| 主权项 |
1. A process for the preparation of rivaroxaban of Formula (1) or its pharmaceutical acceptable salts, solvates, and hydrates thereof,the process comprising:
i) reacting 4-(4-aminophenyl)morpholin-3-one compound of Formula (C) with (R)-glycidyl alkyl ester of Formula (E1), wherein R represents C1-C5 alkyl, in a suitable solvent to obtain (R)-2-hydroxy-3-(4-(3-oxomorpholino)phenylamino)alkyl ester of Formula (EE); ii) reacting (R)-2-hydroxy-3-(4-(3-oxomorpholino)phenylamino)alkyl ester of Formula (EE) with a cyclizing agent in a suitable solvent, optionally in the presence of a catalyst to obtain (R)-(2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)alkyl ester of Formula (FF); iii) reacting (R)-(2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)alkyl ester of Formula (FF) with a base to obtain (R)-4-(4-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one of Formula (GG); iv) reacting (R)-4-(4-(5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl)phenyl)morpholin-3-one of Formula (GG) with a compound of Formula (2), wherein R1 represents C1-C5 alkyl or substituted or unsubstituted aryl, and X represents halide selected from Br, Cl, F or I, in the presence of a base to obtain a compound of Formula (HH); v) reacting the compound of Formula (HH) with phthalimide, optionally in the presence of a base to obtain (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5-yl)methyl)iso-indoline-1,3-dione of Formula (I); vi) reacting the (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5-yl)methyl)iso-indoline-1,3-dione of Formula (I) with a base in a suitable solvent to obtain (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one (J); and vii) converting the (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one (J) to rivaroxaban of Formula (I). |
