Rivaroxaban intermediate preparation method

A technology for rivaroxaban and intermediates, which is applied in the field of preparation of rivaroxaban intermediates, can solve the problems of unfavorable industrial production, difficulty in separation and purification, and low yield, and achieve favorable industrial production, easy availability of raw materials, The effect of high synthesis efficiency

Inactive Publication Date: 2013-04-03
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The technical problem to be solved by this invention is 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} in the prior art The synthetic method of morpholin-3-one hydrochloride has high cost, low yield, difficult separation and purification, and is unfavorable for industrialized production. The invention provides a new method for preparing 4-{4-[(5S)-5-( The method of aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride, the raw material of this method is cheap and easy to get, the reaction conditions are mild, and the operation is simple and convenient , high synthesis efficiency, conducive to industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The preparation of compound IIa (compound IIa is R in compound II 1 benzyl compound)

[0033]

[0034] Add 19.2g of 4-(4-aminophenyl)-3-morpholinone and 12.6g of sodium bicarbonate into the reaction flask, add 200ml of water and 100ml of 1,4-dioxane, and add 20.4g of chloroformic acid dropwise at 0°C The benzyl ester was dropped within 30 minutes, continued to stir at 0°C for 1 hour, raised the temperature to 30°C and stirred for 2 hours, and filtered with suction to obtain 31.1 g of a white solid with a melting point of 200-205°C and a yield of 95.4%.

Embodiment 2

[0036] The preparation of compound IVa (compound IIIa is that X is chlorine in compound III, R 2 for tert-butoxycarbonyl compounds)

[0037]

[0038] Add 10.0g of compound IIa and 14.1g of compound IIIa into the reaction flask, add 10ml of anhydrous N,N-dimethylformamide, add dropwise 10.3g of sodium tert-butoxide dissolved in 40ml of anhydrous tetrahydrofuran at 0°C for 1 hour After the internal drop is completed, continue stirring at 0°C for 2 hours, raise the temperature to 30°C, stir for 25 hours, add saturated ammonium chloride, extract with dichloromethane to obtain an organic layer, and concentrate to obtain 10.5 g of off-white solid, melting point 171-174°C , yield 87.5%.

Embodiment 3

[0040] The preparation of compound IVa (compound IIIa is that X is chlorine in compound III, R 2 for tert-butoxycarbonyl compounds)

[0041]

[0042] Add 30.0g of compound IIa and 34.5g of compound IIIa into the reaction flask, add 75ml of anhydrous N,N-dimethylformamide, add dropwise 26.4g of sodium tert-butoxide dissolved in 150ml of anhydrous tetrahydrofuran at 0°C for 1 hour After the internal drop is completed, continue stirring at 0°C for 2 hours, raise the temperature to 50°C, stir for 20 hours, add saturated ammonium chloride, extract with dichloromethane to obtain an organic layer, and concentrate to obtain 33.5 g of off-white solid, melting point 171-174°C , yield 93.0%.

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Abstract

The invention discloses a rivaroxaban intermediate 4-{4-[(5S0-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-radical]phenyl}morpholine-3-ketohydrochloride preparation method. The method includes the steps: step (1) reacting a compound II and a compound III in organic solvent under the action of alkaline to obtain a compound IV, wherein R1 refers to benzyl, substituent benzyl, aryl or substituent aryl, X refers to halogen and R2 refers to methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, carboxybenzyl or trityl; and step (2) preparing a compound I by means of hydrolysis reaction of the compound IV in organic solvent under the action of acid. The rivaroxaban intermediate preparation method is simple and convenient in operation, mild in reaction condition, stable in quality, simple in post-processing and suitable for industrial production.

Description

technical field [0001] The present invention relates to the intermediate 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-methanol of rivaroxaban Process for the preparation of lin-3-one hydrochloride. Background technique [0002] Venous thromboembolism (VTE) includes deep vein thrombosis (Deep Vein Thrombosis, DVT) and pulmonary embolism (PE). DVT often originates in a deep vein in the lower leg and can partially or completely block blood flow. Symptoms of DVT include chronic pain and swelling in the legs, which can lead to a serious, life-threatening condition called PE if the clot dislodges and travels through the bloodstream through the heart to the lungs, blocking the pulmonary artery. If left untreated or incompletely treated, deep vein thrombosis can also lead to long-term complications such as pulmonary hypertension, refractory venous ulcers of the lower extremities, and increased risk of recurrent thrombosis. [0003] Rivaroxaban (Formula A) is a hig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10
Inventor 陈国华符坚江传亮
Owner CHINA PHARM UNIV
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