Field of the Invention:
The present invention relates to novel process for the preparation of intermediate of GABA analogue, i.e., 3-(carbamoylmethyl)-5-methylhexanoic acid, an intermediate of pregabalin.
Pregabalin is a GABA analogue and is chemically known as (S)-(+)-(aminomethyl)-5-methylhexanoic acid having the following structural formula-5

Pregabalin is also known as y-amino butyric acid or (S)-3-isobutyl GABA. (S)-pregabalin has been found to activate GAD (L-glutamic acid decarboxylase). (S)-pregabalin has a dose dependent protective effect on-seizure, and is a CNS-active compound. (S)-pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-pregabalin has analgesic, anticonvulsant, and anxiolytic activity. (S)-pregabalin is marketed under the trade name LYRICA®.
Background of the Invention:
3-(carbainoylmethyl)-5-methylhexanoic acid is one of the important intermediate in the preparation of GABA analogue such as pregabalin. Several synthesis of pregabalin is reported in the literature. The usage of 3-(carbamoylmethyl)-5-methylhexanoic acid in the preparation of pregabalin synthesis was first disclosed in EP 828704. The disclosed process comprises of treating the 3-isobutylglutaric acid with acetic anhydride to provide the corresponding 3-isobutylglutaric anhydride, which on treating with ammonium hydroxide provides 3-(carbamoylmethyl)-5-methylhexanoic acid. Thus obtained 3-(carbamoylmethyl)-5-methylhexanoic acid is converted into pregabalin by resolving it with (R)-l-phenylethylamine and treatment with an acid, followed by Hoffman degradation with Bra/NaOH to provide (S)-pregabalin.

EP 828704 also disclosed a process for the regeneration of 3-isobutyl glutaxic acid from the filtrate obtained after the resolution and isolation of required (R)-3-(carbamoylmethyl)-5-methylhexanoic acid. The other isomer (3S)-3-(carbamoylmethyl)-5-methylhexanoic acid present in the filtrate is extracted with aqueous sodium hydroxide and then the extracted solution was acidified with hydrochloric acid and heated to reflux for 24 hours, followed by extraction of 3-isobutylglutaric acid with a solvent. The process involves longer reaction time and it requires an additional step to covert the 3-isobutylglutaricacid to 3-(carbamoylmethyl)-5-methylhexanoic acid. There is a need in the art for alternate process for the racemization of unwanted isomer of 3-(carbamoylmethyl)-5-methylhexanoic acid which avoids the said draw backs.
The present invention provides a novel process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid and also the process for the racemization of unwanted isomer, which is economical and commercially viable over the known process.
Brief Description of the Invention:
The first aspect of the present invention is to provide a novel process for the preparation of 3-(carbamoylmethyl)-5-methyIhexanoic acid compound of formula-1, which comprises of the following steps,
a) Reacting the 3-isobutylglutaric acid compound of fonnula-2 with urea at a suitable temperature to provide the 3 -isobutylglutarimide compound of formula-3,
b) hydrolyzing the 3-isobutylglutarimide with a suitable base in presence or absence of a solvent provides the compound of formula-1.
The second aspect of the present invention is to provide a novel process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-1, which comprises of the following steps,
a) Reacting the 3-isobutylglutaric acid compound of formuia-2 with urea in presence of a suitable solvent to provide the 3-isobutylglutarimide compound of formula-3,
b) hydrolyzing the 3-isobutylglutarimide with a suitable base in presence or absence of a solvent provides the compound of formula-1.

The third aspect of the present invention is to provide a novel process for the preparation of 3-(carbamoyImethyl)-5-methyIhexanoic acid compound of formula-1, which comprises of treating (3S)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 with suitable acid in a suitable solvent to provide 3-isobutylglutarimide compound of formula-3, which on hydrolysis with suitable base in presence or absence of a solvent to provide the compound of formula-1.
The fourth aspect of the present invention is to provide a novel process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-1, by heating the (3S)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 at a suitable temperature for a sufficient time to provide the 3-isobutylglutarimide compound of formula-3, which on hydrolysis with suitable base in presence or absence of solvent to provide the compound of formula-1.
Advantages of the present invention:
• Provides a simple and novel process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound
• Economical and commercially viable process.
• Involves less number of steps compared to prior art.
• Provides a novel process for the racemization of unwanted S- isomer of formula-1 into racemic compound using acid instead of base used in the prior art.
Detailed Description of the Invention:
Accordingly the present invention provides a novel process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid and process for the racemization of unwanted (3S)-3-(carbamoylmethyl)-5-methylhexanoic acid.
Unless otherwise specified the term "3-(carbamoylmethyl)-5-methylhexanoic acid" as used herein the present invention refers to racemic 3-(carbamoylmethyl)-5-methylhexanoic acid.

The first aspect of the present invention provides a novel process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-1,


with urea in presence of a suitable solvent at suitable temperature ranges from 0 to reflux temperature of the solvent, for a sufficient period of time provides the 3-isobutylglutarimide compound of formula-3,

with suitable acid such as paratoluene sulfonic acid, hydrochloric acid, sulfuric acid, preferably paratoluene sulfonic acid in a suitable solvent to provide 3-isobutylglutarimide compound of formula-3, b) hydrolyzing the compound of formula-3 with suitable base in presence or absence of a solvent provides the compound of formula-1.
The fourth aspect of the present invention provides a novel process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compoimd of formula-1,


Fonnula-4 at a suitable temperature ranges from 100-200°C for a sufficient period of time to provide the 3-isobutylglutarimide compound of formula-3, b) hydrolyzing the 3-isobutylglutarimide compound of formula-3 with a suitable base in presence or absence of a solvent provides the compound of formula-1.
The suitable solvent used in the present invention is selected from toluene, xylene, heptane, hexane and cyclohexane or mixtures thereof.
The suitable base which is used for hydrolysis of compound of formula-3 is selected from "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide and the like; "alkali metal carbonates" such as sodium carbonate, potassium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal alkoxides" such as sodium methoxide, sodium tertiary butoxide and potassium tertiary butoxide; "organic bases" such as triethylamine, diisopropylethylamine and tributylamine.
Further the 3-isobutylglutarimide compound of formula-3 either isolated as a solid by known methods or by the method disclosed herewith the present invention or can be proceed further without isolation (i.e., through in-situ reaction) of the same.

The compound of formula-1 is obtained as per the above aspects of the present invention further converted into pregabalin by the process disclosed in EP 828704 or by the process known in the art.
The present invention further provides a process for the preparation of pregabalin compound of formula-5
which comprises of preparing the 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-1 according to above aspect of the present invention and converting the same into pregabalin.
(3S)-3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-4 is obtained during the resolution of 3-(carbamoylmethyl)-5-methylhexanoic acid with resolving agent as an unwanted isomer and can be further isolated by a known manner.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of 3-(carbamoylmethyI)-5-methylhexanoic acid
A mixture of 3-isobutylglutaric acid (200 grams) and urea (70 grams) was heated to 160°C and stirred upto completion of the reaction. The reaction mixture was cooled to 90-100° C and toluene (400 ml) was added. The reaction mixture was cooled to 25-3 0°C and water (100 ml) was added then stirred. The solid obtained was filtered and washed with water. Aqueous sodium hydroxide (48 grams in 700 ml of water) was added to the obtained solid and heated it into 60-65 °C then stirred upto complete of the reaction. The reaction mixture was cooled and washed with toluene. Carbon (5 grams) was added to the aqueous layer, stirred for 30 minutes and then filtered through hyflow. The filtrate was acidified using hydrochloric acid, cooled to 10-15 °C and stirred for an hour. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 150 grams
ExampIe-2: Preparation of 3-(carbamoylmethyI)-5-methylhexanoic acid
A mixture of 3-isobutylglutaric acid (50 grams), urea (17.5 grams) and toluene (150 ml) was heated to reflux temperature and stirred upto completion of the reaction under azeotropic mode. The reaction mixture was cooled to 25-30°C, water (25 ml) was added to it, then stirred for an hour. The solid obtained was filtered and washed with water. Aqueous sodium hydroxide (12 grams in 165 ml of water) was added to the obtained solid and heated it into 60-65°C then stirred upto completion of the reaction. The reaction mixture was cooled and washed with toluene. The reaction mixture was acidified using hydrochloric acid, cooled to 10-15°C and stirred for an hour. The solid obtained was filtered, washed with water and dried to get the title compound. Yield: 22 grams

Example-3: Preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid
A mixture of (S)-3-(carbamoylmethyl)-5-methylhexanoic acid (100 grams), paratoluene sulfonic acid (5 grams) and toluene (300 ml) was heated to reflux temperature and stirred upto completion of the reaction under azeotropic mode. Aqueous sodium hydroxide (30 grams in 300 ml) was added to the reaction mixture at 60-65°C then stirred. After completion of the reaction it was cooled to 25-30°C and layers was separated. Aqueous layer was acidified with concentrated hydrochloric acid, cooled to 10-15°C and stirred for 90 minutes. The solid obtained was filtered and washed with water and dried to get the title compound. Yield: 80 grams
Exainple-4: Preparation of 3-(carbamoylmethyI)-5-methyIhexanoic acid
(S)-3-(carbamoylmethyl)-5-methylhexanoic acid (38 grams) was heated to 150°C and maintained for 4 hours. The reaction mixture was cooled to 60-65°C and aqueous sodium hydroxide (9 grams in 100 ml) was added to it. The reaction mixture was stirred up to the completion of the reaction and then cooled to 10-15°C. Acidified the reaction mixture with hydrochloric acid and stirred for 90 minutes. The solid obtained was filtered and washed with aqueous hydrochloric acid and dried to get the title compound. Yield: 28 grams

1. A process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-1,

which comprises of the following steps,
a) Reacting the 3-isobutylglutaric acid compound of formula-2

with urea at a suitable temperature of 70-180°C for a sufficient period of time to provide the 3-isobutylglutarimide compound of formula-S,

b) hydrolyzing the 3-isobutylglutarimide with a suitable base in presence or absence
of a solvent provides the compound of formula-1.
2. A process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-1, which comprises of the following steps, a) Reacting the 3-isobutylgiutaric acid compound of formula-2


with urea in presence of a suitable solvent at suitable temperature ranges from 0 to reflux temperature of the solvent, for a sufficient period of time provides the 3-isobutylglutarimide compound of fonnula-3,

b) hydrolyzing the 3-isobutylglutarimide with a suitable base in presence or absence of a solvent provides the compound of formula-1.
3. A process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid compound of formula-1,

Which comprises of the following steps;
a) Treating (3S)-3-(carbamoylmethyl)-5-methylhexanoic acid compoimd of
fonnula-4
with suitable acid such as paratoluene sulfonic acid, hydrochloric acid, sulfuric acid in a suitable solvent to provide 3-isobutylglutarimide compound of formula-3,
b) hydrolyzing the 3-isobutylglutarimide compound of formula-3 with suitable base
in presence or absence of a solvent provides the compound of formula-1.

4. A process for the preparation of 3-(carbamoylmethyl)-5-methylhexanoic acid
compound of formula-1,

at a suitable temperature ranges from 100-200°C for a sufficient period of time to provide the 3-isobutylglutarimide compound of formula-3, b) hydrolyzing the 3-isobutylglutarimide compound of formula-3 with a suitable base in presence or absence of a solvent provides the compound of formula-1.
5. The process according any of the preceding claims wherein 3-isobutylglutarimide
compound of formula-3 is isolated.
6. The process according any of the preceding claims wherein 3-isobutylglutarimide
compound of formula-3 is not isolated.
7. The process according to any of the preceding claims wherein the suitable solvent is
hydrocarbon solvents and is selected from toluene, xylene, hexane, heptane and
cyclohexane.
8. The process according to any of the preceding claims, wherein the base used is
selected from "alkali metal hydroxides" such as sodium hydroxide, potassium
hydroxide and the like; "alkali metal carbonates" such as sodium carbonate,
potassium carbonate, cesium carbonate and the like; "alkali metal

bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the lilce; "alkali metal alkoxides" such as sodium methoxide, sodium tertiary butoxide and potassium tertiary butoxide; "organic bases" such as triethylamine and tributylamine; and the acid used is selected from hydrochloric acid, sulfriric acid and paratoluene sulfonic acid.
9. A process for the preparation of pregabalin comprises of preparing the
3-(carbamoylmethyl)-5-methylhexanoic acid according to any of the proceeding
claim and converting it into pregabalin or its salts.
10. The usage of recovered 3-(carbamoylmethyl)-5-methylhexanoic acid as well as
3-(carbamoylmethyl)-5-methylhexanoic acid obtained by the process according to
claim 1-4, in the manufacture of pregabalin or its pharmaceutically acceptable salts.