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Method for purifying compound

A compound and mixed solution technology, applied in the direction of organic chemistry, can solve the problems of reducing equipment production efficiency, safety hazards, and increasing production costs, and achieve the effects of easy control, improved production efficiency, and less by-products

Active Publication Date: 2016-12-07
WATERSTONE PHARMA WUHAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In view of the fact that the original research manufacturer uses the materials formamide, sodium methoxide and trimethyl orthoformate to carry out the corresponding ammonolysis reaction, but there are many types of materials used, and the highly flammable trimethyl orthoformate is used, there are problems in safety production. Great hidden danger, so the vast majority of domestic enterprises have switched to cheap ammonia or ammonia water as raw materials for the corresponding ammonolysis reaction
Yet utilize ammonia or ammoniacal liquor to carry out ammonolysis reaction in actual production process and all can produce a common impurity as shown in formula 2, especially in the apixaban crude product that uses ammoniacal liquor to react and obtain, this impurity occupancy can be as high as 10 More than %, it will bring great pressure to the follow-up purification work
[0006] In the prior art, the follow-up purification usually directly uses a single organic solvent for recrystallization, but this method has defects: the amount of solvent is extremely large, for example, methanol is used as the solvent, and under the state of methanol reflux, the amount of methanol is very large, which needs to be used about 50 times The solvent amount of the compound shown in the formula 1; another example is to use acetonitrile as a solvent, under the reflux state of acetonitrile, the amount of acetonitrile is about 60 times the solvent amount of the compound shown in the formula 1; thereby greatly increasing the production cost , reducing equipment productivity
[0007] Therefore, the current method of purifying the compound shown in formula 1 still needs to be improved

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0069] Take a 250ml one-mouth bottle, add 10g of crude apixaban (95.4% purity) and 80ml of ethylene glycol solution containing 10% ammonia, heat to 90°C to dissolve, then add 80ml of water to cool down at 40-50°C and stir for 2 hours , cooled to 0 ~ 10 ℃. Then it was filtered and dried to obtain 8.9 g of off-white solid with a yield of 89% and a HPLC purity of 99.97%.

[0070] Spectral data:

[0071] EI-MS (m / z): 460.2;

[0072] 1 H-NMR (500MHz, CDCl 3 , ppm), δ: 7.49(d, J=8.8Hz, 2H), 7.36(d, J=8.8Hz, 2H), 7.27(d, J=8.8Hz, 2H), 6.95(d, J=8.8Hz , 2H), 6.88(br, 1H), 5.59(br, 2H), 4.13(t, J=6.6Hz, 2H), 3.84(s, 3H), 3.61~3.60(m, 2H), 3.39(t, J=6.8Hz, 2H), 2.57(t, J=5.6Hz, 2H), 1.94~1.96(m, 4H).

Embodiment 2

[0074] Take a 250ml single-necked bottle, add 10g of apixaban crude product (95.4% purity) and 160ml of ethylene glycol solution containing 5% triethylamine, heat to dissolve, then add 100ml of water to cool down and stir at 40-50°C for 2 Hours, cool down to 0-10°C. Then it was filtered and dried to obtain 8.5 g of off-white solid with a yield of 85% and a purity of 99.96% by HPLC.

Embodiment 3

[0076] Take a 250ml single-necked bottle, add 10g of apixaban crude product (purity is 95.4%) and 100ml of methanol solution containing 20% ​​ammonia, heat to dissolve, then add 40ml of water to cool down, stir at 40-50°C for 2 hours, cool to 0~10℃. Then it was filtered and dried to obtain 8.6 g of off-white solid with a yield of 86% and a purity of 99.95% by HPLC.

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Abstract

The invention provides a method for purifying a compound as shown in a formula 1. The method comprises the following step of enabling an alkali and alcohol mixed solution to come into contact with the compound as shown in the formula 1. When the method is utilized, the compound as shown in the formula I can be efficiently purified.

Description

technical field [0001] The present invention relates to the field of chemical synthesis, in particular, the present invention relates to a method for purifying the compound represented by formula 1. Background technique [0002] Apixaban (Apixaban, the compound shown in formula I) belongs to aminobenzoxazole compounds, is a kind of highly selective, reversible thrombin factor Xa inhibitor, so this drug still has a relatively large role in the treatment of advanced thrombosis. Good curative effect. Compared with heparin and warfarin in terms of safety, the total bleeding rate of apixaban is significantly lower. [0003] Apixaban was superior to aspirin in preventing embolic events, including stroke; compared with warfarin, the drug resulted in a 21% reduction in stroke or systemic embolism, an 11% reduction in mortality, and a 31% reduction in major bleeding. Apixaban is more effective than enoxaparin in preventing venous thromboembolism in patients after knee arthroplasty,...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 胡名龙吴豪豪崔健钱丽娜
Owner WATERSTONE PHARMA WUHAN
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