Novel process for the preparation of belinostat
AssigneeBiophore India Pharmaceuticals PVT. Ltd.
InventorsManik Reddy PULLAGURLA, Mecheril Valsan NANDA KUMAR, Bhaskar Reddy PITTA, Jagadeesh Babu RANGISETTY
Life of this patent
Estimating the term…
Abstract
The present invention provides a novel and commercially viable process with high yield for the preparation of (E)-N-hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide, also known as Belinostat (I). The invention also provides process for purification and novel crystalline form of Belinostat in substantially pure form.
Claims29
A process for the preparation of Belinostat of formula I:
- comprising the steps of:
- (a) reacting 3-nitrobenzaldehyde of formula VIII with a Wittig reagent to provide (E)-ethyl 3-(3-nitrophenyl)acrylate of formula VI;
- (b) reducing (E)-ethyl 3-(3-nitrophenyl)acrylate of formula VI with a reducing agent to provide (E)-ethyl 3-(3-aminophenyl)acrylate of formula V;
- (c) diazotizing (E)-ethyl 3-(3-aminophenyl)acrylate of formula V followed by chlorosulphonating with a chlorosulphonating reagent to provide (E)-ethyl 3-(3-(chlorosulfonyl)phenyl)acrylate of formula IV;
- (d) coupling (E)-ethyl 3-(3-(chlorosulfonyl)phenyl)acrylate of formula IV with aniline to provide (E)-3-(3-(N-phenyl sulfamoyl)phenyl)acrylic acid of formula III;
- (e) converting (E)-3-(3-(N-phenylsulfamoyl)phenyl)acrylic acid of formula III to acid chloride with a chlorinating agent to provide (E)-3-(3-(N-phenylsulfamoyl) phenyl) acryloyl chloride of formula II;
- (f) amino hydroxylating (E)-3-(3-(N-phenylsulfamoyl) phenyl) acryloyl chloride of formula II with hydroxyl amine hydrochloride to provide crude Belinostat of formula I;
- and
- (g) optionally, purifying the compound of formula I by re-crystallizing from suitable solvents to provide substantially pure Belinostat of formula I.
A process for the purification of Belinostat of formula I, comprising the steps of:
- (f) suspending crude Belinostat of formula I in suitable solvents selected from ethyl acetate, methanol, ethanol, isopropanol, n-butanol, water, methyl tertiary butyl ether, acetone, diethyl ether, isopropyl ether, dichloromethane, acetonitrile, acetic acid and tetrahydrofuran, toluene, cyclohexane solvents or mixtures thereof;
- (g) heating the reaction mixture to a temperature ranging from 25°-65° C. for 1 to 5 hrs;
- (h) cooling the reaction mixture to 0-5° C.;
- (i) filtering the solid separated under vacuum;
- and
- (j) optionally, washing the solid with the mixture of suitable solvents selected from ethyl acetate, methanol, ethanol, isopropanol, n-butanol, water, methyl tertiary butyl ether, acetone, diethyl ether, isopropyl ether, dichloromethane, acetonitrile, acetic acid and tetrahydrofuran, toluene, cyclohexane solvents or mixtures thereof at 0-5° C.
Crystalline Belinostat of formula I designated as crystalline form 1, characterized by an X-ray diffraction pattern comprising one or more of the reflections at:
- 4.5, 13.5, 14.6, 18.0, 20.7, 21.1 and 26.3±0.2 degrees 2 theta;
- which is further characterized by an X-ray powder diffraction pattern comprising one or more of the reflections at:
- 8.9, 11.1, 15.4, 16.5, 22.4, 22.6 & 28.0±0.2 degrees 2 theta.
Substantially pure Belinostat compound of formula I having purity of greater than 98% and impurities less than 0.05% (w/w) by HPLC.
Dependencies are inferred from the claim text.