Crystal form A of thienopyridine compound, preparation method and pharmaceutical composition of thienopyridine compound

A compound and crystal form technology, applied in the field of medicine, can solve the problems of crystallization or purification of compounds that are not publicly displayed, and achieve the effects of easier quality control, high chemical stability, and convenient storage

Active Publication Date: 2022-06-21
SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Although the patent application discloses methods for the preparation of the compounds, there is no disclosure showing that any of the compounds can be stably crystallized or purified

Method used

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  • Crystal form A of thienopyridine compound, preparation method and pharmaceutical composition of thienopyridine compound
  • Crystal form A of thienopyridine compound, preparation method and pharmaceutical composition of thienopyridine compound
  • Crystal form A of thienopyridine compound, preparation method and pharmaceutical composition of thienopyridine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Weigh 100g of 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[3, 2-b]Pyridin-2-yl)-1H-pyrazolyl-1-yl)ethyl valine ester hydrochloride crude product was added to the reaction flask, and 1000mL of a mixed solution of tetrahydrofuran and water (V tetrahydrofuran: V water = 9: 1), heated and refluxed to 80°C with stirring. After dissolving, stir for 30 minutes, then cool down to 15-25°C, stir and crystallize for 12h, filter with suction, and dry the filter cake to obtain 80 g of solid; add the obtained solid into the reaction flask, add 160ml of methanol, beating at 20-25°C for 4h, Suction filtration; the obtained filter cake was air-dried at 50° C. to obtain 76 g of white powder with a total yield of 76% in two steps. The resulting compound is 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[3 ,2-b] pyridin-2-yl)-1H-pyrazolyl-1-yl) A crystal form of ethyl valine ester hydrochloride, it...

Embodiment 2

[0077] Weigh 100g of 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[3, 2-b]Pyridin-2-yl)-1H-pyrazolyl-1-yl)ethyl valine ester hydrochloride crude product was added to the reaction flask, and 800mL of a mixed solution of methanol and water (V methanol: V water = 9:1), heated and refluxed to 70°C with stirring. After dissolving, stir for 30 minutes, then lower the temperature to 15-25°C, stir and crystallize for 12h, filter with suction, and dry the filter cake to obtain 75 g of solid; add the obtained solid into a reaction flask, add 150ml of methanol, and beat at 20-25°C for 4h, Suction filtration; the obtained filter cake was air-dried at 50° C. to obtain 71 g of white powder with a total yield of 71% in two steps. The resulting compound is 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[3 ,2-b]Pyridin-2-yl)-1H-pyrazolyl-1-yl)ethylvaline ester hydrochloride A crystal form.

Embodiment 3

[0079] Weigh 100g of 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[3, 2-b]Pyridin-2-yl)-1H-pyrazolyl-1-yl)ethyl valine ester hydrochloride crude product, added to the reaction flask, added 1500ml of tetrahydrofuran solution, heated and refluxed to 80 ℃ under stirring . After dissolving, stir for 30 minutes, then cool down to 15-25°C, stir and crystallize for 12h, suction filter, and dry the filter cake to obtain 85g of solid; add the obtained filter cake to the reaction flask, add 170ml of methanol, beating at 20-25°C for 4h , suction filtration; the obtained filter cake was air-dried at 50° C. to obtain white powder 81, and the two-step total yield was 81%. The resulting compound is 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamide)phenoxy)thieno[3 ,2-b]Pyridin-2-yl)-1H-pyrazolyl-1-yl)ethylvaline ester hydrochloride A crystal form.

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PUM

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Abstract

The invention discloses a crystal form A of a compound 2-(4-(7-(2-fluoro-4-(1-((4-fluorophenyl) carbamoyl) cyclopropane-1-formamide) phenoxy) thieno [3, 2-b] pyridine-2-yl)-1H-pyrazolyl-1-yl) ethyl valine ester hydrochloride, a preparation method of the crystal form A and a pharmaceutical composition of the crystal form A. The crystal form is high in chemical stability, resistant to high temperature and high humidity, good in solubility and high in bioavailability, and the pharmaceutical composition of the crystal form has good dissolution rate and is suitable for development of preparations. The structural formula of the compound is shown as a formula (I),

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a new crystal form of a thienopyridine compound, a preparation method thereof, and a pharmaceutical composition containing the crystal form of the compound. Background technique [0002] The same substance has two or more spatial arrangements and unit cell parameters, and the phenomenon of forming multiple crystal forms is called polymorphism. Many crystalline drugs have polymorphism, and different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., thus affecting the stability, bioavailability and efficacy of the drug. Drug polymorphism is one of the important factors affecting drug quality and clinical efficacy. Therefore, when developing drugs with polymorphism, special attention should be paid to the analysis of their crystal forms. [0003] Chinese patent application CN113...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/4365A61P35/00
CPCC07D495/04A61P35/00C07B2200/13
Inventor 夏烨青黄汉敏李汉然郭青石涛冯汉林
Owner SHENZHEN NEPTUNUS PHARMA RES INST CO LTD
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