FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION "AN IMPROVED PROCESS FOR BICALUTAMIDE"
Emcure Pharmaceuticals Limited.,
an Indian Company, registered under the Indian Company's Act 1957
and having its Registered Office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention provides an improved and cost effective process for the preparation of bicalutamide with desired purity. Specifically, the process eliminates the presence of undesired by products in the final product during the isolation of bicalutamide.
BACKGROUND OF THE INVENTION
Bicalutamide of formula (I), a non-steroidal androgen receptor inhibitor and chemically known as 4-Cyano-3-trifluromethyl-N-(3-(4-fluorophenyl-sulfonyl)-2-hydroxy-2-methyl-propionylaniline was approved by USFDA with proprietary name 'Casodex' form oral administration as a tablet having 50 mg strength. Bicalutamide is a racemate with its antiandrogenic activity being almost exclusively exhibited by the R-enantiomer of bicalutamide; the S-enantiomer is essentially inactive.

Various researchers have attempted to synthesize the active pharmaceutical ingredient bicalutamide of formula (I).
US 4,636,505 relates to amide derivatives and more particularly relates to novel acylanilides which possess antiandrogen properties; wherein bicalutamde is prepared by oxidation of 4-Cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfanyl-2-hydroxy-2-methylpropionyl)aniline (formula II) with m-chloroperbenzoic acid (mCPBA) in dichloromethane as solvent. The process employs a abnormally high volume of halogenated solvent (463 volume) and involves long reaction about 18 hour. The reaction is worked up by heating with a solution of sodium sulfite and organic layer was washed with solution of sodium carbonate. The specification does not mention

about the product purity, both prior and after column chromatography. Further, no information was disclosed about the yield.
US 6,583,306 discloses a method for synthesis of pure enantiomer of acylanilides such as bicalutamide from citramalic acid. Further, it also describes a process of oxidation of 4-Cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfanyl-2-hydroxy-2-methyl propionyl )aniline (formula II) with m-chloroperbenzoic acid (mCPBA) in dichloromethane as solvent and stirred over night; ethyl acetate was added to the reaction mixture and organic layer was extracted with successively with a solution of sodium sulfite and solution of sodium bicarbonate, product was isolated after silica gel column chromatography and finally crystals are obtained from benzene / petroleum ether. Herein also, there is no mention about the yield and purity, before and after purification.
Although the above two process are relatively simple but the use of high volume of solvents for the reaction and chromatographic separation required in the process makes it undesired for commercial scale utilization.
Journal of Medicinal Chemistry 1988, Vol. 31, No. page 954-959 describes another method for preparation of oxidation of 4-Cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfanyl-2-hydroxy-2-methylpropionyl)aniline (formula II) with m-chloroperbenzoic acid (mCPBA) in dichloromethane. The process employs abnormally high volume of halogenated solvent (200 volume) and involves long reaction about 16 hour. The reaction is washed with a solution of sodium sulfite and sodium carbonate solution.
In the above prior art references the use of very high volume of the dichloromethane i.e. in the range of 100 to 463 volumes and the use of column chromatography makes the process unfavorable for commercial scale. Additionally, the use of high volume solvent for the coupling reaction results in incomplete oxidation even after stirring the reaction for long time. Further, use of high volume of solvent, requires more time for

distillation also creates burden on effluents which makes it expensive and in turn has an adverse effect on the environment
WO 2005037777 discloses a process for oxidation of compound of formula (II) using m-chloroperbenzoic acid (mCPBA) and halogenated solvents in presence of tungsten, vanadium and chromium compound at temperature as low as -50°C to as high as 80°C. The use of tungsten, vanadium and chromium compound is not only expensive but also creates problem in their disposal.
WO 200224638 discloses oxidation of compound of formula (II) with hydrogen peroxide at a temperature below -50°C, followed by addition of trifluoro acetic anhydride. However, the use of expensive trifluoroacetic anhydride and very low temperature during addition of trifluoroacetic anhydride makes this method uneconomical. Furthermore, because of the corrosive and hygroscopic property of trifluoroacetic anhydride, the method is unsuitable for the industrial production. The use of cryogenic temperature in WO 200503777 and WO 200224638 applications makes the process energy intensive and thereby increases the cost of manufacturing, hence not suitable for commercial scale.
US 20030191337 disclose oxidation of compound of formula (II) to bicalutamide with mono-perphthalic acid, prepared from phthalic anhydride and hydrogen peroxide solution, in presence of sodium tungstate and a phase transfer catalyst. The use of mono-perphthalic acid makes the process expensive because it is not easily available and cannot be stored. Further, the phthalic acid formed in the reaction must be removed which requires additional work-up. Additionally, the use of sodium tungstate creates problem in work-up and waste disposal.
The present inventors have observed that all the prior art methods lacks consistency in getting desired quality of oxidized product i.e. bicalutamide on a large scale; thereby requiring additional steps of purification. Regulatory authorities all over the world have

very stringent norms for permissible limits of such impurities in either the active
ingredient or the final formulation.
Thus, their was a need to develop a process for oxidation of sulfanyl compound which
did not require large volume of halogenated solvents for oxidation and does not require
column chromatography for purification for obtaining in the desired purity and yield of
bicalutamide.
Considering the commercial importance of bicalutamide and to over come the prior art drawbacks, the present inventors have developed a method by using minimum volume of halogenated solvent and getting desired quality without utilizing chromatographic purification techniques by careful manipulation of the isolation method.
OBJECTS OF THE INVENTION
An object of the present invention is to provide an improved process for oxidation of 4-Cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfanyl-2-hydroxy-2-methylpropionyl) aniline with m-chloroperbenzoic acid with minimum volume of solvent and without the use of column chromatography for purification.
Another object of the present invention is to provide a simple convenient, economical and industrial viable method for the preparation of bicalutamide with desired purity, by a novel isolation method.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for oxidation of 4-Cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfanyl-2-hydroxy-2-methylpropionyl)aniline to bicalutamide in presence of m-chloroperbenzoic acid (mCPBA) with lower volume of halogenated solvent.
In another aspect of the present invention is to provide an improved process for preparation of bicalutamide with purity greater than 99.95%, by oxidation of 4-Cyano-

3-trifluoromethyl-N-(3-p-fluorophenylsulfanyl-2-hydroxy-2-methylpropionyl) aniline with m-chloroperbenzoic acid (mCPBA) in an organic solvent, followed by addition of ketonic solvent to the reaction mixture and isolating by washing solution of sodium sulfite and sodium carbonate solution; concentrating the reaction mixture adding a second organic solvent and heating between 75°C to 80°C, cooling the reaction mixture and adding an anti solvent to obtain the desired product.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have developed an improved process for preparation of bicalutamide which obviates the drawbacks of prior art such as:
(i) use of high volume halogenated solvents for oxidation reaction;
(ii) prolonged time for oxidation resulting in formation of impurities;
(iii) circumvent the use of silica gel column chromatography for purification of
crude bicalutamide and (iv) obtaining bicalutamide of desired purity without the formation of undesired impurity formed in the prior art or partially oxidized impurity (formula III).

One embodiment of the present invention relates to an improved process for preparation of bicalutamide. The synthetic sequence for preparation of bicalutamide is represented in Scheme I.


Scheme I: Method for preparation of Bicalutamide
The present invention relates to an improved process for preparation of bicalutamide comprising of oxidation of compound of formula (II) with m-chloroperbenzoic acid with lower volume of halogenated solvent; wherein in prior art methods suggest use of large excess of halogenated solvent for the reaction. Addition of ketonic solvent to get the clear solution; organic layer is washed with aqueous solution of sodium sulfite and aqueous solution of sodium carbonate; finally bicalutamide of formula (I) was isolated from the organic solvent.
In a specific embodiment, die process for the preparation of bicalutamide comprises the oxidation of sulfide compound of formula (II) with m-chloroperbenzoic acid in presence of halogenated solvent to give bicalutamide of formula (I).
The halogenated solvent utilized for the oxidation reaction is selected form dichloromethane, dichloroethane, chloroform, preferable dichloromethane. The volume of solvent is in the range of 10 to 20 with respect to compound of formula (II), preferably 13-15 volumes.
In another embodiment of the invention, reaction mixture is treated with ketonic solvent to get clear solution. The ketonic solvent is selected from the group C3 to C6 carbon atoms. The ketone solvent is selected from acetone, methyl ethyl ketone etc but

preferably methyl ethyl ketone. The ketone solvent was used in the range of 10 to 20 volumes with respect to reactant preferably 12 volumes.
Addition of a ketone solvent helps in the removal of undesired impurities during work up and assists in obtaining the final product having the desired purity.
In an embodiment the reaction mixture is treated with an aqueous solution of sodium sulfate and organic layer separated from the aqueous. Further, the organic layer is washed respectively with aqueous solution of sodium carbonate and with aqueous solution of sodium chloride solution, finally dried with anhydrous sodium sulfate. The crude bicalutamide is obtained after removal of solvent under reduced pressure. The crude product at this stage has purity greater than 95%. Wherein the prior art method show purity in the range of 40 to 79%.
In a specific embodiment of the invention the crude product is treated with organic solvent at 65 to 85°C for 1 to 2 hours and cooled to 25 to 30°C optionally charcoalized and filtered, an anti solvent is added to the cooled solution. Finally product is isolated after filtration and washing with organic solvents. The organic solvent used for the isolation of product is selected from esters preferably ethyl acetate, isopropyl acetate and anti solvent is selected from hexane, heptane, cyclohexane, ethers or mixture thereof.
Another embodiment of the present invention, in which the bicalutamide obtained from present invention, has purity in the range of 99 to 99.5% with over all yields in the range of 90 to 95% from starting material.
The main advantage of the present invention is in the use of lower volume of halogenated solvent for oxidation of compound of formula (II) with m-chloroperbenzoic acid with the desired purity of bicalutamide without any associated impurities like partially oxidized sulfoxide compound of formula (III). The purity of the final bicalutamide is not less than 99.5%, as against prior art method disclosed in US 4,636,505 (example 6) and US 6,583,306 (example 5), thereby resulting in a higher

yield of more than 90%. The addition of a ketonic solvent after completion of reaction helps in removing associated impurities during reaction mixture work up.
Thus, the present invention satisfies the need for developing an improved process for bicalutamide which employs minimum volume of halogenated solvent and do not require any column chromatography for purification.
The present invention has the following advantages over prior art methods:
• Avoids the use of large excess of halogenated solvents as used in the prior art methods;
• Oxidation reaction work-up using a ketone solvent results in bicalutamide purity not less than 99.5%,
• Avoids the use for column chromatography for purification as reported in prior art methods,
• Over all increase in the productivity and reduction in organic waste and
• Process is effective, environmentally friendly and easily implemented in industrial scale.
The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The present invention is described herein below with reference to examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.

EXAMPLE:
Example 1:
Preparation of Bicalutamide (I):
4-Cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfanyl-2-hydroxy-2-methylpropionyl) aniline (formula II; 5g) was suspended in dichloromethane (65 ml), m-chloroperbenzoic acid (7.9g) at 10 to 15°C temperature. The reaction mixture was stirred for 3 hours at 25 to 30°C temperature. After completion, methyl ethyl ketone (60 ml) was added to the reaction mixture at 25 to 30°C; treated with sodium sulfite (aqueous 11%). The organic layer was separated and washed with sodium carbonate (aqueous 10%) and sodium chloride (aqueous saturated solution). The organic layer was concentrated under reduced pressure. The residue was treated with ethyl acetate and heated to 70 to 75°C for 1 hour, and cool to 25 to 30°C. Petroleum ether was added and stirred for 30 minutes and the separated product was filtered to give pure bicalutamide which was dried under reduced pressure to give a yield of 4.72g of formula (I), Purity: > 99.5%.
Example 2:
Preparation of Bicalutamide (I):
4-Cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfanyl-2-hydroxy-2-methylpropionyl) aniline (formula II; 25g) was suspended in dichloromethane (325 ml), m-chloroperbenzoic acid (39.5g) at 10 to 15°C temperature. The reaction mixture was stirred for 3 hours at 25 to 30°C temperature. After completion, acetone (300 ml) was added to the reaction mixture at 25 to 30°C; treated with sodium sulfite (aqueous 11%). The organic layer was separated and washed with sodium carbonate (aqueous 10%) and sodium chloride (aqueous saturated solution). The organic layer was concentrated under reduced pressure. The residue was treated with ethyl acetate and heated to 70 to 75°C for 1 hour, and cool to 25 to 30°C. Petroleum ether was added and stirred for 30 minutes and the separated product was filtered to give pure bicalutamide which was dried under reduced pressure to give a yield of 23.6g of formula (I), Purity: > 99.5%.

We claim,
1. A process for preparation of bicalutamide comprising, oxidation of 4-Cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfanyl-2-hydroxy-2-methylpropionyl) aniline with m-chloroperbenzoic acid (mCPBA) in an organic solvent, a ketonic solvent added and washed with solution of sodium sulfite and sodium carbonate and isolating the product with a combination of organic solvent and anti solvent.
2. The process as claimed in claim 1, wherein the organic solvent is halogenated solvent.
3. The process as claimed in claim 2, wherein halogenated solvents are selected from dichloromethane, dichloroethane, chloroform preferable dichloromethane.
4. The process as claimed in claim 1, wherein the halogenated solvent employed is in 10 to 20 volume of starting material, preferably 13 volumes.
5. The process as claimed in claim 1, wherein the ketonic solvent is selected from acetone, methyl ethyl ketone; preferably methyl ethyl ketone.
6. The process as claimed in claim 1, wherein the bicalutamide has purity more than 99.5%.