WO2007013094A2 - Procede de preparation d'un compose antiandrogene - Google Patents

Procede de preparation d'un compose antiandrogene Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
formula
compound
cyano
phenyl
permanganate
Prior art date
Application number
PCT/IN2006/000131
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English (en)
Other versions
WO2007013094A3 (fr
Inventor
Umangkumar Natubhai Patel
Kamleshkumar Naranbhai Borkhataria
Kanaksinh Jesingbhai Jadav
Trinadha Rao Chitturi
Rajamannar Thennati
Original Assignee
Sun Pharmaceutical Industries Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Sun Pharmaceutical Industries Limited filed Critical Sun Pharmaceutical Industries Limited
Publication of WO2007013094A2 publication Critical patent/WO2007013094A2/fr
Publication of WO2007013094A3 publication Critical patent/WO2007013094A3/fr

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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

Definitions

  • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation d'un composé antiandrogène, N-[4-cyano-3-(trifluorométhyl)phényl]-3-[(4-fluorophényl)sulfonyl]-2-hydroxy-2-méthylpropanamide, un composé de formule 1. Ce procédé consiste à faire réagir du N-[4-cyano-3-(trifluorométhyl)phényl]-2-méthyloxirane-2-carboxamide, un composé de formule 2, avec du 4-fluorothiophénol, un composé de formule 3, en présence d'un catalyseur de transfert de phase ; et à oxyder le N-[4-cyano-3-(trifluorométhyl)phényl]-3-[(4-fluorophényl)thio]-2-hydroxy-2-méthylpropanamide obtenu, un composé de formule 4, avec un réactif permanganate.
PCT/IN2006/000131 2005-04-15 2006-04-13 Procede de preparation d'un compose antiandrogene WO2007013094A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN465/MUM/2005 2005-04-15
IN465MU2005 2005-04-15

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WO2007013094A2 true WO2007013094A2 (fr) 2007-02-01
WO2007013094A3 WO2007013094A3 (fr) 2007-11-01

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001000608A1 (fr) * 1999-06-10 2001-01-04 Richter Gedeon Vegyészeti Gyár Rt. Procede de synthese de n-(4-cyano-3-trifluoromethylephenyle)-3-(4-fluorophenyle-sulfonyle)-2-hydroxy-2-methylepropionamide
CN1458146A (zh) * 2002-05-15 2003-11-26 中国科学院上海药物研究所 抗肿瘤药物比卡鲁胺合成工艺
WO2004039769A1 (fr) * 2002-10-30 2004-05-13 Instytut Farmaceutyczny Procede pour la production de n-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylthio)-2-hydroxy-2-mthylpropanamide hautement pur

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001000608A1 (fr) * 1999-06-10 2001-01-04 Richter Gedeon Vegyészeti Gyár Rt. Procede de synthese de n-(4-cyano-3-trifluoromethylephenyle)-3-(4-fluorophenyle-sulfonyle)-2-hydroxy-2-methylepropionamide
CN1458146A (zh) * 2002-05-15 2003-11-26 中国科学院上海药物研究所 抗肿瘤药物比卡鲁胺合成工艺
WO2004039769A1 (fr) * 2002-10-30 2004-05-13 Instytut Farmaceutyczny Procede pour la production de n-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylthio)-2-hydroxy-2-mthylpropanamide hautement pur

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