Novel process for preparing rac-bicalutamide and its intermediates
AssigneeBiogal Gyogyszergyar Rt.
InventorsBen-Zion Dolitzky, Ofer Reany, Jenny Shammai
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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.
Claims49
A rac-bicalutamide intermediate having the chemical strcuture of [X], wherein [X] is a stable organo lithium salt of 4-fluorophenyl methyl sulfone.
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].
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.
A rac-bicalutamide intermediate having the chemical structure of [Y], wherein [Y] is a stable organo lithium salt of 5-amino-2-cyano-benzotrifluoride.
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].
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.
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.
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.
A micronized rac-bicalutamide, wherein the micronized rac-bicalutamide has a mean particle diameter of less than about 200 μm.
A micronized rac-bicalutamide, wherien the micronized rac-bicalutamide has a mean particle diameter of less than about 100 μm.
A micronized rac-bicalutamide, wherein the micronized rac-bicalutamide has a mean particle diameter of less than 10 μm.
A micronized rac-bicalutamide, wherein the micronized rac-bicalutamide has a mean particle diameter between about 200 μm to about 10 μm.
A pharmaceutical composition of rac-bicalutamide comprising a micronized rac-bicalutamide and a pharmaceutically acceptable salt.
The pharmaceutical composition of rac-bicalutamide wherein the micronized rac-bicalutamide has a mean particle diameter between about 200 μm to about 10 μm.
Dependencies are inferred from the claim text.