Quinazoline derivative salt form crystal form, preparation method and application
A technology of quinazoline and derivatives, applied in the preparation of carboxylate, sulfonate, preparation of organic compounds, etc., can solve problems such as inability to effectively suppress, unfavorable use, etc., and achieves reduction of tablet intake burden and resistance to drug resistance. drug, good pharmacokinetic effect
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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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