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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 poor chiral purity, low yield, inconvenient industrial production, etc., and achieve the effect of low cost, high yield and good product quality

Active Publication Date: 2021-01-01
南京法恩化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The problem of this route is that the yield is low, there are many impurities, and the chiral purity is poor. The purification needs to be used for column chromatography many times, which is not convenient for industrial production.

Method used

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  • Preparation method of rivaroxaban
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  • Preparation method of rivaroxaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] A preparation method of rivaroxaban, specifically comprising the following steps:

[0038] (1) Add 600ml of ethanol to a 1L reaction bottle, add 69g of p-nitroaniline and 99.5g of (S)-N-glycidyl phthalimide, and react at a temperature of 50°C after adding, followed by an HPLC central control. After the reaction is completed, filter, concentrate and crystallize the filtrate, filter, wash the filter cakes together, and dry to obtain 154 g of intermediate I, with a yield of 91%.

[0039] (2) Add 500ml of toluene into a 1L reaction bottle, add 80g of intermediate I, control the temperature at 0-10°C, and add 40g of N, N in ten batches ’ -Carbonyldiimidazole, react at a temperature of 15°C. After the reaction was completed, 300ml of water was added, stirred for 1 hour, separated into layers, the organic phase was concentrated and crystallized, filtered, and dried to obtain 70g of intermediate II with a yield of 87%.

[0040] (3) Add 400ml of ethanol to a 1L reaction bottle...

Embodiment 2

[0046](1) Add 600ml of isopropanol to a 1L reaction bottle, add 69g of p-nitroaniline and 100g of (S)-N-glycidyl phthalimide, and react at a temperature of 50°C after adding, followed by HPLC central control . After the reaction is completed, filter, concentrate and crystallize the filtrate, filter, wash the filter cakes together, and dry to obtain 150 g of intermediate I with a yield of 89%.

[0047] (2) Add 400ml of dichloromethane into a 1L reaction bottle, add 80g of intermediate I, control the temperature at 0-10°C, and add 42g of N, N in ten batches ’ -Carbonyldiimidazole, react at a temperature of 20°C. After the reaction was completed, 300ml of water was added, stirred for 1 hour, separated into layers, the organic phase was concentrated and crystallized, filtered, and dried to obtain 73g of intermediate II with a yield of 91%.

[0048] (3) Add 400ml of isopropanol to a 1L reaction flask, add 73g of intermediate II, add 60ml of 40% methylamine aqueous solution, heat ...

Embodiment 3

[0054] (1) Add 600ml of methanol to a 1L reaction bottle, add 82.8g of p-nitroaniline and 100g of (S)-N-glycidylphthalimide, and react at a temperature of 30°C after adding, followed by an HPLC central control. After the reaction is completed, filter, concentrate and crystallize the filtrate, filter, combine and wash the filter cakes, and dry to obtain Intermediate I.

[0055] (2) Add 400ml of chloroform to a 1L reaction bottle, add intermediate I, control the temperature at 0-10°C, and add bis(chloroform)carbonate in batches (wherein bis(chloroform)carbonate and intermediate The molar ratio of I is 2:1), and the temperature is controlled at 20°C. After the reaction is complete, add 300ml of water, stir for 1 hour, separate layers, concentrate and crystallize the organic phase, filter, and dry to obtain Intermediate II.

[0056] (3) Add 400ml of methanol to a 1L reaction flask, add intermediate II, add 40% methylamine aqueous solution (the molar ratio of methylamine to interm...

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Abstract

The invention relates to a preparation method of rivaroxaban, in particular to a method for efficiently synthesizing rivaroxaban by taking p-nitroaniline and (S)-N-glycidol phthalimide as raw materials through seven steps: an addition reaction, a cyclization reaction, a hydrolysis reaction, an amidation reaction, a reduction reaction, an addition reaction and a cyclization reaction. The provided rivaroxaban preparation method has the advantages of high yield, low cost, few three wastes, and high product purity and is suitable for industrialization.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of rivaroxaban. Background technique [0002] Rivaroxaban (rivaroxaban), the chemical name is 5-chloro-N-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5-yl]methyl]-2-thiophenecarboxamide is a highly selective blood coagulation factor Xa inhibitor jointly developed by Bayer and Johnson & Johnson. Launched in Canada, it is used to prevent and treat deep vein thrombosis in patients undergoing knee or hip replacement surgery. Compared with traditional anticoagulants, it has the characteristics of convenient administration, rapid onset of effect, and high safety. [0003] At present, there are many synthetic routes for synthesizing rivaroxaban, for example: EP1261606, WO00147919, US07157456, CN01262551, WO03000256, US07767702, CN100577162, etc. The main synthetic routes include three routes A, B and C, as follows: [0004] (1) Route A is as f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
CPCC07D413/14
Inventor 王坤鹏
Owner 南京法恩化学有限公司
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