4-(4-Nitrophenyl)­morpholin-3-one and 4-(4-aminophenyl) morpholin-3-one are the key intermediates for rivaroxaban synthesis. A facile and economically efficient process has been developed for the preparation of these intermediates. Excellent yield of 4-(4-nitrophenyl)­morpholine is obtained by condensing 4-chloro nitrobenzene and morpholine, and 4-(4-nitrophenyl)­morpholine is oxidized using inexpensive sodium chlorite to achieve a good yield of the corresponding 4-(4-nitrophenyl)­morpholin-3-one. Finally, the key intermediate of rivaroxaban, 4-(4-aminophenyl) morpholin-3-one, is achieved by the iron­(III)-catalyzed reduction of the nitro group with aqueous hydrazine. No high-cost materials were used, and the process did not require column purification.

By using cheap and innocuous sodium chlorite, a series of tertiary amines have been oxidized to the corresponding lactams with good selectivity and high yield. In this method, neither transition-metal catalyst nor oxidant was used. In the oxidation step, the pH of the sodium chlorite was precisely adjusted to pH around 6 using CO2, such pH is a compromise between oxidative properties, chemical stability, and unwanted precipitation. In addition, buffer salts are not necessary, which allows this oxidation reaction to be performed under safe and environmentally benign conditions.

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