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Crystal form B of Apixaban and preparation method thereof

A technology of apixaban and crystal form, applied in the direction of organic chemistry and the like, can solve the problems of complex preparation process of apixaban, high equipment requirements, great influence on preparation quality, etc., and achieves easy industrial production, simple preparation method, The effect of facilitating the transformation of crystal forms

Inactive Publication Date: 2014-06-04
CHONGQING TOPTECH PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It can be seen that the preparation process of the above-mentioned crystal form of apixaban is complex and requires high equipment, especially the particle size control of micronization has a great impact on the quality of the preparation

Method used

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  • Crystal form B of Apixaban and preparation method thereof
  • Crystal form B of Apixaban and preparation method thereof
  • Crystal form B of Apixaban and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Put compound A (10g) into a 1L reaction flask, add chloroform (600ml) and formamide (100g), stir and heat to reflux, add trimethyl orthoformate (1.5g) and trifluoroacetic acid (0.5g), The mixture was stirred for an additional 30 minutes, cooling below 50°C. A methanol solution (9 g) of sodium methoxide was added, and the reaction was determined to be complete by HPLC. Then, 200 ml of water was added, and the mixture was stirred and separated. The organic layer was concentrated under reduced pressure, 70% of the solvent was removed, cooled to 0°C for crystallization, suction filtered, and dried to obtain 7.3 g of apixaban B crystal form product, with a yield of 77.6%.

Embodiment 2

[0037] Put compound A (5g) into a 1L reaction flask, add toluene (600ml) and formamide (100g), stir and heat to reflux, add trimethyl orthoformate (1.5g) and trifluoroacetic acid (0.5g), the The mixture was stirred for an additional 30 minutes, dropping below 50°C. A methanol solution (5 g) of sodium methoxide was added, and the reaction was determined to be complete by HPLC, and 200 ml of water was added, and the mixture was stirred and separated. The organic layer was concentrated under reduced pressure, 70% of the solvent was removed, cooled to 0°C for crystallization, suction filtered, and dried to obtain 3.5 g of apixaban B crystal form product, with a yield of 74.4%.

Embodiment 3

[0039] Put compound A (10g) into a 1L reaction flask, add tetrahydrofuran (300ml), ethyl acetate (300ml) and formamide (100g), stir and heat to reflux, add trimethyl orthoformate (1.5g) and trifluoroacetic acid (0.5 g), the mixture was stirred for an additional 30 minutes, cooling to below 50°C. A methanol solution (10 g) of sodium methoxide was added, and the reaction was confirmed to be complete by HPLC. Then, 200 ml of water was added, and the mixture was stirred and separated. The organic layer was concentrated under reduced pressure, 70% of the solvent was removed, cooled to 0°C for crystallization, suction filtered, and dried to obtain 6.3 g of apixaban B crystal form product, with a yield of 67%.

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Abstract

The invention relates to a crystal form B of 4, 5, 6, 7-tetrahydro-1-(4-methoyxl phenyl)-7-oxo-6-[4-(2-oxo-1-piperidyl) phenyl]-1H-pyrazolo[3,4] pyridine-3-formamide (apixaban). The X-powder diffraction pattern of the crystal form is shown in the figure. The crystal form is good in solubleness and can be prepared into a formulation which is qualified to dissolve out without controlling the granularity in a micronizing manner. Meanwhile, the invention further provides two methods for preparing the crystal form. One method comprises the following step: carrying out ammonolysis on ester groups of a compound A under the effect of formamide and sodium alkoxide under a proper organic solvent condition to obtain crystal form B of Apixaban. The preparation method is simple and convenient and easy to amplify for industrialized production. The other method comprises the step of obtaining the crystal form B of apixaban by a non-crystal form B apixaban product by way of dissolution and crystallization, so that the crystal form is convenient to convert.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, in particular to 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1 A new crystal form B of -piperidinyl)phenyl]-1H-pyrazolo[3,4-C]pyridine-3-carboxamide and two different preparation methods thereof. Background technique [0002] Apixaban (Apixaban, BMS-562247), chemical name 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2 -Oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-C]pyridine-3-carboxamide, the structural formula is as follows: [0003] [0004] Apixaban is a potent, orally active, reversible, direct, and highly selective factor Xa active site inhibitor with antithrombotic activity independent of antithrombin III. Apixaban inhibits free and thrombus-bound factor Xa and inhibits prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits thrombin-induced platelet aggregation. Through inhibition of factor Xa, a...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 陈捷杜昌勇梁杰刘学国沈君伟袁永勃钟志李斌陈小勇
Owner CHONGQING TOPTECH PHARMA TECH
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