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Preparation method for rivaroxaban intermediate

A technology for rivaroxaban and intermediates, which is applied in the field of preparation of rivaroxaban intermediates, can solve the problems of high price, difficult separation and purification, and high toxicity of reagents, so as to improve the reaction yield and purity, and the operation process is simple , easy to purify effect

Inactive Publication Date: 2013-10-16
ZHEJIANG LIAOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The purpose of the present invention is to overcome the disadvantages of expensive starting raw materials, high toxicity of reagents used, difficult separation and purification, and difficulty in industrialization in the above-mentioned prior art, and provide a new preparation method of rivaroxaban intermediate, which has raw materials in the market It is easy to obtain and low in price; effectively improves the reaction yield and purity; and it is green production; the operation process is simple, and it does not require low temperature and harsh conditions such as anhydrous and oxygen

Method used

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  • Preparation method for rivaroxaban intermediate
  • Preparation method for rivaroxaban intermediate
  • Preparation method for rivaroxaban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: the preparation of formula 2a compound

[0042]

[0043] 1a 2a

[0044] Take 28.5g (0.1mol) of the compound of formula 1a, 7.3g (0.1mol) of DMF, and 120ml of chloroform, put them into a 250ml three-necked flask, and raise the temperature to reflux. Dissolve 11.8g (0.04mol) of triphosgene in 30ml of chloroform, slowly add it dropwise into a three-necked flask, and complete the dropwise addition within 3 hours, then keep it warm for 10 hours, and distill under reduced pressure to remove chloroform to obtain the crude product. 150ml of ethanol was beaten, filtered and dried to obtain 28.8g of the compound of formula 2a as a white powdery solid with a yield of 93%.

Embodiment 2

[0045] Embodiment 2: the preparation of formula 2a compound

[0046]

[0047] 1a 2a

[0048] Take 28.5g (0.1mol) of the compound of formula 1a, 7.9g (0.1mol) of pyridine, and 120ml of chloroform, put them into a 250ml three-necked flask, and raise the temperature to reflux. Dissolve 11.8g (0.04mol) of triphosgene in 30ml of chloroform, slowly add it dropwise into a three-necked flask, and complete the dropwise addition within 3 hours, then keep it warm for 10 hours, and distill under reduced pressure to remove chloroform to obtain the crude product. 150ml of ethanol was beaten, filtered and dried to obtain 29.5g of the compound of formula 2a as a white powdery solid with a yield of 95%.

Embodiment 3

[0049] Embodiment 3: the preparation of formula 2a compound

[0050]

[0051] 1a 2a

[0052] Take 28.5g (0.1mol) of the compound of formula 1a, 11.9g (0.15mol) of pyridine, and 120ml of chloroform, put them into a 250ml three-necked flask, and raise the temperature to reflux. Dissolve 11.8g (0.04mol) of triphosgene in 30ml of chloroform, and slowly add it dropwise into a three-neck flask. The dropwise addition is completed within 3 hours, and then keep warm for 10 hours. The chloroform is removed by distillation under reduced pressure to obtain the crude product. 150ml of ethanol was beaten, filtered and dried to obtain 20.0g of the compound of formula 2a as a white powdery solid with a yield of 97%.

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Abstract

The invention provides a preparation method for a rivaroxaban intermediate. The preparation method is characterized in that a compound represented by formula 1 and triphosgene are used as raw materials and undergo a reaction in an organic solvent at a temperature of 40 to 100 DEG C for 1 to 10 h under the action of an organic amine catalyst, then pressure reduction is carried out to remove the solvent, and an obtained crude product is subjected to refining in the organic solvent so as to prepare a compound represented by formula 2, wherein the formula 1 and the formula 2 are described in the specification. According to the invention, the starting raw materials are easily available on the market and are cheap; triphosgene is used to replace expensive carbonyldiimidazole, CO2 and HCL gas are generated after the reaction, a product is easy to purify, and reaction yield and purity are effectively improved; triphosgene is used to replace expensive carbonyldiimidazole, HCL gas generated after the reaction can be utilized after recovery, so the purpose of green production is achieved; operation process is simple, and rigor conditions like low temperature, no water and no oxygen are not needed.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, in particular to a preparation method of a rivaroxaban intermediate. Background technique [0002] Thrombosis refers to the formation of local blood clots. Among them, arterial thrombosis can lead to myocardial infarction, stroke, acute coronary syndrome and peripheral arterial disease, etc.; venous thrombosis can cause pulmonary embolism. Arteriovenous thrombosis is the leading cause of cardiovascular disease morbidity and death, and it is also one of the leading causes of death in cancer patients. [0003] Venous thromboembolism (VTE) is a type of disease caused by blood coagulation in veins to form thrombus, which can cause deep vein thrombosis and its serious complication—pulmonary embolism, which can quickly endanger the patient's life. Due to the hidden symptoms of these diseases, especially deep vein thrombosis, 80% of patients without clinical manifestations are missed. The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/10
Inventor 胡华南曾青峰王小强屠雄飞杨敏华
Owner ZHEJIANG LIAOYUAN PHARM CO LTD
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