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Refining method for apixaban

A purification method and apixaban technology, applied in the purification field of apixaban, can solve the problems of complicated operation, poor solubility, waste of energy and the like, and achieve the effects of low dissolution temperature, simple operation and high yield

Active Publication Date: 2017-03-22
LEPU PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In this route, apixaban acid often exists in crude apixaban as an impurity, and it is difficult to completely remove it due to its structural similarity with apixaban
The solubility of apixaban in a single solvent is not good, and the general refining operation requires the method of heating, dissolving and crystallizing. Even if repeated refining is performed, it is easy to cause the residue of apixaban acid to exceed the standard, which is not only cumbersome to operate, but also wastes energy. , not conducive to industrial production

Method used

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  • Refining method for apixaban
  • Refining method for apixaban
  • Refining method for apixaban

Examples

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Embodiment 1

[0020] A method for refining Apixaban, the specific steps are as follows:

[0021] Add 14kg of dichloromethane to the 50L reaction kettle, start stirring, add 1.4kg of crude apixaban, then add 14kg of methanol, stir for 30 minutes until completely dissolved, filter out insolubles if necessary; put 2.5kg of 3wt% sodium hydroxide Add the solution into the reaction kettle, stir for 1 hour, and let stand to separate the liquid; transfer the organic layer into a 50L reaction kettle, start stirring, slowly add 28kg of n-hexane, mix well, leave it under natural conditions for 4 hours to precipitate solids, and filter; The solid was air-dried at 60° C. for 8 hours to obtain 1.3 kg of fine apixaban product. HPLC: 99.92%, Apixabanic acid 0%, H 1 NMR (d6-DMSO δ: 7.71(br, 1H), 7.51(m, 2H), 7.43(br, 1H), 7.35(m, 2H), 7.28(m, 2H), 7.00(m, 2H), 4.06 (m,2H), 3.79(s,3H), 3.58(m,2H), 3.20(m,2H), 2.39(m,2H), 1.83(m,4H).

Embodiment 2

[0023] A method for refining Apixaban, the specific steps are as follows:

[0024] At 25°C, add 25kg of dichloromethane into the 50L reaction kettle, start stirring, add 1.8kg of crude apixaban, then add 15kg of methanol, stir for 30 minutes until completely dissolved, filter out insolubles if necessary; put 6.2kg Add 3wt% sodium hydroxide solution into the reaction kettle, stir for 1 hour, let stand to separate the liquid; transfer the organic layer into a 50L reaction kettle, start stirring, slowly add 28kg cyclohexane, mix well, and place it under natural conditions for 4 hours The solid was precipitated and filtered; the solid was air-dried at 60° C. for 8 hours to obtain 1.6 kg of fine apixaban product. HPLC: 99.91%, Apixabanic acid: 0%.

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Abstract

A refining method for apixaban comprises the following steps: 1) dissolving an apixaban crude product in a mixed solvent of dichloromethane and methanol, to obtain an apixaban solution; 2) adding a sodium hydroxide solution, stirring and washing the apixaban solution of the step 1), and then separating to obtain an organic layer; and 3) adding n-hexane to the organic layer of the step 2) under stirring, mixing evenly, placing to separate out a solid under natural conditions, filtering, and drying to obtain refined apixaban. The refined apixaban obtained by the refining method is from white to off-white in color, and has the advantages of high quality and high yield; the method has low required dissolution temperature, has simple operation, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of pharmacy and chemical industry, and in particular relates to a method for refining apixaban. Background technique [0002] Apixaban, chemical name: 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5, 6,7-tetrahydro-1H-pyrazol[3,4-c]-pyridine-3-carboxamide, CAS: 503612-47-3, structure: [0003] [0004] Apixaban is an anticoagulant drug jointly declared by Pfizer and Bristol-Myers Squibb. It has an important clinical effect on the prevention of venous thromboembolism in patients after hip or knee replacement. It may also be used to prevent stroke risk in patients with atrial fibrillation. Apixaban was launched in the European Union and the United States in 2011 and 2012, respectively. [0005] At present, the preparation methods of apixaban and similar methods reported in the literature include: WO2007001385A2, WO03026652A1, WO0039131A1, and their routes are summarized as follows: [0006] [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 刘志康郜慧芳孙冬梅王庆鹏
Owner LEPU PHARMACEUTICAL CO LTD
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