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Preparation method of rivaroxaban

A technology of rivaroxaban and intermediates, applied in the field of medicine, can solve the problems of high risk, large environmental pollution, flammability of lithium tert-butoxide, etc., and achieves high risk reduction, shortened reaction time, and high product purity. Effect

Pending Publication Date: 2022-03-01
ANHUI YOUCARE KAIYUE PHARMA
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  • Abstract
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  • Application Information

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Problems solved by technology

Lithium tert-butoxide is flammable, and thionyl chloride is highly toxic and pollutes the environment
[0004] To sum up, there are many existing synthetic routes of rivaroxaban, all of which have certain shortcomings. Some steps are complicated and difficult to control; some use a large number of highly dangerous and toxic reagents; some have low yields. Raw materials are expensive

Method used

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  • Preparation method of rivaroxaban
  • Preparation method of rivaroxaban
  • Preparation method of rivaroxaban

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Embodiment Construction

[0018] The technical solutions in the embodiments of the present invention will be clearly and completely described below, obviously, the described embodiments are only some of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

[0019] 1. Production principle

[0020] The synthesis of rivaroxaban is based on 4-(4-aminophenyl)-3-morpholinone, (S)-N-epoxypropylphthalimide and 5-chlorothiophene-2-carboxylic acid The starting material undergoes addition reaction, substitution reaction, amine deprotection and condensation reaction to generate crude rivaroxaban, and the crude product is decolorized and refined to obtain the raw material drug of rivaroxaban.

[0021] 2. Preparation of Rivaroxaban Intermediate Ⅰ (PM1)

[0022] (1) Ratio of materials

[00...

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Abstract

The invention discloses a preparation method of rivaroxaban, which comprises the following steps: taking 4-(4-aminophenyl)-3-morpholone, (S)-N-epoxypropylphthalimide and 5-chlorothiophene-2-formic acid as starting materials, and carrying out a reaction at the temperature of 60-80 DEG C to obtain rivaroxaban. A rivaroxaban intermediate I is prepared through a substitution reaction, a rivaroxaban intermediate II is prepared through an aminolysis deprotection reaction, a rivaroxaban intermediate III is prepared through an aminolysis deprotection reaction, a rivaroxaban crude product is generated through a condensation reaction, and a rivaroxaban bulk drug is obtained after the crude product is decolored and refined.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a preparation method of rivaroxaban. Background technique [0002] Rivaroxaban, Chinese chemical name: 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-)-1 ,3-oxazolidin-5-yl]methyl]thiophene-2-carboxamide, molecular formula: C19H18ClN3O5S. Rivaroxaban is an oral, bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (eg, antithrombin III) for activity. Activation of factor X to factor Xa (FXa) through intrinsic and extrinsic pathways plays an important role in the blood coagulation cascade. Rivaroxaban dose-dependently inhibits the activity of factor Xa in humans, application Prothrombin time (PT), activated partial thromboplastin time (aPTT) and Quantitative detection of heparin showed a dose-dependent prolongation. Anti-factor Xa activity was also affected by rivaroxaban. Rivaroxaban is used to prevent ve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 周如国高彬洁田小龙高金鑫
Owner ANHUI YOUCARE KAIYUE PHARMA