FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION (See section 10, rule 13)
"AN IMPROVED PROCESS FOR PREPARATION
OF TOLMETIN"
EMCURE PHARMACEUTICALS LIMITED, a company registered under the companies act of India at ARC-H, P-2, IT-BT Park, Phase II, MIDC, Hinjwadi, Pune 411 057, Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR PREPARATION OF TOLMETIN
FIELD OF THE INVENTION
The present invention relates to a novel, cost-effective process for the preparation of 2-[l-methyl-5-(4-methyl benzoyl)-pyrrol-2-yl] acetic acid. The invention specifically relates to the preparation of methyl-5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate having the desired purity by utilizing a combination of morpholine and a water-miscible organic solvent.
BACKGROUND OF THE INVENTION
Tolmetin of formula (I), chemically known as 2-[l-methyl-5-(4-methyl benzoyl)-pyrrol-2-yl] acetic acid is administered orally as sodium salt. It is a non-steroidal, antiinflammatory agent for 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 treatment of juvenile rheumatoid arthritis.

US 3,752,826 discloses a process for preparation of Tolmetin and its pharmaceutically acceptable salts comprising reaction of N-methylpyrrole acetonitrile with p-toluoyl chloride in the presence of anhydrous aluminium chloride and carbon disulfide as a solvent to yield l-methyl-5-(p-toluoyl)pyrroIe-2-acetonitrile, subsequent hydrolysis with sodium hydroxide in a mixture of ethanol and water provided the sodium salt of Tolmetin.
However, the process which utilizes anhydrous aluminium chloride and carbon disulfide suffers from serious limitations as the use of aluminium chloride requires stringent anhydrous conditions. Also, carbon disulfide as a solvent is quite hazardous due to its low flash point and low boiling point. This solvent requires storage under water to avoid losses due to evaporation.

US 3,846,447 discloses a process for preparing 5-aroyl-pyrrole-2-alkanoic acid derivatives involving reaction of l-methylpyrrole-2-acetonitrile with phosgene in ether to obtain 5-ch!orocarbonyl-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 4,119,639 discloses reaction of 2-aryIdithiolanium 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 pharmaceutical^ 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 cumbersoine, as it requires preparation of p-
toluoyl morpholide followed by subsequent condensation with methyl-1-methylpyrrole-2-acetate in presence of POCb and hydrolysis of the ester. ii) After the condensation step, successive purifications are required for removal of associated impurities, thereby reducing the overall yield.

iii) The low yield for a batch run implies considerable increase in the production cost thus rendering the process unviable for industrial use.
Organic Process Research & Development 2010, 14, 362-368 discloses synthesis of Amtolmetin involving reaction of N,N-dirnethylaminopropyl amine with 5-toluoyl pyrrole-2-acetate. However, although the yield is 95%, but the presence of associated impurities reduces the purity to just 80%, thereby, necessitating several purifications, which reduces the overall yield considerably.
The present inventors have developed a method which provides methyl-5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate of desired purity without the requirement of any subsequent purification. The final product Toimetin of formula (I) thus obtained conforms to regulatory specifications without the need for any purification.
OBJECT OF THE INVENTION
An objective of the present invention is to provide Toimetin (I) by a novel, cost-effective process which does not require the preparation of p-toluoyl morpholide and also avoids the use of aluminum chloride.
Another object of the invention is to provide methyl-5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate of desired purity and in good yield, without involving an additional step of purification.
Yet another object of the present invention is to provide a simple, efficient and cost effective process for preparation of Toimetin (I), which is environmentally safe and industrially feasible.
SUMMARY OF THE INVENTION
The present invention relates to a novel process for the preparation of Toimetin (I) overcoming the limitations faced in the prior art.

An aspect of the present invention relates to a novel, improved and cost-effective process for the preparation of tolmetin (I), comprising reaction of methyl-1 -methyl pyrrole 2-acetate (II) with p-toluoyl chloride (III) followed by treatment with morpholine, isolating methyI-5-(4-methylbenzoyI)-l-methyIpyrroIe-2-acetate of formula (IV) which on hydrolysis gives tolmetin of formula (I).
Yet another aspect of the invention relates to a method of isolating methyl-5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate of formula (IV) by adding a chlorinated solvent to the reaction mixture along with morpholine, stirring the mixture, adding water, concentrating the organic layer, adding a water-miscible organic solvent to the residue and refluxing, adding water to the mixture to obtain compound of formula (IV) of desired purity.
These objectives of the present invention will become more apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have surprisingly found that pure methyl-5-(4-methylbenzoyl)-l-methylpyrrole-2-acetate (IV) can be easily obtained by condensation of 4-toluoyl chloride (III) with methyl-1-methyl pyrrole-2-acetate (II), followed by treatment with morpholine in a water-immiscible organic solvent and isolating by concentrating the organic layer, adding a water-miscible organic solvent, refluxing and separating out compound (IV) by adding water at 50-60°C, cooling and filtering. Moreover, the compound (TV) is obtained in optimum yield, without requiring an additional step of purification.
Tolmetin (I) thus obtained from the compound of formula (IV) by hydrolysis in an water-miscible organic solvent in presence of a base is obtained in optimum yield and conforms to pharmaceutical specification


Scheme-I: Method embodied in the present invention for the preparation ofToImetin (I)
In an embodiment, 4-methylbenzoyl chloride (III) was reacted with methyl-1-methyl -pyrrole-2-acetate (II) in an organic solvent. The mixture was heated at reflux temperature till completion of reaction.
The organic solvent was selected from the group comprising of aromatic hydrocarbons, aliphatic hydrocarbons, esters selected from the group comprising of cyclohexane, toluene, xylene, ethyl acetate, methyl acetate etc.
After completion of reaction, the reaction mass was cooled, an organic solvent such as chlorinated organic solvent like dichloromethane followed by morpholine was added and the subsequent mixture was stirred at ambient temperature for 3-5 hours.
The reaction mixture was quenched with water, the organic layer was concentrated and a water-miscible organic solvent, selected from methanol, ethanol, isopropyl alcohol etc was added to the residue. The mixture was refluxed for 60 minutes and water was then added to the reaction mixture at 55 to 60°C. The compound of formula (IV) which separated out was obtained in optimum yield and had the desired purity.
It is pertinent to mention that refluxing in a water-miscible organic solvent followed by addition of water at 55 to 60°C was necessary to obtain compound (IV) of the desired purity with optimum yield.

Mefhyl-5-(4-methylbenzoyl)-l -methyl pyrrole-2-acetate (IV) thus obtained was then converted to Tolmetin (I) by treating it with a base in an organic solvent. The reaction was carried out in the temperature range of 25°C to 35°C
After completion of the reaction, water was added to the reaction mixture and the pH of the mixture was adjusted between 3.5 and 3.0. Compound of formula (I) separated out, which was filtered, washed with water and dried.
Tolmetin of formula (I) was isolated in good yield and was found to conform to regulatory specifications.
Tolmetin of formula (I) thus isolated did not require any further additional step of purification.
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.
Example 1
Preparation of methyl-5(4-methy]benzoyl) 1-methyl pyrrole-2-acetate
Methyl 1-methyl pyrrole 2-acetate (100 gm) was added to xylene (500ml) in a 2000 ml flask, followed by gradual addition of toluoyl chloride (190 gm). The reaction mixture was stirred at reflux temperature and after completion of reaction, as monitored by TLC, xylene was concentrated under vacuum at 90 to 100°C. The reaction mixture was further cooled to 10 to 15 °C. and dichloromethane (500 ml) was added to it, followed by slow addition of morpholine at 10-20°C. After stirring the mixture for 3hrs, DM water (500ml) was added to it and further stirred for 30 min at 25 to 35°C. The organic layer was separated, washed with DM water (500ml), and was concentrated under reduced pressure. Methanol (100ml) was then added to the reaction mass, heated till reflux (65 to 70°C) with continuous stirring for 60 min. The mixture was then cooled to 55 to 60°C and DM water (1600ml) was added to it. After stirring for 30 min at same temperature, the reaction mixture was further cooled to 20 to 30°C and stirred for 3hrs at same temperature. The solid mass was then filtered, washed with water twice (2 x 200ml) and dried under vaccum to get pure methyl-5(4-methylbenzoyl) 1-methyl pyrrole-2-acetate.

Yield: 65-70% Purity: 99%
Example 2
Preparation of Tolmetin
Methyl-5(4-methylbenzoyl) 1-methyl pyrrole-2-acetate (100 gm) thus obtained was then added to THF (250 ml) at 25 to 30 °C in a 5000 ml flask with continuous stirring. After maintaining the reaction at 25 to 35 °C with stirring for 15 min, aq. NaOH solution (30 g in 700 mL DM water) at 25 to 30 °C was added to the reaction mixture and further stirred for 2 hrs at same temperature. On completion of reaction, as monitored by TLC, DM water (1000 ml) was added to the reaction mixture and the pH was adjusted to 1.5 to 3 with dil. HC1 (60 ml in 100 ml DM water) at 25 to 35 °C. The reaction mass was stirred for 30 min and filtered. The wet cake was washed twice (2 x 100 ml) with DM water and dried under vacuum at 60 to 65 °C for 30 min to obtain Tolmetin. Overall Yield: 100 to 112 gm.

We Claim:
1. A process for the preparation of Tolmetin (I), comprising reaction of methyl-1-
methyl-2-pyrroleacetate of formula (II) with 4-toluoyl chloride of formula (III) in an
organic solvent and isolating compound of formula (IV) in presence of morpholine,
subsequent treatment of compound (IV) with a base gave Tolmetin of formula (I).
2. A process as claimed in claim 1 wherein the organic solvent is selected from ethyl acetate, toluene and xylene.
3. A process as claimed in claim 1, wherein compound of formula (IV) is isolated by adding a chlorinated solvent to the reaction mixture with morphoiine, stirring the mixture and adding water, concentrating the organic layer, adding a water-miscible organic solvent to the residue and refiuxing, adding water to the mixture to obtain compound of formula (IV).
4. A process as claimed in claim 1, wherein the water-miscible organic solvent is
selected from methanol, ethanol and isopropyl alcohol.