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Crystal form and preparation method of a pyrazoloheteroaryl derivative

A technology of crystal form and crystallization, which can be used in organic chemical methods, medical preparations containing active ingredients, drug combinations, etc., and can solve problems such as poor fluidity, poor product stability, and easy agglomeration.

Active Publication Date: 2021-09-03
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally speaking, amorphous pharmaceutical products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, poor fluidity, etc.

Method used

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  • Crystal form and preparation method of a pyrazoloheteroaryl derivative
  • Crystal form and preparation method of a pyrazoloheteroaryl derivative
  • Crystal form and preparation method of a pyrazoloheteroaryl derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Embodiment 1, the preparation of A crystal form

[0120] Crude compound 1f (37.9 g, 99.6 mmol) was added to 379 mL of trifluoroacetic acid, protected by argon replacement, 8.6 mL of concentrated sulfuric acid was added dropwise, heated to 80° C., and stirred until the reaction was complete. The reaction solution was concentrated under reduced pressure, 700 mL of dichloromethane was added to the resulting residue, and saturated sodium bicarbonate solution was added dropwise until the pH of the reaction solution was 7-8. Wash once each with saturated sodium bicarbonate solution and 500 mL saturated saline, dry with anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure, and purify the obtained product by silica gel column chromatography with eluent system (dichloromethane / methanol) As a residue, the title product 1 was obtained (10 g, yield: 26.4%).

[0121] Detected by X-ray powder diffraction, the product is defined as...

Embodiment 2

[0125] Embodiment 2, the preparation of B crystal form

[0126] The compound represented by formula (I) (500 mg, 1.31 mmol) was dissolved in 5 mL of acetonitrile, heated to 80° C. and stirred for 30 minutes, filtered to remove insoluble matter, and the filtrate was naturally lowered to room temperature and stirred for 72 hours. The reaction solution was filtered, and the filter cake was collected and dried in vacuo to obtain the title product (400 mg, yield: 80%).

[0127] Through X-ray powder diffraction detection, the product is defined as crystal form B, and the XRPD spectrum is as follows: image 3 shown.

[0128] Table 2. Characteristic peaks of crystal form B

[0129]

[0130]

[0131] DSC spectrum such as Figure 4 As shown, it shows that the melting endothermic peak begins to appear at about 114.14°C, and the peak value is 115.83°C.

[0132] TGA spectrum such as Figure 5 As shown, it is anhydrous ansolvate.

[0133] DVS spectrum such as Figure 6 As shown...

Embodiment 3

[0134] Embodiment 3, the preparation of B crystal form

[0135] The compound represented by formula (I) (304 mg, 0.80 mmol) was dissolved in 3 mL of isopropyl acetate, heated to 80° C. and stirred for 30 minutes, filtered to remove insoluble matter, and the filtrate was naturally lowered to room temperature and stirred for 16 hours. The reaction solution was filtered, the filter cake was collected, and dried in vacuo to obtain the title product (200 mg, yield: 66%), which was found to be crystal form B by X-powder diffraction detection.

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PUM

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Abstract

The invention relates to a crystal form and a preparation method of pyrazolo heteroaryl derivatives. In particular, the present invention relates to A of 6-butoxy-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Crystal form, B crystal form, C crystal form, D crystal form, E crystal form, F crystal form, G crystal form, H crystal form and preparation methods thereof. The crystal form of the compound of formula (I) of the present invention has good crystal form stability, and can be better used in clinical treatment,

Description

technical field [0001] The present invention relates to crystal form A of 6-butoxy-1-(4-(pyrrolidin-1-ylmethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, B crystal form, C crystal form, D crystal form, E crystal form, F crystal form, G crystal form, H crystal form and preparation methods thereof. Background technique [0002] Toll-like receptors (toll-like receptors; TLRs) are an important class of protein molecules involved in innate immunity. TLRs are monomeric transmembrane non-catalytic receptors, usually expressed in sentinel cells such as macrophages and dendritic cells, which can recognize structurally conserved molecules produced by microorganisms. Once these microbes break through a physical barrier such as the skin or intestinal mucosa, they are recognized by TLRs, which in turn activate an immune cell response. (Mahla, RS. et al., Front Immunol. 4:248 (2013)). The ability of the immune system to widely recognize pathogenic microorganisms is partly due to the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61P31/12A61P31/14A61P31/18A61P31/20A61P31/16A61P35/00A61P11/00A61P11/06A61P1/16A61P1/04A61P1/00
CPCA61P1/00A61P1/04A61P1/16A61P11/00A61P11/06A61P31/12A61P31/14A61P31/16A61P31/18A61P31/20A61P35/00C07B2200/13C07D487/04
Inventor 杨式波尤凌峰冯君贺峰
Owner JIANGSU HENGRUI MEDICINE CO LTD
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