Title of Invention	A PROCESS FOR PREPARING TOLFENAMIC ACID
Abstract	N/A

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See section 10; rule 13) Title :- A process for preparing tolfenamic acid ELDER PHARMACEUTICALS LTD. Elder House, Plot No. C/9, Dalia Indl. Estate, Off. NewLinkRoad,Andheri (W), Mumbai - 400 058, India. 6 The following specification (particularly) . .. describes the nature of this invention (and the manner in which it is to be performed) :- IjgS j^Jr^ } loot, 3 0 H0V VM Title :- A process for the preparation of tolfenamic acid, Field of the invention :- The present invention relates to a process for the preparation of tolfenamic acid , more particularly the present invention relates to 2-[3-chloro-2-methyl phenyl) amino ] benzoic acid to N-(3-chloro-o-tolyl) anthranilic acid ,of the general formula , Inaccordance with the present invention , tolfenamic acid or salts thereof of the above formula are produced by the process as here in described , Back Ground :- The present invention relates to a process for the preparation of tolfenamic acid, USPTO No. 3420871 relates for the preparation of anthranilic acid , in which reactants used to produce anthranilic acid are 2- dimethyl ethyl chloride hydro chloride and N-(2,3-dichloro phenyl) - anthranilic acid using a solvents such as N,N-dimethyl formamide etc, where as in the instant invention particularly for the preparation of tolfenamic acid , the reactants and solvents used are different and new . NL. 6600251 where in the final product colour found to be yellow , but in the instant invention over comes the colour problem by using suitable 1 solvents ans reatants more particularly the techniques usd in the purification NL. 6600251 and US .331 3848 , where in to produce the product used multiple solvents for purification , have been over ruled in the present invention by utilizing a single solvent at a time . The use of expensive solvents such as diethelene glycol dimethyl ether and the Hcl scavenger aftd- N-ethyl morpholine *amyl alcohol as a solvents reported in the above prior art are being successfully replaced by the more economical dimethyl formamide as a solvent and calcium carbonite as Hcl scavenger. Objects ;- The primary object of the present invention to produce tolfenamic acid using a single solvent is economic such as it drastically reduces the cost of manufacturing in industrial level. Description 2 The present invention relates to a process for the preparation of tolfenamic acid comprising the following steps Reaction Scheme 1) O-Chlorobenzoic acid 250 gm, 1.597 mole is reacted with potassium hydroxide 100 gm, 1.782 mole, to produce the potassium salt , this on treatment with calcium carbonate 95 gm , 0.95 mole and copper powder 2 gm, 0.0315 mole in dimethyl formamide 1.5 Ltr was reacted with 3-chloro-2-methyl aniline 100 gm, 0.706 mole at 150°C to afford the crude Tolfenamic acid 161.83 gm. This crude material was purified using Toluene and dimethyl formamide sequentially to obtain Tolfenamic acid 144.64 gm with the purity of 99.95% by HPLC and the impurity 3-chloro-4-methyl-9-oxo-9,10-dihydroacridone below the stipulated pharmacoepial limits. The Tolfenamic acid thus prepared was confirmed by spectrophotometric and chromatographic techniques. Illustrative Examples : Example : 1 The reaction was conducted as per the representative example except with the exclusion of potassium hydroxide. It was found that the impurity was formed to an extent of 19.5%, thereby rendering the process unacceptable on an industrial level. Example : 2 The reaction was performed as per the representative example with cuprous oxide 6 gm, 0.041 mole as the condensation catalyst. In this example the O-Chlorobenzoic acid was not protected, giving rise to undesired impurities, hence the conversion to Tolfenamic acid was very negligible. Example : 3 The reaction was performed as per the representative example including the addition of K2C03 135 gm, 0. 97 mole in lieu of CaC03. 3 The yield of Tolfenamic acid was 53% and the product obtained was off white. Example : 4 The reaction was performed as per the representative example except by replacing copper powder by cuprous bromide 7 gm, 0.048 mole. The conversion of Tolfenamic acid was 70%, which was lower as compared to the representative example (i.e. 95%). The product had a melting point of 210-213°C. Example : 5 The reaction was performed as per the representative example except by replacing copper powder by cuprous acetate 7.5 gm, 0.041 mole. The conversion of Tolfenamic acid was 75%, which was lower as compared to the representative example (i.e. 95%). The product had a melting point of 210-213°C. The effect of reaction temperature on the conversion and yield of Tolfenamic acid was studied in order to deduce the optimum condition for obtaining the best yield and colour of the product. Example : 6 The reaction was performed as per the representative example except that the reaction temperature was maintained at 120°C. The conversion of Tolfenamic acid was 56.6%. The product had a melting point of 210-213°C. Example : 7 The reaction was performed as per the representative example except that the reaction temperature was maintained at 130°C. The conversion of Tolfenamic acid was 65.7%. The product had a melting point of 210-213°C. 4 Example : 8 The reaction was performed as per the representative example except that the reaction temperature was maintained at 140°C. The conversion of Tolfenamic acid was 82.3%. The product had a melting point of 210-213°C. In most of the examples, the product had a slight yellowish tinge. Hence it was inevitable to purify and improve the colour of the product in order to meet the pharmacoepial standards. The following examples have been illustrated with emphasis on colour improvement studies. Example : 9 The product obtained as per the representive example 100 gm was purified in 1.2 Ltr Toluene followed by treatment with the activated carbon in 300 ml dimethyl formamide. The product so obtained was white and matches with the pharmacoepial standards. With acridone impurity less than 0.05% as against 0.1 % reported in EP/BP. Example : 10 The product obtained as per the representative example 100 gm was purified using activated carbon twice in toluene (1.2 Ltr. and 4.5 Ltr. respectively). This product was fluffy and white in nature. 5 We Claim, 1. A process for the preparation of pure tolfenamic acid comprising the following steps a) reacting O-chlorobenzoic acid with potassium hydroxide to produce salt of potassium , b) treating salt obtained at step (a) with calcium carbonate and with copper powder was reacted with 3-chloro -2- methyl aniline at a temperature range from lOOCto 200C to afford a crude tolfenamic acid c) purification of crude tolfenamic acid obtained at step (b) using a solvent sequentially to get pure tolfenamic acid, 2. A process as claimed in claim 1, wherein solvent used is dimethyl formamide 3. A process as claimed in claim 1, wherein the calcium carbonate used as a HC1 scavenger 4. A process as claimed in claim 1, wherein purification is done using tolene and dimethyl formamide , 5. A process for the preparation of pure tolfenamic acid , such as here in described with reference to foregoing examples , Dated this 04 th day of Nov.2004, 6

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