Process for preparing bicalutamide
AssigneeShilpa Medicare Limited
InventorsVimal Kumar Shrawat, Karri Papa Rao, N/A Rafiuddin, Prashant Purohit
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Abstract
The present invention provide processes for the preparation of N-[4-Cyano-3-(trifluoro methyl)phenyl]-3-[(4-fluorophenyl)sulphonyl]-2-hydroxy-2-methyl propanamide (I). The present application also provides a method of purification of N-[4-Cyano-3-(trifluoro methyl)phenyl]-3-[(4-fluorophenyl)sulphonyl]-2-hydroxy-2-methyl propanamide (I) using ethyl acetate solvent resulting in the product, substantially free from process related impurities A, B, C and D. The crystalline product of the process according to the present invention having an XRDP pattern as per FIG. 1, is useful as an active pharmaceutical and has anti-androgenic activity.
Claims11
1) A process of preparation of N-[4′-cyano-3′-(trifluoromethyl)phenyl]-3-[(4″-fluoro-phenyl)sulfonyl]-2-hydroxy-2-methylpropionamide (I)
- comprising the steps of—
- a. Selectively Oxidizing N-[4′-Cyano-3′-(trifluoromethyl)phenyl]-3-[(4″-fluoro phenyl)thio]-2-hydroxy-2-methyl propionamide of Formula (III)—
- in presence of an C1-C3 organic alcohol solvent, 1% ortho tungstic acid and aqueous hydrogen peroxide
- b. Raising the temperature upto about 50° C. or more and maintaining the temperature while stirring until the content of compound of formula (III) achieved till less than about 1%.
- c. Cool the reaction mass and isolating the solid.
- d. Add mixture of water and water immiscible ester solvent (about 1:2).
- e. Separate the organic ester solvent layer.
- f. Optionally repeat the further extraction of aqueous layer with water immiscible ester solvent
- g. Optionally adding activated carbon followed by filtering the extracted organic layer
- h. Evaporating the water immiscible ester solvent
- i. Isolating the compound of formula (I)
2) A process of preparation of N-[4′-cyano-3′-(trifluoromethyl)phenyl]-3-[(4″-fluoro-phenyl)sulfonyl]-2-hydroxy-2-methylpropionamide (I)
- comprising the steps of—
- a. Selectively Oxidizing N-[4′-Cyano-3′-(trifluoromethyl)phenyl]-3-[(4″-fluoro phenyl)thio]-2-hydroxy-2-methyl propionamide of Formula (III)—
- with aqueous hydrogen peroxide in presence of a non-halogenated organic acid solvent.
- b. Admixing the reaction mass of step a) with aqueous sodium bicarbonate solution followed by stirring for duration upto at least 30 minutes
- c. Extract the reaction mass with water immiscible ester solvent
- d. Optionally adding activated carbon followed by filtering the extracted organic layer
- e. Evaporating the water immiscible ester solvent
- f. Isolating the compound of formula (I)
8) N-[4′-cyano-3′-(trifluoromethyl)phenyl]-3-[(4″-fluoro-phenyl)sulfonyl]-2-hydroxy-2-methylpropionamide (I) or Bicalutamide substantially free from impurities A, B, C and D.
9) A process for purifying N-[4′-cyano-3′-(trifluoro methyl)phenyl]-3-[(4″-fluoro-phenyl)sulfonyl]-2-hydroxy-2-methylpropionamide (I) or Bicalutamide comprising mixing Bicalutamide with ethyl acetate and heating the solution containing Bicalutamide up to at least about 50° C. followed recovering ethyl acetate and isolating the product, substantially free from impurities A, B, C and D.
11) Bicalutamide crystalline “Form-S” comprising an X-ray diffraction pattern having characteristic 2θ° and ‘d’ spacing values—6.1 (14.40 d value), 12.2 (7.20 d value), 16.9 (5.23 d value), 19.0 (4.65 d value), 23.8 (3.72 d value), 24.9 (3.56 d value), 29.5 and 31.5±0.2 (±0.1 d value).
Dependencies are inferred from the claim text.