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Polymorph of ALK tyrosine kinase inhibitor and preparation method thereof

A polymorph, isopropyl technology, applied in the polymorph field of pharmaceutical compounds, can solve the problem of drug dissolution rate, different binding force of crystal particles, influence of drug fluidity, particle uniformity, content uniformity and physical stability sexual issues

Inactive Publication Date: 2018-08-28
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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  • Polymorph of ALK tyrosine kinase inhibitor and preparation method thereof
  • Polymorph of ALK tyrosine kinase inhibitor and preparation method thereof
  • Polymorph of ALK tyrosine kinase inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1, N-isopropyl-2-(2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline)-6 , 7-dihydro-5H-pyrrole [2,3-d] pyrimidin-4-ylamine) preparation of benzenesulfonamide polymorph A

[0062] Compound N-isopropyl-2-(2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline)-6,7 -Dihydro-5H-pyrrole[2,3-d]pyrimidin-4-ylamine)benzenesulfonamide (2.0g, 3.15mmol) and N,N-dimethylformamide (10mL) were added to a 50mL three-necked flask heated to 100-105°C, all the solids were dissolved, suction filtered while it was hot, the filtrate was added to a 100mL three-neck flask, heated to 100°C, and isopropanol (30mL) was added dropwise. crystal, filtered, and vacuum dried at 45°C overnight to obtain 1.57 g of a yellow solid, yield: 78.5%.

[0063] HPLC test purity 99.28%.

[0064] DSC detection chart (initial temperature 25°C, end temperature 250°C, heating rate 10°C / min) such as Figure 8 shown.

Embodiment 2

[0065] Example 2, N-isopropyl-2-(2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline)-6 , 7-dihydro-5H-pyrrole [2,3-d] pyrimidin-4-ylamine) preparation of benzenesulfonamide polymorph B

[0066] Compound N-isopropyl-2-(2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline)-6,7 -Dihydro-5H-pyrrole[2,3-d]pyrimidin-4-ylamine)benzenesulfonamide (2.0g, 3.15mmol) and trifluoroethanol (10mL) were added in a 50mL three-necked flask, heated to reflux, Dissolve all the solids, filter while hot, add the filtrate to a 100mL three-necked flask, heat to 40-60°C, add ethanol (20mL) dropwise, after the dropwise addition, stir and crystallize at room temperature, filter with suction, and dry under vacuum at 45°C Overnight, 1.72 g of yellow solid was obtained, yield: 86.0%.

[0067] HPLC test purity 99.31%.

[0068] DSC detection chart (initial temperature 25°C, end temperature 250°C, heating rate 10°C / min)) such as Figure 9 shown.

Embodiment 3

[0069] Example 3, N-isopropyl-2-(2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline)-6 , Preparation of 7-dihydro-5H-pyrrole [2,3-d] pyrimidin-4-ylamine) benzenesulfonamide polymorph C

[0070] Compound N-isopropyl-2-(2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline)-6,7 -Dihydro-5H-pyrrole[2,3-d]pyrimidin-4-ylamine)benzenesulfonamide (2.0g, 3.15mmol) and trifluoroethanol (10mL) were added in a 50mL three-necked flask, heated to reflux, All the solids were dissolved, and suction filtered while it was hot. The filtrate was added to a 100mL three-neck flask, heated to 40-60°C, and isopropanol (20mL) was added dropwise. After the dropwise addition, stirred and crystallized at room temperature, suction filtered, After vacuum drying overnight, 1.75 g of a yellow solid was obtained, yield: 87.5%.

[0071] HPLC test purity 99.23%.

[0072] DSC detection chart (initial temperature 25°C, end temperature 250°C, heating rate 10°C / min) such as Figure 10 ...

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Abstract

The invention relates to a polymorph of N-isopropyl-2-(2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-ylamine)benzenesulfonamide as described in the specification and a preparation method thereof.

Description

technical field [0001] The present invention relates to polymorphic forms of pharmaceutical compounds, in particular to N-isopropyl-2-(2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine- Polymorphs of 1-yl)aniline)-6,7-dihydro-5H-pyrrole[2,3-d]pyrimidin-4-ylamine)benzenesulfonamide and a preparation method thereof. Background technique [0002] N-isopropyl-2-(2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline)-6,7-di Hydrogen-5H-pyrrole[2,3-d]pyrimidin-4-ylamine)benzenesulfonamide is a highly selective small molecule ALK tyrosine kinase inhibitor with nanomolar levels of ALK tyrosine kinase at the cellular level The inhibitory effect of the intensity of the action has a complete inhibitory effect on the tumor growth of non-small cell lung cancer and lymphoma caused by abnormally high expression of ALK (anaplastic lymphoma kinase) fusion protein in animals, and N-isopropyl-2- (2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline)-6,7-dihydro-5H-p...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07B2200/13C07D487/04
Inventor 张传玉杨利民冀冲孙德广张晓军韩军儒
Owner SHOUYAO HLDG BEIJING CO LTD
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