DESC:The following specification describes particularly the invention and in the manner in which it is to be performed:

INTRODUCTION
The present application provides a process for the preparation of Tolmetin and its pharmaceutically acceptable salts.
Tolmetin of formula (I) is chemically known as 2-[l-Methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetic acid is administered as sodium salt. It is a non-steroidal, anti-inflammatory agent for the treatment of inflammation, swelling, stiffness, joint pain associated with rheumatoid arthritis and osteoarthritis, for both acute episodes, and long term treatment, and is also used for the treatment of juvenile rheumatoid arthritis.

Formula (I)
US 375286 disclose a process for the preparation of Tolmetin and its pharmaceutically acceptable salts comprising reaction of N-methylpyrrole acetonitrile with p-toluoylchloride in the presence of anhydrous aluminium chloride in carbon disulfide as a solvent to yield l-methyl-5-(p-toluoyl)pyrrole- 2-acetonitrile, which on hydrolysis with sodium hydroxide in a mixture of ethanol and water leads to the formation of sodium salt of Tolmetin.
However the process disclosed in '826, the use of aluminium chloride and carbon disulfide as reagent or solvent at industrial level is very difficult due to hygroscopic nature of the anhydrous aluminium chloride. Whereas, the solvent carbon disulfide employed in Friedel Craft acylation reaction is stored under water to avoid vapor loss and fire hazard because of its low flash point. Hence, it requires much caution to employ carbon disulfide at commercial scale.
US 3846447 discloses a process for preparing 5-aroyl-pyrrole -2-alkanoic acid derivatives involving the reaction of l-methylpyrrole-2-acetonitrile with phosgene in ether to obtain 5-chlorocarbonyl-l-methylpyrrole-2-acetonitrile, which is hydrolyzed and esterified to yield ethyl-5-chlorocarbonyl-l-methylpyrrolacetate. Subsequent Grignard reaction with p-toluoylmagnesium bromide at -60°C in dry toluene, followed by acid base treatment provided the final product.
However, this process also has several disadvantages since it employs a very hazardous reagent such as phosgene and a solvent like diethyl ether having a low boiling point and low flash point. Additionally, the Grignard reaction requires extremely low temperatures for carrying out the reaction which is quite exorbitant on an industrial scale. Also, the utilization of phosgene requires a lot of safety precautions to take care of its toxic properties.
US 4119639 discloses reaction of 2-aryldithiolanium cation with pyrrole-2-acetic acid to give aryldithiolanyl pyrrole acetic acid derivative, which is further converted to the desired aroyl pyrrole acetic acid compound. The multi-step process involves use of environmentally hazardous reagents such as phosphoryl halides and the obnoxious smelling 1,2 ethanedithiol which are not suitable for industrial use.
WO 2009072139 also discloses a process for the preparation of Tolmetin or its pharmaceutically acceptable salts, wherein toluoyl morpholide is employed for reaction with the methyl ester of l-methylpyrrole-2-acetic acid in presence of an halogenating agent like phosphorous oxychloride to get methyl 5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate, which is treated with a base in a solvent to obtain tolmetin. The process has several limitations due to the following reasons:
i) the process is quite long and cumbersome, as it requires preparation of p-toluoyl morpholide followed by subsequent condensation with methyl-1-methylpyrrole-2-acetate in presence of POCl3 and hydrolysis of the ester.
ii) after the condensation step, successive purifications are required for removal of associated impurities, thereby reducing the overall yield.
Therefore, there is a need to develop a economically viable, safe and industrially feasible process for the preparation of Tolmetin or its pharmaceutically acceptable salts thereof. The inventors of the present application have developed a cost effective process for preparation of tolmetin of desired purity with good yield and without the requirement of any subsequent purification.
SUMMARY OF THE INVENTION
In the first embodiment, the present application provides a process for preparation of Tolmetin or its salts comprising;
a) condensing the compound of formula (II) with methyl ester of 1- methylpyrrole-2-acetic acid to provide compound of formula (III)
;
b) hydrolyzing the compound of formula (III) to obtain Tolemtin or its salts
;
In the second embodiment, the present application further comprising; preparing tolmetin according to the first embodiment and converting to Amtolmetin or its salts.

DETAILED DESCRIPTION

In the first embodiment, the present application provides a process for preparation of Tolmetin or its salts comprising;
a) condensing the compound of formula (II) with methyl ester of 1- methylpyrrole-2-acetic acid to provide compound of formula (III) ;
b) hydrolyzing the compound of formula (III) to obtain Tolemtin or its salts
;
In embodiments, step a) involves the preparation of compound of Formula III by condensation of compound of formula (II) with methyl ester of 1- methylpyrrole-2-acetic acid in the presence of TiCl4 and a suitable solvent.
In embodiments of step a), the reaction may be carried out in the presence of a suitable solvent. Examples of such solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane, and dimethoxyethane; alcohols, such as methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, glycerol, and C1-C6 alcohols; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, and chlorobenzene; aromatic hydrocarbons, such as toluene; aliphatic hydrocarbons, nitriles, esters and polar aprotic solvents such as DMF, DMSO, DMAc; water; any mixtures of two or more thereof. In a preferred embodiment, the reaction may be carried out in presence of dichloromethane.
In embodiments of step a), the reaction may be carried out at a temperature ranging from about 0°C to about boiling temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, under the conditions outlined above, the reaction is effected for a period of about 30 minutes to about 24 hours or longer.
In embodiments of step a), the compound of formula III may be isolated directly from the reaction mixture itself after the reaction is complete, by filtration or after conventional work up with techniques such as quenching with a suitable reagent, extraction, evaporation of solvent or the like.
In embodiments of step a), the compound of Formula III is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. In embodiments of step a), the compound of Formula III is optionally purified by using suitable technique known in the literature. The compound of Formula III may be isolated or may be used directly in the next step without isolation.
In embodiments, step b) involves the preparation of Tolmetin or its salts by hydrolyzing the compound of formula III in the presence of a base and a solvent.
In embodiments, the base used herein is selected from the group of hydroxide, carbonate, alkoxide of alkali metal such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium t-butoxide; alkaline earth metal hydroxide such magnesium hydroxide, calcium hydroxide, preferably sodium hydroxide.
In embodiments, the solvent used herein is selected from the group of but not limited to alcohol such as methanol, ethanol, isopropyl alcohol, n-propanol; ketone such as acetone, methyl ethyl ketone; water or mixture thereof, preferably methanol and water mixture.
In embodiments of step b), the reaction may be carried out at a temperature ranging from about 0°C to about boiling temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, under the conditions outlined above, the reaction is effected for a period of about 30 minutes to about 24 hours or longer.
In embodiments of step b), Tolmetin or its salts may be isolated directly from the reaction mixture itself after the reaction is complete, by filtration or after conventional work up with techniques such as quenching with a suitable reagent, extraction, evaporation of solvent or the like
In embodiments of step b), Tolmetin or its salts obtained may be optionally further dried at suitable temperatures, and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.
In embodiments of step b), Tolmetin or its salts obtained may be optionally further purified by recrystallization or by slurrying in a suitable solvent or by column chromatography or any other suitable technique.
In the second embodiment, the present application further comprising; preparing tolmetin according to the first embodiment and converting to Amtolmetin or its salts by the process reported in the literature.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES

Example-1: Preparation of Compound of Formula II

1,2,4-Triazole (12.28 g), triethylamine (18 g) and toluene (250 mL) were added into a flask at 25-30 oC and stirred for 15 minutes. The reaction mass was cooled to 10°C and p-Toluoyl chloride (25 g) in 125 ml toluene was added slowly. The temperature of the reaction was raised to 40°C and stirred for 3 h. The reaction mass was filtered after completion of the reaction and the filtrate was evaporated to obtain the crude product which was slurried in n-hexane (125 mL). The solid product was obtained by filtration and washed with n-hexane.

Yield: 29.5 g, Yield (%): 97.4 %.

Example-2: Preparation of Tolmetin
Methyl 2-(1-methyl-1H-pyrrol-2-yl)acetate (25 g), compound of formula (II) (29.3 g) obtained from example-1 and dichloromethane (250 mL) were charged in to a flask and cool the reaction mixture to 10°C. The solution of TiCl4 (34.05 g) in dichloromethane (125 mL) was added slowly and stirred for 2 h at 10°C. The reaction was monitored by TLC and after completion of the reaction methanol (12.5 mL) and water (250 mL) were added to reaction mixture. The solvents evaporated and product was isolated from methanol. The obtained product was mixed with methanol (29 mL), water (430 mL) and NaOH (9.8 g) was added in the mixture. The obtained clear solution was washed with toluene and the pH of aqueous solution was adjusted with hydrochloric acid. The obtained solid product washed with water and dried under vacuum.

Yield: 31.5 g. Yield (%): 75 %

HPLC purity: 98.5%
,CLAIMS:CLAIMS:
1. A process for preparation of Tolmetin or its salts, said process comprising;
a) condensing the compound of formula (II) with methyl ester of 1- methylpyrrole-2-acetic acid in a suitable solvent to provide compound of formula (III)
;
b) hydrolyzing the compound of formula (III) to obtain Tolemtin or its salts

;
2. The process according to claim 1, wherein the solvent in step (a) is halogenated hydrocarbon solvent.
3. The process according to claim 1, wherein the solvent in step (a) is dichloromethane.
4. The process according to claim 1, where in the hydrolysis of the compound of formula (III) carried out using base.
5. The process according to claim 4, wherein the base is sodium hydroxide.