Repotrectinib crystal form and preparation method thereof

A crystal form and selected technology, applied in the field of medicinal chemistry, can solve problems such as differences in drug solubility, stability and fluidity, different clinical effects, and effects on drug safety and effectiveness

Inactive Publication Date: 2021-01-05
SHANGHAI ACEBRIGHT PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Different crystal forms can cause differences in the solubility, stability, and fluidity of the drug, which will affect the safety and effectiveness of the drug, and lead to differences in clinical effects

Method used

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  • Repotrectinib crystal form and preparation method thereof
  • Repotrectinib crystal form and preparation method thereof
  • Repotrectinib crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Embodiment 1: Preparation of crystal form CM-I

[0135] Weigh 500 mg of the compound of formula (I), dissolve it in 27 mL of ethanol at 50° C., and filter. The filtrate was added dropwise to 200mL water at 20°C, stirred for 2h, and filtered. The wet filter cake was vacuum-dried at 25°C for 24 hours, and the obtained solid was the crystal form CM-I of the compound of formula (I). Carry out XRPD test to the obtained solid, its X-ray powder diffraction data are as shown in table 1, and its XRPD pattern is as follows figure 1 Shown; Carry out TGA test to gained solid, its spectrogram is as figure 2 As shown, the weight loss is about 10.5% at 25-100°C; DSC test is performed on the obtained solid, and there are two endothermic peaks at 60°C-92°C, and one exothermic peak at 170°C-185°C. image 3 Shown; Gained solid is carried out 1H NMR test, and its spectrogram is as Figure 4 Shown, NMR data: 1H NMR (400MHz, DMSO-d 6)δ9.83(s,1H),8.81(d,J=6.7Hz,1H),8.58(d,J=7.6Hz,1H),8....

Embodiment 2

[0138] Embodiment 2: the preparation of crystal form CM-I

[0139] Weigh 9mg of the compound of formula (I), dissolve it in 0.4mL formic acid / water (4:1, v / v) at room temperature, and filter. The filtrate was added dropwise to 4 mL of water at 28 °C, stirred for 2 h, and filtered. The solid was dried under vacuum at 25°C for 24 hours, and the obtained solid was the crystal form CM-I of the compound of formula (I). The obtained solid was tested by XRPD, and its X-ray powder diffraction data are shown in Table 2.

[0140] Table 2

[0141] 2θ(°) Relative Strength(%) 2θ(°) Relative Strength(%) 3.7 1.9 17.6 4.2 7.5 11.4 20.0 3.2 8.7 100.0 24.9 2.4 11.1 3.8 28.7 1.7

Embodiment 3

[0142] Embodiment 3: the preparation of crystal form CM-I

[0143] Weigh 10 mg of the compound of formula (I), dissolve it in 0.5 mL of tetrahydrofuran at room temperature, and filter. Slowly drop 1mL of water into the filtrate, stir for 2h, and filter. The solid was dried under vacuum at 25°C for 24 hours, and the obtained solid was the crystal form CM-I of the compound of formula (I). The obtained solid was tested by XRPD, and its X-ray powder diffraction data are shown in Table 3.

[0144] table 3

[0145] 2θ(°) Relative Strength(%) 2θ(°) Relative Strength(%) 7.6 8.0 15.3 2.3 8.7 100.0 17.6 5.7 11.1 3.6 19.8 3.1 14.2 1.6 24.9 3.2

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Abstract

The invention provides a new crystal form of (7S, 13R)-11-fluorine- 7, 14-dimethyl-6, 7, 13, 14-tetrahydro-1, 15-ethylene bridge pyrazolo [4, 3-f] [1, 4, 8, 10] -benzoxaza-triazacyclo-tridecyne-4 (5H)-one, and on the other hand, the invention provides a preparation method of the crystal form. Compared with the prior art, the crystal form prepared by the invention is high in stability, low in hygroscopicity, simple and convenient in preparation method, good in solubility and suitable for subsequent preparation research and development and industrial production.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to (7S,13R)-11fluoro-7,14-dimethyl-6,7,13,14-tetrahydro-1,15-vinylpyrazolo[4,3 - A new crystal form of f][1,4,8,10]-benzoxatriazacyclotridecyn-4(5H)-one and a preparation method thereof. Background technique [0002] Lapratinib (TPX-0005) is a potent small molecule multi-target kinase inhibitor that was shown to antagonize wild-type and mutant ALA (anaplastic lymphoma kinase), wild-type and mutant ROS1 (pro-ROS1 Oncogene receptor tyrosine kinases), TRK family kinases (tropomyosin-related receptor tyrosine kinases), JAK2 of Janus family kinases, SRC (Src family protein tyrosine kinases (SFK)) and FAK (adhesion Kinase) activity. It is the fourth-generation ALK inhibitor developed by TP Therapeutics. On June 28, 2017, TP Therapeutics announced that the FDA had granted orphan drug qualification to its clinical drug candidate TPX-0005 for the treatment of NSCLC patients carr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18A61K31/529A61P35/00
CPCC07D498/18A61P35/00C07B2200/13
Inventor 彭欢闵思佳张凤杰张良
Owner SHANGHAI ACEBRIGHT PHARMA CO LTD
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