Title of Invention

A PROCESS FOR PREPARATION OF [2-(2,6-DICHLOROANILINO) PHENYL] ACETOXY ACETIC ACID

Abstract

Process for manufacture of 2-(2,6-dichlooranilino) phenyl acetoxy acetic acid is provided. The process comprises of acid hydrolysis 2-tert-butoxy-2-oxoethyl {2-[(2,6-dichlorophenyl)aminorophenyl}acetate in presence of a stron acid catinic exchange resin with SO3H group on - Divinylbenzene copolmer beads in presence of a solvent to yield compounds of the formul1. The compounds so obtained have shown non-steroidal anti-inflammatory activity.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION. (See sectionlO] Title of the invention A PROCESS FOR PREPARATION OF [2-(2,6-DICHLOROANILINO) PHENYL1 ACETOXY ACETIC ACID1 M/S. J.B.CHEMICALS & PHARMACEUTICALS LTD., an Indian Company, having its Registered Office at Neelam Centre, B" Wing, 4th floor, Hind Cycle Road, Worli, Mumbai 400 030, Maharashta, India. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed. A PROCESS FOR PREPARATION OF [2-(2,6-DICHLORO ANILINO) PHENYL] ACETOXY ACETIC ACID Field: The invention relates to a novel and an improved process for the preparation of phenyl acetic acid derivatives, more particularly [2-(2,6-dichloroanilino) phenyl] acetoxy acetic acid. Background and Prior Art: [2-(2,6-dichloroanilino) phenyl] acetoxy acetic acid commonly known as aceclofenac (compound of formula 1) was first disclosed in US 4548952 and is known to have Anti-inflammatory activity. The compound is a Non-steroidal anti¬inflammatory compound with properties similar to that of diclofenac with better gastrointestinal tolerability. (I) Various processes for the synthesis of these compounds have been disclosed in the prior art. ES 2020146 describes a process of synthesis of compound of formula (I) by selective reaction of compounds of formula (II) where R= alkyl or aryl with chlorotrimethylsilane and anhydrous sodium iodide in a Nitrogen Blanket inert atmosphere. 2 (II) ES 2046141 describes a process for preparation of compound of formula I by selective reaction of compounds of formula III with acetic acid in a mixture of solvents. ° R, (III) (IV) W09962865 describes a process of synthesis of compounds of aceclofenac by acid hydrolysis of compounds of the formula IV in presence of Zinc catalyst. EP-A-119932 describes a process for preparing aceclofenac by hydrogenation of benzyl-2-[(2,6-dichIorophenyl)amine] phenylacetoxyacetate with a palladium catalyst over a long period of time at severe reaction conditions. WO9955660 describes a process of preparation of aceclofenac by reacting a tertiary ammonium salt of [2-(2,6-diclhloroanilino) phenyl] acetic acid with a-haloacetic acid ester and subsequently treating the so obtained compound with a deprotecting agent to form aceclofenac. The processes known for the preparation of aceclofenac pose a number of problems during commercial manufacture. Many of the processes involve hydrogenolysis which inherently is dangerous reaction where in there is a need to handle special equipment. The yield of certain steps is low and the process is time consuming. Moreover the yield so obtained have remained low. The processes hence have lacked commercial viability. It can be hence realized from the prior art that there exists a need for a commercially viable, safe and economical process for manufacture of the said phenyl acetic acid derivative compounds with high yield and purity. The inventors of the present invention have come up with a novel process for the preparation of aceclofenac presenting high yield, purity, safety and commercial viability According to the present invention, there is provided for a novel one step process for the synthesis of aceclofenac with relatively a short reaction time, good yield and high purity. The reaction so described according to the present invention eliminates the use of any dangerous high pressure gases or similar other high-risk conditions thereby rendering the process safe for application. Description: An object of the present invention is to provide for a process of preparation of phenyl acetic acid derivatives for use in therapy as an analgesic or anti-inflammatory compound. More particularly the object of the invention is to provide for a commercially viable process for the synthesis of aceclofenac giving high yield and purity. Another object of the invention is to provide for a process for synthesis of aceclofenac which is safe and poses low risk during manufacture. 4 The present invention relates to a process of preparation of compounds of formula I (aceclofenac) by carrying out acid hydrolysis of the compounds of formula V in presence of trifluoroacetic acid, formic acid, hydrobromic acid, sulphonic acid, hydrochloric acid, trifluroacetic acid, methane sulphonic acid, p-toluene sulphonic acid or a lewis acid (ex. Aluminium chloride, Ferric chloride etc.) bonded cationic exchange resins with SO3H group on Styrene-Di vinyl benzene co-polymer beads. A preferred embodiment of the invention is carried out in presence of formic acid and a strong acid ion-exchange resin. CH-i (V) The reaction is performed in an anhydrous medium in presence of a solvent selected from toluene, xylene, benzene, carbon tetrachloride, ethylene dichloride, chloroform, mythelene chloride, methyl ethyl ketone, methylpropyl ketone, methylisobutyl ketone, ethylpropyl ketone, tetrahydrofuran, methyl-t-butyl ether, dioxane and the like, alone or In combination, the most preferred being toluene. The reaction is carried out at a temperature ranging from 20°C to 40°C, the most preferred range being 30°C to 35°C. A preferred method of isolating the final product from the reaction mass is by filtration under the solubility conditions of the reaction product and then cooling to yield the product. Another aspect of the invention is preparation of compounds of tert-butyl- [2-(2,6-dichloroanilino) phenyl] acetoxy acetate (formula V) by reaction of diclofenac sodium salt with a slight excess of the tert-butyl chloroacetate. The reaction is carried out in at a temperature of 50°C to 60°C and more preferably at a temperature of 55°C to 60°C in presence of a high polarity protic solvent selected like Dimethyl formamide. The reaction mixture is then cooled to room temperature and the reaction mass is quenched in a thin stream in chilled water with continuous stirring at a temperature below 15°C. The resulting product precipitates out, is filtered, washed and dried under vacuum at 50°C to 55°C till constant weight. Recrystalisation of the product is carried out in petroleum ether. t-Butyl chloroacetate used for the preparation of tert-butyl- [2-(2,6-dichloroanilino) phenyl] acetoxy acetate is prepared by the following procedure: Chloroacetyl chloride is added to Dimethyl aniline in a thin stream at a temperature of 10°C. Tert-butanol is then added to the mixture at 10°C-12°C. The addition is done slowly over a period of 1-2 hrs due to the exothermic nature of the reaction. The reaction mass is quenched in water and methylene chloride is added to extract the aqueous layer. The methylene chloride layer so obtained is washed with dilute sulphuric acid, followed by water, bicarbonate solution and finally with water. The organic layer is dried over calcium chloride. The methylene chloride is then distilled out by applying low vacuum (about 240-120 mm Hg below 48°C. The vacuum is increased and fractions are collected. Tert-butyl chloroacetate is collected at 48-52°C at a vacuum of 11-12 mm/Hg. The reaction so performed is environment friendly using easily available reactants. The reaction time is relatively short and the process is carried out without the use of any difficult solvents. The catalyst does not present any problems of separation, corrosivity, attrition, pressure drop or mass transfer limitations. One of the biggest 6 advantages of the process is the high yield and purity. The product obtained from the reaction has high purity, hence eliminating the need for further crystalisation. Moreover, the reaction does not employ any dangerous high-pressure gasses or any other high-risk conditions thereby rendering the process safe for application. It is to be understood that the example and embodiments described hereinabove are for the purpose of providing a description of the present invention by way of example and are not to be viewed as limiting the present invention in any way. Various modifications or changes that may be made to that described hereinabove by those of ordinary skill in the art are also contemplated by the present invention and are to be included within the spirit and purview of this application and the following claims. Example 1: 25 gms of tert-butyl [2-(2,6-dichloroanilino) phenyl] acetoxy acetate is added to a stirred solution of 250ml toluene and 2.5 ml formic acid, containing 2.5 gm of a sulphonic acid cation exchange resin. The reaction mass is stirred for 2 hours at 30 to 35 Deg C. The solution is filtered and cooled below 0 Deg C to afford [2-(2,6-dichloroanilino) phenyl] acetoxy acetic acid with a yield of 95% and a purity of 99%. Example 2 20 gms of Diclofenac sodium is added to 50 ml Dimethyl Formamide under stirring. The solution is warmed to 50 Deg C and 11 ml tert-butyl chloroacetate is added slowly over a period of 15 min. The reaction mass is maintained at 59-60 Deg C for 2 hours. The reaction mass is quenched in 300 ml chilled water (10-15 Deg C) and then stirred for 3 hours at 20 - 25 Deg C. The solid thus obtained is filtered and washed with water. The product is dried under vacuum to afford tert-butyl [2-(2,6-dichloroanilino) phenyl] acetoxy acetate with a yield of 90% . 7 Example 3 The reaction as in example 1 is repeated without the cationic exchange resin. The reaction mass is stirred for about 2 hrs at a temperature of 30°C to 35°C. The solution is filtered & cooled below 0°C. It was observed that the major portion of the reaction does not go to completion & very low yield is obtained. Example 4 The reaction as in example 1 is repeated without the cationic exchange resin. The temperature is increased to 45°C to50°C. The reaction mass is stirred for about 41/2 hrs, filtered & cooled below 0°C. Aceclofenac is obtained as the product with low yields. The purity of the product is also low and recrystalisation is necessary to obtain the product of the required purity. Example 5 : 40g of t-butyl [(2,6-dichloroanilino) phenyl] acetoxy acetate is stirred in 400ml toluene containing resin with SO3H group bound to styrene Divinylbenzene copolymer beads. A mixture of trifluoroacetic acid and formic acid (4.5ml) in a ratio of 2:5 is added to the above solution at a temperature of 35°C-40°C. The reaction mass is stirred for about 2.5 hours, filtered and cooled to 0°C to give aceclofenac. Example 6: The process as in example 5 is carried out at a temperature of about 25°C to 30°C. The reaction went to completion in 51/2 hours and aceclofenac was yielded as the end product. 8 claim: A process for preparation of [2-(2,6-dichloroaniIino) phenyl] acetoxy acetic acid from compounds of the formula Vi wherein the said compound of formula V is treated with an acid or mixture of acids bonded to cationic exchange resin with S03H group on Styrene- Divinylbenzene co-polymer beads in presence of a solvent. 2. A process as in claim 1, where the cationic exchange resin is a resin bonded with S03H group in Styrene Divinylbenzene copolymer beads 3. A process as in claim 1 where the acid or the mixture of acids is selected from trifluoroacetic acid, formic acid, hydrobromic acid, sulphonic acid, hydrochloric acid, , methane sulphonic acid p-toluene sulphonic acid or a lewis acid like Aluminium chloride, Ferric chloride. 4. A process as in claim 3, wherein the acid selected is formic acid. 5. A process as in claim 3, where the acid selected is a mixture of formic acid and trifluroacetic acid. 6. A process as in claim 5, where the ratio of formic acid and trifluroacetic acid is 2:5. 9 A process as in claim 1 where the solvent is selected from toluene, xylene, benzene, carbon tetrachloride, ethylene dichloride, chloroform, mythelene chloride, methyl ethyl ketone, methylpropyl ketone, methylisobutyl ketone, ethylpropyl ketone, tetrahydrafuran, methyl-t-butyl ether, dioxane. A process as in claim 4, where the solvent selected is toluene A process as in claims 1 to 5 where the reaction is carried on at a temperature ranging from 20°C to 40°C. A process as in claim 6 where the reaction is carried out at a temperature between 30°C and 35°C. this ...30th... .. day of January 2004 FOR J. B. CHEMICALS & PHARMACEUTICALS LTD. SHIRISH BHAGWANLAL MODY DIRECTOR

Documents:

105-mum-2004-abstract(30-1-2004).pdf

105-mum-2004-abstract.doc

105-mum-2004-abstract.pdf

105-mum-2004-claims(granted)-(30-01-2004).doc

105-mum-2004-claims(granted)-(30-1-2004).pdf

105-mum-2004-claims.doc

105-mum-2004-claims.pdf

105-mum-2004-correspondence(28-5-2004).pdf

105-mum-2004-correspondence(ipo)-(20-12-2007).pdf

105-mum-2004-correspondence(ipo).pdf

105-mum-2004-correspondence.pdf

105-mum-2004-description(granted).doc

105-mum-2004-description(granted).pdf

105-mum-2004-form 1(30-1-2004).pdf

105-mum-2004-form 1.pdf

105-mum-2004-form 19(30-1-2004).pdf

105-mum-2004-form 19.pdf

105-mum-2004-form 2(granted)-(30-01-2004).doc

105-mum-2004-form 2(granted)-(30-1-2004).pdf

105-mum-2004-form 2(granted).doc

105-mum-2004-form 2(granted).pdf

105-mum-2004-form 2(title page).pdf

105-mum-2004-form 3(30-1-2004).pdf

105-mum-2004-form 3.pdf

105-mum-2004-form 5(30-1-2004).pdf

105-mum-2004-us patent.pdf