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Crystal form of pyridylaminopyrimidine derivative and preparation method thereof

A crystal form and amine-based technology, applied in the field of medicinal chemistry, can solve the problems of different solubility, density, stability and hygroscopicity, which affect the quality stability of raw materials and preparations, clinical efficacy and safety, etc., and achieve simple preparation process , good stability and good repeatability

Inactive Publication Date: 2019-12-24
SHANGHAI ALLIST PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The crystal form has a certain influence on the physical and chemical properties of the compound. For pharmaceutical compounds with multiple crystal forms, different crystal forms may have different appearances such as color and shape, and certain physical and chemical properties such as melting point and solubility. , density, stability, hygroscopicity, etc. will also be different, which will lead to different dissolution and absorption behaviors in the body, which will affect the quality stability, clinical efficacy and safety of raw materials and preparations to a certain extent

Method used

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  • Crystal form of pyridylaminopyrimidine derivative and preparation method thereof
  • Crystal form of pyridylaminopyrimidine derivative and preparation method thereof
  • Crystal form of pyridylaminopyrimidine derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment 1 Preparation of crystal form of compound of formula (I)

[0056] Add formula (I) compound N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethane) to a 250mL three-necked flask Oxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide 10.0g, add acetone 140mL, magnetic Stir, protect with argon, heat up in an oil bath to 50-56°C to completely dissolve the solid, continue to keep warm and stir for 20 minutes after dissolving, then add 70mL of n-heptane dropwise over 40 minutes, and naturally cool down to 38°C in the oil bath , and crystallized at 38°C for 30 minutes, then naturally cooled to 20°C in an oil bath and continued to stir and crystallize for 1 hour, filtered with suction, rinsed with n-heptane, dried in a vacuum oven at 50°C for 48 hours, and weighed to obtain the formula ( I) Compound crystal form 6.38g, yield 63.8%.

[0057] Its XRPD spectrum, DSC spectrum, TGA spectrum are respectively as follows figure 1 , ...

Embodiment 2

[0060] Embodiment 2 Preparation of crystal form of compound of formula (I)

[0061] Add formula (I) compound N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethane) to a 100mL three-necked flask Oxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide 3.0g, add tetrahydrofuran 15mL, magnetic Stir, protect with argon, heat up to 40-45°C in an oil bath to completely dissolve the solid, keep stirring for 10 minutes after dissolution, then add 30 mL of n-heptane dropwise over 15 minutes, keep warm and crystallize at 40-45°C After 18 hours, the temperature was naturally lowered to 20°C in an oil bath and continued to stir and crystallize for 2 hours, then suction filtered and rinsed with n-heptane. It was dried in a vacuum oven at 50° C. for 48 hours, weighed 2.67 g, and the yield was 89%. Its XRPD, DSC, and TGA spectra are basically consistent with the results of Example 1.

Embodiment 3

[0062] Embodiment 3 Preparation of crystal form of compound of formula (I)

[0063] Add formula (I) compound N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethane) to a 250mL three-necked flask Oxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide 10.0g, add tetrahydrofuran 50mL, magnetic Stir, protect with argon, heat up to 40-45°C in an oil bath to completely dissolve the solid, continue to heat and stir for 15 minutes after dissolving, then add 150mL of methyl tert-butyl ether dropwise over 2 hours, at 40-45°C Insulated and crystallized for 18 hours, then naturally cooled to 20°C in an oil bath and continued to stir and crystallize for 2 hours, filtered with suction, and rinsed with methyl tert-butyl ether. Dry in a vacuum oven at 50° C. for 48 hours, weigh 6.3 g, and yield 63%. Its XRPD, DSC, and TGA spectra are basically consistent with the results of Example 1.

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Abstract

The invention discloses a crystal form of N-{2-{[2-(dimethylamino)ethyl](methyl)amido}-6-(2,2,2-trifluoroethoxy)-5-{[4-(1-methyl-1H-indole-3-yl)pyrimidine-2-yl]amido}pyridine-3-yl}acrylamide as well as a preparation method and an application thereof, wherein the X-ray powder diffraction pattern of the crystal form has characteristic peaks when diffraction angles 2[theta] are 6.5 + / -0.2 degrees, 8.2 + / -0.2 degrees, 9.8 + / -0.2 degrees, 11.9 + / -0.2 degrees, 16.4 + / -0.2 degrees, 17.2 + / -0.2 degrees, 19.6 + / -0.2 degrees and 20.3 + / -0.2 degrees. The crystal form is good in stability, simple in preparation method, good in repeatability and suitable for industrial production.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy A crystal form of )-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide and a preparation method thereof. Background technique [0002] The compound N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy)- 5-{[4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide is an epidermal growth factor receptor (EGFR) inhibitor, Its inhibitory activity against EGFR T790M drug-resistant mutations is significantly higher than that of wild-type EGFR (WT EGFR), has good selectivity, and has low toxic and side effects. It can be used to treat cancer, especially non-small cell lung cancer. It is in the clinical stage in China. [0003] [0004] Patent applications CN105315259A, CN107163026A, etc. disclose the compound of formula (I) and its preparation meth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/506A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07B2200/13C07D401/14A61K31/506
Inventor 张强罗会兵
Owner SHANGHAI ALLIST PHARM CO LTD
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