A kind of preparation method of rivaroxaban

Abstract

The invention discloses a preparation method of rivaroxaban, which includes the steps of 1) performing a one-step cyclization reaction to an intermediate, N-(4-aminophenyl)-2-(2-haloethyoxyl)acetamide, to prepare a key intermediate, 4-(4-aminophenyl)-3-morpholinone, of the rivaroxaban; 2) performing a series reactions comprising ring opening with an epoxide, a substitution reaction, a ring formation reaction and the like to the 4-(4-aminophenyl)-3-morpholinone to obtain an intermediate, 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one; and 3) performing a substitution reaction to the 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one with 2-chloroformyl-5-chlorothiophene to obtain the rivaroxaban. The whole preparation process is short in route, is high in yield, is less in pollution, can avoid usage of expensive metal palladium for nitroreduction and is suitable for industrial production.

Description

technical field

[0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of rivaroxaban. Background technique

[0002] Thrombus is a local blood clot in a blood vessel. Arterial thrombosis can lead to myocardial infarction, stroke, acute coronary syndrome and peripheral arterial disease, etc.; venous thrombosis can cause pulmonary embolism. The traditional anticoagulant drugs heparin and warfarin are routine methods for the treatment and prevention of arterial and venous thrombosis. Large-scale clinical trials and clinical applications have established their status as traditional anticoagulant drugs. However, heparin is administered parenterally, and the patient's compliance is poor, so it is not suitable for long-term use. Heparin needs antithrombin to play its role, and has no effect on factor Xa in the prothrombin complex. Long-term application may lead to the risk of osteoporosis and potential heparin-media...

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