CLIAMS:We Claim:

1. An improved process for the preparation of 2-[4-(1-methoxy-1-oxopropan-2-yl)phenoxy]pyridine-3-carboxylic acid of Formula II:

Formula II
which comprises reaction of methyl-2-(4-hydroxyphenyl)-propionate of Formula III

Formula III
with 2-chloronicotinic acid of Formula IV

Formula IV
in presence of base and N-methyl pyrrolidone.

2. The process of claim 1, wherein the base is selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and potassium tert-butoxide.

3. The process of claim 1, wherein the base is potassium tert-butoxide.

4. The process of claim 1, wherein the reaction is conducted in presence of copper iodide.

5. The process of claim 1, wherein the reaction is performed at a temperature of about 100 to about 120 °C.

6. The process of claim 1, wherein the compound of formula II is isolated using a solvent mixture of ethyl acetate and n-hexane.

7. The compound of Formula II obtained according to the process of claim 1 is further converted to Pranoprofen.
,TagSPECI:4. DESCRIPTION

The present invention provides an improved process for preparing intermediate of Pranoprofen, 2-[4-(1-methoxy-1-oxopropan-2-yl)phenoxy]pyridine-3-carboxylic acid of Formula II, by the reaction of methyl-2-(4-hydroxyphenyl)-propionoate with 2-chloronicotinic acid in presence of N-methyl pyrrolidone.

Formula II

Pranoprofen is chemically known as α-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid and is structurally represented by formula (I):

Formula I

Pranoprofen exhibits prominent anti-inflammatory action, analgesic action and antipyretic action. It is a non-steroidal anti-inflammatory drug having a wider safety margin, and is commercially available by the product name of Niflan.

U.S. Patent No. 3,931,205 discloses Pranoprofen and its process.

Japanese patent application 03271290 A discloses a process for the preparation of Pranoprofen from 2-[4-(1-methoxy-1-oxopropan-2-yl)phenoxy]pyridine-3-carboxylic acid. The process for preparing 2-[4-(1-methoxy-1-oxopropan-2-yl)phenoxy]pyridine-3-carboxylic acid involves reaction of methyl-2-(4-hydroxyphenyl)-propionate with 2-chloronicotinic acid in presence of sodium methoxide and methanol. However, the disclosed process does not provide complete conversion of starting material and industrially not feasible for larger scale-up.

Therefore, there is a need to develop an improved process for preparing intermediate of Pranoprofen to provide greater yield, which will improve the yield of Pranoprofen.

The inventors of the present invention developed an improved process for the preparation of intermediate of Pranoprofen, which involves use of simple and selective solvent and optimum reaction temperature to make the invention industrially feasible and inexpensive.

In an aspect of the present invention is to provide an improved process for the preparation of 2-[4-(1-methoxy-1-oxopropan-2-yl)phenoxy]pyridine-3-carboxylic acid which comprises reaction of methyl-2-(4-hydroxyphenyl)-propionate with 2-chloronicotinic acid in presence of base and N-methyl pyrrolidone (NMP).

The base used for conducting the reaction includes but are not limited to inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate and the like; organic base such as potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, triethyl amine, methyl amine, pyridine, tetramethyl ammonium hydroxide, tetrabutyl ammonium hydroxide and the like. The base may be used in combination with copper iodide.

The quantity of the base used for the present invention may range from 1 to 3 molar equivalents per equivalent of methyl-2-(4-hydroxyphenyl)-propionate.

The solvent is N-methylpyrrolidone (NMP) for performing the reaction. The present invention also involves use of solvents such as dimethylformamide, dimethylsulfoxide (DMSO); chlorinated solvents such as dichloromethane, chlorobenzene and chloroform; water or any combination thereof for preparing intermediate of Pranoprofen.

The reaction of the present invention may be conducted at a temperature of about 50 °C to about 120 °C or 100 to 120 °C as per the solvent used or at a reflux temperature. The reaction may be maintained at an elevated temperature for a certain period, for example, 1 to 5 hours or more to improve the yield of the compound.

After completion of the reaction, the reaction mixture may be treated with acid, for example, hydrochloric acid, in presence of water and ethyl acetate to adjust the reaction pH in between 1.5-2.5 and then subjected for isolation of solid which involves separation of layers, concentration and then precipitation of solid using suitable organic solvent such as ethyl acetate and n-hexane.

The overall process of the present invention is depicted in the following scheme:

The obtained compound of Formula II may be converted to Pranoprofen by using conventional processes disclosed in the prior art, for example, JP 03271290 A.

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.

EXAMPLES

Example-1:
Preparation of 2-[4-(1-methoxy-1-oxopropan-2-yl)phenoxy]pyridine-3-carboxylic acid

To a stirred solution of methyl-2-(4-hydroxyphenyl)-propionoate (3.0 g, 0.017 mol) in N-Methyl pyrrolidone (25 ml) 2-chloronicotinic acid (2.5 g, 0.0158 mol) was added. Potassium ter-butoxide (2.5 g, 0.023 mol) and Copper Iodide (3.0 g, 0.0158) were charged. The reaction mixture was heated to 100-120 °C and stirred for 5 to 8 hours. After completion of the reaction, water (50 ml), ethyl acetate (50 ml) and hydrochloric acid were added to adjust pH to 2.0. The reaction mixture was filtered through hyflo bed and then separated layers. The organic layer was washed with brine solution and then passed through sodium sulfate. The organic layer was concentrated and then slurred the reaction mixture in the mixture of ethyl acetate and hexane solution. The solid obtained was filtered and dried under vacuum.

Yield : 2.5 g.
1H-NMR: (CDCl3) - 1.52 (3H, d), 3.6(3H, S), 3.8(1H, q), 7.1 (3H, m), 7.4 (2H, m), 8.3 (1H, d), 8.5 (1H, d).
Mass ES+ 302.1