FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICA TION
[See section 10; rule 13]
"An improved process for the manufacture of 2-[(2,6-dichloro phenyl) amino]
phenyl acetoxy acetyl derivatives "
(a) IPCA LABORATORIES LIMITED
(b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of this invention and the manner in which it is to be performed:


TECHNICAL FIELD OF INVENTION
The present invention relates to an improved process for the manufacture of 2-[(2,6-dichloro phenyl) amino] phenyl acetoxyacetic acid commonly known as aceclofenac.
BACKGROUND OF THE INVENTION
Aceclofenac is a well-known non-steroidal anti-inflammatory (NSAID) drug. Its preparation and medical use has already been disclosed in European patent No. 119932. Formula I represents Aceclofenac, where in R denotes hydrogen.

(I)
Several methods have been disclosed for the preparation of aceclofenac. The compounds (I), wherein R is a suitable carboxylic acid protecting group (an ester forming group) are important intermediates for the preparation of aceclofenac. These intermediates are prepared by the reaction of a compound (II) (2-[(2,6-dichloro phenyl) amino] phenyl acetic acid) with a suitably protected alpha haloacetic acid derivative.

(II)
In the prior art, European patent 119932 described a process for the preparation of 2-[(2,6-dichloro phenyl) amino] phenyl acetoxy acetyl derivative of compound (I), in which

sodium or potassium salts of compound (II) were reacted with benzylhaloacetate at a temperature ranging from 50-150°C in anhydrous solvents like dimethylformamide, dimethyl sulfoxide, acetonitrile etc- for a period of 2 - 20 hour to give aceclofenac ester. The benzyl ester group in compound (I) (R = CH2Ph) is then selectively removed by hydrogenation in presence of 10% Palladium on carbon at temperature 25 - 70°c and hydrogen pressure 1-6 atmosphere to yield the title compound.
Though the process is practical and plant friendly, it uses high loading of the costly catalyst palladium ( i.e., a 20% catalyst {10% Pd on charcoal} on wt/wt relative to aceclofenac benzylester), which escalates the cost of manufacture. Another major drawback of the prior art process is the impurity generation due to the use of reactive solvents like acetic acid, as the molecule is highly susceptible to both acidic and basic conditions. These conditions of deprotection of benzyl ester lead to the formation of compound (II), the penultimate intermediate in the synthetic sequence, as an impurity. This is possibly the effect of high impurity level that the yield of the product of desired quality is obtained only in a range from 50 - 65% . See example 1 & 2 of EP119932 The solvents used in EP 119932, like ethyl acetate and acetic acid are very reactive and the molecule aceclofenac benzyl ester is susceptible to acidic or basic conditions, cleaves to give diclofenac impurity. In case of ethylacetate, during the reaction ethylacetate breaks up into ethanol and acetic acid, where ethanol esterifies the aceclofenac to give ethylester of aceclofenac as impufity. The reactivity of /inertness of a particular solvent solely depends on the substrate and in this particular case the substrate, aceclofenac benzyl ester, is very susceptible to reaction conditions and solvents used. Hence, selection of solvent and catalyst optimization in such solvent is critical for obtaining required purity and yield of aceclofenac.
Subsequent Patents ES 2020146 and ES 2020145 describe a process in which the alkyl or aryl ester of aceclofenac (Compound (I), wherein R = alkyl or aryl) is cleaved by using stoichiometric amounts of trimethylsilylchloride and sodium iodide in acetonitrile as the deprotecting agent.

Although the production yield, as claimed in the patent, is slightly better, this process also suffers from the impurity generation and isolation problems. Also the use of costlier and stoichiometric amounts of reagents like trimethylsilylchloride and sodium iodide leads to the escalation of cost of manufacture.
The other process variants, reported in patents CH 682747 and ES 2046141, deal with the regioselective hydrolysis of tetrahydropyranyl or tetrahydrofuranyl ester of aceclofenac in the presence of hydrochloric acid (HC1), acetic acid or formic acid to give the title compound.
The major drawback of the prior art processes is that it uses corrosive acids for the deprotection of the protecting groups and also lacks in selectivity resulting in the formation of substantial amounts of impurity of compound (II).
Korean Patent No. 2000038941 describes yet another process for the preparation of 2-[(2,6- dichloro phenyl) amino] phenyl acetoxy acetyl derivative, in which sodium or potassium salt of 2-[(2,6-dichloro phenyl) amino] phenyl acetic acid was reacted with tertiarybutylhaloacetate to form a compound (I) wherein R is tert-butyl. The deprotection of tertiary butyl ester group is performed under acidic condition to give final compound.
The formation of the side chain, tertiary butyl ester of halo acetic acid, is difficult on an industrial scale as it uses isobutylene gas for the esterification of haloacetic acid, which is dangerous as it is highly inflammable, and also necessitates the requirement of special reactors and arrangements for handling gas. Also, the deprotection of tertiary butyl group in presence of acids like HC1 is known to give non-selective hydrolysis and the formation of impurity of compound (II).
The study of the prior art clearly indicates that the regio-selective removal of protecting group of the aceclofenac esters is key to a practical and economically viable process. Since deprotection of benzyl esters are known to be best in a scenario like this and therefore, a route starting from the aceclofenac benzyl ester appears to be most reliable,

provided this can be performed under milder conditions, the subject of the present invention.
OBJECTIVES
The main objective of the present invention is to provide a high yielding process for the preparation of 2-[(2,6-dichloro phenyl) amino] phenyl acetoxy acetic acid derivatives (Aceclofenac) of high quality.
The further objective of the present invention is to provide optimum conditions for the Palladium catalyzed debenzylation of compound (I) (R = CH2PI1) necessary to achieve the required transformation in the absence of solvents like acetic acid coupled with minimal usage of noble metal catalyst making the process more economically viable.
SUMMARY OF THE INVENTION
The present invention discloses improved process of manufacture of Aceclofenac, an NSAID, which involves essentially modification of reaction parameters such as temperature and pressure, selection of non-reactive and neutral solvents as the reaction medium, and optimization of reagents quantities in the debenzylation of aceclofenac benzylester. This modified process of the present invention eliminates mostly the drawbacks of the prior art and yields pure aceclofenac with a substantial increase in the overall yield and thereby best suited to the manufacturing conditions.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for manufacture of 2-[(2,6-dichloro phenyl) amino] phenyl acetoxy acetyl derivatives of compound (I) for medicinal use wherein R denotes benzyl, hydrogen.

The starting benzyl ester of compound (I) used in the present invention was made by optimizing the conditions of reacting sodium salt of diclofenac (II) with 2-chloro acetic acid benzyl ester (III) (X = CI) over the method described in the European patent No. 119932.

The process of the prior art deals with the debenzylation using 10% Palladium on carbon as the catalyst with a high loading of 15-16 % (wt/wt) of 10% Pd charcoal with respect to the starting material. It was of interest to find the viability of a regioselective process by reducing the high loading of the precious noble metal catalyst and thereby make the transformation with minimal impurity formation. Also of interest to select suitable non-reactive and neutral solvents and conditions to effect the transformation regio-selctivily, as against solvents and conditions reported in the prior art.
Surprisingly we found the overall impurity generation is minimized by reducing the catalyst quantity. Also by selecting solvent like toluene and acetone as the reaction medium, the transformation of compound (I) (R = CH2Ph) to a compound (I) (R = H) takes place regioselctivily without the generation of the impurity of (II). This becomes the substance of the present invention. According to the present invention a 5% Palladium adsorbed on Carbon is best suited for the debenzylation and the catalyst quantity with respect to the aceclofenac benzyl ester was reduced even to 0.8% weight/weight. The invention was found to work well when the catalyst quantity is in the range of 1.5 % to 0.8% (50% wet : % wet herein means the weight percentage of moisture present in the catalyst).
The reduction in the amount of catalyst, i.e., 15-16 % of 10% Pd charcoal to 0.8 - 1.5% of 5% Pd charcoal, is very much significant and this improvement coupled with the

selection of solvent reduces the impurity generation and yields product of high purity in very high output.
The solvent selection is very critical in any hydrogenation for reasons of solubility, nonreactive/inertbness and compatibility with catalyst. The reaction of the present invention was preformed in solvents selected from toluene, Xylene, acetone, methyl ethyl ketone or their mixture thereof. Reaction in these solvents found to reduce the formation of impurity of compound (II) and resulted the complete transformation into compound (I) (R-H).
A comparative example of EP119932 was performed in our laboratory, where ethylacetate is used as solvent. The result of this example clearly indicates that the reaction goes only at higher pressure like 5 to 6 Kg hydrogen pressure, and takes longer time for completion. Hence, the conditions of the catalytic hydrogenation were optimized. The optimized temperature during the debenzylation was ranging from 25 °C to 60°C and the hydrogenation pressure used was in the range of 10 -15 kg/cm2. A hydrogenation pressure of 2 to 9 kg/cm2 also works well but takes a little longer duration of reaction and therefore preferably a hydrogenation pressure of 10 to 15 kg/cm is used at a lower temperature of 25 to 40°C.
After completion of the reaction the product is isolated by normal work-up and crystallization from toluene. The improved process according to the present invention increased the yield of debenzylation to 90-95% with a tight control on the formation of impurities, especially impurity of compound II.
The following non-limiting examples presented to illustrate the best mode of carrying out the process of the present invention. However the invention is not limited to the particular embodiments illustrated herein but includes the permutations, which are obvious set forth in the description.
Example 1

125gm of benzyl 2-[(2,6 -dichlofo phenyl) amino] phenyl acetoxy acetate ( formula I) was added in 600ml of acetone and the resulting mixture was mixed with 1.2 gm (1% wt/wt relative to formula I) of 5% Pd on carbon (wet 50%) and then hydrogenated at pressure of 10-15 kg/cm2 to a temperature of 35-40°C for a period of 5 - 6hr. The catalyst was filtered, and the resulting solution was concentrated. 1.0 L of water was added to the concentrated reaction mixture to precipitate the product, compound (I) (R=H). The crude product was then crystallized from toluene to give pure 2-[(2,6-dichloro phenyl) amino] phenyl acetoxy acetic acid. Melting point 150 -152 °C Yield = 95 gm (yield 96%) Purity - 99.5% (HPLC)
Example 2
125gm of benzyl 2-[(2,6 -dichloro phenyl) amino] phenyl acetoxy acetate was added in 600ml of toluene and the resulting mixture was mixed with 1.2 gm (1% wt/wt relative to formula I) of 5% Pd on carbon (wet 50%) and then hydrogenated under hydrogen atmosphere at pressure of 10-15 kg/cm2 and a temperature of 35-40°C for a period of 8-10 hrs. The reaction mixture was dissolved by the addition 300 ml acetone. The catalyst was filtered, acetone was distilled and product, compound (I) (R=H) was precipitated from toluene, filtered and dried. Melting point 150 -152 °C
Yield = 94 gm (yield 95%) Purity - 99.5% (HPLC)
Example 3
125gm of benzyl 2-[(2,6 -dichloro phenyl) amino] phenyl acetoxy acetate was added in 300ml of toluene and 300 ml acetone, and the resulting mixture was mixed with 1 gm(0.8% wt/wt relative to formula I) of 5% Pd on carbon (wet 50%) and then hydrogenated under hydrogen atmosphere at pressure of 10-15 kg/cm2 and a

We claim,

1. A process for manufacture of 2-[(2,6- dichlorophenyl) amino] phenyl acetoxy acetyl
derivative of Formula I, wherein R=H, (aceclofenac) comprising;

hydrogenation of aceclofenac benzylester of Formula III (wherein R= CH2 Ph) using palladium on carbon wherein said process is characterized by selective deprotection of benzyl ester of Aceclofenac in solvents selected from acetone, toluene, methyl ethyl ketone, xylene or mixture thereof under hydrogen atmosphere in presence of an effective quantity of less than 10% wt/wt of palladium on carbon relative to compound of Formula III, and isolating Aceclofenac of Formula I from the reaction mixture by crystallization from toluene..
2. The process as claimed in claim 1, wherein the hydrogenation catalyst is 5% palladium on carbon.
3. The process as claimed in claim 1 or 2, wherein the effective catalyst quantity of 5% palladium on carbon is in the range of 0.8% to 1.5% wt/wt relative to compound of Formula III.
4. The process as claimed in any one of the preceding claims, wherein the hydrogenation is carried out at a temperature of 25°C to 60°C.
5. The process as claimed in any one of the preceding claims, wherein the hydrogenation pressure in the debenzylation is 10 to 15 kg/cm2.