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Pyridine amino pyrimidine derivative mesylate crystal forms, preparation method thereof and application

A mesylate and amine-based technology, which is applied in the crystal form of pyridylaminopyrimidine derivative mesylate and its preparation and application, can solve the problems affecting the clinical efficacy and safety, melting point and solubility of medicinal compounds , density, stability, hygroscopicity and other issues

Active Publication Date: 2017-09-15
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 properties of the compound. For pharmaceutical compounds with multiple crystal forms, because of their different crystal lattice structures, they may not only have different appearances such as color and shape, but also cause certain physical properties such as Different melting points, solubility, density, stability, hygroscopicity, etc., lead to different dissolution and absorption behaviors in the body, which will affect the clinical efficacy and safety of medicinal compounds to a certain extent

Method used

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  • Pyridine amino pyrimidine derivative mesylate crystal forms, preparation method thereof and application
  • Pyridine amino pyrimidine derivative mesylate crystal forms, preparation method thereof and application
  • Pyridine amino pyrimidine derivative mesylate crystal forms, preparation method thereof and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] Example 1: 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

[0104] Intermediate 1c: N 2 -Methyl-N 2 -[2-(Dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxy)-3-nitropyridine-2,5-diamine, the preparation method cited patent application CN201410365911. 4 Examples

[0105]

[0106] Intermediate 2a: 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole, the preparation method refers to the example of patent application CN201410365911.4

[0107]

[0108] Compound (II): N 2 -Methyl-N 2 -[2-(Dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxy)-N 5 Synthesis of -[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]-3-nitropyridine-2,5-diamine

[0109]

[0110] In a round bottom flask was added 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (73mg, 0.3mmol), N 2 -Methyl-N 2 -[2-(Dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxy)-3-nitropyridine-2,5-diamine (100mg, 0.3mmol), three (Dibenzylideneacet...

Embodiment 2

[0119] Example 2: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy)-5-{[ Preparation of Form I of Mesylate of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide

[0120]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 (451.5g, 0.77mol) was added to a 10L reactor, and acetone aqueous solution (5.42 L, the volume ratio of the two is 15:1), stirring, replacing with nitrogen, and raising the temperature to 35-40°C. A solution of methanesulfonic acid (74.2 g, 0.76 mol) in acetone (1.35 L) was added dropwise. After the dropwise addition is completed, the mixture is stirred at a temperature of 35-40° C. for 15-18 hours. Ethyl acetate (3.39 L) was added dropwise. After the addition was complete, the temperature was slowly lowered to 20-25° C., filtered, and the filter cake was washed with ethyl acetate (0.45 L). Vacuum-dried at 50°C for 40-48 h...

Embodiment 3

[0123] Example 3: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy)-5-{[ Preparation of Form I of Mesylate of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide

[0124] 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 (5g, 8.8mmol) was added to a 100mL reaction flask, and tetrahydrofuran aqueous solution (42.5mL , the volume ratio of the two is 19:1), stirring, replacing with nitrogen, and raising the temperature to 40-45°C. A solution of methanesulfonic acid (0.84 g, 8.7 mmol) in tetrahydrofuran (7.5 mL, volume ratio 19:1) was added dropwise. After the dropwise addition is completed, the mixture is stirred at a temperature of 40-45° C. for 15-18 hours. Slowly cool down to 20-25°C and filter. Vacuum drying at 50°C for 40-48 hours gave Form I (3.4g), yield 57.95%.

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Abstract

The invention provides a crystal form I and a crystal form II of mesylate of a compound as shown in a formula (I), a preparation method of the crystal forms, a medicine composition with the crystal forms and an application of the crystal forms to treatment of EGFR (epidermal growth factor receptor) activated or drug-resistant mutant mediated diseases, particularly cancers of mammals, particularly human bodies. The crystal forms of the mesylate of the compound as shown in the formula (I) have good solubility and are high in bioavailability in animal bodies.

Description

technical field [0001] The present invention relates to crystalline forms of pyridylaminopyrimidine derivatives mesylate, in particular, the present invention relates to N-{2-{[2-(dimethylamino)ethyl](methyl)amino}- 6-(2,2,2-Trifluoroethoxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridine-3- The crystalline form of acrylamide mesylate, its preparation method, the pharmaceutical composition comprising the crystalline form and the use of the crystalline form in the treatment of mammals, especially human diseases mediated by EGFR activation or drug-resistant mutants, especially application in cancer. Background technique [0002] Epidermal growth factor receptor (EGFR) has been identified as a critical driver in cell growth and proliferation. The epidermal growth factor receptor family consists of EGFR (Erb-B1), Erb-B2 (HER-2 / neu), Erb-B3 and Erb-B4. Epidermal growth factor receptor is related to the disease process of most cancers, such as lung cancer, colon can...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/506A61P35/00A61P35/02
CPCC07D401/14C07B2200/13A61P35/00A61P35/02A61K31/506
Inventor 罗会兵张强
Owner SHANGHAI ALLIST PHARM CO LTD
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