A Process For The Preparation Of Gabapentin Hydrochloride


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Abstract

The present invention relates to a process for the preparation of substantially pure 1-(aminomethyl)-l-cyclohexane acetic acid hydrochloride of formula (II) viz. gabapentin hydrochloride through gabalactam (I) which in turn arises from 3,3-pentamethylene glutarimide of formula (IV). The imide, 3,3-pentamethylene glutarimide of formula (IV) is obtained in a reaction between the diacid and urea under special conditions. The imide thus obtained, without isolation, is subjected to reaction with sodium hypobromite orsodium hypochlorite to yield 2-azaspiro [4,5] decan-3-one (gabalactam) of formula (I), which is transformed to gabapentin hydrochloride (II) by heating with concentrated hydrochloric acid under rigorously worked out conditions. Alternatively, the gabalactam (I) on treatment with dry hydrogen chloride gas in an alcohol preferably isopropyl alcohol yields gabalactam hydrochloride, which is transformed to gabapentin hydrochloride (II) by heating with water. Gabapentin hydrochloride (II) can then be easily converted to gabapentin in a known manner.

Information

Application ID 1845/CHE/2005
Invention Field CHEMICAL
Date of Application
Publication Number 35/2007

Applicants

Name Address Country Nationality
HIKAL LIMITED 32/1 KALENA AGRAHARA BANNERAGHATTA ROAD BANGALORE 560 076 India India

Inventors

Name Address Country Nationality
DR ASHOK PATEL HIKAL LTD PANOLI PLANT PLOT NO 629/630 GIDC INDL.AREA PANOLI India India
SUSHIL KUMAR TIWARI HIKAL LTD PANOLI PLANT PLOT NO 629/630 GIDC INDL.AREA PANOLI India India
MARIADAS ARUL SELVAN 32/1 KALENA AGRAHARA BANNERAGHATTA ROAD BANGALORE 560 076 India India
SUVARNA KRISHNANAND SHENVI 32/1 KALENA AGRAHARA BANNERAGHATTA ROAD BANGALORE 560 076 India India
PATHALINGAPPA HARESH KUMAR 32/1 KALENA AGRAHARA BANNERAGHATTA ROAD BANGALORE 560 076 India India
DR RAJENDRA PERSHAD GUPTA 32/1 KALENA AGRAHARA BANNERAGHATTA ROAD BANGALORE 560 076 India India
DR KUPPUSWAMY NAGARAJAN 32/1 KALENA AGRAHARA BANNERAGHATTA ROAD BANGALORE 560 076 India India
DR LYER VENKATACHALAM SANKAR 36/301 EMAMI NEST 16TH CROSS 8TH MAIN MALLESWARAM BANGALORE 560 003 India India

Specification

A PROCESS FOR THE PREPARATION OF GABAPENTIN HYDROCHLORIDE
Field of invention
The present invention provides a process for the preparation of a substantially pure 1-(aminomethyl)-l-cyclohexane acetic acid hydrochloride (Gabapentin hydrochloride) of formula (II) from an imide obtained in a single-pot process and through a precursor 2-azaspiro [4,5] decan-3-one (Gabalactam) of formula (I).

Background of the invention
Gabapentin is an active ingredient used as an anti epileptic, anti seizure or anti
convulsant medication. Gabapentin has other medical applications also and is now
available as a generic drug. Gabapentin is a generic term used to identify chemical
compound l-(aminomethyl)-l-cyclohexane acetic acid, which is generally isolated from its
hydrochloride salt (II). Gabapentin is useful in therapy of certain cerebral disorders such as
certain forms of epilepsy, faintness, attacks and hypokinesia and carnial traumas.
US 4024175 and 4087544 and DE2460891 cover the compound and its uses. The authors
disclose an acid salt, i.e., gabapentin hydrochloride hydrate and sodium salt of gabapentin
hydrate.
US 4894476 describes gabapentin monohydrate and a process for its production.
The above-mentioned patents describe various processes for the preparation of gabapentin
and similar compounds. These patents depend upon the known methods used for the
preparation of primary amines. Specifically they involve Curtius reaction of cycloalkane-1,
1-diacetic acid monoesters, Hofman reaction of cycloalkane-1, 1-diacetic acid monoamides
or Lossen Rearrangement of 1 -carboxymethylcycloalkane-1 -acetohydroxamic acid
sulfonate esters. In a variation of the last process, Lossen Rearrangement can be carried out
on O-sulfonyloxycycloalkane-1,1-diacetic (N-hydroxy) imides (US 4152326 & Canadian

Patent No. 1085420). All these procedures go through an isocyanate or urethane as intermediates that are converted to the desired l-(aminomethyl)-l- cycloalkane acetic acid by acidic or basic hydrolysis using acids such as hydrochloric acid or suitable bases. The amino acid is then isolated as its hydrochloride and then freed to the base by appropriate treatment with base following methods well known to those skilled in the art. In particular the Hofman reaction solution is acidified with 12 N hydrochloric acid and evaporated to dryness to obtain the amino acid hydrochloride mixed with inorganic salts. In the ensuing years, there have been several patents on other routes which involve the formation of 2-azaspiro[4,5]decan-3-one (I), known conveniently and generally as 'gabalactam'. This compound can be hydrolyzed using 1:1 hydrochloric acid (US 5095567 & 5068413 and W09914184A1) to afford gabapentin hydrochloride in good to acceptable yields. In two other patents the lactam with an extra carboethoxy group has been synthesized and hydrolyzed using 1:1 hydrochloric acid, with concomitant removal of the carboethoxy group to afford gabapentin hydrochloride (US 4956473 & US 4958044). Even though there are several methods for synthesizing this important drug intermediate with out going through the hydrochloride route, by far the most widely used industrial procedure for the production of gabapentin appears to be through the formation of gabapentin hydrochloride (II). Hence, gabapentin hydrochloride forms an important intermediate in the manufacture of gabapentin. Several methods have been known to generate gabapentin from its hydrochloride salt, whatever be the method of choice, finally gabapentin has to be prepared from this very important intermediate viz. gabapentin hydrochloride (II).
2-Azaspiro[4,5]decan-3-one (I) (gabalactam) possesses neuro-protective properties and is useful in the treatment of Huntington's disease, which was demonstrated in transgenic mouse model [Nanyn-Schmiedeberg's Archives of Pharmacology, 2004, 370(2), 131-139]. Further evidence of the neuro-protective properties of gabalactam has been highlighted by Knoerle Rainer in their article in Arzneimittel Forschung, 2004, 54(3), 139-142 and also by Pielen Amelie in their reference Garaefe's Archive for Clinical and Experimental Opthalmology, 2004, 242(3), 240-244.
Furthermore, the thio analogue of gabalactam viz., 2-azaspiro [4,5] undecane-3-thione and related compounds have been shown to exhibit significantly higher analgesic activity than

gabapentin or gabalactam and these compounds have been claimed useful as analgesic and anti-inflammatory agents (WO 2003074486). T. Jehle et al. have shown that gabalactam is neuro-protective in retinal ischemia and diminishes the release of excitatory neuronic amino acid glutamic acid (Opthalmology, 2001, 98(3), 237-241). These references cited indicate the importance of gabalactam as a therapeutically useful entity. 2-Azaspiro[4,5]decan-3-one (Gabalactam) (I) was first prepared and identified by Sircar in 1928 (J. Indian Chem. Soc, 1928, 5, 549), in a multi-step process having a low yield of gabalactam. However, the formation of gabapentin was not realized in the above reaction. There are several methods of synthesis of gabapentin described in literature starting from a variety of starting materials. US 4024175 describes at least three methods for the synthesis of gabapentin and other l-(aminomethyl)-l-cyclohexylacetic acids.
The processes involved are the Hofmann reaction of the monoamide of the diacid of formula (III), the Curtius reaction of the monoester with hydrazoic acid or the Lossen rearrangement of the N-benzene-sulphonyl derivative of the monohydroxamic acid.

The required l-(aminomethyl)-l-cycloalkane acetic acid e.g., gabapentin, is invariably obtained as the acid addition salt and gabapentin, which is isolated from the reaction mixture by cumbersome extraction, ion exchange treatment, evaporation of water, etc., involve high energy consumption and engagement of other infrastructure. US5086413 discloses the hydrolysis of diethyl-1-cyanocyclohexyl malonate to 1-cyanocyclohexyl malonic acid followed by decarboxylation and reduction to gabapentin. US5091567 discloses the synthesis of gabapentin in a five step process comprising reaction of cyclohexanone with triethyl phosphonoacetic acid and a base to produce cyclohexylidene acetate followed by reaction of ethyl cyclohexylidene acetate with nitromethane to produce 1-nitromethyl-l-cyclohexane acetate and reducing the nitro compound with hydrogen in presence of noble metal catalysts to give a mixture of ethyl-1-aminomethyl-1-cyclohexane acetate and 2-azaspiro [4,5] decan-3-one. This mixture is

further treated with hydrochloric acid to obtain gabapentin hydrochloride (II), which is
purified by methods reported in the earlier patents. The process is uneconomical and
involves the use of uncommon chemicals like triethyl phosphonoacetic acid, high-pressure
hydrogenation and expensive noble metal catalysts.
US 5362883 describes another method of preparing gabapentin through gabalactam.
Gabalactam (I) is prepared from 1 -cyanocyclohexane acetonitrile through catalytic
hydrogenation employing hydrogen and noble metal catalysts under high hydrogen
pressure.
European Patent No. 414262 also describes the preparation of gabapentin from gabalactam
(I) by acidic hydrolysis.
US 4024175 discloses preparation of gabapentin by the Hofmann rearrangement of 1,1-
cyclohexanediacetic acid monoamide using sodium hypobromite, a complex mixture of
gabapentin, gabalactam (I) and some unidentified impurities are obtained. In order to
isolate pure gabapentin from such a complex mixture one has to remove (a) unwanted side
products, (b) large quantities of inorganic salts like sodium bromide, sodium chloride, and
(c) high volumes of water. The formation of significant amounts of gabalactam by this
method was invariably a serious drawback for industrial production of gabapentin.
The formation of gabalactam (I) as a side product in the synthesis of gabapentin from N-
benzenesulphonyloxy-1,1 -cyclohexanediacetic acid imide by heating with aqueous
sodium hydroxide has been reported in US 4152326.
It is to be emphasized that the literature procedure (J.G. Handly et al., Aust. J. Chem.,
I960, 13, 129) heats the diacid (0.5 mole) with urea (1.0 mole) in an oil bath at 170 to
180°C for 2-3 hrs to obtain the corresponding imide.
Nagarajan et al. have developed an efficient process for the synthesis of gabalactam (I)
which has been reported in their patent application WO 2004046108. In this patent the
monoamide of 1,1-cyclohexane diacetic acid was added to a solution of bromine in sodium
hydroxide at a very low temperature and then the mixture was heated to 80-85°C for a
period of 10 hours and extracted with toluene to isolate the gabalactam (I). To improve the
efficiency of the process, the aqueous layer resulting after the extraction with toluene was
further heated to 85°C for another 6 hours, cooled and extracted with toluene. The
distillation of the combined toluene layers gave gabalactam (I) in good yield. In this

process, the monoamide has to be first synthesized from 1,1-cyclohexane di acetic acid, which involves the extensive use of ammonia and sulfuric acid resulting in an environmental overload and disposal of large amounts of aqueous ammonium sulfate poses a problem.
Another group of Indian Chemists had described the synthesis of gabalactam (I) in the Indian patent 182685. Gabalactam (I) along with gabapentin was obtained as a mixture when 1,1-cyclohexane diacetic acid monoamide was subjected to the treatment of a hypohalite like sodium hypobromite or sodium hypochlorite.
The method for the isolation of gabalactam (I) was identified from the US 4024175 and following that the Indian Chemists tried to isolate the gabalactam (I) whereby they obtained an impure material. This suggested that gabalactam (I) might be undergoing decomposition during the work up procedure (Organic Reactions Vol. Ill, p. 267, 1946). After elaborate studies the patent holder converted the mixture containing gabapentin and gabalactam along with impurities to gabalactam (I) by treatment with alkali at pH 7.5 at 80°C. The lactam (I) was isolated by laborious extraction procedure into an organic solvent by conventional means. Again as mentioned earlier, the starting monoamide has manufacturing problems.
All the processes described above involve substantial amounts of solvents, water, acid and base, which are unattractive to industry with respect to environmental concerns. Hence it was our objective to find out a safe and efficient process for the synthesis of gabapentin hydrochloride (II) and its intermediate, particularly gabalactam (I).
In a patent application, WO 2004/031126 A2, the reaction of imide of formula (IV) with sodium hypochlorite and sodium hydroxide is reported. The product, gabapentin is isolated by the usual cumbersome procedure.


In a known method (WO 2004 046108), gabalactam (I) is prepared by the Hofmann
reaction of cyclohexane 1,1- diacetic acid mono amide. The later compound was described
by J. Sircar, J. Indian Chem. Soc, 1928, 5, 549 by the dehydration of diacid at a high
temperature in the presence of carcinogenic solvents like ortho-dichlorobenzene and
treating the anhydride thus obtained with liquor ammonia, and acidification with sulfuric
acid.
It is clear from the above-described state of the art that a simple inexpensive method is
needed for the preparation of gabapentin hydrochloride (II), which in turn can be
converted to gabapentin in the most economical manner. The gabapentin hydrochloride salt
(II) thus obtained should enable to be converted to gabapentin of the quality confirming
the stringent specification of Pharmacopoeia forum and more stringent specifications of
individual users.
In contrast to this, according to the teaching of US 6054182 wherein gabalactam (I) is
refluxed with 1:1 HC1 and the solution is evaporated to dryness in vacuo to obtain
gabapentin hydrochloride (II) in 60% yield.
According to US 658146 Bl, the lactam (I) is hydrolyzed by about 22% HC1 and the
gabapentin hydrochloride (II) is obtained in three lots by progressively concentrating in
three steps in 58.2, 18.7 and 8.5% yields.
In US 6521788, the lactam (I) is hydrolyzed by 1:1 HC1 and the solution is evaporated to
dryness to give gabapentin.HCl (II) in 73% yield.
Objects of the present invention
The primary object of the present invention is to provide a process for the preparation of a
substantially pure l-(aminomethyl)-l-cyclohexane acetic acid hydrochloride (Gabapentin
hydrochloride) of formula (II) from an imide obtained in a single-pot process and through
a precursor 2-azaspiro [4,5] decan-3-one (Gabalactam) of formula (I).
An object of the present invention is to provide a process to convert 1,1-cyclohexane di
acetic acid to gabalactam (I) through the imide of fomula (IV) without resorting to
monoamide route.
Another object of the present invention is to provide a process for the preparation of
gabapentin hydrochloride (II) by obtaining directly gabalactam (I) from the imide of
formula (IV).

Another object of the present invention is to provide a process for the preparation of
gabapentin hydrochloride (II) without using the dangerous (corrosive) reagents such as
acetic anhydride and ammonium acetate.
It is a further object of the present invention to provide a process for the preparation of
gabapentin hydrochloride (II) through gabalactam (I) formation and its hydrolysis using
concentrated hydrochloric acid.
Yet another object of the present invention is to provide a process for the preparation of
gabapentin hydrochloride (II) through gabalactam hydrochloride formation and its
hydrolysis using water.
Summary of the invention
The present invention relates to a process for the preparation of substantially pure 1-
(aminomethyl)-l-cyclohexane acetic acid hydrochloride of formula (II) viz. gabapentin hydrochloride through gabalactam (I) which in turn arises from 3,3-pentamethylene glutarimide of formula (IV). The imide, 3,3-pentamethylene glutarimide of formula (IV) is obtained in the reaction between a diacid and urea under special conditions. The imide thus obtained however is not isolated but is subjected to reaction with sodium hypobromite or sodium hypochlorite to yield 2-azaspiro [4,5] decan-3-one (gabalactam) of formula (I), which is transformed to gabapentin hydrochloride (II) by heating with concentrated hydrochloric acid under rigorously worked out condition. Alternatively, the gabalactam (I) on treatment with dry hydrogen chloride gas in alcohol yields gabalactam hydrochloride, which is transformed to gabapentin hydrochloride (II) by heating with water. Gabapentin hydrochloride of formula (II) can then be easily converted to gabapentin in a known manner.
Description of the present invention
Accordingly, the present invention provides a single-pot process for the preparation of a
substantially pure l-(aminomethyl)-l-cyclohexane acetic acid hydrochloride (Gabapentin hydrochloride) of formula (II) from an imide and through a precursor 2-azaspiro [4,5] decan-3-one (Gabalactam) of formula (I).
The embodiments of the present invention are initially described by providing process steps for the preparation of gabalactam of formula (I) or gabalactam hydrochloride followed by conversion of gabalactam (I) or gabalactam hydrochloride to substantially

pure 1 -(aminomethyl)-1 -cyclohexane acetic acid hydrochloride (Gabapentin
hydrochloride) of formula (II).
A single pot process for the preparation of gabapentin hydrochloride (II)
(a) Process steps for obtaining imide (IV)
Initially, the 1,1-cyclohexane diacetic acid, which is treated with urea in the ratio 1:0.3 to 1:0.5 w/w, preferably 1:0.3 w/w, at a moderately high temperature of 90-180°C and preferably from about 120-150°C and most preferably at 140° C and maintaining the said temperature for 1-5 hrs and preferably for about 1-2 hrs. The desired temperature is achieved by using superheated steam. The usage of superheated steam is preferred in this reaction, to avoid hazardous and expensive oil heating systems.
During this process, ammonia and carbon dioxide are evolved which are scrubbed with ice-cold water. Once the gas evolution stops, the reaction mass having the 3,3-pentamethylene glutarimide (IV) is allowed to cool and dissolved in an alkaline solution without isolating the imide (IV). The alkaline solution is selected from an alkali or alkaline earth hydroxides, preferably NaOH or KOH. The imide (IV) prior to dissolution in alkali has a melting point of 165-167°C and purity of 96% (HPLC area %). By way trituration with water and filtration the melting point improves to 169-170°C and the purity to above 99%. The yield of imide (IV) is in the range of 85%. The imide (IV) thus obtained is free from impurities, thereby obviating the requirement of an additional step, which is subjecting the imide (IV) for purification.
(b) Process steps for converting imide (IV) to gabalactam (I)
This solution having the imide (IV) is then heated at a moderate temperature of 80-85°C with an alkaline sodium hypohalite, preferably alkaline sodium hypobromite or sodium hypochlorite and extracting with an aromatic hydrocarbon solvent, to obtain gabalactam (I) in a single pot reaction. The aromatic hydrocarbon solvent is selected from benzene, toluene and xylene, preferably toluene. The organic layer having gabalactam (I) is washed with water and evaporated to obtain gabalactam (I) as a white solid with a purity of 98-99% and melting point 88-90°C and in about 70% yield. This method is a one-pot reaction and no purification of the 3,3-pentamethylene glutarimide (IV) is necessary at this stage and it can proceed to the synthesis of gabalactam (I) of high purity.

The reaction scheme of the present invention using 1,1-cyclohexane diacetic acid and urea to obtain the gabalactam of formula (I), is schematically shown below in Scheme I.
SCHEME I

Observations on acid hydrolysis of gabalactam (I)
The inventors have conducted investigations on the acid hydrolysis of gabalactam (I) at about 100°C, with concentrated hydrochloric acid of various strengths: 1) concentrated hydrochloric acid containing 30-40% HC1 gas w/w in water, 2) 2 volumes of concentrated acid diluted with 1 volume of water, 3) 1 volume of concentrated acid diluted with 1 volume of water, 4) 1 volume of concentrated acid diluted with 2 volumes of water. Additionally one experiment was conducted by heating with concentrated acid in a closed vessel. Since during the hydrolysis, HC1 is consumed, the residual acid loses its potency. To supplement this in one experiment, HC1 gas is bubbled into the vessel and heating continued. The hydrolysis mixtures are analyzed by HPLC. In all these experiments, it is surprisingly observed that the resulting solutions constituted a mixture of gabapentin as HC1 salt and gabalactam (I) in almost a constant ratio of 3: 1.
From these experiments it is apparent that the hydrolysis of gabalactam (I) can be advantageously carried out with concentrated hydrochloric acid and accordingly an optimal procedure is worked out. (c) Process steps for the conversion of gabalactam (I) into gabapentin hydrochloride
(ii)
Gabalactam (I) is refluxed with water containing 30-40% w/w of dry hydrogen chloride gas, and preferably ranging in concentration from 30-36 % w/w of dry hydrogen chloride gas. The preferred ratio of hydrochloric acid to gabalactam (I) ranges from 0.65-2 v/w and preferably from 0.7-1.5v/w. The ideal ratio for obtaining the maximum yield of gabapentin hydrochloride (II) has been found to be 1-1.5 volumes of hydrochloric acid with respect to the weight of gabalactam (I).

The solution is preferably heated at 95-100°C for approximately 15-25 hrs, cooled and then slurried with a hydrocarbon solvent, C5-C8 aliphatic hydrocarbons, preferably high boiling hydrocarbons like the aromatic hydrocarbon solvent like toluene, xylene, or solvents like dioxane, etc., more preferably toluene. The reaction mixture containing the aqueous organic mass is cooled to a temperature ranging from 25-45°C to obtain the maximum yield of gabapentin hydrochloride (II). It is observed that cooling the reaction mass to lower temperature does not have any significant advantage in the yield. On the other hand, the yield of gabapentin hydrochloride (II) and its purity depend on the isolation temperature. The isolation temperature ranges from 25-45°C and most preferably from 35-45°C and the ideal temperature has been found to be 45°C.
The use of organic solvent is justified by the fact that it acts as a purifying medium by removing unwanted impurities arising out of this reaction. The residual hydrochloric acid, water and obnoxious organic material are removed by washing the gabapentin hydrochloride (II) with a solvent like an alkyl, aryl or aralkyl ketone, preferably acetone or methyl ethyl ketone, particularly acetone. A HPLC assisted systematic study of the hydrolysis with various concentrations of hydrochloric acid showed surprisingly very limited variations in the proportion of unhydrolyzed starting material viz. the lactam (I). It is found during this experimentation that additional quantities of the gabapentin hydrochloride (II) can be obtained by further heating of the mother liquor to the desired temperature, followed by cooling and further workup. The total yield of the salt is found to be about 81%, with a purity of 96-98%.
The use of concentrated rather than diluted hydrochloric acid offers a significant advantage. The use of concentrated HC1 allows separating the gabapentin hydrochloride (II) by simple filtration. By simply cooling the hydrolysis solution, gabapentin hydrochloride (II) is obtained in high yield without subjecting the solution to evaporation. The mother liquor after the recovery of the gabapentin hydrochloride (II) still contains some gabapentin hydrochloride (II) and unreacted lactam (I) in the dissolved form, which could not be easily isolated by methods described above. The recovery of the material in the mother liquor involves expensive and industrially hazardous operations such as evaporation of aqueous hydrochloric acid. The mother liquor is treated with hot sodium hydroxide solution to obtain corresponding lactam (I), which is then extracted into a

suitable solvent like toluene and recovered from the extract by evaporation. Considering the additional recovery of gabalactam (I) from the mother liquor, the yield of gabapentin.HCl (II) is found to be 85%.
In another embodiment of the present invention, the conversion of gabalactam (I) into gabapentin hydrochloride (II) is also performed by reacting 1,1-cyclohexane diacetic acid with urea at moderately high temperatures to yield 3,3-pentamethylene glutarimide (IV), which is followed by the dissolution of 3,3-pentamethylene glutarimide (IV) in an alkaline solution and treating with alkaline sodium hypohalite and extracting with an aromatic hydrocarbon solvent, to obtain gabalactam (I). The gabalactam (I) thus obtained is treated with dry hydrogen chloride gas in an alcohol to get gabalactam hydrochloride. The alcohol is selected from methanol, ethanol, 2-propanol, preferably 2-propanol. The gabalactam hydrochloride is dissolved in water and heated at about 95-100°C for about 15-25 hours to get gabapentin hydrochloride (II). The gabapentin hydrochloride (II) is further cooled and slurried at 25-45°C, preferably 35-45° C, and most preferably 45°C, in the presence of a hydrocarbon solvent followed by filtration to obtain crude gabapentin hydrochloride (II). The crude gabapentin hydrochloride (II) is washed with a solvent to obtain pure gabapentin hydrochloride (II).
The complete reaction scheme of the present invention using 1,1-cyclohexane diacetic acid and urea to obtain the gabalactam of formula (I), converting lactam (I) and lactam hydrochloride into gabapentin hydrochloride of formula (II) using concentrated HC1 and water respectively, is schematically shown below in Scheme II.


It is apparent to the persons skilled in the art that process steps of the present invention for the generation of gabapentin hydrochloride (II) and in turn gabapentin can be extended to other l-(aminomethyl)- cycloalkane-1-acetic acid of the general formula (VI) from precursor lactams of general formula (V), through the intermediacy of the hydrochloride salts. Thus the method for the synthesis of the hydrochloride salt from the lactam forms an important part in the synthesis of gabapentin.
In an embodiment of the present invention, a process for the preparation of (1-aminoethyl)-l-cyclohexane acetic acid hydrochloride (generally known as gabapentin hydrochloride) (II) is described, which comprises heating a solution of 2-azaspiro [4,5] decan-3-one (I) (generally known as gabalactam) with concentrated hydrochloric acid

ranging from 30-40% in concentration of hydrogen chloride gas to a temperature of 95-100°C, for a period of 15-25 hours or by heating gabalactam hydrochloride with water and isolating the gabapentin hydrochloride (II) after the addition of any hydrocarbon solvent at temperature ranging from 25-45°C, preferably 35-45°C, and most preferably 45°C to obtain an optimum yield of the product satisfying the purity norms.
It is also an embodiment of the present invention that the steps of reaction to obtain gabapentin hydrochloride (II) of the present invention is accomplished in a single pot synthesis by using a diacid to form a corresponding imide (IV) and lactam (I) and hydrolysis of the lactam (I) to obtain gabapentin hydrochloride (II) without isolating the intermediates. Alternatively, hydrolysis of lactam hydrochloride can be carried out by water to obtain gabapentin hydrochloride (II).
The invention is further defined by reference to the following examples describing in detail the preparation and composition of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of the invention. The process of the present invention is described by the following examples, which are illustrative only and should not be construed as limit to the scope of the reaction in any manner.
Example-1 Preparation of substantially pure 2-azaspiro 14,51 decan-3-one(gabalactam) (I) - using sodium hypobromite
a) A round-bottomed flask equipped with stirrer, thermometer and heating arrangement and scrubber for scrubbing carbon dioxide and ammonia is charged with 1,1-cyclohexane diacetic acid (diacid-200g, 1.00 mol) and urea (60g, LOO mol). The mixture is slowly heated so as to attain a temperature of 90-95 °C when it changes to a molten mass. At this stage evolution of ammonia and carbon dioxide is noticed; the stirrer is started now and the homogeneously stirring mixture is heated to 140°C slowly and steadily over a period of 30-40 minutes. Once the desired temperature is reached, the material is kept stirring at that temperature for a period of 1-2 hours or until the evolution of gases has ceased. The reaction mixture is allowed to cool down to 140°C. If it is cooled further the imide (IV) is obtained as a solid of 96% purity. If the melt is

dropped into water the imide (IV) is precipitated and can be filtered off, purity 99% andm.p. 169-170°C.
b) In another flask equipped with stirrer and cooling facility is charged caustic lye (48%, 400g, 22.2 mol) and heated to 50°C. The reaction mixture obtained above from the condensation of diacid with urea is added to the caustic lye over a period of 1 hour so as to maintain the temperature below 65°C. Once the addition is complete the mixture is stirred vigorously for another 1 hour and cooled to room temperature or 30°C.
c) In another round bottomed flask, caustic lye (300ml) and water (800 ml) are taken and cooled to 0-5°C. The reaction mixture is stirred well and bromine (165g, 1.03 mol) is added slowly keeping the temperature of the reaction below 5°C. Once the bromine addition is completed, the reaction mixture is stirred at this temperature for another 30-45 min.
d) To the hypobromite solution as obtained in step (c), is added the solution obtained in step (b) over a period of 2-3 hours maintaining the temperature of the reaction below 5°C. Once the addition is complete, the reaction mass is stirred for another 1 hour. Slowly the temperature of the reaction mixture is raised to room temperature or up to 30°C. The reaction mixture is heated to 80-85°C and maintained at this temperature for another 2-3 hours. The reaction mass is then cooled to 50-55°C and toluene (330g) is added to the mixture and stirred. The stirring is stopped and allowed to separate into layers. The aqueous layer is extracted with toluene (2 times) and the organic layers are combined. Activated charcoal is added to the toluene layer and stirred at room temperature. Charcoal is removed by filtration and the organic layer is taken up for concentration under vacuum. The solvent is distilled off completely under vacuum to obtain gabalactam (I), m.p 88-90°C and above 99% purity (105-1 lOg, 68-72% or 0.525-0.55 w/w based on diacid input).
Example 2
Preparation of substantially pure 2-azaspiro[4,51decan-3-one(gabalactam) (I) - using sodium hypochlorite
a) A 1 1 round bottomed flask equipped with stirrer, thermometer, heating arrangement and scrubber for carbon dioxide and ammonia is charged with 1,1-cyclohexane diacetic acid (diacid, 200g, 1 mol) and urea (60g, 1 mol). The mixure is slowly heated so as to

obtain a temperature of 70-95°C. When it changes to a molten mass, evolution of ammonia and carbon dioxide is noticed. The stirrer is started now and the homogeneously stirring mixture is heated slowly and steadily to 140°C and maintained at 140°C for 1 hour till the evolution of gases ceases.
b) In another 1 1 round bottomed flask fitted with overhead stirrer, thermometer and condenser, caustic soda lye (48%, 1.1 mol) and water (400g, 22.2 mol) are charged and the solution is heated to 50°C. The molten mass from step (a) is slowly dropped into this solution during lA hour and the temperature of the reaction mixture is kept at 65°C for 2 hours. The solution is cooled to 30°C.
c) In a four-necked 3 1 flask provided with a stirrer, thermometer and condenser caustic lye (310g, 48% 3.7 mole) and water (400g, 22.2 mole) are charged and the flask is cooled down to -5°C. Chlorine gas (78. lg, 1.1 mol) is bubbled in slowly during 2 hour, maintaining the temperature at -5°C to 0°C. The hypochlorite solution is stirred at the same temperature range for another lA hour.
The solution from step (b) is now dropped in during 2 hours, maintaining the temperature at -5 to 0°C. The solution is stirred for a further lA hour. The temperature is then slowly raised to 30°C. Then the temperature is raised to 80-85°C and maintained at that level for 2 hours. The reaction mass is cooled to 50-55°C and extracted with toluene (330g) by stirring together for lA hour. The layers are separated. The aqueous layer is again heated at 80-85°C for 2 hours, cooled to 50-55°C and extracted with toluene (330g) by stirring together for Vi hour. The layers are separated. The aqueous layer is heated once again at 80-85°C for 2 hours, cooled to 50-55°C and extracted with toluene (146g). The combined toluene layers are stirred with activated charcoal (7g) for lA hour at 30°C and filtered through a hyflo bed (10g). The filtrate is washed with water (400ml) three times; the toluene layer is separated and the solvent is distilled off completely to give gabalactam (I), m.p. 88-90°C and purity 98.2% (105-HOg; yield 68-72%).
Example -3
Hydrolysis of gabalactam (I) to gabapentin hydrochloride (II)
A solution of 2-azaspiro [4,5] decan-3-one (I) (gabalactam) (250g) in concentrated
hydrochloric acid (33%w/w, 375 ml) is heated under vigorous stirring to 95-100°C and

maintained at that temperature for 15 hours. The reaction mass is cooled to about 70°C and
toluene (500 ml) is added to it. The stirred mixture is cooled to 25-30°C and aged for 1
hour. The precipitated solid is filtered off to obtain a moist gabapentin hydrochloride (II)
(325g).
The filtrate is heated again to 40°C and the aqueous layer is separated into another flask.
The aqueous mass is now heated to 95-100°C for another 10 hours. The reaction mass is
cooled and toluene (500ml) is added to it. The entire mixture is cooled to 0-5°C and aged
for 1-2 hours. The precipitated solid is filtered off to obtain a second crop of gabapentin
hydrochloride (II) (35g).
The combined salts are slurred with acetone (750ml) at 25-35°C and filtered to obtain
gabapentin hydrochloride (II) (267g) of 96-98% purity by HPLC.
The aqueous hydrochloric acid mother liquor and evaporates from the acetone washings
are made strongly alkaline (pH 12) with 50% sodium hydroxide solution and heated to 80-
85°C. The solution is extracted with toluene. The toluene layer is collected in a separate
vessel. The aqueous layer is mixed with another lot of toluene and heated to 85°C and the
organic layer is removed under hot condition. The combined organic layer is washed with
water and evaporated to dryness to obtain gabalactam (I) (30g). Based on the recovery the
yield of gabapentin hydrochloride (II) is calculated to be 85%.
Example -4 Hydrolysis of gabalactam (I) to gabapentin hydrochloride (II)
A solution of 2-azaspiro [4,5] decan-3-one (I) (gabalactam) (250g) in concentrated hydrochloric acid (33%w/w, 250 ml) is heated under vigorous stirring to 95-100°C and maintained at that temperature for 15 hours. The reaction mass is cooled to about 70°C and toluene (500 ml) is added to it. The stirred mixture is cooled to 40-45 °C and aged for 1 hour. The precipitated solid is filtered off to obtain a moist gabapentin hydrochloride (II) (361g).
The filtrate is heated again to 40°C and the aqueous layer is separated into another flask. The aqueous mass is now heated to 95-100°C for another 10 hours. The reaction mass is cooled and toluene (500ml) is added to it. The entire mixture is cooled to 0-5 °C and aged for 1-2 hours. The precipitated solid is filtered off to obtain a second crop of gabapentin hydrochloride (II) (35g).

The combined salts are slurred with acetone (750ml) at 25-30°C and filtered to obtain
gabapentin hydrochloride (II) (297g) of 96-98% purity by HPLC.
The aqueous hydrochloric acid mother liquor and evaporates from the acetone washings
are made strongly alkaline (pH 12) with 50% sodium hydroxide solution and heated to 80-
85°C. The solution is extracted with toluene. The toluene layer is collected in a separate
vessel. The aqueous layer is mixed with another lot of toluene and heated to 85°C and the
organic layer is removed under hot condition. The combined organic layer is washed with
water and evaporated to dryness to obtain gabalactam (I) (30g). Based on the recovery the
yield of gabapentin hydrochloride (II) is calculated to be 94%.
Example 5 Synthesis of gabapentin.HC1 (II) from gabalactam.HCI
Gabalactam (I) (lOOg) in toluene (400ml) is treated with HC1 gas in isopropanol (25%) (114g) and the precipitated gabalactam hydrochloride is filtered off (110g). The above HC1 salt (15g) is dissolved in water (10ml) and heated to 95°C and maintained at 95-100°C for 15hours. The mass is cooled to 40-45°C and maintained at 40-45°C for 30min. The product is filtered to give 13g (82%) of gabapentin hydrochloride (II) of 98% purity. The filtrate can be heated and cooled as provided in the earlier example to get a further quantity of gabapentin hydrochloride (II). Total yield 88%.
Example 6
Direct synthesis of gabapentin .HO (II) from diacid
Cyclohexane-l,l-diacetic acid (50g) is treated with urea (15g) in xylene (100ml) at about 140°C for 15 hours. Then the mass is cooled to 25-30°C and the slurry is added to aqueous sodium hydroxide solution (lOOg, 12.0% w/w) at less than 50°C over 30 min. The two phase reaction mass is heated to about 60°C and maintained at 60°C for 90 min. Then the mass is cooled to 25-30°C, added to hypobromite solution (prepared by adding bromine (14.25g) into sodium hydroxide solution (250g ~ 15%) at less than 0°C and stirred for 15 min. at less than 0°C over 60 min. and at -5°C to 0°C for 30 min. The temperature of the reaction mass is raised to 25-30°C over 60 min. and then further to 80-85°C over 60 min. It is maintained at 80-85°C for 2 hours and cooled to ~ 60°C. The first organic layer is separated and preserved. Aqueous layer is once again heated to 80-85°C and maintained at

80-85°C for 2 hours, cooled to ~ 60°C, extracted with xylene (100ml) and the second organic layer is preserved. The operation is repeated by heating, maintaining the temperature and then extracting with xylene (50ml) to obtain a third organic layer. The first, second and third organic layers are combined and concentrated to a volume of ~ 60ml at less than 90°C under vacuum. Concentrated HCl (30ml) is added to above concentrated mass and heated to 95-100°C for 15 hours. Then the mass is cooled to 40-45°C and filtered and sucked dry to get 32.5g of gabapentin hydrochloride (II). The filtrate is heated to 95-100°C and maintained the temperature for 10 hours. Then the mass is cooled to 25-30°C, then to 5 °C and maintained at 0-5°C for 30minutes. The mass is filtered to get lOg of gabapentin hydrochloride (II). The two crops of gabapentin hydrochloride (II) are combined (32.5g) and slurried with acetone (80ml) at 25-30°C for 15 min. and filtered to give 32g (61.5% of pure gabapentin hydrochloride (II) of purity 99% by HPLC). Advantages of the present invention
1. The process as adopted in the present invention in obtaining gabalactam (I) by going through the imide (IV) is a commercially viable process.
2. The present invention avoids three most polluting operations in this process as compared to the earlier mentioned one viz. dehydration of diacid at high temperature, avoiding recovery of expensive and carcinogenic solvents like ortho-dichlorobenzene, reaction of the anhydride thus obtained with liquor ammonia, and acidification with sulphuric acid to give half amide acid which undergoes Hofmann reaction to give gabalactam (I).
3. The process of the present invention is a single-pot process wherein the imide (IV) thus obtained is directly used to prepare gabalactam hydrochloride (II).
4. The process of the present invention provides gabapentin hydrochloride (II), which is free from inorganic salts.

We claim:
1. A process for the preparation of hydrochloride salt of 1 -(aminomethyl)-1 -cyclohexane acetic acid (gabapentin hydrochloride) of formula (II), said process comprising the steps of; reacting 1,1-cyclohexane diacetic acid with urea at moderately high temperatures to yield 3,3-pentamethylene glutarimide (IV), dissolving the 3,3-pentamethylene glutarimide (IV) in an alkaline solution, treating the solution with alkaline sodium hypohalite and extracting with an aromatic hydrocarbon solvent, to obtain gabalactam (I) in a single pot reaction, heating the gabalactam (I) with concentrated hydrochloric acid with the concentration ranging from 30-40% and at 95-100°C for about 15-25 hours to get gabapentin hydrochloride (II), cooling and slurrying the reaction mixture in the presence of a hydrocarbon solvent, to obtain crude gabapentin hydrochloride (II), and purifying the crude gabapentin hydrochloride (II) by washing with a solvent to obtain pure gabapentin hydrochloride (II).
2. A process for the preparation of hydrochloride salt of 1 -(aminomethyl)-1 -cyclohexane acetic acid (gabapentin hydrochloride) of formula (II), said process comprising the steps of; reacting 1,1-cyclohexane diacetic acid with urea at moderately high temperatures to yield 3,3-pentamethylene glutarimide (IV), dissolving the 3,3-pentamethylene glutarimide (IV) in an alkaline solution, treating the solution with alkaline sodium hypohalite and extracting with a hydrocarbon solvent, to obtain gabalactam (I), treating the gabalactam (I) with dry hydrogen chloride gas in an alcohol to get gabalactam hydrochloride, dissolving the gabalactam hydrochloride in water and heating at 95-100°C for about 15-25 hours to get gabapentin hydrochloride (II), cooling and slurrying the reaction mixture at 25-45°C temperature in the presence of a hydrocarbon solvent and filtering to obtain gabapentin hydrochloride (II), and washing the gabapentin hydrochloride (II) with a solvent to obtain pure gabapentin hydrochloride (II).

3. The process as claimed in claims 1 and 2, wherein the ratio of 1,1-cyclohexane diacetic acid to urea is 1:0.3 tol:0.5 w/w, preferably 1:0.3 w/w.
4. The process as claimed in claims 1 and 2, wherein the moderately high reaction temperature of 1,1-cyclohexane diacetic acid with urea, is performed by a superheated

steam, in the temperature range of 90-180°C, preferably 120-150°C and most preferably 140°C.
5. The process as claimed in claims 1 and 2, wherein the reaction 1,1-cyclohexane
diacetic acid with urea is carried out for 1-5 hours, preferably for 1-2 hours.
6. The process as claimed in claims 1 and 2, wherein the alkaline solution is selected from
alkali or alkaline earth hydroxides, preferably NaOH or KOH.
7. The process as claimed in claims 1 and 2, wherein the alkaline sodium hypohalite is
selected from sodium hypochlorite or sodium hypobromite.
8. The process as claimed in claim 1, wherein the aromatic hydrocarbon solvent is
selected from benzene, toluene or xylene, preferably toluene.
9. The process as claimed in claim 1, wherein concentration of hydrogen chloride is
preferably 30-36% w/w.
10. The process as claimed in claim 1, wherein the ratio of gabalactam to hydrochloric acid
is in the range of 1:1 to 1:2 w/v, preferably 1:1 to 1:1.5 w/v.
11. The process as claimed in claim 2, wherein the alcohol is selected from methanol,
ethanol, 2-propanol, preferably 2-propanol.
12. The process as claimed in claims 1 and 2, wherein the reaction mixture of gabapentin
hydrochloride (II) is cooled at a temperature in the range of 25-45°C, preferably 35-
45°C, and most preferably 45°C.
13. The processes as claimed in claims 1 and 2, wherein the solvent used for washing the
crude gabapentin hydrochloride (II) is selected from alkyl, aryl or aralkyl ketones,
preferably acetone or methyl ethyl ketone.

Documents

Name Date
1845-CHE-2005 FORM-13 08-10-2010.pdf 2010-10-08
1845-che-2005-form 5.pdf 2011-09-03
1845-che-2005-form 3.pdf 2011-09-03
1845-che-2005-form 26.pdf 2011-09-03
1845-che-2005-form 1.pdf 2011-09-03
1845-che-2005-description(provisional).pdf 2011-09-03
1845-che-2005-abstract.pdf 2011-09-03
1845-che-2005-correspondnece-others.pdf 2011-09-03
1845-che-2005-description(complete).pdf 2011-09-03
1845-che-2005-claims.pdf 2011-09-03
1845-CHE-2005 CORRESPONDENC E OTHERS 25-10-2011.pdf 2011-10-25
1845-CHE-2005 AMENDED CLAIMS 25-10-2011.pdf 2011-10-25
1845-CHE-2005 CORRESPONDENCE OTHERS 30-05-2012.pdf 2012-05-30
1845-CHE-2005 AMENDED PAGES OF SPECIFICATION 25-10-2011.pdf 2011-10-25
1845-CHE-2005 AMENDED CLAIMS 30-05-2012.pdf 2012-05-30
Form 27 [04-03-2017(online)].pdf 2017-03-04
1845-CHE-2005_EXAMREPORT.pdf 2016-07-02
1845-CHE-2005-RELEVANT DOCUMENTS [30-03-2018(online)].pdf 2018-03-30
1845-CHE-2005-RELEVANT DOCUMENTS [16-03-2019(online)].pdf 2019-03-16
1845-CHE-2005-RELEVANT DOCUMENTS [29-03-2020(online)].pdf 2020-03-29
1845-CHE-2005-RELEVANT DOCUMENTS [30-09-2021(online)].pdf 2021-09-30

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