FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION (See section 10; rule 13)


"An improved process for the preparation of Bicalutamide and its intermediates thereof'
Aarti Healthcare Limited
An Indian Company
Registered under Indian Companies Act 1960,
Having its registered Office at
71, Udyog Kshetra, 2nd Floor,
Mulund-Goregaon link Road,
Mulund (West), Mumbai- 400080,
Maharashtra, 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 relates to an improved process for the preparation of Bicalutamide of formula I and its intermediates which is simple, cost effective and environment friendly.
BACKGROND OF THE INVENTION
Bicalutamide, which is chemically known as N-[4-Cyano-3-(trifluoromethyI)phenyl]-3-[(4-fluorophenyl)suIphonyl]-2-hydroxy-2-methylpropanamide and it can be represented by formula (I).

BICALUTAMIDE I Bicalutamide (I) is a non-steroidal anti-androgen used in combination therapy with Luteinizing Hormone Releasing Hormone (LHRH) analogue for treatment of advance prostate cancer.
The first synthesis of Bicalutamide (I) is disclosed by Tucker in US-4636505. Various methods of synthesizing Bicalutamide of formula I are also disclosed in US-6562994 and WO-2001/00608. According to the above patents, epoxypropanamide of formula (1) is reacted with p-fluoro thiophenol of formula (2) to give thioether derivative of formula (3) which further undergoes oxidation using m-chloroperbenzoic acid to give Bicalutamide of formula I. The synthesis of Bicalutamide can be summarized in Scheme-1. Scheme-1:

N-[4-cyano-3-(trifluoromethyl)Phenyt]- 2 N-[4-cyano-3-(trifluoromethyl)PhenyQ-2-methyl-
2-methyl-2-3-epoxypropanamide ((4-fluorophenyl)-thiol-2-hydroxy-2-methylpropanamide
3
2


CH, O
Oxidation
N-[4-cyano-3-(trifiuoramethyl)Phenyl}-2-methyl-
[(4-fluort^)hefiyl)-thio]-2-Hydroxy-2-methylpropanamide BICALUTAMIDE I
3
According to the US-4636505 and US-6562994, epoxypropanamide of formula (1) is reacted with p-fluoro thiophenol of formula (2) in presence of base such as sodium hydride in inert solvent like THF to give thioether derivative of formula (3). The reaction conditions and the example for the preparation of thioether derivative of formula (3) are given in the above patents.
US-4636505 also mentions that the oxidizing agent and conditions used in the reaction will determine whether a sulphinyl or a sulphonyl compound is obtained. Thus oxidation with sodium metaperiodate in methanol solution at or below laboratory temperature will generally convert a thio compound into the corresponding sulphinyl compound; and oxidation with a per-acid, for example m-chloroperbenzoic acid, in MDC solution at or above laboratory temperature will generally convert a thio compound into the corresponding sulphonyl compound. Thus thioether derivative of formula (3) is oxidized using m-chloroperbenzoic acid in MDC as solvent to give Bicalutamide of formula I which is further purified using column chromatography method with solvent mixtures ethyl acetate: petroleum ether.
Further according to the US-4636505, in the process for the preparation of thioether of formula (3), sodium hydride is used which is a flammable solid and difficult to handle. THF is used as solvent in the reaction which is an expensive solvent and thus increases the cost for commercial scale production. Use of sodium hydride and THF further make work up of the reaction complicated by the fact that the thioether derivative of formula (3) formed in the reaction cannot be isolated directly from the reaction mass thus the process itself is not commercially viable. Even the purification of Bicalutamide of formula I using column chromatography with the ethyl acetate: petroleum ether mixture
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is not commercially viable due to its lengthy procedure and high quantity of solvents required for the column chromatography.
In addition, US-6562994 also describes the use of other bases including alkali metal alkoxides, alkali metal amides and alkyllithiums, however sodium hydride is discussed as being more preferred. This disclosure also generally describes the use of only aprotic solvents, preferably ether based such as the above mentioned THF. Further US-6562994 describes a process of oxidizing the thioether derivative of formula (3) with a suitable oxidizing agent in the presence of aprotic solvents. The oxidizing agent is a combination of hydrogen peroxide and trifluoroacetic anhydride in MDC as solvent which generates in situ trifluoroperacetic acid as an oxidant to give Bicaiutamide of formula I:
US-6740770 describes a process for the preparation of Bicaiutamide of formula I by oxidizing thioether derivative of formula (3) with hydrogen peroxide in the presence of sodium tungstate, phenylphosphonic acid and a phase transfer catalyst in ethyl acetate. The addition of sodium tungstate, phenylphosphonic acid and phase transfer catalyst increase the cost of production and the work up procedure after reaction completion is also lengthy and complicated which makes the process commercially not viable.
US-20070027211 has disclosed the process for the preparation of Bicaiutamide of formula I wherein epoxypropanamide of formula (1) is reacted with p-fluoro thiophenol of formula (2) in presence of 1-1.2 mole equivalent of base such as alkali metal hydroxide in solvent mixtures of water and a solvent selected from C1 -C4alcohols, cyclic or acyclic amides, C3-C8 sulphoxides and sulfones, C3-C5 alkyl nitriles to obtain thioether derivative of formula (3) followed by oxidation reaction using sodium metaperiodate in solvent like acetic acid or formic acid to give Bicaiutamide of formula I. The synthesis of Bicaiutamide of formula I as per US-20070027211 can be summarized in scheme-2. In US-20070027211, in the process for the preparation of thioether derivative of formula (3), base is used in the quantity of 1-1.2 mole equivalent and thus after completion of the reaction, neutralization is required using concentrated hydrochloric acid.
4


Scheme-2:
It is also mentioned that after methanol distillation, reaction mass is stirred for 3 hours at 5 C. The product obtained by the above process needs to be dried into the oven for longer time to remove water and methanol from the product thus the process is industrially not feasible.
WO-2005/09946 has disclosed the process for the purification and isolation" of Bicalutamide of formula I wherein Bicalutamide is combined with a solvent, crystallizing it from the solvent and collecting the crystals from solvent. The solvent for the crystallization is selected from the solvents like MDC, methanol, ethanol, isopropanol, ethylene dichloride, toluene, chloroform, hexane, diethyl ether and propanol. In addition, WO-2005/09946 has also disclosed another process for the purification and isolation of Bicalutamide of formula I wherein Bicalutamide is combined with first solvent like DMF, second solvent such as water is added into the mass, crystallizing Bicalutamide from the solvents, collecting the pure Bicalutamide from the solvents.
WO-2006/103689 has disclosed the process for the preparation of substantially pure Bicalutamide of formula I wherein Bicalutamide is dissolved in methyl ethyl ketone and an antisolvent such as hexane added to precipitate of pure Bicalutamide of formula I.
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Based on the disadvantages in the above processes, it would be highly desirable to have a simple, low cost, highly efficient, environment friendly process for the preparation of Bicalutamide thereby overcoming the deficiencies of the prior art.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide an environment friendly, simple and convenient method for the preparation of Bicalutamide of formula (1) and its intermediate of formula (3).
It is another object of the invention to provide a process that avoids the use of expensive and hazardous reagents like metal hydrides and costly solvents like THF.
It is yet another object of the invention to provide a process that does not require elaborate work up or purification processes like column chromatography for the isolation of products which leads to a lengthy process thus minimizing the yield of the product.
It is a further object of the invention to provide a process by which quantitative yields of the product are obtained.
It is also an object to provide a process for the preparation of thioether derivative of formula (3) an intermediate used for the preparation of Bicalutamide of formula I.
It is yet another object of the invention to provide a process by which more than 99.5% of purity and more than 90% yield of thioether derivative of formula (3) is obtained.
It is yet another object to provide an efficient process for the preparation of pure Bicalutamide of formula I wherein the thioether derivative of formula (3) is prepared by reacting epoxypropanamide of formula (1) with p-fluoro thiophenol (2) in presence of catalytic amount of polyoxyethylene ether (surfactant) of formula (4) and an inorganic base. As the reaction is carried out in a minimum solvent, the ratio of solvent used in the reaction should not be more than 1:1 when compared to the starting material i.e. epoxypropanamide of formula (I).
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It is yet another object to provide a process for the preparation of pure Bicalutamide of formula 1 which comprises:
a. Reacting epoxyprop an amide of formula (1) with p-fluoro thiophenol of formula (2) in
presence of polyoxyethylene ether of formula (4) as a catalyst and an inorganic base to
obtain thioether derivative of formula (3).
b. Oxidizing thioether derivative of formula (3) to give Bicalutamide of formula I.
c. Crystallizing Bicalutamide of formula I with ethyl formate solvent to give pure
Bicalutamide of formula I.
SUMMARY OF THE INVETION
The present invention provides an improved process for the preparation of Bicalutamide of formula 1 and its intermediate thioether derivative of formula (3). In the process for the preparation of thioether derivative of formula (3), the reaction is carried out in presence of the substituted polyoxy ethylene ether of formula (4) as a catalyst and an inorganic base.

4 Wherein R is an aryl, alkyl or arylalkyl group having from 1 to 20 carbon atoms and x has a value between from about 9 to about 150.
In the method of the invention, at least one inorganic base is brought into contact with epoxypropanamide of formula (1) in the presence of substituted polyoxyethylene ether of formula (4) in a minimum solvent. The catalyst, substituted polyoxyethylene ether of formula (4) acts as surface media for the reaction which accelerates the rate of the reaction.
Treatment of the epoxypropanamide of formula (1) with p-fluoro thiophenol of formula (2) and an inorganic base in the presence of catalytic amount of the substituted polyoxyethylene ether of formula (4) produces thioether derivative of formula (3) by a nucleophilic addition reaction. The process for the preparation of thioether derivative of formula (3) which is useful synthetic intermediate for the preparation of Bicalutamide of formula I proceeds to near quantitative yield and is practical and economically attractive.
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Thioether derivative of formula (3) produced by the above process can be used as an intermediate in the process for the preparation of Bicalutamide of formula I wherein thioether derivative of formula (3) is oxidized with the oxidizing agent in a suitable solvent system.
Further the present invention also relates to the process for the preparation of pure Bicalutamide of formula I wherein Bicalutamide obtained from the above oxidation step is crystallized using ethyl formate as a solvent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for producing Bicalutamide of formula I and its intermediate i.e. thioether derivative of formula (3). Thioether derivative of formula (3) which is an intermediate of Bicalutamide of formula 1 can be prepared by a process wherein the substituted polyoxyethylene ether of formula (4) is used as a catalyst in presence of an inorganic base in presence of solvent. The method of the invention proceeds neatly, in a minimum solvent under homogeneous or heterogeneous conditions and in the presence of a catalytic amount of substituted polyoxyethylene ether of formula (4).
In one of the embodiment of the invention, the process employs a system whereby the substituted polyoxyethylene ether (surfactant) of formula (4) is used as a catalyst in conjugation with the inorganic base. The substituted polyoxyethylene ether of formula (4) offers the capability to increase liquid-liquid interface area. In addition it enables selective complexation of metal ions, thereby resulting in solubilization of the inorganic base in the substituted polyoxyethylene ether media thus it helps to increase the rate of the reaction. The resulting product can be separated by giving extraction of dichloro methane or using any other suitable solvent in which thioether derivative is soluble.
The present invention thus provides a process for preparing thioether derivative of formula (3) in a minimum solvent by using catalytic amount of substituted polyoxyethylene ether of formula (4). The term "minimum solvent" is a functional term and is meant to include those reactions carried out either with no solvent or with such a
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minimal amount that the solvent would not function as a significant or controlling part of the reaction. Preferably, the solvent ratio in the reaction should not be more than 1:1 compared to the ratio of solvent: epoxypropanamide of formula (1), more preferably 0.5:1 compared to the starting material i.e. epoxypropanamide of formula (1). The reaction can also be carried out using excess of solvent i.e. more than 1:1 compared to the starting material i.e. epoxypropanamide of formula (I).
Synthesis of the thioether derivative of formula (3) can be represented as Scheme 3. Scheme-3:

As per the scheme-3, substituted epoxypropanamide of formula (1) is reacted with p-fluoro thiophenol of formula (2) in presence of substituted polyoxyethylene ether i.e. surfactant of formula (4) as a catalyst and an inorganic base in a solvent to give thioether derivative of formula (3).
The reaction is carried out in presence of solvent at a temperature below 10°C, preferably -10°C to 10°C, more preferably at -5 °C to 0°C which goes to completion within 30 minutes to 2 hrs. The solvent used in a minimum quantity can be selected from polar protic solvents, polar aprotic solvents or mixtures thereof. E.g. C1-C4 alcohol, ketonic solvents, DMF, DMSO, N-methyl pyrolidinone (NMP), dioxane, acetonitrile and water or mixtures thereof can be used without limiting the invention. More preferably acetone is used as a solvent in the reaction.
Preferred substituted polyoxyethylene ethers (surfactants) are selected from the formula (4).
9


4 Wherein R is an aryl. alkyl or arylalkyl group having 1 to 20 carbon atoms and x has a value from 9 to about 150, preferably a value between from about 9 to about 70. Selectively substituted polyoxyethylene ethers are those of the family octyl or nonyl phenoxypolyoxyethoxyethanol commercially available and sold under the name triton and tergitol respectively.
Triton has known brands like Triton X-100 wherein X of formula (4) is about 9 to 9.5 as well as Triton X-405, wherein x is about 40 or 41. Likewise other brands are such as Triton X-15, Triton X-35, Triton X-45, Triton X-114, Triton X-165, Triton X-365, Triton X-705 can also be used as substituted polyoxyethylene ether.
Tergitol has also known brands wherein Tergitol NP-30, Tergitol NP-40, Tergitol NP-45, Tergitol NP-55, and Tergitol NP-70 can be used as substituted polyoxyethylene ether in the reaction.
The amount of catalyst i.e. substituted polyoxyethylene ether of formula (4) used in the reaction is of 0.02 to 0.1 mole equivalent compared to the starting material i.e. epoxypropanamide of formula (I). More preferably 0.02 to 0.05 mole equivalent compared to the starting material i.e. epoxypropanamide of formula (1).
The inorganic bases used in the reaction can be selected from alkali or alkaline earth metal hydroxides as for example NaOH, KOH-.
It is believed that the substituted polyoxyethylene ether of formula (4) functions as a catalyst with the inorganic base such that the ether moiety of the substituted polyoxyethylene ether complexes the metal ion of the inorganic base, thereby solubilizing the inorganic base in an organic solvent. Thus in presence of catalytic amount of the substituted polyethylene ether of formula (4), quantity of inorganic base required for completion of the reaction is minimized.
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The amount of inorganic base used in the reaction is of 0.02 to 0.1 mole equivalent compared to the starting material i.e. epoxypropanamide of formula (1). More preferably in an amount of 0.02 to 0.05 mole equivalent to the starting material i.e. epoxypropanamide of formula (1).
The surfactant i.e. polyoxyethylene ether of formula (4) and base combination plays an important role in the rate of the reaction as surfactant improves the thioether reaction rate. After the completion of the reaction, the mass is extracted in polar water immiscible solvents. Organic solvent layer is collected and distilled out completely and rest of the solvent is stripped out using toluene or alternatively with hexane or heptane. Reaction on cooling and filtration gives thioether derivative of formula (3). The thioether derivative of formula (3) is thus obtained can be directly utilized for the next step in a synthetic sequence.
The reaction carried out with base alone in quantity of 1-1.2 mole equivalent can generate more impurities compared to the use of surfactant in the reaction which shows that surfactant can increase the rate of reaction thus controlling the formation of impurities during the reaction with more than 90% yield and more than 99.5% of purity of the thioether derivative of formula (3) obtained.
In another embodiment of the invention, a process for the preparation of Bicalutamide of formula 1 from thioether derivative of formula (3) is described wherein thioether derivative of formula (3) is oxidized with an oxidizing agent in a suitable solvent.
Synthesis of Bicalutamide can be represented as Scheme-4 as follows:
The oxidizing agent is selected from peracids like peracetic acid, m-chloro perbenzoic acid, trifluoro acetic acid, and monoperphthalic acid, sodium perborate. The suitable solvent is selected from acetic acid, formic acid, MDC, EDC, preferably acetic acid. More preferably hydrogen peroxide and acetic acid can be used for the oxidation reaction.
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Scheme-4:

The oxidation reaction is carried out at 40-70°C, more preferably at 55-60°C. After completion of the reaction, reaction mass is cooled to 0-5°C, quenched in water and stirred for 30 minutes. The product precipitated in the reaction mass is filtered and washed with water or with diluted aq. base solution till neutral pH. The product is dried in oven at 45-50°C to obtain crude Bicalutamide. The crude Bicalutamide is further purified using ethyl formate.
Yet in another embodiment, the process for the preparation of pure Bicalutamide of formula 1 comprises:
a. Reacting epoxypropanamide of formula (1) with p-fluoro thiophenol of formula (2) in
presence of polyoxyethylene ether of formula (4) and an inorganic base to obtain
thioether derivative of formula (3)
b. Oxidizing thioether derivative of formula (3) to give crude Bicalutamide of formula I
c. Crystallizing crude Bicalutamide of formula I using ethyl formate to give pure
Bicalutamide of formula I.
According to the step-a,
The reaction is carried out in presence of solvent at a temperature below 10°C, preferably -I0°C to 10°C, more preferably at -5 °C to 0°C which goes to completion within 30 minutes to 2 hrs. The solvent used in the minimized quantity can be selected from polar solvents, polar aprotic solvents or mixtures thereof for eg. C1-C4 alcohol, ketonic solvents, DMF, DMSO, N-methyl pyrolidinone (NMP), dioxane, acetonitrile and water or mixtures thereof can be used without limiting the invention. More preferably acetone is used as solvent in the reaction.
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Preferred substituted polyoxyethylene ethers (surfactant) are selected from the formula (4).
4 Wherein R is an aryl, alkyl or arylalkyl group having 1 to 20 carbon atoms and x has a value from 9 to about 150, preferably a value between from about 9 to about 70. Selectively substituted polyoxyethylene ethers are those of the family octyl or nonyl phenoxypolyoxyethoxyethanol commercially available and sold under the name triton and tergitol respectively.
Triton has known brands like Triton X-I00 wherein X of formula (4) is about 9 to 9.5 as well as Triton X-405, wherein x is about 40 or 41. Likewise other brands are such as Triton X-15, Triton X-35, Triton X-45, Triton X-l 14, Triton X-165, Triton X-365, Triton X-705 can also be used as substituted polyoxyethylene ether.
Tergitol has also known brands wherein Tergitol NP-30, Tergitol NP-40, Tergitol NP-45, Tergitol NP-55, and Tergitol NP-70 can be used as substituted polyoxyethylene ether in the reaction.
The amount of catalyst i.e. substituted polyoxyethylene ether of formula (4) used in the reaction is of 0.02 to 0.1 mole equivalent compared to the starting material i.e. epoxypropanamide of formula (I). More preferably 0.02 to 0.05 mole equivalent compared to the starting material i.e. epoxypropanamide of formula (1).
The inorganic bases used in the reaction can be selected from alkali or alkaline earth metal hydroxides as for example NaOH, KOH.
It is believed that the substituted polyoxyethylene ether of formula (4) functions as a catalyst with the inorganic base such that the ether moiety of the substituted polyoxyethylene ether complexes the metal ion of the inorganic base, thereby solubilizing the inorganic base in an organic solvent. Thus in presence of catalytic amount of the
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substituted polyethylene ether of formula (4), quantity of inorganic base required for completion of the reaction is minimized.
The amount of inorganic base used in the reaction is of 0.02 to 0.1 mole equivalent compared to the starting material i.e. epoxypropanamide of formula (1). More preferably in an amount of 0.02 to 0.05 mole equivalent to the starting material i.e. epoxypropanamide of formula (1).
The surfactant i.e. polyoxyethylene ether of formula (4) and base combination plays an important role in the rate of the reaction as surfactant improves the thioether reaction rate. After the completion of the reaction, the mass is extracted in polar water immiscible solvents. Organic solvent layer is collected and distilled out completely and rest of the solvent is stripped out using toluene or alternatively with hexane or heptane. Reaction on cooling and filtration gives thioether derivative of formula (3). The thioether derivative of formula (3) is thus obtained can be directly utilized for the next step in a synthetic sequence.
The reaction carried out with base alone in quantity of 1-1.2 mole equivalent can generate more impurities compared to the use of surfactant in the reaction which shows that surfactant can increase the rate of reaction thus controlling the formation of impurities during the reaction with more than 90% yield and more than 99.5% of purity of the thioether derivative of formula (3) obtained.
According to the step-b,
The oxidizing agent is selected from peracids like peracetic acid, m-chloro perbenzoic
acid, trifluoro acetic acid, and monoperphthalic acid, sodium perborate. The suitable
solvent is selected from acetic acid, formic acid, MDC, EDC, preferably acetic acid.
More preferably hydrogen peroxide and acetic acid can be used for the oxidation
reaction.
The oxidation reaction is carried out at 40-70°C, more preferably at 55-60°C. After
completion of the reaction, reaction mass is cooled to 0-5 C, quenched it into water and
stirred for 30 minutes. The product precipitated in the reaction mass is filtered and
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washed it with water or with diluted aq. base solution till neutral pH. The product is dried in oven at 45-50°C to obtain crude Bicalutamide of formula I. The purity of the crude product is not less than 99.5% and further purification is required to comply as per the 1CH guidelines.
According to the step-c,
The product obtained in step-b is mixed with ethyl formate and heated the reaction mass to 55-60°C. The Bicalutamide of formula I is dissolved in a solvent and the solution optionally treated with activated carbon. The solvent from the reaction mass is distilled out till the product is precipitated out in the reaction mass. The reaction mass then cooled and filtered and washed with ethyl formate to give pure Bicalutamide of formula I which complied as per the ICH guidelines.
The present invention will now be described in detail with reference to the following examples, which are not intended to limit the scope of the present invention.
EXAMPLES
Example-1:
Process for the preparation of thioether derivative of formula (3):
In a three necked round bottom flask, epoxypropanamide of formula (1) (100 Gms), acetone (100 ml), saturated aqeous KOH solution (4ml) and Triton-X-100 (2 ml) is charged under nitrogen atmosphere. The reaction mass is cooled to 0-5 C and p-fluoro thiophenol of formula (2) (91.02 gms) is added into the reaction mass under stirring at 0-5°C. The reaction mass is stirred at room temperature for 1 hr. Water (100 ml) is added into the reaction mass and stirred for 15 minutes. The reaction mass is then extracted with MDC (200 ml) twice. MDC layer is collected and dried it over sodium sulfate. MDC is distilled out from the reaction mass completely and traces of the MDC are removed using toluene as solvent under vacuum at 45-50°C. The reaction mass is then cooled to 0-5 C and filtered, washed it with toluene to give thioether derivative of formula (3). Dry weight of the product: 141 Gms %Yield: 96.0% %HPLC purity: 99.8%
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Example-2:
Process for the preparation of Bicalutamide (Crude):
In a 3-necked RBF, acetic acid (80 ml), thioether derivative of formula (3) (20 gms) is
charged and heated it to 50-55°C under stirring. 50% hydrogen peroxide (40 ml) is added
in the reaction mass at 50-55°C under stirring. The reaction mass is stirred at 50-55°C for
4 hrs. The reaction mass then cooled to 0-5°C and quenched it into demineralised water
(600 ml) at 0-5°C. The reaction mass is stirred for 1 hour at 0-5°C. Product precipitated in
the mass is filtered and washed with water till pH=6-7 is obtained. Product is dried into
oven at 55-60°C.
Dry weight of the product - 20.0 Gms
% Yield: 92.5%
% HPLC Purity: 99.82%
Example-3:-
Process for the preparation of Pure Bicalutamide:-
ln a three necked round bottom flask, crude bicalutamide (40 gms), ethyl formate (600
ml) is charged and heated the reaction mass to 50-60°C and stirred it till the product get
dissolved in the solvent. Clear, transparent reaction mass is obtained. Activated charcoal
(1 gm) is added in the reaction mass and stirred the reaction mass for 1 hr at 55-60°C.
The reaction mass is then filtered and collected in another 3-necked round bottom flask.
The reaction mass is taken for distillation of solvent till the volume of the solvent remains
80 ml in the reaction mass. The reaction mass is then cooled, filtered and washed with
ethyl formate to give pure Bicalutamide of formula I. The product is dried in oven at 45-
50°C.
Dry weight of the product: 39 Gms
%Yield: 98.0%
% HPLC purity: 99.93%
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Example-4:-
Process for the preparation of thioether derivative of formula (3):
In a three necked round bottom flask, epoxypropanamide of formula (1) (100 Gms), acetone (400 ml), saturated aqeous KOH solution (4ml) and Triton-X-100 (2 ml) is charged under nitrogen atmosphere. The reaction mass is cooled to 0-5°C and p-fluoro thiophenol of formula (2) (91.02 gms) is added into the reaction mass under stirring at 0-5°C. The reaction mass is stirred at room temperature for 1 hr. Water (200 ml) is added into the reaction mass and stirred for 15 minutes. The reaction mass is then extracted with MDC (200 ml) twice. MDC layer is collected and dried it over sodium sulfate. MDC is distilled out from the reaction mass completely and traces of the MDC are removed using toluene as solvent under vacuum at 45-50°C. The reaction mass is then cooled to 0-5°C and filtered, washed it with toluene to give thioether derivative of formula (3). Dry weight of the product; 139 Gms %Yield: 95.0% % HPLC purity: 99.6%
The product obtained from the above process is highly pure and also complies with the 1CH guidelines.
What is claimed is:

comprising,
a. reacting an epoxypropanamide of formula (1)
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1. A process for the preparation of pure Bicalutamide of formula I wherein preparation of its intermediate thioether derivative of formula (3)

with p-fluoro thiophenol of formula (2)
SH

in presence of catalyst selected from substituted polyoxyethylene ether of formula (4)

and an inorganic base in presence of solvent.
2. The process for the preparation of thioether derivative of formula (3) as claimed in claim 1 wherein inorganic base is selected from alkali or alkaline earth metal hydroxides.
3. The process for the preparation of thioether derivative of formula (3) as claimed in claim 1 & 2 wherein inorganic base is selected from NaOH, KOH.
4. The process for the preparation of thioether derivative of formula (3) as claimed in claim 1 wherein polyoxyethylene ether of formula (4) is

4 Wherein R is an aryl, alkyl or arylalkyl group having 1 to 20 carbon atoms and x has a value from 9 to about 150, preferably a value between from about 9 to about 70.
5. The process for the preparation of thioether derivative of formula (3) as claimed in
claim 1 wherein solvent is selected from polar solvents, polar aprotic solvents or mixtures
thereof.
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6. The process for the preparation of thioether derivative of formula (3) as claimed in claim 1 and 4 wherein solvent is C1-C4 alcohol, ketonic solvents, DMF, DMSO, N-methyl pyrolidinone (NMP), dioxane, acetonitrile and water or mixtures thereof.
7. A process for the preparation of pure Bicalutamide of formula I

BICALUTAMIDE I
comprising:
a. Reacting epoxypropanamide of formula (1)

with p-fluoro thiophenol of formula (2)
SH


in presence of polyoxyethylene ether of formula (4)

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and an inorganic base to obtain thioether derivative of formula (3)



b. Oxidizing thioether derivative of formula (3) using oxidative agent
to give crude Bicalutamide of formula I.
c. Crystallizing crude Bicalutamide of formula I using ethyl formate to give pure
Bicalutamide of formula I.
8. The process for the preparation of pure Bicalutamide of formula I as claimed in claim
6(a) wherein polyoxyethylene ether of formula (4) is

4 Wherein R is an aryl, alkyl or arylalkyl group having 1 to 20 carbon atoms and x has a value from 9 to about 150, preferably a value between from about 9 to about 70.
9. The process for the preparation of pure Bicalutamide of formula I as claimed in claim
7(a) wherein inorganic base is selected from alkali, alkaline earth or metal inorganic
hydroxide.
10. The process for the preparation of pure Bicalutamide of formula I as claimed in claim 7(a) and 9 wherein inorganic base is selected from NaOH, KOH.
11. The process for the preparation of pure Bicalutamide of formula I as claimed in claim 7(a) wherein the reaction is carried out in presence of solvent.
12. The process for the preparation of pure Bicalutamide of formula I as claimed in claims 7(a) and 11 wherein solvent is selected from polar solvents, polar aprotic solvents or mixtures thereof.
13. The process for the preparation of pure Bicalutamide of formula I as claimed in claims 7(a), 11, and 12 wherein solvent is C1-C4 alcohol, ketonic solvents, DMF, DMSO, N-methyl pyrolidinone (NMP), dioxane, acetonitrile and water or mixtures thereof.
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14. The process for the preparation of pure Bicalutamide of formula I as claimed in claim 7(b) wherein oxidizing agent is selected from peracetic acid, trifluoroacetic acid, m¬ch loroperbenzoic acid and sodium perborate.
15. The process for the preparation of pure Bicalutamide of formula I as claimed in claim 7(b) wherein the reaction is carried out in solvent selected from acetic acid, formic acid, MDC, ethylene dichloride,
16. The process for the preparation of pure Bicalutamide of formula I as claimed in claims 7(b), 14 and 15 wherein the reaction is carried out using hydrogen peroxide and acetic acid.
Dated this f°i day of,/u*1g_. 2008
Name of Applicant: Desai Parimal Hasmukhlal
t:
Signature of Applicant:
(Director) (Aarti Healthcare Limited)

To,
The Controller of Patents,
The Patent Office,
Mumbai.

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