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Method for removing BMS-591329 impurities from Apixaban raw medicine

A technology of BMS-591329 and apixaban, applied in the field of synthesis of chemical raw materials

Inactive Publication Date: 2018-06-08
HEBEI CHANGSHAN BIOCHEM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The invention provides a method for removing the specific impurity BMS-591329 in apixaban raw material medicine, so as to solve the problems existing in the prior art

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Example 1: After adding 10ml of absolute ethanol and 10ml of dichloromethane into a 250ml glass reaction bottle, add 1g of apixaban crude drug, stir and dissolve at room temperature, then add 15ml of 30% hydrogen peroxide to the above solution, and Stir the reaction. After 1 hour of reaction, add 20-40ml of water. After stirring for 1-1.5 hours, the product formed by impurities enters the water phase, collects the organic phase, and then evaporates the solvent in the organic phase to dryness to obtain the fine product of apixaban.

Embodiment 2

[0014] Example 2: The difference between this example and Example 1 is that the volume of the mixed solvent of absolute ethanol and dichloromethane is increased to 40 times the mass of the bulk drug of apixaban. After adding 20ml of absolute ethanol and 20ml of dichloromethane into a 250ml glass reaction bottle, add 1g of apixaban crude drug, stir at room temperature to dissolve, then add 15ml of 30% hydrogen peroxide to the above solution, and stir at room temperature for reaction. After 1 hour, add 20-40 ml of water, stir for 1-1.5 hours, and then the product formed by impurities enters the water phase, collects the organic phase, and then evaporates the solvent in the organic phase to dryness to obtain the refined product of apixaban.

Embodiment 3

[0015] Embodiment 3: The difference between this embodiment and Embodiment 1 is that the volume ratio of absolute ethanol to dichloromethane is 1:5. After adding 10ml of absolute ethanol and 15ml of dichloromethane into a 250ml glass reaction bottle, add 1g of apixaban raw material drug, stir at room temperature to dissolve, then add 15ml of 30% hydrogen peroxide to the above solution, and stir at room temperature for reaction. After 1 hour, add 20-40 ml of water, stir for 1-1.5 hours, and then the product formed by the impurities enters the water phase, collects the organic phase, and then evaporates the solvent in the organic phase to dryness to obtain the refined product of apixaban.

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PUM

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Abstract

The invention discloses a method for removing BMS-591329 impurities from an Apixaban raw medicine. The method is characterized by comprising the following steps: mixing the Apixaban raw medicine and amixed solvent of absolute ethanol and dichloromethane according to the mass volume ratio of 1:20 to 1:40, and stirring and performing dissolved classification at room temperature, wherein the volumeratio of the absolute ethanol to the dichloromethane in the mixed solvent is 1:1 to 1:5; adding hydrogen peroxide of 30 percent in the solution and performing stirring reaction at room temperature, wherein the volume of the hydrogen peroxide of 30 percent is 15 to 30 times the mass of the Apixaban raw medicine; and after reacting for 1 to 4 hours, adding water and stirring, collecting organic phases after stirring for 1 to 1.5 hours and evaporating the organic phases to dryness. By a method of performing hydrogen peroxide oxidation by the Apixaban raw medicine, the specific impurities BMS-591329 generated in the reaction process are removed.

Description

technical field [0001] The invention belongs to the technical field of synthesis of chemical raw materials, in particular to a method for removing impurities of BMS-591329 in apixaban raw materials. Background technique [0002] In the synthetic process of Apixaban API, the impurity 1-(4-chlorophenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl ]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-C]pyridine-3-carboxamide (impurity BMS-591329), due to the structure and solubility of the impurity and apixaban The bulk drug is very similar, and the impurity is difficult to completely remove by conventional purification methods such as recrystallization, and the impurity remains in the final product of the bulk drug of apixaban, which has an adverse effect on the quality of the bulk drug. Therefore, it is very necessary to adopt necessary methods to remove the above-mentioned impurity BMS-591329 during the synthesis of apixaban bulk drug. Contents of the invention [0003] The invention provides...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 贾玉涛魏微李志永戚亦宁高树华白文举
Owner HEBEI CHANGSHAN BIOCHEM PHARMA