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Crystalline form of indazole derivative and preparation method thereof

A technology of indazole and crystal form, applied in the field of crystal form of indazole derivatives and preparation thereof, can solve the problems of easy agglomeration, fine crystallization, poor product stability and the like

Pending Publication Date: 2022-06-21
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally speaking, amorphous pharmaceutical products have no regular crystal structure, and are often accompanied by defects such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity.

Method used

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  • Crystalline form of indazole derivative and preparation method thereof
  • Crystalline form of indazole derivative and preparation method thereof
  • Crystalline form of indazole derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Embodiment 1: Formula I compound (E)-1-morpholinyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H -indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one preparation of

[0105]

[0106] The first step: tert-butyl (1-(((5-iodopyridin-2-yl)oxy)methyl)cyclopropyl)carbamate 1c

[0107] Dissolve sodium hydride (0.4g, 10.7mmol) in N,N-dimethylformamide (20mL), add tert-butyl 1-(hydroxymethyl)cyclopropylcarbamate 1b (1.0g, 5.3mmol) at room temperature , prepared by the known method "Journal of Organic Chemistry, 2002, 67(11), 3965-3968"), after the addition was completed, 2-fluoro-5-iodopyridine 1a (1.8g, 8.0mmol) was slowly added. The reaction was stopped after stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography using developer system B to obtain the title product 1c (2.4 g), yield: 86%.

[0108] MS m / z(ESI):391.0[M+1]

...

Embodiment 2

[0169] Embodiment 2: Preparation of formula I compound A crystal form

[0170] Add the compound shown in formula I (1.5g, 2.36mmol) into 10mL of butanone, heat to reflux, stir and clarify, then add 10mL of n-hexane, and reflux the clear liquid for 1 minute. When the temperature is slowly lowered to 60°C, a white solid is precipitated, and it naturally falls to After stirring at room temperature for 16 hours, a white turbid liquid was formed, which was filtered to collect the filter cake and dried in vacuo to obtain the title product (1.0 g, yield: 66.7%).

[0171] Through X-ray powder diffraction detection, the product is defined as crystal form A, and the XRD spectrum is as follows: figure 1 , and the characteristic peaks are shown in Table 1.

[0172] The DSC spectrum shows an endothermic peak at 188.26°C; the TGA spectrum shows a weight loss of 0.58% at 25°C-90°C.

[0173] DVS detection shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moist...

Embodiment 3

[0177] Embodiment 3: Preparation of formula I compound A crystal form

[0178] Add the compound shown by formula I (10 mg, 15.73 μmol) into 0.5 mL of ethyl acetate and n-hexane (V / V=1:2), dissolve it, then add 1 drop of n-hexane to gradually precipitate a white solid, stir at room temperature After 16 hours, filter, collect the filter cake, and vacuum dry. The title product (5 mg, yield: 50%) was obtained.

[0179] According to X-ray powder diffraction detection, the product is crystal form A.

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Abstract

The invention provides a crystal form of an indazole derivative and a preparation method thereof. Specifically, the invention provides an A-K crystal form of a compound (E)-1-morpholinyl-4-((1-(((5-((Z)-4, 4, 4-trifluoro-1-(3-fluoro-1H-indazole-5-yl)-2-phenylbutyl-1-en-1-yl) pyridine-2-yl) oxy) methyl) cyclopropyl) amino) butyl-2-en-1-one (formula I) and a preparation method of the A-K crystal form of the compound (E)-1-morpholinyl-4-((1-(((5-((Z)-4, 4, 4-trifluoro-1-(3-fluoro-1H-indazole-5-yl)-2-phenylbutyl-1-en-1-yl) pyridine-2-yl) oxy) methyl) butyl-2-en-1-one (formula I).

Description

technical field [0001] The disclosure belongs to the field of medical technology, and relates to a crystal form of indazole derivatives and a preparation method thereof, in particular to compound (E)-1-morpholinyl-4-((1-((((5-((Z )-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy ) A, B, C, D, E, F, G, H, I, J, K crystal forms of methyl) cyclopropyl) amino) but-2-en-1-one and a preparation method thereof. Background technique [0002] Breast cancer is one of the most common malignant tumors in women. According to GLOBALCAN statistics in 2012 (CACANCER J CLIN 2015; 65:87–108), there are about 1.7 million new cancer cases and 520,000 deaths worldwide each year. The morbidity and mortality rate rank first in female malignant tumors. According to the 2017 China Cancer Registration Annual Report released by the National Cancer Center, breast cancer ranks first in the incidence of female malignant tumors, with about 279,000 new cases each year,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/06A61K31/5377A61P35/00
CPCC07D401/06A61P35/00C07B2200/13
Inventor 王林邵启云冯君贺峰赵苗苗王捷
Owner JIANGSU HENGRUI MEDICINE CO LTD
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