WO2007013094A2 - A process for preparation of antiandrogen compound - Google Patents

A process for preparation of antiandrogen compound Download PDF

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WO2007013094A2
WO2007013094A2 PCT/IN2006/000131 IN2006000131W WO2007013094A2 WO 2007013094 A2 WO2007013094 A2 WO 2007013094A2 IN 2006000131 W IN2006000131 W IN 2006000131W WO 2007013094 A2 WO2007013094 A2 WO 2007013094A2
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formula
compound
cyano
phenyl
permanganate
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WO2007013094A3 (en
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Umangkumar Natubhai Patel
Kamleshkumar Naranbhai Borkhataria
Kanaksinh Jesingbhai Jadav
Trinadha Rao Chitturi
Rajamannar Thennati
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Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
    • C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides

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  • the present invention relates to a process for the preparation of an antiandrogen compound.
  • the present invention provides a process for preparation of N-[4- cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluoiOphenyl)sulfonyl]-2-hydroxy-2- methylpropanamide, a compound of formula 1, known as bicalutamide.
  • Bicalutamide is an effective non-steroidal antiandrogen, the racemic form of which is marketed for use in the treatment of advanced prostate cancer.
  • United States Patent No. 4636505 (equivalent Indian reference not available and Tucker et al. J. Med. Chem., 31, page 954, 1988) teach that the compound of formula 1, viz. bicalutamide, can be prepared by reacting 4-cyano-3-trifluoromethylaniline with methacryloyl chloride, followed by epoxidation of the resultant vV-(3-trifluoromethyl-4- cyanophenyl)methacrylamide to form the epoxide compound of formula 2, viz., N-[4- cyano-3-(trifiuoromethyl)phenyl]-2-methyloxirane-2-carboxamide.
  • the compound of formula 2- is reacted with 4-fluorothiophenol, a compound of formula 3, in tetrahydrofuran (THF) in. presence of sodium hydride (NaH), to form iV-[4-cyano-3- (lrifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydiOxy-2-methylpropanamide, viz., the compound of formula 4, which is then oxidized using met ⁇ -chloroperbenzoic acid (MCPBA) in dichloromethane to form the compound of formula 1 (as depicted in Scheme 1).
  • MCPBA met ⁇ -chloroperbenzoic acid
  • THF is an expensive solvent and NaH is hazardous for large-scale operations.
  • MCPBA is an expensive reagent and handling and transportation on large scale can pose hazards and also a large excess of dichloromethane (470 volumes) has been used.
  • the reagents used for oxidizing the compound of formula 4 to the compound of formula 1, in the prior art like hydrogen peroxide/acetic acid can form peracids, which are potentially explosive and hazardous.
  • hydrogen peroxide can form explosive mixtures.
  • hydrogen peroxide can react with the nitrile group present in the compound to form perimidates, which can decompose to amides, generating side products.
  • the present invention provides a convenient one-pot preparation of the compound of formula 1 by reacting the compound of formula 2 with the compound of formula 3 to form the compound of formula 4 in-situ, which is then efficiently oxidized to form the compound of formula 1 using a permanganate reagent.
  • the compound of formula 1 prepared by the process of the present invention is devoid of the sulfoxide impurities that can result from incomplete oxidation of the compound of formula 4.
  • the present invention provides a process for preparation of an antiandrogen compound, N-[4-cyano-3-(lrifluoiOmethyl)phenyl]-3-[(4-fluoiOphenyl)sulfonyl]-2-hydroxy-2- methylpropanamide, a compound of formula 1 ,
  • Formula 1 comprising: a) reacting ⁇ r -[4-cyano-3-(trifluoiOmethyl)phenyl]-2-methyloxirane-2-carboxamide, a compound of formula 2 with 4-fluorothiophenol, a compound of formula 3, in presence of a phase transfer catalyst to form N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4- fluorophenyl)thio]-2-hydroxy-2-methylpropanamide, a compound of formula 4,
  • the present invention provides a process for preparation of N-[4-cyano-3- (lrifluorometliyl)phenyl]-3-[(4-fluorophenyl)lhio]-2-hydiOxy-2-methylpropanamide, a compound of formula 4
  • Formula 4 comprising reacting N-[4-cyano-3-(lrifluoromethyl)phenyl]-2-methyloxirane-2- carboxamide, a compound of formula 2 with 4-fluorothiophenol, a compound of formula
  • the present invention provides a process for preparation of an antiandrogen compound, ⁇ /-[4-cyano-3-(lrifiuoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2- hydiOxy-2-methylpropanamide, a compound of formula 1,
  • Formula 1 comprising reacting ⁇ / -[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2- hydroxy-2-melhylpropanamide, a compound represented by formula 4,
  • the present invention provides a simple process for preparation of bicalutamide starting from a compound of formula 2.
  • the compound of formula 2 may be prepared by a method known in the art, for example by epoxidation of ⁇ f-(3-trifluoromethyl-4- cyanophenyl)methacrylamide, such as in United States Patent No. 4636505 incorporated herein by reference.
  • Optical isomers of compound of formula 1 may be obtained by carrying out the epoxidation step under asymmetric conditions to give chiral compounds.
  • epoxidation can be carried out with a chiral dioxirane to form a chiral epoxide and then to form a chiral sulfide, which can be oxidized to form optical isomer of compound of formula 1.
  • biclutamide has a chiral carbon it can form two enantiomeric forms, viz., R and S isomers.
  • the bicalutamide prepared by the process of the present invention can be racemic or an enriched optical isomer including a pure or substantially pure optical isomer. As used herein enriched means greater than about 60% optically pure and substantially pure means greater than about 90% optically pure.
  • the enriched optical isomer of compound of formula 1 can be obtained by using enriched optical isomer of compound of formula 4.
  • the enriched optical isomer of compound of formula 4 may be prepared from enriched epoxide compound of formula 2.
  • the enriched optical isomers or the substantially pure optical isomers can be prepared by using chiral reagents or by separation methods after formation of racemic compounds. Suitable separation methods are known in the art like derivatization with a chiral substrate and resolution of the derivative, fractional crystallization of a salt with a chiral substrate, chromatography separation using a chiral stationary phase etc.
  • the compound of formula 2 in a single enantiomeric form is reacted with a compound of formula 3 in a biphasic system in presence of a phase transfer catalyst and a suitable organic or inorganic base Io form a compound of formula 4 in a single enantiomeric form, which is then further oxidized by treatment with a permanganate reagent to obtain the compound of formula 1 in a single enantiomeric form.
  • the compound of formula 2 in racemic form is reacted with a compound of formula 3 in a biphasic system in presence of a phase transfer catalyst and a suitable organic or inorganic base to form a compound of formula 4 in a racemic form, which is the further oxidized by treatment with a permanganate reagent to obtain the compound of formula 1 in a racemic Form.
  • the biphasic system can be formed by using water and a water-immiscible solvent.
  • the solvent usable for forming the biphasic system are ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, rert-butyl acetate and the like; ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; hydrocarbon or halogenated hydrocarbon solvents such as benzene, toluene, chlorobenzene, methylene chloride, ethylene dichloride, chloroform and the like.
  • inorganic bases examples include hydroxides, carbonates, or fluorides of alkali or alkaline earth metals.
  • the organic base may be selected from secondary or tertiary amines, which may be cyclic or acyclic.
  • the base is selected from hydroxide of an alkali metal.
  • a permanganate reagent is added, preferably an alkali metal permanganate like potassium permanganate, sodium permanganate or lithium permanganate.
  • a permanganate reagent can be added to the reaction mixture containing the compound of formula 4 or if so desired, the compound of formula 4 may be isolated from the reaction mixture and then oxidized to the compound of formula 1 by using a permanganate reagent.
  • the amount of the permanganate reagent that may be conveniently used is about 1.5 to 4 mole equivalent, preferably 2 to 3 mole equivalent with reference to compound of formula 2 or compound of formula 4.
  • phase transfer catalyst that may be used in the process of the present invention are not particularly limited and is exemplified by quaternary ammonium salt or a tetralkylphosphonium salt; for example tetrabulylammonium hydrogen sulfate, tetrabutyl- ammonium bromide, tetrabutylphosphonium bromide, benzyltriethylammonium chloride, cetyltrialkylammonium salts; Tweens (polyoxyethylene sorbitan esters) such as Tween ® 20, Tween ⁇ 40, Tween ® 60, Tween ⁇ 80, Tween ® 85; crown ethers, for example, 18- Crown-6; alkylated polyethylene glycols, for example, poly(ethylene glycol)dimethyl ether.
  • the amount of the phase transfer catalyst that may be conveniently used is about 0.01 to 0.25 mole equivalent, preferably 0.1 to 0.2 mole equivalent with reference to compound of
  • aprotic organic solvent for example acetonitrile, ethyl acetate, 1 ,2-dimethoxyethane, diisopropyl ether, tetrahydrofuran, 1,4-dioxane can be used.
  • reaction of compound of formula 2 with a compound of formula 3 may be earned out at a temperature between the range of about 0 0 C to about 100 0 C, preferably at about
  • the permanganate reagent may be added and reaction continued further at temperature between the range of about 0 0 C to about 100 0 C, preferably at about 20 0 C to 3O 0 C for a suitable period, for example, about 2 to about 3 hours to obtain the compound of formula
  • the reaction mixture may be washed with aqueous sodium metabisulfite, filtered, washed with dilute acid and the compound of formula 1 may be isolated after removal of organic solvent by concentration, cooling, evaporation and/or crystallization techniques. If desired, the isolated compound of formula 1 may be further purified by recrystallizalion from a suitable organic solvent or a solvent mixture.
  • a protic solvents such as methanol, ethanol, isopropanol
  • aprotic solvents such as ethyl acetate, dichloromethane, acetonitrile, or a solvent mixture such as ethyl acetate-ethanol, aetonitrile-methanol etc.
  • the present invention provides a process for preparation of the compound of formula 4 comprising reacting a compound represented by the formula 2 with a compound represented by the formula 3, in presence of a phase transfer catalyst.
  • the reaction may be preferably earned out in a biphasic system as described earlier in presence of a suitable organic or inorganic base, at a temperature in the range of 0 to 100 0 C, preferably at 20-30 0 C, for a suitable time, generally for about 2 to about 3 hours.
  • the amount of the phase transfer catalyst that may be conveniently used is about 0.01 to 0.25 mole equivalent, preferably 0.1 to 0.2 mole equivalent with reference to compound of formula 2.
  • the present invention provides a process for preparation of the compound of formula 1 by reacting the compound of formula 4 with a permanganate reagent.
  • the reaction may be preferably carried out in a biphasic system in presence of a phase transfer catalyst cited above, at a temperature in the range of 0 to 100 0 C, preferably at 20-30 0 C, for a suitable time, generally for about 2 to about 3 hours.
  • the amount of the phase transfer catalyst that may be conveniently used is about 0.01 to 0.25 mole equivalent, preferably 0.1 to 0.2 mole equivalent with reference to compound of formula 4.
  • a triphasic mixture of compound of formula 4 (250.Og, 0.627mol), potassium permanganate (253.Og, 1.56mol), ethyl acetate (1500ml), water (2500ml) and tetrabutyl ammonium hydrogen sulfate (21.28g, 0.0627mol) was stirred for 2.5 hours at 25-3O 0 C.
  • a solution of sodium metabisulfite (75Og) in water (1500ml) was then added, followed by ethyl acetate ( 1000ml). The mixture stirred for lhour, the insoluble inorganic material is filtered, and the upper organic layer containing product was separated. The organic layer was washed sequentially with 5% HCl solution and water, concentrated and degassed under vacuum to obtain bicalutamide, 27Og (100% yield).
  • Example 2 Process for one-pot preparation of bicalutamide from compound of formula 2
  • a solution of sodium metabisulfite (45g) in water (90ml) was added to the reaction mixture and stirred at about 50 0 C for 1 hour.
  • the insoluble inorganic material was filtered, and the upper organic layer containing product was separated, The organic layer was washed sequentially with 2% HCl solution and water, concentrated and degassed under vacuum to obtain bicalutamide, 15.5g (97.3% yield).
  • a suspension of bicalutamide (15.5g) in 2-propanol (100ml) was heated to reflux for 1 hour, and then gradually cooled to ambient temperature.
  • the resultant slurry was filtered, washed with 2-propanol, and dried at about 5O 0 C to obtain bicalutamide of HPLC purity 99.16%.

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Abstract

The present invention provides a process for the preparation of an antiandrogen compound, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide, a compound of formula 1, comprising reacting N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide, a compound of formula 2 with 4-fluorothiophenol, a compound of formula 3 in presence of a phase transfer catalyst and oxidizing the resultant N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methylpropanamide, a compound of formula 4 with a permanganate reagent.

Description

A PROCESS FOR PREPARATION OF ANTIANDROGEN COMPOUND
The present invention relates to a process for the preparation of an antiandrogen compound. Particularly the present invention provides a process for preparation of N-[4- cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluoiOphenyl)sulfonyl]-2-hydroxy-2- methylpropanamide, a compound of formula 1, known as bicalutamide.
Figure imgf000002_0001
Formula 1
Bicalutamide is an effective non-steroidal antiandrogen, the racemic form of which is marketed for use in the treatment of advanced prostate cancer.
United States Patent No. 4636505 (equivalent Indian reference not available and Tucker et al. J. Med. Chem., 31, page 954, 1988) teach that the compound of formula 1, viz. bicalutamide, can be prepared by reacting 4-cyano-3-trifluoromethylaniline with methacryloyl chloride, followed by epoxidation of the resultant vV-(3-trifluoromethyl-4- cyanophenyl)methacrylamide to form the epoxide compound of formula 2, viz., N-[4- cyano-3-(trifiuoromethyl)phenyl]-2-methyloxirane-2-carboxamide. The compound of formula 2- is reacted with 4-fluorothiophenol, a compound of formula 3, in tetrahydrofuran (THF) in. presence of sodium hydride (NaH), to form iV-[4-cyano-3- (lrifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydiOxy-2-methylpropanamide, viz., the compound of formula 4, which is then oxidized using metø-chloroperbenzoic acid (MCPBA) in dichloromethane to form the compound of formula 1 (as depicted in Scheme 1).
Figure imgf000003_0001
Scheme 1
However, THF is an expensive solvent and NaH is hazardous for large-scale operations. MCPBA is an expensive reagent and handling and transportation on large scale can pose hazards and also a large excess of dichloromethane (470 volumes) has been used.
The PCT application WO 0224638 (equivalent Indian reference not available, equivalent United States Patent No. 6562994) prepares the compound of formula 4 by reacting the epoxide compound of formula 2 with 4-fluoiOthiophenol in THF in presence of NaH. Then the compound of formula 4 is isolated and oxidized to form the compound of formula 1 using hydrogen peroxide in dichloromethane.
The PCT application WO 03053920 (equivalent Indian .reference not available, equivalent United States Patent No. 6740770) prepares the compound of formula 4 by reacting the epoxide compound of formula 2 with 4-fluorothiophenol in THF in presence of NaH or NaOH. Then the compound of formula 4 is isolated and oxidized to form the compound of formula 1 using mono-perphthalic acid in ethyl acetate. The reagent mono- perphthalic acid is expensive, and isolation of compound of formula 4 is not without problems as the unreacted 4-fluorothiophenol has an offensive odour and on large scale operations it can be inconvenient. A one-pot preparation method, wherein the compound of formula 4 is generated in-situ and oxidized further to obtain the compound of formula 1 would therefore be convenient and advantageous.
The reagents used for oxidizing the compound of formula 4 to the compound of formula 1, in the prior art like hydrogen peroxide/acetic acid can form peracids, which are potentially explosive and hazardous. In ether solvents, hydrogen peroxide can form explosive mixtures. In presence of a base, hydrogen peroxide can react with the nitrile group present in the compound to form perimidates, which can decompose to amides, generating side products.
There is thus a need to improve the synthetic process for bicalutamide, which is economical, less hazardous, operationally convenient and environmentally safe.
The present invention provides a convenient one-pot preparation of the compound of formula 1 by reacting the compound of formula 2 with the compound of formula 3 to form the compound of formula 4 in-situ, which is then efficiently oxidized to form the compound of formula 1 using a permanganate reagent.
There is no teaching of use of a permanganate for preparation of a compound of formula 1 by oxidation of a compound of formula 4 in the prior art.
We have found a simple method for preparation of bicalutamide without the need to isolate the intermediate compound of formula 4 and obviating the use of hazardous oxidizing agents like peracids or the peroxides. The compound of formula 1 prepared by the process of the present invention is devoid of the sulfoxide impurities that can result from incomplete oxidation of the compound of formula 4.
SUMMARY OF THE INVENTION The present invention provides a process for preparation of an antiandrogen compound, N-[4-cyano-3-(lrifluoiOmethyl)phenyl]-3-[(4-fluoiOphenyl)sulfonyl]-2-hydroxy-2- methylpropanamide, a compound of formula 1 ,
Figure imgf000005_0001
Formula 1 comprising: a) reacting Λr-[4-cyano-3-(trifluoiOmethyl)phenyl]-2-methyloxirane-2-carboxamide, a compound of formula 2 with 4-fluorothiophenol, a compound of formula 3, in presence of a phase transfer catalyst to form N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4- fluorophenyl)thio]-2-hydroxy-2-methylpropanamide, a compound of formula 4,
Figure imgf000005_0002
Formula 2 Formula 3
Figure imgf000005_0003
Formula 4
b) adding a permanganate reagent to the reaction mixture to afford the compound of formula 1.
In one aspect, the present invention provides a process for preparation of N-[4-cyano-3- (lrifluorometliyl)phenyl]-3-[(4-fluorophenyl)lhio]-2-hydiOxy-2-methylpropanamide, a compound of formula 4
Figure imgf000006_0001
Formula 4 comprising reacting N-[4-cyano-3-(lrifluoromethyl)phenyl]-2-methyloxirane-2- carboxamide, a compound of formula 2 with 4-fluorothiophenol, a compound of formula
3,
Figure imgf000006_0002
Formula 2 Formula 3 in presence of a phase transfer catalyst.
In one aspect the present invention provides a process for preparation of an antiandrogen compound, Λ/-[4-cyano-3-(lrifiuoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2- hydiOxy-2-methylpropanamide, a compound of formula 1,
Figure imgf000006_0003
Formula 1 comprising reacting Λ/-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2- hydroxy-2-melhylpropanamide, a compound represented by formula 4,
Figure imgf000006_0004
Formula 4 with a permanganate reagent. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a simple process for preparation of bicalutamide starting from a compound of formula 2. The compound of formula 2 may be prepared by a method known in the art, for example by epoxidation of Λf-(3-trifluoromethyl-4- cyanophenyl)methacrylamide, such as in United States Patent No. 4636505 incorporated herein by reference.
Optical isomers of compound of formula 1 may be obtained by carrying out the epoxidation step under asymmetric conditions to give chiral compounds. For example, epoxidation can be carried out with a chiral dioxirane to form a chiral epoxide and then to form a chiral sulfide, which can be oxidized to form optical isomer of compound of formula 1.
As biclutamide has a chiral carbon it can form two enantiomeric forms, viz., R and S isomers. The bicalutamide prepared by the process of the present invention can be racemic or an enriched optical isomer including a pure or substantially pure optical isomer. As used herein enriched means greater than about 60% optically pure and substantially pure means greater than about 90% optically pure. The enriched optical isomer of compound of formula 1 can be obtained by using enriched optical isomer of compound of formula 4. The enriched optical isomer of compound of formula 4 may be prepared from enriched epoxide compound of formula 2.
The enriched optical isomers or the substantially pure optical isomers can be prepared by using chiral reagents or by separation methods after formation of racemic compounds. Suitable separation methods are known in the art like derivatization with a chiral substrate and resolution of the derivative, fractional crystallization of a salt with a chiral substrate, chromatography separation using a chiral stationary phase etc.
In one embodiment, the compound of formula 2 in a single enantiomeric form is reacted with a compound of formula 3 in a biphasic system in presence of a phase transfer catalyst and a suitable organic or inorganic base Io form a compound of formula 4 in a single enantiomeric form, which is then further oxidized by treatment with a permanganate reagent to obtain the compound of formula 1 in a single enantiomeric form.
In one embodiment, the compound of formula 2 in racemic form is reacted with a compound of formula 3 in a biphasic system in presence of a phase transfer catalyst and a suitable organic or inorganic base to form a compound of formula 4 in a racemic form, which is the further oxidized by treatment with a permanganate reagent to obtain the compound of formula 1 in a racemic Form.
The biphasic system can be formed by using water and a water-immiscible solvent. Examples of the solvent usable for forming the biphasic system are ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, rert-butyl acetate and the like; ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; hydrocarbon or halogenated hydrocarbon solvents such as benzene, toluene, chlorobenzene, methylene chloride, ethylene dichloride, chloroform and the like.
Examples of inorganic bases that may be used are hydroxides, carbonates, or fluorides of alkali or alkaline earth metals. The organic base may be selected from secondary or tertiary amines, which may be cyclic or acyclic. Preferably, the base is selected from hydroxide of an alkali metal.
To the resultant compound of formula. 4, a permanganate reagent is added, preferably an alkali metal permanganate like potassium permanganate, sodium permanganate or lithium permanganate. A permanganate reagent can be added to the reaction mixture containing the compound of formula 4 or if so desired, the compound of formula 4 may be isolated from the reaction mixture and then oxidized to the compound of formula 1 by using a permanganate reagent. The amount of the permanganate reagent that may be conveniently used is about 1.5 to 4 mole equivalent, preferably 2 to 3 mole equivalent with reference to compound of formula 2 or compound of formula 4. The phase transfer catalyst that may be used in the process of the present invention are not particularly limited and is exemplified by quaternary ammonium salt or a tetralkylphosphonium salt; for example tetrabulylammonium hydrogen sulfate, tetrabutyl- ammonium bromide, tetrabutylphosphonium bromide, benzyltriethylammonium chloride, cetyltrialkylammonium salts; Tweens (polyoxyethylene sorbitan esters) such as Tween®20, Tweenφ40, Tween®60, Tweenφ80, Tween®85; crown ethers, for example, 18- Crown-6; alkylated polyethylene glycols, for example, poly(ethylene glycol)dimethyl ether. The amount of the phase transfer catalyst that may be conveniently used is about 0.01 to 0.25 mole equivalent, preferably 0.1 to 0.2 mole equivalent with reference to compound of formula 2.
It is also possible to carry out the reaction of compound of formula 2 with a compound of formula 3 in anhydrous biphasic conditions by using solid permanganate, in aprotic organic solvents in presence of a phase transfer catalyst, cited above. Any suitable aprotic organic solvent, for example acetonitrile, ethyl acetate, 1 ,2-dimethoxyethane, diisopropyl ether, tetrahydrofuran, 1,4-dioxane can be used.
The reaction of compound of formula 2 with a compound of formula 3 may be earned out at a temperature between the range of about 00C to about 1000C, preferably at about
20°C to about 300C for a suitable reaction time, generally for about 2 to about 3 hours.
To the reaction mixture containing the resultant compound of formula 4, the permanganate reagent may be added and reaction continued further at temperature between the range of about 00C to about 1000C, preferably at about 200C to 3O0C for a suitable period, for example, about 2 to about 3 hours to obtain the compound of formula
1.
Li a general work up procedure, the reaction mixture may be washed with aqueous sodium metabisulfite, filtered, washed with dilute acid and the compound of formula 1 may be isolated after removal of organic solvent by concentration, cooling, evaporation and/or crystallization techniques. If desired, the isolated compound of formula 1 may be further purified by recrystallizalion from a suitable organic solvent or a solvent mixture. For example, a protic solvents such as methanol, ethanol, isopropanol, and aprotic solvents such as ethyl acetate, dichloromethane, acetonitrile, or a solvent mixture such as ethyl acetate-ethanol, aetonitrile-methanol etc.
In another aspect, the present invention provides a process for preparation of the compound of formula 4 comprising reacting a compound represented by the formula 2 with a compound represented by the formula 3, in presence of a phase transfer catalyst. The reaction may be preferably earned out in a biphasic system as described earlier in presence of a suitable organic or inorganic base, at a temperature in the range of 0 to 1000C, preferably at 20-300C, for a suitable time, generally for about 2 to about 3 hours. The amount of the phase transfer catalyst that may be conveniently used is about 0.01 to 0.25 mole equivalent, preferably 0.1 to 0.2 mole equivalent with reference to compound of formula 2.
In another aspect, the present invention provides a process for preparation of the compound of formula 1 by reacting the compound of formula 4 with a permanganate reagent. The reaction may be preferably carried out in a biphasic system in presence of a phase transfer catalyst cited above, at a temperature in the range of 0 to 1000C, preferably at 20-300C, for a suitable time, generally for about 2 to about 3 hours. The amount of the phase transfer catalyst that may be conveniently used is about 0.01 to 0.25 mole equivalent, preferably 0.1 to 0.2 mole equivalent with reference to compound of formula 4.
The present invention is illustrated by examples and not to be construed as limiting. EXAMPLES
Example 1 : Preparation of bicalutamide from compound of formula 4
A triphasic mixture of compound of formula 4 (250.Og, 0.627mol), potassium permanganate (253.Og, 1.56mol), ethyl acetate (1500ml), water (2500ml) and tetrabutyl ammonium hydrogen sulfate (21.28g, 0.0627mol) was stirred for 2.5 hours at 25-3O0C. A solution of sodium metabisulfite (75Og) in water (1500ml) was then added, followed by ethyl acetate ( 1000ml). The mixture stirred for lhour, the insoluble inorganic material is filtered, and the upper organic layer containing product was separated. The organic layer was washed sequentially with 5% HCl solution and water, concentrated and degassed under vacuum to obtain bicalutamide, 27Og (100% yield).
Purification: A suspension of bicalutamide (376g) in 2-propanol (3.761it) was heated to reflux for 2 hours, and then gradually cooled to ambient temperature. The resultant slurry was filtered, washed with 2-propanol and dried at about 500C to obtain bicalutamide of HPLC purity 99.79%.
Example 2: Process for one-pot preparation of bicalutamide from compound of formula 2
A biphasic mixture of compound of formula 2 (10. Og, 0.037mole), 4-fluorothiophenol (4.33ml, 0.041mol), sodium hydroxide (0.74g, O.OI Smol), tetrabutylammonium hydrogen sulfate (1.88g, 5.5mmol), ethyl acetate (100ml) and water (20ml) was stirred at 25-300C for 3 hours. Potassium permanganate (17.54g, O. l l lmol) and water (80ml) was then added to the reaction mixture and stirring was continued for further 2.5 hours. A solution of sodium metabisulfite (45g) in water (90ml) was added to the reaction mixture and stirred at about 500C for 1 hour. The insoluble inorganic material was filtered, and the upper organic layer containing product was separated, The organic layer was washed sequentially with 2% HCl solution and water, concentrated and degassed under vacuum to obtain bicalutamide, 15.5g (97.3% yield). A suspension of bicalutamide (15.5g) in 2-propanol (100ml) was heated to reflux for 1 hour, and then gradually cooled to ambient temperature. The resultant slurry was filtered, washed with 2-propanol, and dried at about 5O0C to obtain bicalutamide of HPLC purity 99.16%.

Claims

CLAIMS:
1) A process for preparation of an antiandrogen compound, 7V-[4-cyano-3- (trifluoromethyl)phenyl]-3-[(4-fiuorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide, a compound of formula 1 ,
Figure imgf000013_0001
Formula 1 comprising: a) reacting N-[4-cyano-3-(trifiuoromethyl)phenyl]-2-methyloxirane-2-carboxamide, a compound of formula 2 with 4-fluorothiophenol, a compound of formula 3, in presence of a phase transfer catalyst to form N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4- fluorophenyl)thio]-2-hydiOxy-2-methylpropanamide, a compound of formula 4,
Figure imgf000013_0002
Formula 2 Formula 3
Figure imgf000013_0003
Formula 4
b) adding a permanganate reagent to the reaction mixture to afford the compound of formula 1. 2) The process as claimed in claim 1, wherein the permanganate reagent is an alkali metal permanganate.
3) The process as claimed in claim 2, wherein the alkali metal permanganate is potassium permanganate.
4) The process as claimed in claim 1, wherein the reaction of compound 2 and compound 3 is earned out in a biphasic system comprising water and organic solvent.
5) A process for preparation of Λf-[4-cyano-3-(trifluoiOmethyl)phenyl]-3-[(4- fluoiOphenyl)thio]-2-hydroxy-2-methylpiOpanamide, a compound of formula 4
Figure imgf000014_0001
Formula 4 comprising reacting N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2- carboxamide, a compound of formula 2 with 4-fluorothiophenol, a compound of formula
3,
Figure imgf000014_0002
Formula 2 Formula 3 in presence of a phase transfer catalyst.
6) The process as claimed in claim 5, wherein the reaction of compound 2 and compound 3 is carried out in a biphasic system comprising water and organic solvent. 7) A process for preparation of an aπtiandrogen compound, /V-[4-cyano-3- (trifluoiOmethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydiOxy-2-methylpropanaraide, a compound of formula 1,
Figure imgf000015_0001
Formula 1 comprising reacting /V-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2- hydroxy-2-methylpropanamide, a compound represented by formula 4,
Figure imgf000015_0002
Formula 4 with a permanganate reagent.
8) The process as claimed in claim 7, wherein the permanganate reagent is an alkali metal permanganate.
9) The process as claimed in claim 8, wherein the alkali metal permanganate is potassium permanganate.
PCT/IN2006/000131 2005-04-15 2006-04-13 A process for preparation of antiandrogen compound Ceased WO2007013094A2 (en)

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HU223950B1 (en) * 1999-06-10 2005-03-29 Richter Gedeon Vegyészeti Gyár Rt. Process for producing racemic and r-(-)- and s-(+)-n-[4-cyano-3-(trifluoromethyl)-phenyl]-3-[(4-fluorophenyl)-sulfonyl]-2-hydroxy-2-methyl-propanecarboxamide
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