FIELD OF INVENTION

[0001] The present invention relates to a process for the preparation of Pregabalin Intermediate, 3-Cyano-5-methylhexanoic acid methyl ester.

BACKGROUND OF INVENTION

[0002] Pregabalin, (S)-3-(aminomethyl)-5-methylhexanoic acid is an anticonvulsant drug. Convulsion is a medical condition which results in rapid, uncontrolled spasmodic contraction and relaxation of muscles. Convulsions are usually seen as symptoms during epileptic seizures, neuropathic pain, uremia, tetanus, rabies, tumors etc. Gamma-Aminobutyric acid (GABA) is an endogenous inhibitory neurotransmitter which plays an important role in regulating brain neuronal activity. It is thought that convulsions are a result of decreased GABA concentration in the body. Pregabalin, also referred to as isobutyl-GABA, is an analogue of GABA and therefore, can substitute GABA and acts as an anti convulsant. Pregabalin, therefore, mimics the action of GABA and regulates neuronal activity. Pregablin also has analgesic and anxiolytic activity.

[0003] 3-Cyano-5-methylhexanoic acid methyl ester is an intermediate used in the preparation of Pregabalin. Many processes have been developed to synthesize Pregabalin from 3-Cyano-5-methylhexanoic acid methyl ester.

[0004] US5616793 refers to a process for the preparation of Pregabalin through the intermediate, 2-cyano-5-methylhex-2-enoic acid alkyl ester. The process described in US5616793 for the preparation of 2-cyano-5-methylhex-2-enoic acid alkyl ester comprises of, condensation of Isovaleraldehyde and Alkyl cyanoacetate in the presence of a base.

[0005] Further, US20050283023 provides a method to produce enantiomerically enriched Pregabalin. It describes the preparation of (3S)-cyano-5-methylhexanoic acid by enzymatic kinetic resolution of a cyano-dialkylester, followed by converting the resolved enantiomer to various intermediates, which are then converted to the intermediate (3S)-cyano-5-methylhexanoic acid.

Furthermore, US5637767 provides a method of making (S)-Pregabalin through the intermediate 3-Cyano-5-methylhexanoic acid alkyl ester, wherein Isovaleraldehyde is condensed with compound of formula (a) to yield formula (b) which further yields 3-cyano-5-methylhexanoic acid alkyl ester.

Formula (a)

Formula (b)

The present invention provides a process for the production of 3-Cyano-5-methylhexanoic acid methyl ester of high purity, by reductive condensation of Isobutyraldehyde and methylcyanoacetate.

OBJECT OF INVENTION

[0006] The primary object of the invention is to provide a process for the preparation of 3-Cyano-5-methylhexanoic acid methyl ester by condensation of Isobutyraldehyde and Methyl cyanoacetate.

STATEMENT OF INVENTION

[0007] Accordingly the invention provides a process for the preparation of pregabalin intermediate, 3-Cyano-5-methylhexanoic acid methyl ester, by condensation of Isobutyraldehyde and Methyl cyanoacetate.

[0008] An aspect of the invention provides a process for the preparation of pregabalin intermediate, 3-cyano-5-methylhexanoic acid methyl ester, wherein the process comprises of, reductive condensation of Isobutyraldehyde and methyl cyanoacetate to yield 4-methyl-2-cyanopentanoic acid methyl ester, which on reaction with methyl chloroacetate yields 3-carbomethoxy-3-cyano-5-methylhexanoic acid methyl ester. Further, krapcho decarboxylation of 3-carbomethoxy-3-cyano-5-methyl hexanoic acid methyl ester with sodium chloride-water and DMSO yields 3-cyano-5-methylhexanoic acid methyl ester.

[0009] This and other aspects of the embodiments herein will be better appreciated and understood when considered in conjunction with the following description and the accompanying drawings. It should be understood, however, that the following descriptions, while indicating preferred embodiments and numerous specific details thereof, are given by way of illustration and not of limitation. Many changes and modifications may be made within the scope of the embodiments herein without departing from the spirit thereof, and the embodiments herein include all such modifications.

DETAILED DESCRIPTION OF INVENTION

[001] The embodiments herein and the various features and advantageous details thereof are explained in greater depth with reference to the non-limiting embodiments that are detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

[002] In an embodiment of the invention, the process for the preparation of pregabalin intermediate, 3-Cyano-5-methylhexanoic acid methyl ester, comprises of condensing Isobutyraldehyde and methyl cyanoacetate in the presence of acetic acid and piperidine to give a reaction mixture. The condensation reaction takes place at a temperature in the range of 0°C to 25°C, preferably in the range of 20°C to 25°C. The reaction mixture is further hydrogenated in the presence of palladium on carbon catalyst to yield 4-methyl-2-cyanopentanoic acid methyl ester. The hydrogenation reaction is carried out by pressurizing the reaction mixture with hydrogen gas at a pressure in the range of 5 to 10 Kg/cm².

[003] Further the 4-methyl-2-cyanopentanoic acid methyl ester obtained is reacted with methyl chloroacetate and sodium alkoxide in the presence of a suitable solvent to obtain 3-carbomethoxy-3-cyano-5-methylhexanoic acid methyl ester. Sodium alkoxides includes sodium methoxide, sodium ethoxide or sodium n-propoxide. Suitable solvent includes C1-C4 alcohols such as methanol, ethanol etc, or other solvents such as toluene, tetrahydrofuran and xylene, preferably toluene.

The 3-carbomethoxy-3-cyano-5-methyl hexanoic acid methyl ester is further heated in the presence of sodium chloride, water and dimethyl sulfoxide (DMSO), to a temperature in the range of 130°C to 150°C, to yield 3-cyano-5-methylhexanoic acid methyl ester. The ratio of Water and DMSO is in the range of 1:20 to 10:1, preferably in the ratio of 1:10

[004] The invention is further defined by reference to the following example. 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 scope of the invention.

EXAMPLES

Example 1: Preparation of 3-Cyano-5-methylhexanoic acid methyl ester.
Stage 1: Preparation of 2-Cyano-4-methyl pentanoic acid, methyl ester by reductive condensation.

Representation of the reaction at Stage 1 is as follows:

[005] Procedure: A 10L four necked round bottom flask, fitted with a water cooled condenser, an overhead stirrer, a thermometer pocket and a 100 mL dropping funnel is charged with 0.874 Kg of Isobutyraldehyde (12.122 mol, 1.201 equiv), 1.0 Kg of methyl cyanoacetate (10.093 mol, 1.00 equiv), 2.33L of toluene and 0.070 L of acetic acid(1.223 mol, 0.121 equiv). The mixture is then cooled to a temperature of about 0°C to 5°C with an ice bath. Stirring of the mixture is started at this point. As the stirring continues, 0.042 Kg of piperidine (0.493 mol, 0.049 equiv) is added through the dropping funnel, while maintaining the temperature of the reaction mixture at <20°C. The mixture is further stirred at room temperature for 30 mins and transferred to a 10L autoclave. It is then charged with 0.025 Kg of 10% palladium on carbon catalyst containing 50% moisture and pressurized with hydrogen gas at 10 Kg/cm² at 40°C. Initially, the rate of absorption of hydrogen is ~9-10 Kg/cm² per 5 min for 45 min, which is gradually reduced to ~5 Kg/cm² per 1hour. The reaction is continued until the hydrogen uptake stops (approximately 7 h). The reaction mixture is then cooled to room temperature, following which the catalyst is filtered out and washed with 0.5L toluene. The combined filtrate is then taken into a separating funnel. The organic layer is washed with water (3 x 2.5 L) and dried over anhydrous sodium sulfate. The solvent is then removed by distillation and the residue is distilled under reduced pressure (90-100°C /10 mm Hg) to get 1.44 Kg of colourless liquid of 2-Cyano-4-methyl pentanoic acid, methyl ester (purity: 93%, yield: 91.9%).

Stage 2: Preparation of 3-carbomethoxy-3-cyano-5-methylhexanoic acid methyl ester.

Representation of the reaction at Stage 2 is as follows:

[006] Procedure: A 10L four necked round bottom flask, fitted with a water cooled condenser, an overhead stirrer, a thermometer pocket and a 100 mL dropping funnel, is charged with 1.0 Kg of 2-Cyano-4-methyl pentanoic acid, methyl ester (obtained from Stage 1) (6.444 mol, GC purity 93%, 1.00 equiv) and 5.0L of Toluene. The mixture is stirred with the overhead stirrer. 0.385 Kg of sodium methoxide(7.127 mol, 1.106 equiv) is then added to the mixture in portions, for about 45 minutes. The temperature of the reaction mixture rises to about 50°C during the addition of sodium methoxide. The reaction mixture is then cooled to 0° to 5°C using an ice bath. Maintaining the temperature of the reaction mixture at 0° to 5°C 0.805Kg of methyl chloroacetate (7.418 mol, 1.151 equiv) is added through a dropping funnel. Addition of methyl chloroacetate takes about 45 minutes. Following the addition, the reaction mixture is heated to 55°C and maintained at this temperature for 7 hours. The reaction mixture is then cooled to room temperature and diluted with 3.0 L of water. Further, the organic layer is separated and extraction of water layer with toluene (3 x 0.5 L) is carried out. The combined organic layers are further washed with water (3 x 1.0 L) and dried over anhydrous sodium sulphate, and the toluene is removed by distillation to get 1.23 Kg of the pale yellow liquid, 3-carbomethoxy-3-cyano-5-methylhexanoicacid (purity: 93%, yield: 88.47%).

Stage 3: Preparation of 3-Cyano-5-methyl hexanoic acid methyl ester.

Representation of the reaction at Stage 3 is as follows:

[007] Procedure: A 20 L four necked round bottomed flask fitted with a water cooled condenser and an overhead stirrer, is charged with 3.0Kg of 3-carbo methoxy-3-cyano-5-methylhexanoicacid (obtained from stage-2) (13.2 mol, GC purity: 93%, 1.00 equiv), 0.475 L of water (26.39 mol, 2.149 equiv), 4.50 L of DMSO (63.428 mol, 5.166 equiv) and 0.882 Kg of sodium chloride (15.095 mol, 1.23 equiv). The reaction mixture is stirred and heated slowly to about 137°C to 140°C and maintained at this temperature for 10 h. The reaction mixture is then allowed to attain room temperature and poured into 10L of ice-water mixture. The mixture is stirred for about 15 min, and the layers formed are separated. Water layer is extracted with toluene (3 x 0.7 L) and the combined organic layer is washed with water (5 x 0.4 L). It is then dried on anhydrous sodium sulfate and the solvent is further removed to get 0.62 Kg of 3-Cyano-5-methyl hexanoic acid methyl ester (purity: 90.6%, yield: 83.27%).

[008] The pregabalin intermediate, 3-Cyano-5-methyl hexanoic acid methyl ester, obtained may further be converted to Pregabalin by conventional methods.

[009] The purity of 3-Cyano-5-methyl hexanoic acid methyl ester obtained was analysed by Gas Chromatography (GC). GC was performed on a Shimadzu GC 2014 instrument equipped with FID detector. The purity of 3-cyano-5-methylhexanoic acid methyl ester by area % was performed using a BP-624 column (30 m x 0.53 mm), with nitrogen carrier gas. The programme and other parameters are given below.

Column oven temperature programme:

Initial : 50oC, hold time: 5min
Rate : 10.4oC /min
Final temperature: 220oC, hold time:15min
Injector temp : 140oC
Detector temp : 250oC
Carrier gas flow rate: 53.4ml/min
Injection volume: 0.2mL
Diluent : Dichloromethane
Runtime : 36.35min

Peak Table - Channel 1

[0010] The foregoing description of the specific embodiments will very well reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and adapt for various applications such specific embodiments without departing from the generic concept and therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the appended claims.

STATEMENT OF CLAIMS

We claim:

1. A process for the preparation of pregabalin intermediate of formula 1

Formula 1

comprising:

(a) condensing Isobutyraldehyde and methyl cyanoacetate in the presence of acetic acid and piperidine to give a reaction mixture;

(b) hydrogenating said reaction mixture in the presence of palladium on carbon catalyst to yield 4-methyl-2-cyanopentanoic acid methyl ester;

(c) reacting 4-methyl-2-cyanopentanoic acid methyl ester with methyl chloroacetate and sodium alkoxide in the presence of a solvent to obtain 3-carbomethoxy-3-cyano-5-methylhexanoic acid methyl ester; and

(d) heating 3-carbomethoxy-3-cyano-5-methyl hexanoic acid methyl ester with sodium chloride, water and DMSO, to a temperature in the range of 130°C to 150°C , to yield 3-cyano-5-methylhexanoic acid methyl ester.

2. The process for the preparation of pregabalin intermediate as claimed in claim 1, wherein the reaction of step (a) takes place at a temperature in the range of 0°C to 25°C, preferably in the range of 20°C to 25°C.

3. The process for the preparation of pregabalin intermediate as claimed in claim 1, wherein said hydrogenation of step (a) is done using hydrogen gas, wherein the hydrogen gas is in the range of 5 to 10 Kg/cm².

4. The process for the preparation of pregabalin intermediate as claimed in claim 1, wherein said sodium alkoxide of step (c) is selected from the list consisting of sodium methoxide, sodium ethoxide and sodium n-propoxide

5. The process for the preparation of pregabalin intermediate as claimed in claim 1, wherein said solvent of step (c) is selected from the list consisting of methanol, ethanol, toluene, tetrahydrofuran and xylene, preferably toluene.

6. The process for the preparation of pregabalin intermediate as claimed in claim 1, wherein said water and DMSO of step (c) is present in a ratio range of 1:20 to 10:1, preferably in the ratio of 1:10.

Dated this 10th November 2010