Crystal form of polycyclic anaplastic lymphoma kinase inhibitor

A crystal form and solvent technology, applied to the crystal form of polycyclic anaplastic lymphoma kinase inhibitor, the application field of medicine, can solve the problems of high expression of fusion protein, malignant transformation, etc., achieve good inhibitory effect, easy preparation , the effect of good liquidity

Pending Publication Date: 2021-07-20
SHANDONG XUANZHU PHARMA TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The gene analysis of these fusion proteins shows that they all contain the gene sequence of the 3' end of the ALK gene encoding the intracellular kinase region, and the gene fragments fused with ALK all contain promoter elements and sequences that encode and mediate self-dimerization, thereby Lead to high expression and overactivation of fusion protein with ALK kinase activity in cells, causing malignant transformation of cells

Method used

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  • Crystal form of polycyclic anaplastic lymphoma kinase inhibitor
  • Crystal form of polycyclic anaplastic lymphoma kinase inhibitor
  • Crystal form of polycyclic anaplastic lymphoma kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] The preparation of the crystal form B of embodiment 1 formula (1) compound

[0134] Method 1: Add 10.0 g of the compound of formula (1) and 40 g of absolute ethanol to a 250 ml three-necked flask, stir mechanically at a speed of 150 r / min, and the system becomes a suspension. The temperature of the oil bath was raised to 62°C, and the system was dissolved. Continue to heat up until the internal temperature is 68°C (first temperature), add purified water (50g) dropwise, after the dropwise addition, the system becomes turbid and the internal temperature is 59°C, continue stirring and heating. The internal temperature was 65°C and the system was dissolved again. The internal temperature starts to drop at 75°C (the second temperature), and then the temperature is lowered at 5-7°C / h until the system drops to 26°C. Suction filtration, 10ml of mixed solvent (5ml of absolute ethanol, 5ml of water) rinses the filter cake. The filter cake was transferred to a carton to dry na...

Embodiment 2

[0138] The preparation of the crystal form A of embodiment 2 formula (1) compound

[0139] Add the compound of formula (1) (15.00g) into a 250ml three-necked flask, add 60.00g of absolute ethanol, stir and raise the temperature to an internal temperature of 66°C (the first temperature) to dissolve the raw material, and heat filter at an internal temperature of 75°C (0.45um organic filter membrane), keep warm at 70-75°C for 0.5h, add purified water (57ml) dropwise, after 5min, the inner temperature is 62°C, stir and heat up to 72°C (second temperature), keep warm at 70-72°C for 0.5h, add seed crystals A slurry, the internal temperature is 71°C, start to cool down slowly, cool down to 55°C within 3 hours, keep stirring at 55-57°C for 18 hours, cool down to 24°C in 3 hours, keep stirring at 20-25°C for 2 hours, filter, and rinse the filter cake with 30ml purified water The filter cake was vacuum-dried at 50°C for 18 hours to obtain 13.46 g of Form A product, yield: 89.73%.

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Embodiment 3

[0141] The preparation of the crystal form X of embodiment 3 formula (1) compound

[0142] Dissolve 35 g of the compound of formula (I) in acetonitrile (350 mL), heat to 70°C, dissolve, cool down to 25°C, a solid precipitates, filter, and dry in vacuo to obtain Form X as a white solid.

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Abstract

The invention relates to a crystal form of a polycyclic anaplastic lymphoma kinase inhibitor, a preparation method of the crystal form, a pharmaceutical composition containing the crystal form, and application of the crystal form or the pharmaceutical composition. Specifically, the invention relates to a crystal form of a compound 5-chloro-N4-(2-(isopropyl sulfonyl) phenyl)-N2-(7-methyl-8-(piperidine-4-yl)-2, 3-dihydrobenzo [b] [1, 4] dioxin-5-yl) pyrimidine-2, 4-diamine as shown in a formula (1) as an anaplastic lymphoma kinase inhibitor, a preparation method of the crystal form, a pharmaceutical composition containing the crystal form, and an application of the crystal form or the pharmaceutical composition in medicines for preventing and / or treating anaplastic lymphoma kinase mediated cancers or non-cancerous related diseases.

Description

[0001] 1. Technical field [0002] The invention belongs to the field of medicine, and relates to a polycyclic anaplastic lymphoma kinase inhibitor crystal form, a preparation method of the crystal form, a pharmaceutical composition containing the crystal form, and the crystal form or pharmaceutical composition Application in the preparation of medicines for treating and / or preventing ALK-mediated diseases. [0003] 2. Background technology [0004] Formula (1) compound 5-chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(7-Methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrimidine-2,4-diamine (abbreviated as the compound of formula (1) in the specification, which has been described in the patent application PCT / CN2015 / 090712) is an inhibitor of anaplastic lymphoma kinase, and anaplastic lymphoma kinase (Anaplastic lymphoma kinase, ALK) is a receptor tyrosine Kinase family members can recruit downstream proteins through autophosphorylation, and then express specif...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): C07D405/14A61P35/00A61K31/506
CPCC07D405/14A61P35/00C07B2200/13A61P17/00A61P13/08A61K45/06C07D401/14A61K31/506
Inventor韩国辉王海波
OwnerSHANDONG XUANZHU PHARMA TECH CO LTD