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Crystal form, salt form and preparation method of n-phenyl-2-aminopyrimidine compound

A pyrimidine and crystal form technology, applied in the field of N-phenyl-2-aminopyrimidine compounds, can solve the problems of unsatisfactory stability, solubility and bioavailability of compound 1, and achieve the effect of excellent stability

Active Publication Date: 2019-08-30
HAINAN YUEKANG BIOMEDICINES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the process of drug research, the inventors found that compound 1 was still unsatisfactory in terms of stability, solubility and bioavailability.

Method used

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  • Crystal form, salt form and preparation method of n-phenyl-2-aminopyrimidine compound
  • Crystal form, salt form and preparation method of n-phenyl-2-aminopyrimidine compound
  • Crystal form, salt form and preparation method of n-phenyl-2-aminopyrimidine compound

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0140] Preparation Example 1: The preparation method of the benzoate crystal form IV of compound 1

[0141] Compound 1 (700g, 1.39mol) was added into a mixed solution of methanol (700ml) and acetone (8.4L), heated to 60°C, and stirred to dissolve. A solution of benzoic acid (170.7 g, 1.39 mol) in acetone (1.4 L) was added dropwise, stirred at 60°C for 1 h, cooled to 20-25°C and stirred for 2 h. After filtering, the filter cake was rinsed with acetone (3.4 L) and dried to obtain 770 g of benzoate of compound 1 with a yield of 88% and a purity of 99.0%. m / z(ES+)(M+H + )=501.2.

[0142] 1 H NMR (400MHz,DMSO)δ=10.07(s,1H),9.68(s,1H),8.65(s,1H), 8.55(d,J=11.6Hz,2H),8.35(d,J=5.1Hz ,1H),7.96(d,J=7.0Hz,2H), 7.58(d,J=7.2Hz,1H),7.48(t,J=7.3Hz,2H),7.33(d,J=5.2Hz,1H ), 7.23(d, J=6.3Hz, 1H), 7.06(s, 1H), 6.82(s, 1H), 6.48(dd, J=16.7, 10.2Hz, 1H), 6.18(d, J=16.8Hz ,1H),5.71(d,J=10.1Hz,1H),3.80(s,3H),2.97(t, J=6.9Hz,2H),2.74(s,3H),2.58–2.43(m,5H) ,2.30(s,6H).

[0143] The benzoate of...

preparation Embodiment 2

[0149] Preparation Example 2: The preparation method of the hydrochloride salt form I of compound 1

[0150] Add 1 mL of acetonitrile to 25.28 mg of raw drug H (compound 1), and stir to dissolve at 60°C. After adding 150 μL of 1M methanolic hydrochloric acid solution for a while, a brownish-yellow solid precipitated out of the reaction solution. Stir at room temperature for 30 minutes and filter the solid. The samples were vacuum dried overnight at room temperature.

preparation Embodiment 3

[0151] Preparation Example 3: The preparation method of the mesylate salt crystal form II of compound 1

[0152] Add 1000 μL ethyl acetate / 500 μL ethanol to 25.40 mg of API H (compound 1), stir at 60°C to dissolve. After adding 3.25 μL methanesulfonic acid (1 eq.) for a while, a solid precipitated out, and the reaction was heated for 1 h and then cooled down; stirred at room temperature overnight, the solid was filtered, and vacuum-dried at 40° C. for 4 h.

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Abstract

The present invention relates to new crystal forms of N-phenyl-2-aminopyrimidine compounds, crystal forms of pharmaceutically acceptable salts of said compounds and preparation methods and applications of these crystal forms, and also relates to crystal forms comprising said compound and said crystal forms. Pharmaceutical compositions and pharmaceutical preparations of pharmaceutically acceptable salt crystal forms of the above-mentioned compounds, and the application of these crystal forms, pharmaceutical compositions and pharmaceutical preparations for the treatment of diseases or disorders related to cell epidermal growth factor receptor (EGFR), for example, Treat or ameliorate abnormal cell proliferative disorders, such as cancer.

Description

technical field [0001] The present invention relates to a crystal form and salt of an N-phenyl-2-aminopyrimidine compound that has inhibitory effect on cell epidermal growth factor receptor (EGFR) and can be used for treating or improving abnormal cell proliferation disorders (such as cancer) A type and a preparation method thereof belong to the technical field of medicine. Specifically, the present invention relates to N-phenyl-2-aminopyrimidine compound N-(2-methoxy-4-(N 1 ,N 2 ,N 2 - Trimethyl-1,2-ethylenediamine-1-yl)-5-acrylamidophenyl)-4-(8-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine- Crystal form, salt form and preparation method of 2-amine. Background technique [0002] Cancer is the second leading cause of death after cardiovascular disease. According to the data released by the World Health Organization, there were 14 million new cancer patients and 8.2 million cancer-related deaths worldwide in 2012. According to the 2016 statistics of researchers from the C...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/506A61P35/00
CPCC07B2200/13C07D471/04A61K31/506A61P35/00
Inventor 段茂圣
Owner HAINAN YUEKANG BIOMEDICINES CO LTD