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BTK inhibitor polymorph and preparation method thereof

A polymorph, crystal form technology, applied in the direction of organic chemistry, organic chemistry, etc., can solve the problem of different binding force of crystalline particles, affecting drug dissolution rate, affecting drug fluidity, particle uniformity, content uniformity and physical stability. issues of sex

Inactive Publication Date: 2018-09-25
SHOUYAO HLDG BEIJING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Different crystal forms affect the dissolution rate of drugs, and the difference in surface free energy of different crystal forms will cause different binding forces between crystal particles, which will affect the fluidity, particle uniformity, content uniformity and physical stability of drugs

Method used

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  • BTK inhibitor polymorph and preparation method thereof
  • BTK inhibitor polymorph and preparation method thereof
  • BTK inhibitor polymorph and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1, (R, E)-5-amino-1-(1-(4-methoxybut-2-enonyl)pyrrol-3-yl)-3-(4-phenoxyphenyl ) Preparation of -1H-pyrazole-4-amide polymorph A

[0041] The compound (R, E)-5-amino-1-(1-(4-methoxybut-2-enonyl)pyrrol-3-yl)-3-(4-phenoxyphenyl)- 1H-Pyrazole-4-amide (55.0g), ethyl acetate (200mL) and dichloromethane (10mL) were added to a 1000mL single-necked flask, heated to 85°C, all solids were dissolved, filtered while hot, and the filtrate was added to Put it into another 1000mL single-necked flask, cool to room temperature, slowly stir and crystallize, filter, and vacuum dry at 50°C overnight to obtain 40.8g of off-white solid, yield: 74.2%.

[0042] DSC detection chart (initial temperature 25°C, end temperature 250°C, heating rate 10°C / min) such as Image 6 shown.

Embodiment 2

[0043]Example 2, (R, E)-5-amino-1-(1-(4-methoxybut-2-enonyl)pyrrol-3-yl)-3-(4-phenoxyphenyl )-1H-pyrazole-4-amide polymorph B preparation

[0044] The compound (R, E)-5-amino-1-(1-(4-methoxybut-2-enonyl)pyrrol-3-yl)-3-(4-phenoxyphenyl)- 1H-pyrazole-4-amide (polymorphic form A: 10.5g) and purified water (20mL) were added to a 50mL single-necked flask, heated to 50°C, stirred for 4 days, suction filtered, and vacuum-dried overnight at 50°C. 10.2 g of off-white solid was obtained, yield: 97.0%.

[0045] DSC detection chart (initial temperature 25°C, end temperature 250°C, heating rate 10°C / min)) such as Figure 7 shown.

Embodiment 3

[0046] Example 3, (R, E)-5-amino-1-(1-(4-methoxybut-2-enonyl)pyrrol-3-yl)-3-(4-phenoxyphenyl ) Preparation of -1H-pyrazole-4-amide polymorph C

[0047] The compound (R, E)-5-amino-1-(1-(4-methoxybut-2-enonyl)pyrrol-3-yl)-3-(4-phenoxyphenyl)- 1H-Pyrazole-4-amide (15.0g) and ethyl acetate (100mL) were added to a 500mL single-necked flask, heated to reflux, all the solids were dissolved, filtered while hot, and the filtrate was added to another 500mL single-necked flask , cooled to room temperature, slowly stirred for crystallization, filtered, and vacuum-dried at 50° C. overnight to obtain 13.5 g of off-white solid, yield: 90.0%.

[0048] DSC detection chart (initial temperature 25°C, end temperature 250°C, heating rate 10°C / min) such as Figure 8 shown.

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Abstract

The present invention relates to a BTK inhibitor polymorph and a preparation method thereof. The structure formula of the BTK inhibitor polymorph is defined in the specification.

Description

technical field [0001] The present invention relates to polymorphic forms of pharmaceutical compounds, in particular to (R,E)-5-amino-1-(1-(4-methoxybut-2-enonyl)pyrrol-3-yl)-3- Polymorphs of (4-phenoxyphenyl)-1H-pyrazole-4-amide and methods for their preparation. Background technique [0002] (R, E)-5-amino-1-(1-(4-methoxybut-2-enonyl)pyrrol-3-yl)-3-(4-phenoxyphenyl)-1H- Pyrazole-4-amide is a highly selective irreversible small molecule Bruton's tyrosine kinase (BTK) inhibitor, which has nanomolar inhibitory effect on BTK at the cellular level, and has an abnormally high inhibitory effect on BTK in animals Expression resulted in complete inhibition of tumor growth in chronic lymphocytic leukemia and mantle cell lymphoma. The structural formula is as follows: [0003] [0004] The synthesis method of this compound is disclosed in WO2014082598, but it does not involve the crystal form of the compound, and there is no other literature report (R, E)-5-amino-1-(1-(4-methox...

Claims

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Application Information

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IPC IPC(8): C07D403/04
CPCC07B2200/13C07D403/04
Inventor 杨利民孙德广冀冲杨嘉铭张传玉张晓军刘洋健李毅
Owner SHOUYAO HLDG BEIJING CO LTD
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