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A crystalline form of malate salt of a tyrosine kinase inhibitor and a preparation method thereof

A technology of crystallization and interplanar spacing, applied in the directions of pharmaceutical formulations, medical preparations containing active ingredients, organic chemistry, etc., can solve problems such as instability of crystal form I, achieve good crystal form stability, and the production process is repeatable and reproducible. control, the effect of stable production process

Active Publication Date: 2020-10-20
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have found that the I crystal form is unstable under light conditions, so it is necessary to find a more stable crystal form

Method used

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  • A crystalline form of malate salt of a tyrosine kinase inhibitor and a preparation method thereof
  • A crystalline form of malate salt of a tyrosine kinase inhibitor and a preparation method thereof
  • A crystalline form of malate salt of a tyrosine kinase inhibitor and a preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Take (1.0g, 1.84mmol) the compound represented by formula (I) (prepared according to the method disclosed in WO2007085188) and add it to a 250ml single-necked bottle, add 208ml of ethanol, heat to dissolve, then cool to room temperature, stand for crystallization, and suction filter , dried in vacuo to obtain 0.57 g of solid, with a yield of 57.0%. The X-ray diffraction spectrum figure of this crystalline sample is shown in figure 1 . The crystallization at about 6.62 (13.33), 11.02 (8.02), 12.55 (7.05), 13.34 (6.63), 15.27 (5.80), 16.55 (5.35), 17.46 (5.08), 19.26 (4.60), 19.99 (4.44), 20.75 There are characteristic peaks at (4.28), 22.07(4.02), 22.75(3.91), 23.80(3.74), 25.70(3.46), 27.38(3.26), 28.27(3.16) and 30.83(2.90). See the DSC spectrum figure 2 , with a melting endothermic peak at 230.65°C, this crystal form is defined as II crystal form.

Embodiment 2

[0039] Take (1.0g, 1.84mmol) the compound represented by formula (I) (prepared according to the method disclosed in WO2007085188) and add it to a 250ml single-necked bottle, add 50ml ethanol and 50ml water, heat to dissolve, then cool to room temperature, and stand for crystallization , suction filtration, and vacuum drying to obtain 0.64 g of solid, with a yield of 64.0%. The X-ray diffraction spectrum figure of this crystalline sample is shown in image 3, the peak list of the X-ray diffraction spectrum is shown in Table 1. The crystallization at about 7.34 (12.02), 10.09 (8.76), 11.06 (7.99), 12.25 (7.22), 13.03 (6.79), 14.69 (6.02), 15.11 (5.86), 15.42 (5.74), 16.00 (5.54), 17.17 (5.16), 17.72(5.00), 19.86(4.47), 20.35(4.36), 21.96(4.04), 22.77(3.90), 23.37(3.80), 25.33(3.51), 25.96(3.43), 26.52(3.36), 28.77 There are characteristic peaks at (3.10), 30.17 (2.96) and 31.65 (2.83). See the DSC spectrum Figure 4 , with a sharp melting endothermic peak at 240.64°C, this c...

Embodiment 3

[0043] Take (1.0g, 1.84mmol) the compound represented by formula (I) (prepared according to the method disclosed in WO2007085188) and add it to a 250ml single-necked bottle, add 90ml methanol, heat to dissolve, then cool to room temperature, stand for crystallization, and suction filter , dried in vacuo to obtain 0.45 g of an orange-yellow solid compound represented by formula (I), with a yield of 45.0%. Its X-ray powder diffraction and DSC patterns are researched and compared, and it is determined that the product is in the II crystal form.

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Abstract

The invention relates to a crystallization form of malate of a tyrosine kinase inhibitor, and a preparation method thereof, and concretely relates to an II type crystal of L-malate of 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (a compound of formula (I)), and a preparation method thereof. The II type crystal of the compound (I) obtained in the invention has the advantages of good crystal form stability and chemical stability, and a crystallization solvent used in the invention has low toxicity and low residual, so the II type crystal of the compound (I) can be well used in clinic treatment.

Description

technical field [0001] The present invention relates to a crystalline form of the malate salt of a tyrosine kinase inhibitor, in particular 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2 -Dihydro-indol-3-ylidene-methyl)-3-methyl-1,5,6,7-tetrahydro-pyrrole[3,2-c]pyridin-4-one L-malate type II crystals. Background technique [0002] In recent years, with the advancement of molecular biology technology and the further understanding of tumor pathogenesis from the molecular level of cell receptors and proliferation regulation, treatments targeting cell receptors, key genes and regulatory molecules have begun to enter the clinic. People call it "molecular targeted therapy". These areas include targeted epidermal growth factor receptor (EGFR) blockers, monoclonal antibodies against certain specific cell markers, drugs against certain oncogenes and cytogenetic markers of cancer, anti-tumor vascular Generated drugs, anti-tumor vaccines and gene therapy, etc. [0003] The anti-tum...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00
Inventor 武乖利吴兵卢韵
Owner JIANGSU HENGRUI MEDICINE CO LTD
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