CLIAMS:1. A process for preparation of a process for the preparation of compound of formula II

Formula II

or pharmaceutically acceptable salt thereof, which comprises:

a) reaction of p-Hydroxybenzoic acid or its salt with Methyl ester of Pregabalin or its salt in presence of condensing agent and solvent to provide compound of Formula III;

Formula III
b) reaction of compound of formula III with base to provide the compound of Formula II or its salt.

2. The process of claim 1, wherein the condensing agent of step a) is selected from N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride and 1-Hydroxybenzotriazole.

3. The process of claim 1, wherein the condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride and 1-Hydroxybenzotriazole.

4. The process of claim 1, wherein the solvent of step a) is dichloromethane.

5. The process of claim 1, wherein the reaction of step a) conducted at a temperature of about 0 to 35 °C.

6. The process of claim 1, wherein the base of step b) is selected from inorganic base or organic base.

7. The process of claim 1, wherein the base is inorganic base such as lithium hydroxide.

8. The process of claim 1, wherein the reaction of step b) is conducted in presence of solvent such as mixture of tetrahydrofuran and water.

9. The purity of compound of formula II, 3-((4-hydroxybenzamido)methyl)-5-methylhexanoic acid according to claim 1, is greater than 95% by HPLC.
,TagSPECI:Field of Invention

The present invention provides a process for preparing the compound of 3-((4-hydroxybenzamido)methyl)-5-methylhexanoic acid of Formula II or its salt, which is useful as reference marker or a key intermediate to provide pure pregabalin.

Formula II

Background of the invention

Pregabalin of Formula I is chemically known as (S)-3-(aminomethyl)-5-methylhexanoic acid.

Formula I
Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy, management of posterpetic neuralgia, adjunctive therapy for adult patients with partial onset seizures, and management of fibromyalgia. Pregabalin is an analog of 4-aminobutyric acid (GABA), a neurotransmitter that is thought to play a major inhibitory role in the central nervous system (CNS). Pregabalin is available under the trade name LYRICA® in tablets for 25, 50, 75, 100, 150, 200, 225, 300 mg doses.

Various processes for the preparation of pregabalin and related compounds are disclosed in U.S. Pat. Nos. 5,599,973 and 5,616,793, PCT Publication No. WO 2006/122258 and U.S. application no. 2011/0245536. However, none of the prior art provided process pure compound of 3-((4-hydroxybenzamido)methyl)-5-methylhexanoic acid, which is useful as an reference marker or as an intermediate for pregabalin.

The skilled in the art of drug manufacturing research and development understand that a compound in a relatively pure state can be used as a "reference standard." A reference standard is similar to a reference marker, which is used for qualitative analysis only, but is used to quantify the amount of the compound of the reference standard in an unknown mixture, as well. A reference standard is an "external standard," when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique. (Strobel p. 924, Snyder p. 549, Snyder, L. R.; Kirkland, J. J. Introduction to Modern Liquid Chromatography, 2nd ed. (John Wiley & Sons: New York 1979)). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response.

The reference standard can also be used to quantify the amount of another compound in the mixture if a "response factor," which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined. (Strobel p. 894). For this purpose, the reference standard is added directly to the mixture, and is known as an "internal standard." (Strobel p. 925, Snyder p. 552).

To use a compound as a reference marker or an intermediate for preparing pregabalin in its pure form requires to have input as substantially pure compound, 3-((4-hydroxybenzamido)methyl)-5-methylhexanoic acid.

Therefore, there is a need to develop a simple and inexpensive process to provide pure compound of formula II, which will be useful as reference marker as well as a key intermediate to provide pure pregabalin or pharmaceutically acceptable salt thereof.

Summary of the invention

The present inventors involves a simple, conventional and industrial feasible process to provide compound of Formula II or pharmaceutically acceptable salt thereof.

In an aspect, the present invention provides a process for preparing compound of formula III:

Formula III

which comprises reaction of p-Hydroxybenzoic acid or its salt with Methyl ester of Pregabalin or its salt in presence of condensing agent and solvent.

In another aspect, the present invention provides a process for the preparation of compound of formula II:

Formula II
or pharmaceutically acceptable salt thereof, which comprises:

a) reaction of p-Hydroxybenzoic acid or its salt with Methyl ester of Pregabalin or its salt in presence of condensing agent and solvent to provide compound of Formula III;

Formula III
b) reaction of compound of formula III with base to provide the compound of Formula II or its salt.

Detailed description of the invention

The term “substantially pure” as used herein, unless otherwise defined, refers to compound of formula II or its salt that has purity greater than 95%.

In an aspect, the present invention provides a process for preparing compound of formula III:

Formula III

which comprises reaction of p-Hydroxybenzoic acid or its salt with Methyl ester of Pregabalin or its salt in presence of condensing agent and solvent.

In another aspect, the present invention provides a process for the preparation of compound of formula II or pharmaceutically acceptable salt thereof, which comprises:

a) reaction of p-Hydroxybenzoic acid or its salt with Methyl ester of Pregabalin or its salt in presence of condensing agent and solvent to provide compound of Formula III;

Formula III
b) reaction of compound of formula III with base to provide the compound of Formula II or its salt.

The process for preparing compound of formula III of the present invention involves reaction of p-Hydroxybenzoic acid or its salt with Methyl ester of Pregabalin or its salt in presence of condensing agent and solvent to provide compound of Formula III.

The reaction is performed in presence of condensing agent such as N,N'-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-Hydroxybenzotriazole, O-(1H-Benzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate, O-(1H-Benzotriazol-1-yl)-N, N, N', N'-tetramethyluronium tetrafluoroborate and the like, or mixture thereof.

The reaction may be conducted at a temperature of about 0 to about 35 °C or more for period of about 5 to 10 hours or more. Generally, the reaction of the present invention is conducted in presence of solvent, for example, water, alcohol, hydrocarbon and the like.

The reaction for providing the compound of formula III is performed in the presence of solvent such as chlorinated solvent such as dichloromethane, dichloroethane, chloroform, chlorobenzene and the like; hydrocarbon such as hexane, heptane, cyclohexane and the like; esters such as ethyl acetate, isopropyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; water; or any combination thereof.

After completion of the reaction, the reaction mixture may be quenched by using quenching agent such as water, acid, for example, hydrochloric acid, and the like; the resultant solution may be subjected for isolation of solid by using suitable known techniques, for example, recrystallization, or it may be directly used for further reaction.

The process for preparing the compound of formula II involves reaction of the compound of formula III, obtained from the present invention, with base at a suitable temperature.

The reaction may be performed in the presence of solvent includes but are not limited to water, ether such as diethyl ether, diisopropyl ether, tetrahydrofuran and the like; chlorinated solvent such as dichloromethane, chloroform, dichloroethane, chlorobenzene and the like; hydrocarbon such as hexane, heptane, cyclohexane and the like; or combination thereof. In an embodiment, the reaction is conducted in presence of mixture of tetrahydrofuran and water.

The base used for the production of the compound of formula II includes but are not limited to inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia and the like; organic base includes but are not limited to triethylamine, pyridine, N-methylpyrrolidine, methyl amine, and the like, or combination thereof.

The reaction may be conducted at a temperature of about 25 to about 35 °C for a period of about 1 hour to about 24 hours or more to provide pure compound of Formula II or its salt.

After completion of the reaction, the reaction mixture may be subjected for precipitation of the solid by using suitable technique. The process may involve separation of aqueous layer and adjustment of pH to 3-4 by using acid to provide precipitation of solid. The acid may include hydrochloric acid, hydrobromic acid, sulfuric acid and the like.

The resultant compound of formula II of the present invention may have the purity greater than 95% as determined by the HPLC method.

The pharmaceutically acceptable salt of the present invention includes inorganic and organic salt such as hydrochloride, sulfate, phosphate, acetate, fumarate, tartrate and the like. In the case of resultant compound is free-base, it is converted to its pharmaceutically acceptable salt by the treatment of free-base with an acid, for example, hydrochloric acid, sulfuric acid, acetic acid, and the like.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLE:

Example-1:

Process for the Preparation of 3-((4-hydroxybenzamido)methyl)-5-ethylhexanoic acid

To the solution p-Hydroxybenzoic acid (1.25 g) and methyl ester of pregabalin hydrochloride (2.0 g) in dichloromethane (40 ml) at room temperature, was added 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (2.60 g) and 1-Hydroxybenzotriazole (1.22 g) simultaneously. The reaction mass was cooled to 10°C and then added triethyl amine (1.37 g). The reaction mass was stirred for 24 hours. After completion of reaction, the reaction mass was subjected for quenching with water (50 ml) and then washed with brine solution (100 ml). The obtained reaction mass was concentrated to provide compound of formula III (2.1 g).

Spectral data:
1H NMR (400 MHz, CDCl3): d 9.70(1H,bs), 8.17(1H,t), 7.68(2H,d), 6.75(2H,d), 3.5(3H,s), 3.25(1H,m), 3.05(1H,m), 2.34(1H,m), 2.15(1H,m), 1.62(1H,m), 1.04-1.16(2H,m), 0.83(6H,m),
Mass: 294.2 (M+1)

To the solution compound of Formula III (1.0g) and (1:1) Tetrahydrofuran-water (20 ml) at 5-10°C, was added lithium hydroxide (0.43 g). The reaction mass was stirred for 24 hours at room temperature. After completion of reaction, the reaction mass was concentrated and then extracted the aqueous layer with dichloromethane (50 ml). The pH of the aqueous layer was adjusted to 3-4 with dilute hydrochloric acid. The obtained solid product was filtered and washed with water and dried under vacuum at 40°C to afford pure product, 3-((4-hydroxybenzamido)methyl)-5-methylhexanoic acid (0.6 g).

Spectral data:
1H NMR (400 MHz, CDCl3): d 11.98(1H,bs), 9.9(1H,bs), 8.16(1H,t), 7.68(2H,d), 6.76(2H,d), 3.10-3.30(2H,m), 2.24-2.48(1H,m), 2.0-2.10(2H,m), 1.64-1.69 (1H,m), 1.03-1.19(2H,m),.0.83(6H,m).
13C NMR (400 MHz, CDCl3): d 174.1;166.2; 160.0; 129.1;125.4; 114.7; 42.8; 41.5; 37.5; 33.1; 24.8; 22.8; 22.5.

Mass: 280.1 (M+1)
HPLC purity= 95.24%