Crystals, salts and preparation methods of resorcinol derivatives
A technology of crystallization and compounding, which is applied in the field of crystallization, salt and preparation of resorcinol derivatives, can solve the problems of drug efficacy, pharmacokinetics, water solubility, druggability, etc., and achieve the goal of overcoming toxicity Large, easily available, and water-soluble improvement effect
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Embodiment 1
[0134] Embodiment 1: the preparation of formula (I) compound
[0135] Preparation of Compound 10:
[0136]
[0137] step 1:
[0138] Benzyl bromide (8.66 kg, 50.61 mol, 6.01 liters, 2.20 equivalents), potassium iodide (190.93 grams, 1.15 moles, 0.05 equivalents) and potassium carbonate (9.54 kilograms, 69.01 moles, 3.00 equivalents), then heated to 85 ° C and stirred for 16 hours. After the reaction, the reaction solution was filtered and concentrated through a Bush funnel to obtain a crude oil. Petroleum ether (12.8 liters) was added in the crude product, stirred at 45 ℃ for 1 hour then, slowly cooled to room temperature in about 1 hour, filtered to obtain milky white solid product 1-(2,4-dibenzyloxyphenyl)ethanone ( 7 kg, 87.4% yield, 95.4% purity). m / z 333[M+H] + .
[0139] Step 2:
[0140] Under the protection of nitrogen, the internal temperature is controlled between 0-40°C, and slowly added to a solution of 1-(2,4-dibenzyloxyphenyl)ethanone (7.00 kg, 19.88 mol...
Embodiment 2
[0177] Embodiment 2: the preparation of the various crystals of formula (I) compound
[0178] Preparation of type A crystal:
[0179] method 1:
[0180] Take 20 g of the compound of formula (I), add 400 mL of tetrahydrofuran, and stir at 80° C. until completely dissolved, about 1 hour. Then the temperature was lowered to 40°C, and under the condition of 40°C, it was distilled to 100mL under normal pressure. The reaction mixture was naturally cooled to 15°C-30°C under stirring, and stirred at 15°C-30°C for a total of 12 hours. The solid was collected by filtration, rinsed twice with 20 mL of tetrahydrofuran, and dried under vacuum at 40°C-45°C to obtain 13 g of a white solid. According to XRPD identification, the solid crystal is type A crystal.
[0181] Method 2:
[0182] Take 54g of the compound of formula (I), add 1100mL of tetrahydrofuran, and stir at 70°C until completely dissolved. Then the temperature was lowered to 40°C, and under the condition of 40°C, it was dis...
Embodiment 3
[0219] Embodiment 3: formula (I) compound salt-forming research
[0220] Weigh about 84mg of the compound of formula (I), add it into an 8mL vial, add 3mL of THF, heat to 50°C to dissolve, then slowly add 17.5μL of hydrochloric acid (diluted 10 times with THF, take the corresponding volume and add slowly), and observe the phenomenon. Stir overnight at 25°C. The sample with precipitation was centrifuged quickly to obtain the salt-forming product.
[0221] Weigh about 84mg of the compound of formula (I), add it into an 8mL vial, add 3mL of THF, heat to 50°C to dissolve, then slowly add 11.4μL of sulfuric acid (diluted 10 times with THF, take the corresponding volume and add slowly), and observe the phenomenon. Stir overnight at 25°C. The sample with precipitation was centrifuged quickly to obtain the salt-forming product.
[0222] Weigh about 84mg of the compound of formula (I), add it into an 8mL vial, add 3mL of THF, heat to 50°C to dissolve, then slowly add 13.6μL of met...
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