Facile Preparation of 4-(4-Nitrophenyl)morpholin-3-one via the Acid-Catalyzed Selective Oxidation of 4-(4-Nitrophenyl)morpholine by Sodium Chlorite as the Sole Oxidant

Abstract

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.

Review on Synthetic Approaches toward Rivaroxaban (Xarelto), an Anticoagulant Drug

“…Morpholine is much more nucleophilic than morpholin-3-one; thus, S N Ar reactions with 1-halo-4-nitrobenzenes are relatively easy (X = F or Cl, Y = H 2 , Z = NO 2 ). Such reports are numerous, and yields higher than 90% could be achieved when X = F or Cl. , Analogously, metal-catalyzed arylations of morpholine with 1-bromo- and 1-iodo-4-nitrobenzene are well known, but this approach is not discussed here since the use of the cheaper chloride without any metal participation gave satisfactory results.…”

“…Though the product yields obtained with hydrogenation and non-hydrogen reductants are essentially in the same range, the former way is preferred because it is significantly more environmentally benign. Inorganic wastes are inevitably generated when metals or salts are used in addition to chemoselectivity issues that were found to occur with hydrazine as a hydrogen source …”

“…Such reports are numerous, and yields higher than 90% could be achieved when X = F or Cl. 36,37 Analogously, metal-catalyzed arylations Scheme 1. Synthesis of (S)-GPI via the Mitsunobu Reaction Scheme 2.…”

A Facile Oxidation of Tertiary Amines to Lactams by Using Sodium Chlorite: Process Improvement by Precise pH Adjustment with CO2

“…In some cases, the reaction mixture is quite complex, which is attributed to the pH imbalances during the reaction procedure; this was described in our previous study by using a variety of acids in different amounts. 15 At the beginning of the oxidation reaction, the mixture of amine and acetic acid (30 mol%) generates a low pH (about 4-5) condition, which cleaves some sodium chlorite to chloride dioxide, and elevates the oxidation ability of the oxidant. Furthermore, at low pH, the formed HOCl will chlorinate the aromatic ring by electrophilic substitution, which leads to low reaction selectivity.…”

“…Inspired by this protocol, we have developed an acetic acid promoted oxidation of 4-(4-nitrophenyl) morpholine with sodium chlorite as the sole oxidant (Scheme 1, eq. 2), 15 which is a very useful and simple method for the preparation of the key intermediate of rivaroxaban (marketed as XARELTO). Thus, we would like to extend this method to the oxidation of a broad range of tertiary amines.…”