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Polymorphs of isopropylsulfonylphenylpyrimidines or salts thereof

A technology of polymorphs and compounds, applied in the field of medicine, can solve problems affecting dissolution, absorption, clinical efficacy and safety of drugs, and no research on polymorphs of compounds of formula I

Active Publication Date: 2022-03-11
SUZHOU ZELGEN BIOPHARML +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Since different crystal forms and salt forms of drugs may affect their dissolution and absorption in the body, which may affect the clinical efficacy and safety of drugs to a certain extent, especially for some insoluble oral solid or semi-solid preparations, the crystal form the impact will be greater
At present, there is no research on the polymorphic form of the compound of formula I, and no polymorphic form of the compound of formula I has been developed

Method used

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  • Polymorphs of isopropylsulfonylphenylpyrimidines or salts thereof
  • Polymorphs of isopropylsulfonylphenylpyrimidines or salts thereof
  • Polymorphs of isopropylsulfonylphenylpyrimidines or salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0173] 5-Chloro-N 2 -(5-Methyl-4-(piperidin-4-yl)-2-((propan-2-yl-d 7 )oxy)phenyl)-N 4 -(2-((Propan-2-yl-d 7 ) Preparation of polymorph I of sulfonyl)phenyl)pyrimidine-2,4-diamine

[0174] In the 200L reactor, 5-chloro-N was added successively 2 -(5-Methyl-4-(piperidin-4-yl)-2-((propan-2-yl-d 7 )oxy)phenyl)-N 4 -(2-((Propan-2-yl-d 7 )sulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride (5.05 kg), acetone (21.0 kg) and purified water (7.2 kg). The temperature was raised to 55±5°C, and stirred at this temperature until the solid was dissolved. Purified water (15.0kg) and sodium hydroxide (0.93kg) were mixed, and the solution was stirred to prepare a sodium hydroxide solution. After the sodium hydroxide solution was filtered by pressure, it was added to the above kettle. After adding, keep stirring at 55±5°C, and then lower the temperature to 20±3°C. Purified water (38.0 kg) was slowly added, followed by stirring for 2±0.5 h. The obtained mixture was separated by cen...

Embodiment 2

[0183] 5-Chloro-N 2 -(5-Methyl-4-(piperidin-4-yl)-2-((propan-2-yl-d 7 )oxy)phenyl)-N 4 -(2-((Propan-2-yl-d 7 ) Preparation of polymorph I of sulfonyl)phenyl)pyrimidine-2,4-diamine

[0184] Take 7g of 5-chloro-N 2 -(5-Methyl-4-(piperidin-4-yl)-2-((propan-2-yl-d 7 )oxy)phenyl)-N 4 -(2-((Propan-2-yl-d 7 )sulfonyl)phenyl)pyrimidine-2,4-diamine dihydrochloride was added to the reaction flask, followed by adding 21 mL of a mixed solution (ethanol / water=3:1). The resulting mixture was heated to 55±3°C and stirred at this temperature until the solution was clear, then 25.4 g of aqueous sodium hydroxide solution (5.8% wt) was slowly added dropwise. After the addition, keep the temperature and continue to stir for 2 hours, then cool down to 20±3°C, then dropwise add water, and filter with suction after the addition. After the filter cake was washed with water three times, it was vacuum-dried to obtain a white solid, which weighed 5.6 g, and the yield was 90%. Its X-ray powder d...

Embodiment 3

[0186] 5-Chloro-N 2 -(5-Methyl-4-(piperidin-4-yl)-2-((propan-2-yl-d 7 )oxy)phenyl)-N 4 -(2-((Propan-2-yl-d 7 ) Preparation of polymorph I of sulfonyl)phenyl)pyrimidine-2,4-diamine

[0187] Take 500mg of 5-chloro-N 2 -(5-Methyl-4-(piperidin-4-yl)-2-((propan-2-yl-d 7 )oxy)phenyl)-N 4 -(2-((Propan-2-yl-d 7 )sulfonyl)phenyl)pyrimidine-2,4-diamine was added to the reaction flask, followed by 3 mL of ethanol and 1 mL of water. The obtained mixture was heated to 65°C, stirred and dissolved, and refluxed for 1 h; then 10 mL of water was added dropwise, a solid was precipitated, stirred for 0.5 h, then cooled to room temperature and filtered with suction. The filter cake was vacuum-dried to obtain a white solid, weighing 0.35 g, yield: 70%. Its X-ray powder diffraction pattern is Figure 1a same.

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Abstract

The invention provides a polymorphic form of isopropylsulfonylphenylpyrimidine compound or its salt, specifically, relates to 5-chloro-N 2 ‑(5‑Methyl‑4‑(piperidin‑4‑yl)‑2‑((propan‑2‑yl‑d 7 )oxy)phenyl)‑N 4 ‑(2‑((C‑2‑base‑d 7 )sulfonyl)phenyl)pyrimidine-2,4-diamine or a polymorphic form of its hydrochloride. The polymorphic form is convenient to process, suitable for making medicine, and suitable for preparing medicine or pharmaceutical composition for inhibiting tyrosine kinase (such as ALK kinase and ROS1 kinase).

Description

technical field [0001] The invention relates to the field of medicine, in particular to a kind of isopropylsulfonylphenylpyrimidine compound 5-chloro-N 2 -(5-Methyl-4-(piperidin-4-yl)-2-((propan-2-yl-d 7 )oxy)phenyl)-N 4 -(2-((Propan-2-yl-d 7 )sulfonyl)phenyl)pyrimidine-2,4-diamine or a polymorph of its hydrochloride salt. Background technique [0002] Compounds of formula I 5-chloro-N 2 -(5-Methyl-4-(piperidin-4-yl)-2-((propan-2-yl-d 7 )oxy)phenyl)-N 4 -(2-((Propan-2-yl-d 7 )sulfonyl)phenyl)pyrimidine-2,4-diamine (5-chloro-N 2 -(5-methyl-4-(pipidin-4-yl)-2-((propan-2-yl-d 7 )oxy)phenyl)-N 4 -(2-((propan-2-yl-d 7 )sulfonyl)phenyl)pyrimidine-2,4-diamine), the structure is as follows: [0003] [0004] The molecular formula of the compound of formula I is C 28 H 22 D 14 ClN 5 O 3 S, with a molecular weight of 572.22, is a class of tyrosine kinase (such as progressive lymphoma kinase (ALK) tyrosine kinase and ROS1 kinase) inhibitors, suitable for the preparat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12A61K31/506A61P35/00A61P35/02A61P29/00
CPCC07D401/12A61P35/00A61P35/02A61P29/00C07B2200/13
Inventor 吕彬华刘连军
Owner SUZHOU ZELGEN BIOPHARML
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