Crystal form and preparation method of cyclin-dependent kinase inhibitor

A crystal form and compound technology, applied in the field of chemical medicine, can solve the problems of low humidity stability of the monosuccinate crystal form, easy conversion into other crystal forms, unfavorable drug development and storage, etc., to simplify the preparation and post-treatment process , Facilitate absorption and utilization, reduce material storage and quality control costs

Inactive Publication Date: 2015-12-02
CRYSTAL PHARMATECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] During the research process, the inventors found that the existing monosuccinate crystal form has low humidity stability and is easily converted into other crystal forms under high humidity, which is not conducive to the development and storage of drugs

Method used

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  • Crystal form and preparation method of cyclin-dependent kinase inhibitor
  • Crystal form and preparation method of cyclin-dependent kinase inhibitor
  • Crystal form and preparation method of cyclin-dependent kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] The preparation method of hemisuccinate crystal form A:

[0073] Dissolve 10.5 mg of the free base of the compound of formula (I) in ethanol, add 3.0 mg of succinic acid, stir at room temperature for 12 hours, and obtain crystallization. The crystal form A that present embodiment obtains passes through XRPD, DSC, TGA and 1 HNMR detection. Its X-ray powder diffraction data are shown in Table 1. DSC data showed that an endothermic peak appeared when heated to 180°C, and TGA data showed a 12.5% ​​weight loss when heated from room temperature to 118°C. Its XRPD pattern is as follows figure 1 , 1 HNMR picture as shown figure 2 .

[0074] The compound hemisuccinate of formula (I) prepared by the above-mentioned method, its 1 HNMR identification data are as follows:

[0075] 1 HNMR (400MHz, DMSO) δ9.29(s, 1H), 8.76(s, 1H), 8.16(d, J=9.0Hz, 1H), 8.00(d, J=2.9Hz, 1H), 7.44(dd, J=9.2,3.0Hz,1H),6.60(s,1H),3.15–2.93(m,14H),2.32(s,2H),1.98(s,4H),1.65(s,2H).

[0076] Tabl...

Embodiment 2

[0079] The preparation method of hemisuccinate crystal form A:

[0080] Dissolve 10.2 mg of the free base of the compound of formula (I) in tetrahydrofuran, add 2.8 mg of succinic acid and stir at room temperature for 12 hours to obtain crystallization. Table 2 shows the X-ray powder diffraction data of Form A obtained in this example.

[0081] Table 2

[0082] 2theta

[0083] 33.72

Embodiment 3

[0085] Stability study of hemisuccinate form A under high humidity conditions:

[0086] Take about 10 mg of the crystal form A of the present invention to perform a dynamic moisture adsorption test with a dynamic moisture adsorption (DVS) instrument, and detect XRPD before and after the test. The results show that the crystal form A of the present invention has a weight gain of 3.543% at 80% relative humidity, and its hygroscopicity is low, and its DVS diagram is as follows image 3 shown. The crystal form remains unchanged before and after the dynamic water adsorption test, and its XRPD comparison chart is as follows Figure 4 shown.

[0087] Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2010 edition appendix XIXJ drug hygroscopicity test guidelines, experimental conditions: 25 ° C ± 1 ° C, 80% relative humidity):

[0088] Deliquescence: the absorption of sufficient water to form a liquid

[0...

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Abstract

The invention relates to a novel crystal form and a preparation method of hemisuccinate of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-yl amino)-7H-pyrrolo[2,3-D]pyrimidine-6-carboxylic acid dimethylamide and a novel crystal form and a preparation method of monosuccinate. The novel crystal forms of hemisuccinate and monosuccinate of a compound represented by a formula (I) (shown in the specification) have the beneficial performance of good stability, relatively low hygroscopicity, process exploitability and tractability, are low in cost and have important values on the optimization and development of drugs in further, and the preparation methods are simple.

Description

technical field [0001] The present invention relates to the field of chemical medicine, in particular to 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-D]pyrimidine-6 - A crystalline form of carboxylic acid dimethylamide hemisuccinate. Background technique [0002] Cyclin-dependent kinase 4 / 6 (cyclin-dependent kinase4 / 6, CDK4 / 6) is a kind of serine / threonine kinase that binds to cyclin D (cyclinD) and regulates the transition of cells from G1 phase to S phase. In many tumors, there is an abnormality of "cyclinD-CDK4 / 6-INK4-Rb pathway". The change of this pathway accelerates the process of G1 phase, which accelerates the proliferation of tumor cells and obtains a survival advantage. Therefore, its intervention has become a therapeutic strategy, and CDK4 / 6 has therefore become one of the anti-tumor targets. [0003] LEE011 is a small molecule inhibitor of cyclin-dependent kinase 4 / 6, developed by Novartis Pharmaceuticals for the treatment of drug-resista...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00
CPCC07B2200/13C07D487/04
Inventor 陈敏华张炎锋刘凯张晓宇王鹏李丕旭
Owner CRYSTAL PHARMATECH CO LTD
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