Facile approach for the synthesis of rivaroxaban using alternate synthon: reaction, crystallization and isolation in single pot to achieve desired yield, quality and crystal form

Abstract

Abstract

An efficient and high yielding process for the production of impurity free rivaroxaban (1), an anti-coagulant agent using alternate synthon is reported. The key components of the process involve; synthesis of 4-(4-aminophenyl)-3-morpholinone (5) using easily available inexpensive nitro aniline (17), condensation of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (9) with alternate synthon 4-nitrophenyl 5-chlorothiophene-2-carboxylate (11) in dimethylsulfoxide (DMSO) as a solvent and triethylamine as a base and isolation of the rivaroxaban (1) by designing the crystallization in same reaction pot using specific combination of acetonitrile and methanol as anti-solvents to obtain highly pure rivaroxaban (1) with desired ploymorphic form with an overall yield of around 22% (Calculated from 17). The developed process avoids the use of hazardous chemicals, critical operations and tedious work-ups. Potential impurities arouse during the reaction at various stages and carry-over impurities from starting materials were controlled selectively by designing reaction conditions and tuning the crystallization parameters.

Graphical abstract

[Figure not available: see fulltext.]