A kind of crystalline form and preparation method of btk kinase inhibitor

A crystallization and organic solvent technology, applied in the field of crystallization and preparation of BTK kinase inhibitors, can solve the problems of poor stability of amorphous and I crystal forms, and achieve repeatable and controllable production process, stable production process, The effect of good crystal stability

Active Publication Date: 2021-09-03
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patented new chemicals are very well-stable even at low temperatures or when exposed to water vapor during manufacturing processes. These small particles help with better quality control over their final product's properties such as size distribution, surface smoothness, strength, moisture content, solubility, bioavailability, and shelf life.

Problems solved by technology

This patented technical problem addressed in this Patents describes how to develop stable and effective drugs that can specifically block certain types of cancer called B Cell Lung Cancer (BLCLCs).

Method used

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  • A kind of crystalline form and preparation method of btk kinase inhibitor
  • A kind of crystalline form and preparation method of btk kinase inhibitor
  • A kind of crystalline form and preparation method of btk kinase inhibitor

Examples

Experimental program
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Embodiment 1

[0039] The compound (i) shown in Formula (I) (prepared in WO 2016 / 007185) was added to 100 mL of a single mouth bottle, and 50 ml of acetonitrile was added, and heated to all dissolved, cooling crystallization, stirring overnight. The next day, filtration, dried solid 4.03 g, and the yield was 80.6%. X-ray diffraction of this crystalline sample image 3Among them, in about 4.64 (19.04), 5.18 (17.05), 5.62 (15.71), 10.84 (8.5), 11.13 (7.94), 11.43 (7.74), 12.21 (7.24), 12.87 (6.87), 14.03 (6.31), 14.47 (6.12), 14.8 (5.37), 17.78 (4.53), 17.78 (4.98), 18.4 (4.82), 19.60 (4.53), 20.47 (4.34), 21.31 (4.17), 24.16 (3.68), 25.13 (3.54), 26.87 (3.32) and 28.50 (3.13) are characterized at a feature. DSC spectrum Figure 4 There is a molten heat absorbing peak near 165 ° C, which is defined as the II crystal form.

Embodiment 2

[0041] The compounds (I) were taken from the compound of formula (I) (prepared according to the method disclosed in WO 2016 / 007185) in a 25 ml single-mouth bottle, and 2 mL of ethanol was added, heated, dissolved, cooling crystallization, stirring overnight. The next day, filtration was filtered, and the solid was dried 241 mg, and the yield was 80.3%. X-ray diffraction of this crystalline sample Figure 5 It is from about 4.29 (20.56), 6.58 (13.42), 7.58 (11.66), 10.7 (8.7.68 (7.57), 12.49 (7.08), 13.74 (6.44), 14.12 (6.26), 15.86 (5.58) and 19.98 (4.44) have a characteristic peak. DSC spectrum Image 6 There is a molten heat absorbing peak near 141 ° C, which is defined as the I crystalline form.

Embodiment 3

[0043] The compound (prepared according to Example 2) was taken from 200 mg of the formula (I), and 2 ml of acetonitrile was added, stirred overnight. The next day, filtration was filtered, and the solid was dried 172 mg, and the yield was 86.0%. The X-ray diffraction and DSC map of the crystalline sample were determined to be a crystalline form.

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Abstract

The invention relates to a crystalline form and a preparation method of a BTK kinase inhibitor. In particular, the present invention relates to (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1 , Type II crystal of 6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (compound of formula (I)) and its preparation method. The type II crystal of the compound of formula (I) obtained in the present invention has good chemical stability and crystal form stability, and the crystallization solvent used has low toxicity and low residue, and can be better used in clinical treatment.

Description

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Claims

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Application Information

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Owner JIANGSU HENGRUI MEDICINE CO LTD
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