Novel process for preparing rac-bicalutamide and its intermediates

Abstract

The present invention relates to a new process for the synthesis of racemic and optically active bicalutamide starting from ethyl pyruvate and methyl methacrylate. The present invention discloses processes of preparing bicalutamide intermediates including ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionate, 1,2-epoxy-2-methyl propionate and 2-hydrox-2-methyl-3-(4-fluorophenylthio) propionic acid. The present invention further discloses micronized rac-bicalutamide and the preparation thereof.

What is claimed is:  
     
         1 . A rac-bicalutamide intermediate having the chemical strcuture of [X], wherein [X] is a stable organo lithium salt of 4-fluorophenyl methyl sulfone.  
     
     
         2 . A process of preparing a rac-bicalutamide intermediate having the chemical structure of [X], comprising the steps of: 
 a) dissovling 4-fluorophenyl methyl sulfone in an organic solvent; and    b) adding butyl lithium to the solution, wherein butyl lithium reacts with 4-fluorophenyl methyl sulfone to form [X].    
     
     
         3 . The process according to  claim 2 , wherein the organic solvent is selected from the group consisting of tetrahydrofuran and diethyl ether.  
     
     
         4 . The process according to  claim 2 , wherein the reaction between butyl lithium with 4-fluorophenyl methyl sulfone occurs in the presence of an anion stabilizer.  
     
     
         5 . The process according to  claim 4 , wherein the anion stabilizer is 1,4 diazabicylo[2.2.2]octane.  
     
     
         6 . The process according to  claim 2 , wherein the reaction between butyl lithium with 4-fluorophenyl methyl sulfone occurs in a temperature range between about −40° C. to about +10° C.  
     
     
         7 . The process according to  claim 2 , wherein the reaction between butyl lithium with 4-fluorophenyl methyl sulfone occurs in a temperature range between about −2° C. and about +2° C.  
     
     
         8 . A process of preparing ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionate, comprises the steps of: 
 a) preparing a mixture of 4-fluorophenyl methyl sulfone and butyl lithium in an organic solvent;    b) adding ethyl pyruvate; and    c) recovering ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionate.    
     
     
         9 . The process according to  claim 8 , wherein the organic solvent is tetrahydrofuran.  
     
     
         10 . The process according to  claim 8 , wherein the ethyl pyruvate is added to the mixture at a temperature of about −65° C.  
     
     
         11 . The process according to  claim 8 , wherein the recovering step comprises evaporating the mixture containing ethyl pyruvate.  
     
     
         12 . The process according to  claim 8 , wherein the recovering step further comprises separating the ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionate.  
     
     
         13 . A rac-bicalutamide intermediate having the chemical strcuture of [Y], wherein [Y] is a stable organo lithium salt of 5-amino-2-cyano-benzotrifluoride.  
     
     
         14 . A process of preparing a rac-bicalutamide intermediate having the chemical structure of [Y], comprising the steps of: 
 a) dissovling 5-amino-2-cyano-benzotriflouride in an organic solvent; and    b) adding butyl lithium to the solution, wherein butyl lithium reacts with 5-amino-2-cyano-benzotrifloride to form [Y].    
     
     
         15 . The process according to  claim 14 , wherein the organic solvent is selected from the group consisting of tetrahydrofuran and diethyl ether.  
     
     
         16 . The process according to  claim 14 , wherein the reaction between butyl lithium with 5-amino-2-cyano-benzotrifloride occurs in the presence of an anion stabilizer.  
     
     
         17 . The process according to  claim 16 , wherein the anion stabilizer is 1,4 diazabicylo[2.2.2]octane.  
     
     
         18 . The process according to  claim 14 , wherein the reaction between butyl lithium with 5-amino-2-cyano-benzotrifloride occurs in a temperature range between about −40° C. to about +10° C.  
     
     
         19 . The process according to  claim 14 , wherein the reaction between butyl lithium with 5-amino-2-cyano-benzotrifloride occurs in a temperature range between about −2° C. and about +2° C.  
     
     
         20 . A process of preparing rac-bicalutamide, comprising the steps of: 
 a) preparing a mixture of 5-amino-2-cyano-benzotrifluoride and butyl lithium in an organic solvent;    b) adding ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionic acid to the mixture; and    c) recovering rac-bicalutamide.    
     
     
         21 . The process according to  claim 20 , wherein the organic solvent is selected from the group consisting of tetrahydrofuran and diethyl ether.  
     
     
         22 . The process according to  claim 20 , wherein the ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionic acid is added to the mixture at a temperature of about −65° C.  
     
     
         23 . The process according to  claim 20 , wherein recovering step comprises evaporating the mixture containing ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionic acid.  
     
     
         24 . The process according to  claim 20 , wherein the recovering step further comprises separating the ethyl-[2-{4-fluorophenyl sulfone}]-2-hydroxy propionic acid.  
     
     
         25 . The process according to  claim 20 , wherein the rac-bicalutamide is an R-isomer.  
     
     
         26 . The process according to  claim 20 , wherein the rac-bicalutamide is an S-isomer.  
     
     
         27 . A process of preparing methyl 1,2-epoxy-2-methyl propionate, comprising the steps of: 
 a) dissolving oxone in a basic solution;    b) adding methyl methacrylate to the oxone solution;    c) adding an acid to the oxone solution to form methyl 1,2-epoxy-2-methyl propionate; and    d) recovering methyl 1,2-epoxy-2-methyl propionate.    
     
     
         28 . The process according to  claim 27 , wherein the basic solution is selected from the group consisting of potassium hydroxide and sodium hydroxide.  
     
     
         29 . The process according to  claim 28 , wherein the potassium hydroxide has a concentration of 10 M.  
     
     
         30 . The process according to  claim 27 , wherein the oxone is 50% KHSO 5 .  
     
     
         31 . The process according to  claim 27 , wherein the methyl methacrylate is added in methanol.  
     
     
         32 . The process according to  claim 27 , wherein the oxone solution containing methyl methacrylate is maintained at about pH 6.  
     
     
         33 . The process according to  claim 27 , wherein the acid is selected from the group consisting of hydrochloric acid, nitric acid and phosphoric acid.  
     
     
         34 . The process according to  claim 33 , wherein the hydrochloric acid has a concentration of about 0.05 N to about 5 N.  
     
     
         35 . A process of preparing 2-hydroxy-2-methyl-3-(4-fluorophenylthio) propionic acid, comprising the steps of: 
 a) preparing a solution of 4-fluorothiophenol in methanol;    b) adding methyl-1,2-epoxy-2-methyl propionate to form a mixture;    c) adding ethyl acetate to the mixture; and    d) recovering 2-hydroxy-2-methyl-3-(4-fluorophenylthio) propionic acid.    
     
     
         36 . The process according to  claim 35 , wherein the preparation of 4-fluorothiophenol solution is performed by adding a basic solution under N 2  flow.  
     
     
         37 . The process according to  claim 36 , wherien the basic solution is selected from the group consisting of sodium hydroxide and potassium hydroxide.  
     
     
         38 . The process according to  claim 37 , wherein the sodium hydroxide has a concentration of 2 N.  
     
     
         39 . The process according to  claim 35 , wherein the mixture is formed by stirring.  
     
     
         40 . The process according to  claim 39 , wherein the stirring is performed at room temperature for 90 minutes.  
     
     
         41 . The process according to  claim 35 , wherein the recovering step is extraction.  
     
     
         42 . The process according to  claim 41 , wherein the extraction is achieved by chloroform.  
     
     
         43 . The process according to  claim 35 , wherein the recovering step further involves solidifying 2-hydrox-2-methyl-3-(4-fluorophenylthio) propionic acid.  
     
     
         44 . A micronized rac-bicalutamide, wherein the micronized rac-bicalutamide has a mean particle diameter of less than about 200 μm.  
     
     
         45 . A micronized rac-bicalutamide, wherien the micronized rac-bicalutamide has a mean particle diameter of less than about 100 μm.  
     
     
         46 . A micronized rac-bicalutamide, wherein the micronized rac-bicalutamide has a mean particle diameter of less than 10 μm.  
     
     
         47 . A micronized rac-bicalutamide, wherein the micronized rac-bicalutamide has a mean particle diameter between about 200 μm to about 10 μm.  
     
     
         48 . A pharmaceutical composition of rac-bicalutamide comprising a micronized rac-bicalutamide and a pharmaceutically acceptable salt.  
     
     
         49 . The pharmaceutical composition of rac-bicalutamide wherein the micronized rac-bicalutamide has a mean particle diameter between about 200 μm to about 10 μm.