Background of the invention;
The present invention relates to an improved process for the preparation of (Bicalutamide) . Bicalutamide, which is (N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[4- fluorophenyl)sulfonyl)-2-hydroxy-2-methyl propanamide having the formula-I given below is useful for the treatment of prostate cancer.

Processes for the preparation of Bicalutamide is described in EP No. 0100172 which was th
published on 8 February 1984. Two routes for the preparation of Bicalutamide of the formula-I have been disclosed in EP no 0100172.
The first process has been illustrated in the route shown in scheme -I Scheme-I:
The method illustrated in the Scheme-I comprises (i) the epoxidation of methyl methacrylate of the formula (II) with meta chloro perbenzoic acid (MCPBA} in refluxing chloroform yielding 2-methyl oxiran-2-carboxylic acid methyl ester of the formula (III), which is reacted with 4-Fluoro thiophenol in tetrahydrofuran at 60°C affords 2-hydroxy-
2- methyl-3-(4-fluoro phenyl) thio propionic acid methyl ester of the formula (IV). The hydrolysis of the compound of the formula (IV) with refluxing aqueous potassium hydroxide gives rise to 2-hydroxy-2-methyl-3-(4-fluoromethyl)thio propionic acid which when reacted with thionyl chloride at -15 °C in DMF solvent yields 2-hydroxy-2-methyl-
3- (4-fluoromethyl)-thiopropionyl chloride of the formula (VI). The compound of the formula (VI) when condensed with 4-cyano-3-trifluoromethyl aniline of formula (VII) affords corresponding amide of the formula (VIII). Finally this compound was oxidized
with meta chloro perbenzoic acid [MCPBA] in dichloromethane to give bicalutamide of the formula-IX
The following are the observations after we implemented the process in our laboratory.
1. Exact synthetic route for bicalutamide is not disclosed in the patent i.e., reaction parameters, work-ups and purification procedures are described in general in connection with the preparation of similar compounds. When the method is applied to the synthesis of bicalutamide, in particular, resulted in poor yields (about 25% overall yield) having purity of 95%
2. The process involves the usage of meta chloro perbenzoic acid (MCPBA) for the preparation of compounds of the formulae (I) and (III). As per the disclosed data for epoxidation of compound of formula-Ill two moles of meta chloro perbenzoic acid is required. But with these moles the reaction is not going to completion. As per our experimental data six moles of meta chloro perbenzoic acid is required for the reaction to complete. Meta chloro perbenzoic acid is an expensive reagent and using in large scale effects the cost economics of the process.
3. Reaction of compound of formula (V) with thionyl chloride for preparing the compound of the formula (VI) resulted forming a by-product of formula (A)

Thus by this route it is not possible to prepare the compound of formula (VI) which is key intermediate in the above scheme. Ultimately with this route compound of formula - IX is not formed.
Another process is illustrated in the route shown in scheme-2.


The method illustrated in the scheme -2 comprises the reaction of methacryloyl chloride of the formula (X) with 4-cyano-3-trifluoromethyl aniline of formula (VII) to yield corresponding amide of the formula (XI).Compound of formula(XI) when epoxidised with meta chloro perbenzoic acid yielded epoxides of the general formula (XII). The compound of the formula (XII) when reacted with sodium hydride in tetrahydrofuran at 60°C yielded compounds of the general formula (VIII). Finally this compound was oxidized with 2.4 moles of meta chloro perbenzoic acid in dichloromethane at RT yielded compounds of formula IX.
The following are the observations after we implemented the process in our laboratory
1. Exact synthetic route for bicalutamide is not disclosed in the patent i.e., Here also the reaction parameters, work-ups and purification procedures are described in general for preparing similar compounds. When the method is applied to the synthesis of bicalutamide, there is poor yields of bicalutamide (about 25% overall yield) having purity 95%.
2. The process involves the usage of meta chloro perbenzoic acid (MCPBA) for the preparation of the compound of the formulae (XII) and (IX). As per the procedure described for the general epoxidation 2 moles of meta chloro perbenzoic acid is required for preparation of compound of the formula (XII). But with these moles the reaction is not completed. As per the our experimental data six moles of meta chloro perbenzoioc acid is required for completion of the reaction. Meta chloro perbenzoic acid is an expensive reagent and using in large scale effects the cost economics of the process.
3. For the preparation of the compound of the formula -I as per the disclosed data 2.4 moles of meta chloro perbenzoic acid sulfoxide impurity of the formula (XIII) is formed predominantly in the reaction which is difficult to remove by the usual crystallization processes thus affecting the purity of bicalutamide of the formula(IX)
As per our experimental data 4.8 moles of meta chloro perbenzoic acid (MCPBA) is required to prepare compound of the formula -IX . Meta chloro perbenzoic acid is an expensive reagent and using in large scale effects the cost economics of the process.
It is very important to examine a process for the preparation of bicalutamide from the point of industrial applicability whether the procedure fulfills the following requirements.
1. The starting materials and reagents used for the process should be easily available and as cheap as possible.
2. The use of harmful reagents should be avoided in the process.
3. The process should be safe from the point of environmental protection.
4. The formation of by-products and ballast which cannot be used or processed further should be minimized in the process.
5. The reaction vessels generally used in pharmaceutical and chemical industry should be applicable for the process.
6. It is very important, that the process should give the final product of high purity(more than 99.8%), which does not need further expensive purification.
The prior art processes described above do not fulfil one or other of the above requirements.
Taking into consideration the above mentioned requirements , we undertook R&D with the aim of developing an improved process for the preparation of highly pure (99.8%) bicalutamide of the formula I and in high yields (about 50% overall yield) ,which process is environmentally protective, safe, industrially applicable, devoid of the deficiencies of the known procedures .
Therefore the main objective of the present invention is to provide an improved process for the preparation of Bicalutamide, which is (N-[4-cyano-3-(trifluoromethyl)phenyl]-3- [4-fluorophenyl)sulfonyl)-2-hydroxy-2-methyl propanamide having the formula-I
Another objective of the present invention is to provide an improved process for the preparation of Bicalutamide, in which the use of meta chloro perbenzoic acid for the preparation of Bicalutamide is avoided.
Another objective of the present invention is to provide an improved process for the preparation of bicalutamide employing commercially available cheap raw materials phthalic anhydride and 30% hydrogen peroxide in diethyl ether medium and to avoid its isolation.
Still another objective of the present invention is to provide an improved process for the preparation of Bicalutamide, in an environmentally safe method..
Yet another objective of the present invention is to provide an improved process for the preparation of Bicalutamide, having improved overall yields (about 50%) and highly pure (greater than 99.8%)
Accrodingly , the present invention provides an improved process for the preparation of bicalutamide which is (N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[4- fluorophenyl)sulfonyl)-2-hydroxy-2-methyl propanamide having the formula-I which comprises
(i) reacting thionyl chloride and , methacrylic acid in the presence of a solvent to yield methacrylolyl chloride of the formula (X)

Reacting the resulting methacryloyl chloride of the formula (X) with aniline of the formula (VII) to yield the corresponding amide , N-[4-cyano-3- (trifluoromethyl)phenyl]methacrylamide of the formula (XI) with greater than 98.0% purity and about 85% yield.
(ii)
(ii) Reacting the resulting amide, N-[4-cyano-3-(trifluoromethyl)phenyl]methacrylamide of the formula (XI) with mono perphthalic acid in the presence of a solvent to obtain 4- cyano-3-trifluoromethyl-2,3-epoxy-2-methyl propionamide of the formula (XII) with greater than 99.0% purity and with 80% yield after involving simple purification techniques.
CH3
CH2=C-C-NH-F VCN
0 O ^CFs
(XII)
(iii) Reacting the 4-cyano-3-trifluoromethyl-2,3-epoxy-2-methyl propionamide of the formula (XII) obtained in step (ii) with 4-fluoro thiophenol in the presence of a solvent to obtain to get N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]2-hydroxy- 2-methyl propanamide of the formula (VIII) greater than 99.5% purity and with 95% yield.
CH3
OH O CF3
(VIII)
(iv) reacting the N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]2- hydroxy-2-methyl propanamide of the formula (VIII) obtained in step (iii) with mono perphthalic acid in the presence of a solvent to obtain bicalutamide of the formula I and if desired
(v) recrystallising the bicalutamide of the formula I formed from a solvent selected from. chloroform,methylene chloride or ethyl acetate, greater than 99.9% purity and with about 50% overall yield
In step( i) for the preparation of methacrylolyl chloride of the formula (X) the number of moles of thionyl chloride to the methacrylic acid used may be in the range of 1-1.5 preferably in the range of 1-1.1 moles . The number of moles of compound of the formula (VII) to methacrylolyl chloride of the formula (X) used in step (i) may be in the range of 1-2 preferably in the range of 1-1.5. After the acid chloride formation, for the condensation reaction and for purification the solvent used may be selected from Methylene chloride, chloroform or isopropyl ether preferably methylene chloride.
In step(ii) for the preparation of compound of the formula (XII) the moles of mono perphthalic acid used may be in the range of 3-6 preferably in the range of 4-5 moles. The solvent used in the reaction may be selected from a group of chloroform,methylene chloride or ethyl acetate preferably chloroform . For mono perphthalic acid preparation in step (ii) the concentration of hydrogen peroxide used may be 50% or 30% preferably 50%.The moles of hydrogen peroxide to phthalic anhydride used may be in the range of 3-6 preferably in the range of 4-5 moles.
In step-(iii) for the preparation of compound of the formula (VIII) the number of moles of 4-fluoro thiophenol used may be in the range of 1.5-3.5 preferably in the range of 2-2.5. The number of moles of sodium hydride used may be in the range of 2-4 moles preferably in the range of 2-2.5. The recrystallization solvents may be selected from a group of mixture of solvents selected from chloroform and hexane or methylene chloride and hexane or isopropyl ether and hexane preferably isopropyl ether and hexane.
In step(iv) for the preparation of bicalutamide of the formula I the number of moles of mono perphthalic acid used may be in the range of 3-6 preferably in the range of 4-5 moles. The solvent used in the reaction may be selected from a group of chloroform,methylene chloride or ethyl acetate preferably ethyl acetate. The recrystallization solvent may be selected from a group of chloroform,methylene chloride or ethyl acetate preferably ethyl acetate
The details of the inventions are given in the Example provided below which is given for illustration purposes only and therefore it should not be construed to limit the scope of the invention.
Example-1
Preparation of (N-[4-cyano-3-(trifluoromethyl)phenyI]-3-[4-fluorophenyl)sulfonyl)- 2-hydroxy-2-methyl propanamide (Bicalutamide) (I) :
A. Preparation of N-[4-cyano-3-(trifluoromethyl)phenyl]methacrylamide of the formula (XI):
2 kgs (23.26M) of methacrylic acid and 20 gms of hydroquinone were charged into 2L of dimethyl formamide .2.76 kgs (23.20M)of thionyl chloride was added slowly during 0.5br at 25-30°C.Reaction mass was refluxed for 4 hrs and the product mathacryloyl chloride(198 gms;81%) was distilled under normal pressure .It was added immediately to a solution of 4-amino-2-(trifluoromethyl)benzonitrile of the formula (VII) dissolved in 20L of Dimethyl acetamide at -15-10 °C during 0.5hr.It was stirred at the same temperature for one more hour and brought to room temperature and maintained at the same temperature for 15 mins. Reaction mass was poured into 400L of D.M.water , filtered and washed throughly with D.M.water. The wet crude product was dissolved in 20L of methylene chloride ,water layer was separated and the organic layer was dried on sodium sulfate. Organic layer was concentrated under vacuum to a residual volume of 4-5L .cooled to 0-5°C and maintained at the same temperature fori-2 hrs. filtered,washed with chilled methylene chloride and dried to yield 3 kgs(85.7%) of N-[4-cyano-3- (trifluoromethyl)phenyl]methacrylamide of the formula (XI).
Purity by HPLC is 98.4%
B. Preparation of 4-cyano-3-trifluoromethyl-2,3-epoxy-2-methyl propionamide of compound of formula (XII):
Preparation of mono perphthalic acid :
17.6 kgs of pulverized phthalic anhydride was charged into 60L diethyl ether at 25- 30°C. 29L of 50% hydrogen peroxide was charged at the same temperature during 15 minutes.The reaction mass was stirred for 24 hrs at 25-30°C . Ether layer was separated and washed with 3x20L of 40% aqueous ammonium sulphate solution. Dried over sodium sulphate and used in the reaction directly, [chemical assay - 9.6%]
3 kgs of compound of the formula (XI) obtained by the process described in step (A ) and 165.5 gms of butylated hydroxy toluene[BHT] were charged into 60L of chloroform. Ether layer of monoperphthalic acid prepared as described above was charged. Reaction mass was heated to reflux temperature and distilled off diethyl ether simultaneously at normal pressure during 2-3 hrs . Reaction mass was brought to room temperature , filtered and washed with chloroform. Chloroform layer was washed respectively with 90L of saturated sodium sulphite solution 2x90L sodium bicarbonate solution , 2x90L brine solution. Dried chloroform layer over sodium sulfate and distilled off completely under vacuum. To the residue 3-4L Isopropyl ether was added ,cooled 0-5 °C, filtered and dried to yield 2.5kgs(78%) 4-cyano-3-trifluoromethyl-2,3-epoxy-2-methyl propionamide of compound of formula (XII)
Purity by HPLC is 99.2%
C. Preparation of N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio] 2-hydroxy-2-methyl propanamide of the formula (VIII) :
0.77 kgs of sodium hydride was charged into 20L of THF under nitrogen atmosphere at 0-5°C . A solution of 2.4 kgs of 4-Fluoro thiophenol in 12.5L Of THF was added slowly during 0.5hr. Reaction mass was brought to 25-30 °C and maintained at the same temperature for 15 minutes. A solution of 2.5kgs of the Compound of (XII) prepared by the process desrbed at (B ) above in 12.5L THF was added slowly during 0.5hr and maintained at 25-30 °C for lhr. Reaction mass was poured into 20L D.M.water and extracted with 3x6L Isopropyl ether. Ether layer was dried over sodium sulphate and distilled off completely under vacuum. To the residue a mixture of 2.5L isopropyl ether and 10L of hexane was charged , cooled to 0-5 °C, filtered and dried to yield 3.4 kgs(95%) of N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]2-hydroxy- 2-methyl propanamide of the formula (VIII) . .Purity by HPLC is 99.6%
D. Preparation of (N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[4- fluorophenyl)sulfonyl)-2-hydroxy-2-methyl propanamide (Bicalutamide) of the formula (I):
13.0 kgs of pulverized phthalic anhydride was charged into 100L diethyl ether at 25- 30°C. 20L of 50% hydrogen peroxide was charged at the same temperature during 15 minutes. The reaction mass was stirred for 24 hrs at 25-30°C . Ether layer was separated and washed with 3x30L of 40% aqueous ammonium sulphate solution. Dried over sodium sulphate and used in the reaction directly, [chemical assay - 9.8%]
3.4 kgs of compound of the formula (VIII) obtained by the process described in step above was charged into 100L of Ethyl acetate. Ether layer of monoperphthalic acid prepared above was charged. Reaction mass was heated to reflux temperature and distilled off diethyl ether simultaneously at normal pressure during 2-3 hrs . Reaction mass was refluxed for one more hour was brought to room temperature , filtered and washed with Ethyl acetate. Ethyl acetate layer was washed respectively with 80L of saturated sodium sulphite solution 2x80L sodium bicarbonate solution , 2x80L brine solution. Dried Ethyl acetate layer over sodium sulfate and distilled to a residual volume of 15-20L under vacuum. Reaction mass was brought to 25-30°C, filtered to yield 2.5 kgs of (N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[4-fluorophenyl)sulfonyl)-2-hydroxy-2- methyl propanamide compound of formula (I).
It was recrystallised with 40L of Ethyl acetate to yield 1.96 kgsof compound of formula (I) of 99.99% purity. Second crop worked up from Ethyl acetate mother liquors yielded further 0.8 kgs of compound formula (I) of 99.8% purity with overall yield of 75%.
Advantages of the present invention :
1. Process stabilization in multi kilogram scale preparation.
2. High yielding ( about 50% overall yield) by the process.
3. Bicalutamide obtained is of high purity ( 99.8%)
4. Avoiding expensive reagent meta chloro perbenzoic acid and replacing it with less expensive mono perpthalic acid thereby making the process economical
5. Simple and industrially applicable process.

We claim:-
1. An improved process for the preparation of bicalutamide of the formula-I
H H*\PH I
which comprises:
(i) reacting thionyl chloride and methacrylic acid in Dimethyl formamide at reflux temperature for 4 hours to yield methacrylolyl chloride of the formula (X) and,
CH3
CH2=C—COCI
Methacryloyl chloride (X)
reacting the resulting methacryloyl chloride of the formula (X) with aniline of the formula (VII) in Dimethyl acetamide at -15 to 10° C for 30 minutes to yield the corresponding amide , N-[4-cyano-3-(trifluoromethyl)phenyl]methacrylamide of the formula (XI) with greater than 98.0% purity and 85% yield.
O HP,
4-Cyano-3-trifluoro methylaniline
(v) recrystallizing the bicalutamide of the formula I formed from a solvent selected from. chloroform,methylene chloride or ethyl acetate, greater than 99.9% purity and with 50% overall yield
2. The process as claimed in claim 1 wherein in the step (i) the number of moles of thionyl chloride to the methacrylic acid used is in the range of 1-1.5 , preferably in the range of 1-1.1 moles, more preferably in the range of 1-2 most preferably in the range of 1-1.5.
3. The process as claimed in claims 1 & 2 wherein in the step (i)the number of moles of compound of the formula (VII) to methacrylolyl chloride of the formula (X) used is in the range of 1-2, preferably in the range of 1-1.5.
4. The process as claimed in claims 1 to 3 wherein in step (ii) the moles of mono perphthalic acid used is in the range of 3-6, preferably in the range of 4-5 moles.
5. The process as claimed in claims 1 to 4 wherein in step (ii) the moles of hydrogen peroxide to phthalic anhydride used is in the range of 3-6, preferably in the range of 4-5 moles.
6. A process as claimed claims 1 to 5 wherein in step (iii) the number of moles of 4- fluoro thiophenol used is in the range of 1.5-3.5 , preferably in the range of 2-2.5.
7. The process s claimed in claims 1 to 6 wherein in step (iii) the number of moles of sodium hydride used is in the range of 2-4 moles, preferably in the range of 2-2.5.
8. The process as claimed in claims 1 to 7 wherein in step (iv) the moles of mono perphthalic acid used is in the range of 3-6, preferably in the range of 4-5 moles.
9. The process as claimed in claims 1 to 8 wherein in Step (i) the solvent used is selected from methylene chloride , chloroform or isopropyl ether , preferably methylene chloride.
10 A process as claimed in claims 1 to 9 wherein in Step (ii) the solvent used is selected from a group of chloroform, methylene chloride or ethyl acetate preferably chloroform.
11. The process as claimed in claims 1 to 10 wherein the concentration of hydrogen peroxide used in steps (ii) and (iv) ranges from 50% or 30% preferably 50%.
12. The process as claimed in claims 1 to 11 wherein the solvents used in step(iii) is selected from a group of mixture of solvents selected from chloroform and hexane or methylene chloride and hexane or isopropyl ether and hexane preferably isopropyl ether and hexane.
(ii) reacting the resulting amide , N-[4-cyano-3-(trifluoromethyl)phenyl]methacrylamide of the formula (XI) with mono perphthalic acid in chloroform solvent at reflux temperature for 2-3 hours to obtain 4-cyano-3-trifluoromethyl-2,3-epoxy-2-methyl propionamide of the formula (XII) with greater than 99.0% purity and with 80% yield after involving simple purification techniques.

(iii) reacting the 4-cyano-3-trifluoromethyl-2,3-epoxy-2-methyl propionamide of the formula (XII) obtained in step (ii) with 4-fluoro thiophenol in presence of sodium hydride base in THF (tetrahydrofuran) solvent at room temperature for one hour to get N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]2-hydroxy- 2-methyl propanamide of the formula (VIII) greater than 99.5% purity and with 95% yield.

(iv) reacting the N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]2- hydroxy-2-methyl propanamide of the formula (VIII) obtained in step (iii) with mono perphthalic acid in ethyl acetate solvent at reflux temperature for 2-3 hours to obtain bicalutamide of the formula I and if desired
13. The process as claimed in claims 1 to 12 wherein in step (iv) the solvent used for recrystallisation is selected from the group of chloroform, methylene chloride or ethyl acetate preferably ethyl acetate.
14. An improved process for the preparation of bicalutamide of the formula I substantially as herein described with reference to the Example.