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Quinazoline derivative salt-type crystal forms and preparation method and application thereof

A technology of quinazoline and derivatives, applied in directions such as carboxylate preparation, sulfonate preparation, organic compound preparation, etc., can solve problems such as unfavorable use, inability to effectively suppress and the like

Active Publication Date: 2019-10-18
WEISHANG (SHANGHAI) BIO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The problem to be solved by the present invention is that the existing EGFR inhibitors cannot effectively inhibit the EGFR activation mutation EGFRVIII and effectively pass through the blood-brain barrier to reach an effective blood concentration in the brain, and the quinazoline derivatives (R )-6-[(3,3-difluoro-1-methylpiperidin-4-yl)oxy]-nitrogen-(3-ethynyl-2-fluorophenyl)-7-methoxyquinazole The properties of the free base of line-4-amine (I) are unfavorable for the problem of using in pharmaceutical processing and pharmaceutical compositions, providing a kind of quinazoline derivative salt form crystal that is more conducive to pharmaceutical processing and pharmaceutical compositions Types, preparation methods and applications, providing more qualitative and quantitative information for the efficacy and safety research of solid drugs

Method used

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  • Quinazoline derivative salt-type crystal forms and preparation method and application thereof
  • Quinazoline derivative salt-type crystal forms and preparation method and application thereof
  • Quinazoline derivative salt-type crystal forms and preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0352] The preparation of embodiment 1. quinazoline derivatives (I)

[0353] 1.1 Synthesis of intermediates 5-fluoro-4-methoxy-2-nitrobenzonitrile A6 and 1-bromo-5-fluoro-4-(deuteromethoxy)-2-nitrobenzene C1

[0354] The synthetic route is as follows:

[0355]

[0356] Step 1: To a solution of A1 (2.0 g, 10.5 mmol) and triethylamine (1.3 g, 12.6 mmol) in dichloromethane (10 mL) was added dropwise ethyl chloroformate in dichloromethane (3 mL) at 0 °C Ester (1.4 g, 12.6 mmol) solution. The reaction mixture was stirred at 0 °C for 1 h and allowed to reach room temperature. The reaction mixture was then washed twice with water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to afford product A2 (2.7 g, 100% yield) as a colorless oil.

[0357] Step 2: To a solution of A2 (2.7 g, 10.3 mmol) in concentrated sulfuric acid (4.6 mL) was added dropwise fuming nitric acid (0.73 mL, 15.5 mmol) at 10°C. After 1 hour, the reaction mixture was poured into i...

Embodiment 2

[0384] Embodiment 2. Preparation of the hydrochloride crystal form A of quinazoline derivatives (I) of the present invention

[0385] Weigh about 20 mg of quinazoline derivatives shown in formula (I) (i.e., (R)-6-[(3,3-difluoro-1-methylpiperidin-4-yl) oxy]- Nitrogen-(3-ethynyl-2-fluorophenyl)-7-methoxyquinazolin-4-amine (I)) sample in 1.5 milliliter vials, add 0.6 milliliters of methyl alcohol and 46 microliters of hydrochloric acid (1mol / L), after stirring at room temperature for about two days, centrifuge to separate the lower layer of wet sample solid. According to XRPD detection, the solid is hydrochloride crystal form A.

Embodiment 3

[0386] Embodiment 3. Preparation of the hydrochloride crystal form B of quinazoline derivatives (I) of the present invention

[0387] Take by weighing the quinazoline derivative sample shown in formula (I) of about 160 milligrams, add 5 milliliters of tetrahydrofuran / water (19 / 1, v / v), and in this suspension, add the hydrochloric acid of 0.37 milliliters (1mol / L ), stirred at room temperature for about two days, and centrifuged to separate the lower layer of wet sample solid. According to XRPD detection, the solid is hydrochloride crystal form B.

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Abstract

The invention discloses quinazoline derivative salt-type crystal forms and a preparation method and application thereof. The quinazoline derivative salt-type crystal forms are specifically the hydrochloride crystal forms A, B, C, D, F, H, I, the sulphate crystal form A, the maleate crystal form A, the succinate crystal form A, the adipate crystal form A, the glycollate crystal form A, the malate crystal form A, the fumarate crystal form A, the benzene sulfonate crystal forms A, B, C, the benzoate crystal form A, the hippurate crystal form A and the oxalate crystal form A of a quinazoline derivative shown in a formula (I). The salt-type crystal form provided by the invention has good stability, can be applied to drugs for treatment of non-small cell lung cancer brain metastasis, meningeal metastases, primary brain cancer or glioma and the like, has good bioavailability, and has great significance for further study of the therapeutic effect of the solid drugs.

Description

technical field [0001] The present invention relates to a quinazoline derivative salt form and its crystal form; specifically to (R)-6-[(3,3-difluoro-1-methylpiperidin-4-yl)oxyl]-nitrogen -(3-ethynyl-2-fluorophenyl)-7-methoxyquinazolin-4-amine (I) hydrochloride crystal form A, B, C, D, F, H, I, sulfuric acid Salt Form A, Maleate Form A, Succinate Form A, Adipate Form A, Glycolate Form A, Malate Form A, Fumarate Form A, Besylate crystal forms A, B, C, benzoate crystal form A, hippurate crystal form A and oxalate crystal form A and their preparation methods and applications. Background technique [0002] Biological signal transduction refers to the sending of stimulating or inhibiting signals into cells, and through a series of signal transmissions, biological responses occur in cells. Many signaling pathways and their biological responses have been studied extensively. Distinct defects in signaling pathways have been found to be responsible for many diseases, including var...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07C51/41C07C57/15C07C55/10C07C57/145C07C59/06C07C55/07C07C59/245C07C63/08C07C303/32C07C309/29C07C231/12C07C233/83A61K31/517A61P35/00
CPCA61P35/00C07B2200/13C07D401/12
Inventor 钟卫张金强
Owner WEISHANG (SHANGHAI) BIO PHARMA CO LTD
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