Salts of substituted pyrrolopyrimidine cdk inhibitors and their crystallization and use

A crystallization and solvent technology, applied in the field of medicinal chemistry, can solve the problems of difficult to meet industrial production, affecting drug stability, difficult to store, etc.

Active Publication Date: 2022-04-12
CHIA TAI TIANQING PHARMA GRP CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have found that the compound of formula I and its hydrochloride are highly hygroscopic, which has adverse effects on drug production, storage and preparation, such as significantly affecting the fluidity of the drug after moisture absorption, not easy to store, and even affecting the stabil...

Method used

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  • Salts of substituted pyrrolopyrimidine cdk inhibitors and their crystallization and use
  • Salts of substituted pyrrolopyrimidine cdk inhibitors and their crystallization and use
  • Salts of substituted pyrrolopyrimidine cdk inhibitors and their crystallization and use

Examples

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preparation example Construction

[0048] In another aspect, the present application provides a method for preparing crystals of the compound of formula II, said method comprising the step of precipitating the compound of formula II from a solvent.

[0049] In some embodiments, the method for preparing crystals of the compound of formula II comprises precipitation of the compound of formula II from a solvent selected from methanol, ethanol, isopropanol, N-methylpyrrolidone or dimethyl sulfoxide. In some embodiments, the solvent is ethanol.

[0050] In some embodiments, the preparation method of the crystal of the compound of formula II comprises the following steps:

[0051]

[0052] 1) maleic acid reacts with a compound of formula I in a solvent;

[0053] 2) Precipitation of solid.

[0054] In some embodiments, step 1) is: mixing maleic acid with a solvent, mixing the compound of formula I with a solvent, and reacting the two mixtures formed above.

[0055] In some embodiments, the molar ratio of maleic ...

Embodiment 1

[0081] The preparation of embodiment 1 formula I compound

[0082]

[0083] The product obtained by referring to the preparation method of Example 6 in WO2017162215 was dissolved in heated ethanol, the temperature was lowered to precipitate a solid, filtered, and the filter cake was dried under reduced pressure to obtain crystals of the compound of formula I-1 (melting point<210°C).

[0084]Add the above-mentioned compound of formula I-1 (2.26Kg) into anhydrous methanol (22.6L), stir and dissolve at 10-30°C; add 2 mol / L sodium hydroxide aqueous solution dropwise, adjust the pH to 9-10, and drop , stirred for more than 1 h; filtered, the filter cake was washed with purified water until the pH of the washing solution was about 7, and the wet product was dried under reduced pressure at 45-55 °C for more than 8 h to constant weight to obtain crystals of the compound of formula I (1.71Kg). HRMS (ESI+, [M+H]+) m / z 432.2511, melting point 215-217°C.

[0085] The preparation of em...

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Abstract

The application belongs to the field of medicinal chemistry, and relates to salts of substituted pyrrolopyrimidine CDK inhibitors, in particular to the compound 7-cyclopentyl-6-N, N-dimethylcarbamoyl-N-(5-(1,2 ,3,6-4H-pyridin-4-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine maleate (compound of formula II), compound of formula II The crystal form, its preparation method and pharmaceutical composition also relate to the use of the compound salt and its pharmaceutical composition in the preparation of medicines for treating diseases related to the inhibition of CDK4 and/or CDK6.

Description

[0001] Cross References to Related Applications [0002] This application claims the priority and rights of the Chinese Invention Patent Application No. 201811068352.5 submitted to the State Intellectual Property Office of the People's Republic of China on September 13, 2018. The disclosure of said application is incorporated herein by reference in its entirety. technical field [0003] This application belongs to the field of medicinal chemistry, and relates to salts, crystal forms, preparation methods and pharmaceutical compositions of substituted pyrrolopyrimidine CDK inhibitors, and also relates to the use of such compounds and pharmaceutical compositions in the treatment and / or prevention of CDK4 / Use in a disease associated with CDK6 inhibition. Background technique [0004] WO2017162215 discloses the compound 7-cyclopentyl-6-N, N-dimethylcarbamoyl-N-(5-(1,2,3,6-4H-pyridin-4-yl) as a CDK4 / CDK6 inhibitor )pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (hereinafter re...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D519/00A61K31/519A61P35/00A61P35/02
CPCC07D487/04C07D519/00A61P35/00A61P35/02A61K31/519
Inventor 高鹏徐洋平孟庆义刘飞孙中英张克茹陈智林江金凤陆成晖
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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