Study On The Synthetic Technology Of Rivaroxaban

Rivaroxaban is a novel oral anticoagulants, which combines with the coagulation factor Xa with a high selectivity and competivity, and thus it plays a role of anticoagulation. It’s clinical application contain: reducing non-valvular atrial fibrillation stroke risk in patients with coronary syndrome and recurrence prevention in patients with knee or hip joint made of pulmonary embolism and deep vein thrombosis after replacement surgery. As an oral medication it is easy to take, so it is widely used in clinical and has great prospects. Thus it has important practical significance of research synthesis, we can improve the existing route of the drug synthesis, reduce synthesis costs, improve productivity and so on. Therefore, this paper from the following three parts introduce the synthesis of rivaroxaban. 1. Bromophenyl as a raw material is used to synthesize 4-(4-amino-phenyl)-3-morpholinone(7); 2. Phthalimide as raw material is used to synthesize(S)-N-glycidyl phthalimide(10); 3. Intermediate(7) and intermediate(10) are used to synthesize rivaroxaban(1).In the first part of this work, bromobenzene(2) as a raw material, through a four-step reaction,which include nitration, aromatic amines, acylation and hydrogenation reaction, gave a product of 2-[2-chloro-N-(4-aminophenyl)acetylamino]ethyl-2-chloroacetate(6). Finally, the compound(6) occurred in the ring and the reaction gave the 4-(4-aminophenyl)-3-morpholinone(7) the total yield of the synthesis is 29.7%.In the second part of the work, phthalimide(8) and(S)-epichlorohydrin is under a ringopening reaction in phase transfer catalyst tetrabutylammonium bromide, then without purification in the potassium t-butoxide cyclization to give(S)-N- glycidyl phthalimide(10), and the total yield is 76.7%.In the last part of the work, use of the two portions of already prepared 4-(4-aminophenyl)-3-morpholinone(7) and(S)-glycidol phthalimide(10) under a ring-opening reaction to get the compound(11), after bis(trichloromethyl) carbonate to give(12) hydroformylation, and methylamine deprotection(13), the last(13) and 5-chloro-2-thenoyl chloride by amidation to give rivaroxaban, with a total yield of 72.5%.In summary, bromobenzene and phthalimide as a raw material through nine-step reactions to give rivaroxaban, with a total yield of 16.4%.The paper has the following innovations:Firstly, the intermediate(6) is a new compound was never reported. Secondly,the product of each step is solid.so it has many features, such as easy purification and separation, simple operation, high yield and so on. Finnally, exploring the synthesis of rivaroxaban optimum route, we actual a lot of experimental operations to improve conditions for partial reactions, optimize synthesis routes and explore the recrystallization methods for purifying the intermediate. The routes for industrial synthesis of rivaroxaban may provide some reference value.