-cyano-cyclohexane acetic acid i.e compound of formula 2 which on catalytic hydrogenation yields gabapentin.
Accordingly, in an aspect, the present invention discloses a process for manufacture of gabapentin which comprises the steps of;
1. reacting nitrile of Formula 2 or its ester of Formula 7;

Formula 2 Formula 7
a) with amine of Formula 4(R1R2NH) to obtain imidine intermediate of Formula
3 or its ester of Formula 8respectively; or
b)with alcohols to obtain iminoether of formula 9 or 10 respectively; or

c) with aqueous calcium chloride in presence of a base and a solvent or with alcoholic ammonia to obtain the corresponding calcium salt and ammonium salts respectively; and 2. catalytic hydrogenation of imidines/calcium salt/ammonium salts/iminoethers to obtain gabapentin, compound of Formula 1or its ester.
In an aspect, the imidine intermediate of Formula 3 is treated with aq. calcium chloride to obtain the calcium salt of Formula 6 which on catalytic hydrogenation yields gabapentin.

Formula 6 whereRl,R2 is alkyl from one to six carbon atoms.
In an aspect, the present invention discloses a novel intermediate of Formula 3;

Formula 3 In another aspect, the present invention discloses a novel intermediate of Formula 8;

Formula 8 In yet another aspect, the present invention discloses a novel intermediate of Formula 5a-l;


Formula 5a-1 In yet another aspect, the present invention discloses a novel intermediate of Formula 5b;

Formula 5b In another aspect, the present invention discloses a novel intermediate of Formula 9 and 10;

Formula 9 Formula 10
R, Rl, R2, R3 and R4 in the aforementioned compounds are selected individually from H, alkyl from one to six carbon atoms.
DETAILED DESCRIPTION OF THE INVENTION
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.
The present invention relates to a novel process for the manufacture of Gabapentin, a compound of Formula 1, or its ester through novel imidine and iminoether intermediates

in high yields. The process also relates to preparation of calcium or ammonium salt of 1-cyanocyclohexane acetic acid (compound of formula 2) and its subsequent conversion to gabapentin.
In an embodiment, the process for the preparation of Gabapentin, a compound of Formula 1, or its ester comprises;
1. reacting nitrile of Formula 2 or its ester of Formula 7,

Formula 2 Formula 7
where R3 is alkyl from one to six carbon atoms.
a) with amine of Formula 4 to obtain imidine intermediate of Formula 3 or its ester of
Formula 8 respectively; ;
or
b) with alcohols to obtain iminoether of Formula 9 and 10; or
c) with aqueous calcium chloride solution with a solvent or with alcoholic ammonia to obtain the corresponding calcium or ammonium salts of Formula 5a-1,5b and;
d) catalytic hydrogenation of imidine/iminoether/calcium salt/ammonium salt
intermediates of step 1, in presence of water and a protic solvent, to obtain compound of Formula lor its ester.
In another embodiment, the present invention relates to a process for the preparation of novel imidine and iminoether intermediates.
Accordingly, the process for preparation of novel imidine intermediate include reaction of nitriles of Formula 2or its ester of Formula 7 with suitable amines of general formula 4;


Formula 4 to obtain respective imidines of Formula 3 or Formula 8.

Formula 3 Formula 8
whereR1,R2 and R3 is H,alkyl from one to six carbon atoms.
Alternately, the imidine intermediate of Formula 3 is treated with aq.calcium chloride to obtain the calcium salt of Formula 6.

Formula 6 whereRl,R2is alkyl from one to six carbon atoms.
The amines for the preparation of imidine intermediate of Formula 3 or Formula 6 are selected from ammonia, methyl amine, dimethyl amine etc. Typically, the reaction is carried out in presence of a solvent such as lower alcohols, ether and in presence of a n acid at 0-5°C.
In another embodiment, novel imino ether intermediate is prepared by reaction of nitriles of Formula 2or its ester of Formula 7with suitable alcohols in presence of mineral acid to obtain imino ether of formula 9 or 10.


Formula 9 Formula 10
/here R, R1 is H, alkyl from one to six carbon atoms.
yet another embodiment, nitriles of Formula 2or its ester of Formula 7is reacted with queous calcium chloride in presence of a base and alcohol to obtain calcium salt of Formula 5a-1;

Formula 5a-1
In yet another embodiment, nitriles of Formula 2 or its ester of Formula 7 is reacted with alcoholic ammonia to obtain ammonium salt of Formula 5b;

Formula 5b
The reaction may be conducted in the presence or absence of a solvent, but advantageously in presence of aqueous or organic solvents. For example, but not limited to water, alcohols, ketones, and ethers or their mixtures, preferably alcohols.
R, R1,R2, R3 and R4 in the aforementioned intermediates is H, alkyl from one to six carbon atoms.

The novel imidine/calcium salt/ammonium salt/iminoether intermediates of formula 3,5a-1,5b, 6 and 9 on catalytic hydrogenation directly leads to Gabapentin, whereas, hydrogenation of intermediate of Formula 8 and formula 10 leads to respective ester of gabapentin which on hydrolysis yields gabapentin.
The catalysts used for hydrogenation is selected from palladium, platinum, rhodium, Raney-nickel etc, preferably Raney nickel and the process may be carried out in water and solvent selected from protic solvents such as methanol, ethanol, isopropanol or mixtures thereof. The catalyst loading is in the range of 10-30%.The reaction is preferably performed under hydrogen pressure.
The process for the preparation of gabapentin through the formation of novel intermediates is given below in Scheme I, II and III.
Scheme II:
Scheme I


Scheme III:



Formula 3
In an embodiment, the present invention discloses a novel imidine intermediate of Formula 3;

In another embodiment, the present invention discloses a novel imidine intermediate of Formula 8;

Formula 8
In yet another embodiment, the present invention discloses a novel intermediate of Formula 5a-1;

Formula 5a-1
In yet another embodiment, the present invention discloses a novel intermediate of Formula 5b;

Formula 5b In another embodiment, the present invention discloses a novel intermediate of Formula 9;


Formula 9
In another embodiment, the present invention discloses a novel intermediate of Formula 10,

Formula 10
R, R1, R2, R3 and R4 in the aforementioned compounds are selected individually from H, alkyl from one to six carbon atoms.
In an embodiment, the novel process of the present invention is advantageous in that the imidines serve as functional groups which can be hydrogenated with lower catalyst loading and minimum side reactions. The preparation of ammonium salts (salt of a weak base) and calcium salts (Calcium hydroxide is a non ionic base relative to sodiumhydroxide and potassium hydroxide, moreover, calcium is divalent as compared to monovalent sodium and potassium, influences the solubility, catalyst loading, reaction stoichiometry and reaction period favorably.
In another embodiment, on complete conversion, gabapentin of Formula 1 is crystallized in solvents advantageously selected from aliphatic alcohols like methanol, ethanol, Isopropanol etc.

The process for preparation of gabapetin, compound of formula lor its ester, thus' obtained by the process of present invention is having substantial purity greater than 99%.
Gabapentin of formula 1 or its ester obtained by the process of the present invention may be further converted to its pharmaceutically active salts. Gabapentin or its ester may be thereafter incorporated in a pharmaceutical composition along with suitable pharmaceutical excipients and made into dosage forms such as tablet, capsules etc. for the treatment of for the treatment of epilepsy, to relieve pain, especially neuropathic pain, as well as major depressive disorder.
Having thus described the application with reference to particular embodiments and illustrative examples, those in the art may appreciate modification to the application as described and illustrated that do not depart from the spirit and scope of the application as disclosed in the specification.
The examples are set forth to aid in understanding the application but are not intended to, and should not be constructed to limit its scope in any way.
The following Examples are given for the purpose of illustrating the present embodiments.
Examples
Example 1 : Preparation of (l-carbamimdoylcyclohexyl)acetic acid
Dry HC1 gas was purged through a cooled solution of 91.8 g (550 mmol) (1-cyanocyclohexyl)acetic acid in a mixture of 50 ml methanol and 200 ml diethyl ether under stirring at 0°C for a period of 1 hr. Reaction mixture was maintained for 6hr , then diluted with diethyl ether and solid precipitated was filtered. The crude solid obtained was dissolved in mixture of 400 ml methanol andlOO ml 2M ammonia in alcohol. Reaction mixture was cooled to 0°C and ammonia gas was bubbled for 2 hr. The reaction mixture was maintained for 4hr, filtered and filtrate was concentrated under vacuum. The residue was redissolved in methanol and concentrated till the partial precipitation and diethyl ether was added. The resulting solid was dried under vacuum for 8hr to yield the desired product.

Example 2: Ethyl (l-carbamimdoylcyclohexyl)acetate
Purge dry HC1 gas through a cooled solution of 10.7 g (55 mmol ) Ethyl-(1-cyanocyclohexyl)acetate dissolved in a mixture of 5 ml methanol and 20 ml diethyl ether at 0°C for a period of 1 hr. Maintained the reaction for 6 hr, then dilute with diethyl ether resulting in the precipitation. Digest the reaction mixture for lhr between 0 - 5°C and filtered the product. The crude solid obtained was dissolved in mixture of 40 ml methanol, cool to 0°C and ammonia gas was bubbled for 2 hr. Maintained the reaction mixture for 4 hrs and filter. Filtrate was concentrated under vacuum. The residue was redissolved in methanol and concentrated till partial precipitation and diethyl ether was added. The resulting solid was filtered and dried under vacuum for 8hr to yield the desired product.
Example 3 : Preparation of {l-[imino(methoxy)methyl]cyclohexyl}acetic acid
In a R.B flask, 10 gm 1 -Cyanocyclohexyl acetic acid was dissolved in 20 ml ethanol at a temperature of 0- 5°C. HC1 gas was purged into the reaction mixture and maintained for 5hr. After the completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain 12.2 gm of white crystalline powder.
Example 4 : Preparation of calcium l-cyanocyclohexyl)acetate
To a 10.5g, 50.9 mmol of (l-cyanocyclohexyl)acetic acid was added 20 ml water and cooled the reaction mixture to 15 -20°C. Adjusted the pH to 6.8 to 7.2 followed by gradual addition of aqueous calcium chloride solution(prepared by dissolving 4g calcium chloride in 40 ml water) over a period of 30 minutes. Maintained the reaction mixture for 1 hr between 15-20°C. Filtered the product and washed with 20 ml water. Resulting solid was dried under vacuum between 60 -65°C for 8 hr to yield calcium salt
Example 5: Preparation of ammonium salts
In a R.B flask, 10 gm 1-Cyanocyclohexyl acetic acid was reacted with 10 ml methanolic ammonia and stirred at RT for lhr. the precipitated product was filtered to yield 11.1 gm of white crystalline powder. The product obtained was of 99% purity.

Example6: Hydrogenation of Imidines/Ammonim salts/calcium salts/iminoethers:
In a R.B flask, 40 gm of free acid Imidines/or calcium/ammonium salts/ iminoethers was hydrogenated in an autoclave in the presence of 4 gm 50% wet Raney Nickel catalyst with 10 kg hydrogen pressure for 10 -12 hr. Reaction mixture was filtered and the filtrate was concentrated under vacuum to obtain residue. Residue was dissolved in water and pH was adjusted to 7.1 -7.2 with hydrochloric acid. Reaction mixture was filtered and the filtrate was concentrated to 50% volume and cooled to 5°C. Product precipitated was filtered.

We claim,
1. A process for the preparation of gabapentin, compound of formula 1 ,or its esters thereof;

formula. 1 comprising the steps of; i. reacting nitrile of Formula 2 or its ester of Formula 7,

Formula 2 Formula 7
a) with an amine of Formula 4 to obtain imidine intermediate of Formula 3 and 8;

Formula 3 Formula 8
Or b) with alcohols in presence of acid to obtain iminoether of Formula 9,and 10;


Formula 9 Formula 10
c) with aq. calcium chloride or with alcoholic ammonia to obtain the corresponding calcium or ammonium salt of Formula5a or 5b,

Formula 5a formula 5b
where Rl, R2, R3 and R4 is H, alkyl from one to six carbon atoms. and; ii. Catalytic hydrogenation of imidine/iminoether/calcium salt intermediates of step 1, in presence of water and a protic solvent, to obtain compound of Formula 1 or its ester. 2. The process according to claim 1, wherein, nitrile of Formula 2 or Formula 7 is treated with an amine of Formula 4, in presence of Lewis acid to give intermediate of Formula 3 or Formula 8 respectively;

Formula 3 Formula 8
followed by catalytic hydrogenationto obtain compound of Formula 1 or its ethyl ester.

3. The process according to claim 1 or 2, wherein, an amine of Formula 4 is,

wherein, R1 and R2 is H or alkyl from one to six carbon atoms. 4. The process according to claim 1, wherein, nitrile of Formula 2 or Formula 7 is treated with alcohols in presence of acid to obtain imino ether of formula 9 or 10;

Formula 9 Formula 10
wherein, R, R3 and R4 is H or alkyl from one to six carbon atoms. followed by catalytic hydrogenation to obtain compound of Formula 1 or its ethyl ester.
5. The process according to claim lor 5, wherein, the alcohols are selected from methanol, ethanol, propanol etc in the presence of an acid.
6. The process according to claim 6, wherein, the acid is a mineral acid such as sulphuric acid, hydrochloric acid, phosphoric acid etc.
7. The process according to claim 1, wherein, nitrile of Formula 2 or Formula 7 is reacted with aq. calcium chloride or with alcoholic ammonia to obtain corresponding calcium salts of formula 5a-1 or ammonium salts or formula 5b respectively;

Formula 5a-1 Formula 5b

followed by catalytic hydrogenation to obtain compound of Formula 1 or its ethyl ester.
8. The process according to claim 1, wherein, the alcohol for formation of ammonium salt of formula 5b is selected from methanol, ethanol, isopropanol etc.
9. The process according to any of the preceding claims, wherein, the catalysts used for hydrogenation is selected from palladium, platinum, rhodium, Raney-nickel.
10. The process according to claim 11, wherein, the catalyst used for hydrogenation is Raney-nickel.
11. The process according to claim 11, wherein the hydrogenation is carried out in water andsolvent selected from protic solvents such as methanol, ethanol, isopropanol or mixtures thereof.
12. The process according to in claim 11, wherein the catalyst loading is 10-30%.