Title of Invention

PROCESS FOR PREPARATION OF GABAPENTIN

Abstract A process for preparation of gabapentin comprising a step of obtaining 1, 1cyclohexane diacetic acid monoamide from 1, 1-cyclohexane diacetic acid anhydride, wherein said reaction is characterized by the use of ammonia precursor or pre-generated ammonia isopropanol solution. The invention further preparation of gabapentin and isolation of gabapentin in polymorphic Form II with high yield and purity.
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION: "Process for preparation of Gabapentin"
2. APPLICANT (S)
(a) NAME: IPC A LABORATORIES LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai-400 067
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field of invention:
The present invention relates to an improved method of preparation of gabapentin, a known pharmaceutical drug, starting from the intermediate 1,1-cyclohexyl diacetic acid anhydride via Hofmann rearrangement. More specifically it relates to a new process for the preparation of 1,1-cyclohexane diacetic acid monoamide, an intermediate useful in the manufacture of gabapentin or its salts.
Background of the invention:
Gabapentin which is chemically known as 1-aminomethyl-l-cyclohexaneacetic acid is a very well known pharmaceutical drug useful for the treatment of epilepsy and other cerebral disorders. The structure of gabapentin is shown in the Formula I. This compound, its process for preparation and use are first disclosed in US patents Nos. 4024175 & 408754 respectively.
.—\ NH2
COOH Formula I
The processes disclosed in these patents for gabepentin like derivatives are outlined in the following general scheme which falls in u._ Iv.own meti...Js used for the preparation of primary amines, for example by 1) Curtius rearrangement of cycloalkane diacetic acid monoesters, 2) Hofmann rearrangement of cycloalkane diacetic acid monoamides or 3) the Lossen rearrangement of 1- carboxymethyl cycloalkane acetohydroxamic acid sulphonate esters. The isolation of pure gabapentin is reported to be based on the ion exchange column separation from gabapentin hydrochloride salt.
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Scheme:

OH

OTs



X

Base/TsCI

>
Lossen Aq.NaOH




0^/NH2
^r COOH
NaOBr/NaOH Mcffman
OMe
Y CON3 MeO
Curtius
°%/°x^o
NH3
Acid Anhydride ,MeOH
0.

O OMe ^f COOH
CICOOC2H5/Base
NaN3 *

NH2 COOH

NCO
Gabapentin

A specific method for gabapentin given in US patent Nos. 4024175 and 4087544 is as follows: monomethyl ester of cyclohexane-1,1- di acetic acid was transformed to the corresponding azide which was decomposed (Curtius reaction) in boiling toluene. The resultant isocyanate was hydrolyzed with aqueous hydrochloric acid. The resultant solution was evaporated to dryness to givel-aminomethylcyclohexane-1- acetic acid hydrochloride, which was converted to gabapentin with a basic ion-exchange resin.
The US patent No. 4024175 describes the synthesis of the lower cyclic homologous derivative of gabapentin, in particular 1 - (methylamino) -1-cyclopentaneacetic acid,
T,

through the preparation of cyclopentane diacetic acid monoamide, carried out by reaction of the corresponding anhydride with an aqueous ammonia solution. Then Hofmann rearrangement of the obtained monoamide, IV. L wed by aerification and the extraction of the obtained gabapentin followed by a final purification step consisting in the elution through a basic ion exchange resin followed by recrystallization from alcohols.
In the patent CN 1297885, the preparation of 1,1-cyclohexyl diacetic acid monoamide is described through the reaction of the corresponding anhydride with aqueous or gaseous ammonia in the presence of an organic solvent.
Another report, the International patent application WO 03/002517, having familiar with the above synthetic techniques, describes a process for the synthesis of 1,1- cyclohexane diacetic acid monoamide comprising: a) amination of the anhydride of 1, 1-cyclohexane diacetic acid with aqueous ammonia, b) ."^'tr. lization of ;he reaction mixture, whereby crude 1,1-cyclohexane diacetic acid monoamide is precipitated and filtered, c) purification of crude 1,1-cyclohexane diacetic acid monoamide through a crystallization from solvent.
Yet another report, WO2005044779, claims to improve the process for 1,1-cyclohexane diacetic acid monoamide through amination of 1,1-cyclohexane diacetic acid anhydride using aqueous ammonia characterized by temperature below 30°C and molar amounts of ammonia lower than 3 moles relative to anhydride compound.
Although the processes mentioned above can be considered as an improvement of the process described in the US4024175 patmt hut these presses are of not much value when applied in industry, since both methods attempt to use aqueous ammonia solution which leads to partial decomposition of anhydride and lower yield & purity. Though Chinese patent (CN1297885) describes ammonia gas with organic solvents selected from toluene, benzene etc. as alternative to aqueous ammonia, but the process suffered from its incapability to large scale production due to lack of effective mixing of reactants and reagents since ammonia gas has less solubility in these solvents.
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In particular, these methods utilize a considerable amount of reagents and solvents. For example, amination requires considerable amount of ammonia solution which has to be disposed and this constitutes extra costs and disposal time. In aqueous reaction system the pH of the solution was required to keep at a specific ranged the reaction to maximum conversion levels and assuring such homogeneity is difficult in industrial level.
Consequently, it is an objective of the present invention to study alternative methodologies allowing the implementation of the reaction under more favourable conditions from the view point of the industrial application of the process, product quality, and purity, which become the subject of the present invention.
Summary of the present invention:
Thus the object of the present invention is to provide a modification of the known methods for the synthesis of Gabapentl: which inert., s yield and minimizes byproducts / impurities and which also minimizes the cost of production. A further object is to provide such a method which enables the making of gabapentin in polymorphic form II substantially free from inorganic salts and gabalactam impurity.
These objects and other objects are achieved by studying the process of amidation under varying conditions and have surprisingly found improved reaction conditions for the synthesis of 1,1-cyclohexane diacetic acid monoamide, intermediate for the synthesis of gabapentin which ameliorates most of the problems associated with known procedures and is easy to translate to industrial production.
Therefore, the present invention provide ? process for '. 1-cyclohexane diacetic acid monoamide, useful in the synthesis of gabapentin and an improved process for gabapentin, wherein the improvement comprises a new process for isolation of Form II polymorphic form of Gabapentin. The method is characterized by the use of a precursor of ammonia during the reaction of 1,1-cyclohexane diacetic acid anhydride to obtain 1,1-cyclohexane diacetic acid monoamide. The 1,1-cyclohexane diacetic acid monoamide obtained in this manner is used for the formation of gabapentin.
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Thus, according to one embodiment of the present invention, there is provided an improved process for preparation of gabapentin which comprises the steps of:
a) providing a solution of 1,1 -cyclohexane diacetic acid anhydride in a solvent
b) combining it with a precursor which generates ammonia in situ in the reaction solution
c) effectuating the transformation of 1,1-cyclohexane diacetic acid anhydride into 1,1-cyclohexane diacetic acid monoamide
d) isolating said 1,1-cyclohexane diacetic acid monoamide from the reaction solution;
e) subjecting to a Hofmann rearrangement reaction using an aqueous solution of 1,1-cyclohexane diacetic acid monoamide sodium salt with an aqueous solution of sodium hypobromite at a temperature in the range of-5 to -10°C, and further at 35 - 40°C to obtain gabapentin wherein the content of gabapentin lactam is less than 7%;
f) acidifying the reaction solution with hydrochloric acid followed by distillation of water;
g) extracting gabapentin hydrochloride using ethanol; and
h) treating the solution of gabapentin hydrochloride in ethanol with an organic base
to liberate gabapentin; i) evaporating ethanol solution to obtain a residue comprising gabapentin and
hydrochloride salt of organic base; j) adding a solvent mixture comprising water and acetone to form a solution / slurry; k) crystallizing gabapentin form II from said solution by cooling.
In a second embodiment, according to the present invention, an improved process for gabapentin is provided which is characterized by preparation of 1,1-cyclohexane diacetic acid monoamide by treatment of 1,1-cyclohexane diacetic acid anhydride in an alcohol solvent having dissolved ammonia followed by evaporation of solvent to recover 1,1-cyclohexane diacetic acid monoamide. It is further reacted to produce gabapentin in the aforementioned manner. The process enables the production of gabapentin with high yield and purity.
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Detailed description of the invention
While the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Thus the present invention provides an improved industrial method for manufacturing gabapentin, more specifically a process for the intermediate 1,1-cyclohexane diacetic acid monoamide for use in the synthesis of gabapentin, wherein the new method ameliorates problems associated with use of aqueous ammonia in 1,1-cyclohexane diacetic acid monoamide formation and isolation of gabapentin substantially free of salts of inorganic or organic acids & lactam impurity, and provides reproducibly high yields.
In accordance with the main thrust of the invention, there is provided a new process for preparing the 1,1-cyclohexane diacetic acid monoamide intermediate from 1,1-cyclohexane diacetic acid anhydride characterized in that the 1,1-cyclohexane diacetic acid anhydride is contacted with a precursor of ammonia which liberates ammonia in situ to react with the anhydride to produce the target monoamide derivative. The precursor which liberates ammonia is selected from ammonium carbonate or ammonium chloride & sodium hydroxide. The inventors have found that these new reagents slowly release ammonia to react with the anhydride derivative to produce the monoamide compound. The new method has good control on the use of ammonia in the reaction and produce 1,1-cyclohexane diacetic acid monoamide steadily and reproducibly with high purity.
This reaction may be carried out in organic solvent or water or their mixture. It is preferably carried out in an organic solvent which includes, but not limited to, alcohols, ketone, chlorinated hydrocarbons or toluene. Particularly preferred solvent is toluene, when the ammonia precursor is ammonium carbonate. When the precursor is ammonium chloride, the reaction is preferably carried out in presence of water or mixture of water and organic solvent which forms an aqueous single phase. The reaction may be carried at room temperature or with cooling or heating.
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In a second embodiment of the present invention, there is provided a second method for preparation of 1,1-cyclohexane diacetic acid monoamide characterized in that the 1,1-cyclohexane diacetic acid anhydride is treated with a pregenerated ammonia-alcohol solution. The method is simple and isolation of 1,1-cyclohexane diacetic acid monoamide, as no solid or liquid waste generated, is by simple distillation of the alcoholic solvent. The solvent is recovered for reuse. The process is economical; operation conditions are mild and can be scaled to industrial production. Preferably the alcohol used in the ammonia-alcohol solution is isopropyi alcohol. It is preferred to use ammonia-alcohol solution having 11 to 14% ammonia in isopropyi alcohol. The reaction may be carried out with appropriate cooling or heating or at ambient temperature, and preferably it is carried out under chilling at about 0 to 10°C temperature range. After complete conversion of 1,1-cyclohexane diacetic acid anhydride to 1,1-cyclohexane diacetic acid monoamide, it is isolated by concentration of the solvent alcohol. The crude product may be used directly for gabapentin formation or purified by neutralization and crystallization from suitable solvents.
In case where aqueous solvents are used, the isolation of 1,1-cyclohexane diacetic acid monoamide is carried out using conventional methods such as extractive work-up after neutralization. Neutralization may be carried out in a conventional manner with organic or inorganic acid.
The process for conversion of 1,1-cyclohexane diacetic acid monoamide into gabapentin is illustrated as follows.
A solution of 1,1-cyclohexane diacetic acid monoamide in aqueous sodium hydroxide is provided at one place. This solution is added to a hypobromite aqueous solution. Preferably the hypobromite aqueous solution is prepared prior to the addition of 1,1-cyclohexane diacetic acid monoamide by combining bromine solution with aqueous sodium hydroxide. Preferably the addition of 1,1-cyclohexane diacetic acid monoamide sodium salt solution to the sodium hypobromite soluti. is carried out with chilling, preferably at a temperature range of-5 to -10°C and maintained the reaction solution at this temperature for about 30 minutes and then further maintained at 35-40°C for 1 hour. The reaction mixture then acidified with hydrochloric acid to form gabapentin
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hydrochloride. The aqueous solution may be washed with an organic solvent such as a chlorinated hydrocarbon solvent to remove any organic lactam impurity if present. The mixture there after concentrated and the gabapentin hydrochloride extracted with ethanol. The extraction may be repeated one or more times and the ethanol solution as such used for formation of gabapentin. Alternately ethanol may be evaporated and gabapentin hydrochloride is re-extracted with ethanol for getting better purity.
The ethanol solution of gabapentin hydrochloride is treated with an organic base like triethylamine to get a solution of gabaprtion ethane" "Ethanol from this solution is evaporated to form a residue comprising gabapentin and hydrochloride salt of organic base. The mass is then heated to dissolve in acetone -water solvent mixture, cooled and chilled to precipitate pure gabapentin. The polymorphic form of gabapentin isolated shows the characteristics of Form II as given in the US6255526B) & XRD pattern as given in WO2004093779.
In a second aspect of the invention there is provided an improved method for the manufacture of gabapentin using 1,1-cyclohexane diacetic acid monoamide manufactured in accordance with the present invention wherein the isolation of gabapentin free of chloride ions and contaminating gabalactam impurity, yet avoiding the use of ion exchange column taught in the prior art. TV method comprises the following:
1) subjecting 1,1-cyclohexane diacetic acid monoamide to a Hofmann degradation reaction using an aqueous solution of 1,1-cyclohexane diacetic acid monoamide sodium salt with an aqueous solution of aqueous sodium hypobromite at a temperature in the range of -5 to -10 °C to obtain gabapentin;
2) acidifying the reaction solution with hydrochloric acid followed by distillation of water;
3) extracting gabapentin hydrochloride using ethanol from the residue obtained in step 2; and
4) treating a solution of gabapentin hydrochloride in ethanol with an organic base to liberate gabapentin;
5) evaporating ethanol solution to obtain a residue comprising gabapentin and hydrochloride salt of organic or inorganic bases;
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6) adding a solvent mixture comprising water and acetone to form a solution;
7) crystallizing gabapentin form II from said solution by cooling.
It can be seen from the prior art literatures that the process for the preparation of gabapentin is to access gabapentin hydrochloride by a suitable method and then subjecting it to ion exchange treatment. This process leads to the formation of gabapentin, mostly in a very dilute aqueous solution, during the extraction process lactamisation happens which is leading to contamination. Water being difficult to distill, and the resulting aqueous solution having very low concentration of gabapentin, the process of evaporation is a very tedious and time & energv consuming operation. Such processes are not cost-inefficient and user un-friendly and therefore may not be suitable for industrial applications.
On the contrary the improved process of the present invention employs a crystallization process to isolate the pure gabapentin substantially free of both chloride ions and gabalactam.
The following examples, which include preferred embodiments, is intended to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples:
Example 1: Preparation of Cyclohexane -1,1 - diacetic acid monoamide:
In 1.0 lit R B Flask charged water (135 ml), and ammonium chloride (161.6 g), under cooling. Aqueous sodium hydroxide solution (110 g in 200 ml water) was added drop wise under stirring maintaining temperature below 20°C. After complete addition the reaction mass is further maintained at 0 - 5°C for 30 min. Charged cyclohexane diacetic acid anhydride maintaining temperature below 5°C. Maintained the reaction mass for 2.0 hrs at ~ 0°C, then raise the temperature to 25 - 30°C and maintained 2 hrs at room temperature. Adjusted pH of the solution to 2-3 with aqueous HC1. Cooled the reaction
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mass to 0°C and maintained 1.0 hr, filtered the solid mass and washed with chilled water. The wet cake was dried to get 105 g Cyclohexane diacetic acid monoamide.
Example 2: Preparation of Cyclohexane - 1,1 - diacetic acid monoamide:
In 1.0 lit R B Flask charged Toluene (500 ml) and cyclohexane -1,1- diacetic acid anhydride. Heated the reaction mixture to 35 - 40°C and charged slowly ammonium carbonate (47 g). Raised the temperature gradually to 70°C and maintained for 6-8 hrs at ~70°C. Cooled the reaction mass to 0°C and filtered. The solid obtained was taken in water and adjusted the pH to 2 - 3 with cone. HCl. The solution was cooled to 0°C and maintained 2- 3 hrs, filtered and washed with chilled water. The wet cake was dried to get 107 gm Cyclohexane diacetic acid monoamide.
Example 3: Preparation of Cyclohexane - 1,1 - diacetic acid monoamide:
In 1.0 lit R B Flask charged 600ml 12 - 14% ammonia solution in iso propyl and cooled to 0°C. Slowly charged cyclohexane -1,1- diacetic acid anhydride (l00g) maintaining temperature below 5°C. Stirred 1.0 hr after complete addition and raised the temperature to room temperature. Then cooled to 15 - 20°C and adjusted the pH to 2 - 3 with aq. HCl solution. The reaction mass was stirred further for about 15 hrs, Filtered and washed the solid with chilled water. The wet cake was dried to get 95g cyclohexane diacetic acid monoamide. The filtrate was further concentrated to recover second crop 7 gm.
Dated this 24th day of October 2006
Dr. Gopakumar G. Nair Agent for the Applicant
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Documents:

1762-MUM-2006-ABSTRACT(26-10-2006).pdf

1762-MUM-2006-ABSTRACT(29-4-2009).pdf

1762-MUM-2006-ABSTRACT(AMENDED)-(29-4-2009).pdf

1762-MUM-2006-ABSTRACT(GRANTED)-(27-9-2011).pdf

1762-MUM-2006-CANCELLED PAGES(18-8-2011).pdf

1762-MUM-2006-CLAIMS(26-10-2006).pdf

1762-MUM-2006-CLAIMS(29-4-2009).pdf

1762-MUM-2006-CLAIMS(AMENDED)-(18-8-2011).pdf

1762-MUM-2006-CLAIMS(AMENDED)-(29-4-2009).pdf

1762-MUM-2006-CLAIMS(GRANTED)-(27-9-2011).pdf

1762-MUM-2006-CLAIMS(MARKED COPY)-(18-8-2011).pdf

1762-mum-2006-correspondance-po.pdf

1762-mum-2006-correspondance-received.pdf

1762-MUM-2006-CORRESPONDENCE(28-3-2008).pdf

1762-MUM-2006-CORRESPONDENCE(29-4-2009).pdf

1762-MUM-2006-CORRESPONDENCE(IPO)-(27-9-2011).pdf

1762-mum-2006-description (provisional).pdf

1762-MUM-2006-DESCRIPTION(COMPLETE)-(26-10-2006).pdf

1762-MUM-2006-DESCRIPTION(COMPLETE)-(29-4-2009).pdf

1762-MUM-2006-DESCRIPTION(GRANTED)-(27-9-2011).pdf

1762-MUM-2006-FORM 1(26-10-2006).pdf

1762-MUM-2006-FORM 1(29-4-2009).pdf

1762-MUM-2006-FORM 18(26-12-2007).pdf

1762-mum-2006-form 2(29-4-2009).pdf

1762-MUM-2006-FORM 2(COMPLETE)-(26-10-2006).pdf

1762-MUM-2006-FORM 2(GRANTED)-(27-9-2011).pdf

1762-MUM-2006-FORM 2(TITLE PAGE)-(26-10-2006).pdf

1762-MUM-2006-FORM 2(TITLE PAGE)-(29-4-2009).pdf

1762-MUM-2006-FORM 2(TITLE PAGE)-(GRANTED)-(27-9-2011).pdf

1762-MUM-2006-FORM 2(TITLE PAGE)-(PROVISIONAL)-(26-10-2006).pdf

1762-MUM-2006-FORM 26(26-10-2006).pdf

1762-MUM-2006-FORM 3(26-10-2006).pdf

1762-MUM-2006-FORM 3(28-3-2008).pdf

1762-MUM-2006-FORM 3(29-4-2009).pdf

1762-MUM-2006-FORM 5(29-4-2009).pdf

1762-MUM-2006-FORM 5(8-10-2007).pdf

1762-mum-2006-form-1.pdf

1762-mum-2006-form-2.doc

1762-mum-2006-form-2.pdf

1762-mum-2006-form-3.pdf

1762-MUM-2006-REPLY TO HEARING(18-8-2011).pdf


Patent Number 249045
Indian Patent Application Number 1762/MUM/2006
PG Journal Number 39/2011
Publication Date 30-Sep-2011
Grant Date 27-Sep-2011
Date of Filing 26-Oct-2006
Name of Patentee IPCA LABORATORIES LIMITED
Applicant Address 48, KANDIVLI INDUSTRIAL ESTATE, CHARKOP, KANDIVLI (W) MUMBAI - 400 067,
Inventors:
# Inventor's Name Inventor's Address
1 KUMAR, ASHOK 123/AB, CRD, IPCA Laboratories Ltd. Kandivli Industries Estate, Charkop, Kandivli(w) Mumbai 400067
2 SOUDAGAR, SATISH RAJANIKANT 123/AB, CRD, IPCA Laboratories Ltd. Kandivli Industries Estate, Charkop, Kandivli(w) Mumbai 400067
3 NIJASURE, AVINASH MANOHAR 123/AB, CRD, IPCA Laboratories Ltd. Kandivli Industries Estate, Charkop, Kandivli(w) Mumbai 400067
4 PANDA, NALINAKSHYA BALARAM 123/AB, CRD, IPCA Laboratories Ltd. Kandivli Industries Estate, Charkop, Kandivli(w) Mumbai 400067
5 GAUTAM, PRASHANT 123/AB, CRD, IPCA Laboratories Ltd. Kandivli Industries Estate, Charkop, Kandivli(w) Mumbai 400067
6 THAKUR, GAJENDRASINGH RAMSINGH 123/AB, CRD, IPCA Laboratories Ltd. Kandivli Industries Estate, Charkop, Kandivli(w) Mumbai 400067
PCT International Classification Number A61K31/195
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA