Macitentan crystal and its preparation method, its pharmaceutical composition and use
一种马西替坦、组合物的技术,应用在药物化学结晶领域,能够解决限制活性成分浓度和速率、片剂溶出速度慢、影响药效等问题
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preparation example 1
[0125] N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]- Form I of ethoxy]-4-pyrimidinyl]-N'-propylsulfonamide (macitentan). Specifically:
[0126]Sodium hydride (1.67g, 69.6mmol, 55% content in mineral oil) was washed twice with 10mL of n-hexane, the n-hexane solution was discarded, and the washed sodium hydride was dissolved in 200mL of tetrahydrofuran, and N-[5-(4 -Bromophenyl)-6-[2-[(hydroxyethoxy)-4-pyrimidinyl]-N'-propylsulfonamide (10.0g, 23.2mmol), the mixture was stirred for 15 minutes, diluted with 400mL DMF, and finally 5-Bromo-2-chloropyrimidine (5.38 g, 27.8 mmol) was added, the temperature of the reaction solution was raised to 60° C., and the temperature was maintained for 2 hours, and the reaction was completed. Pour the reaction solution into 250 mL of 10% citric acid aqueous solution, add ethyl acetate to extract twice, each time 300 mL of ethyl acetate, combine the organic phases, wash with water twice, each time 200 mL of water, add magnesium sulfat...
Embodiment 1
[0131] Take 9.8 mg of macitentan in a 5 mL glass vial, add 0.9 mL of methanol to form a suspension, stir at 60°C for 1 day, white crystals precipitate, separate by filtration, rinse twice with methanol, and dry in vacuum at room temperature for 1 hour. Crystals of macitentan methanolate were obtained. Yield 8.6 mg, 85% yield.
[0132] XRPD patterns such as Figure 8 shown.
[0133] 1 HNMR (CDCl 3 ):8.52(s,2H),8.50(s,1H),7.59-7.61(m,2H),7.17-7.19(m,2H),5.65(t,J=6.2Hz,1H),4.73-4.76( m,2H),4.63-4.65(m,2H),3.52(s,2H), 2.98(q,J=6.8Hz,2H),1.58-1.63(m,2H),1.30-1.52(m,7H) , 0.97 (t, J=7.4Hz, 3H). It shows that compared with the macitentan crystal form I prepared in Preparation Example 1, the macitentan methanolate crystal contains methanol, and each molecule of macitentan contains about 2 / 3 methanol molecules.
[0134] PLM map such as Figure 9 As shown, it has a better morphology.
Embodiment 2
[0136] Take 50.0 mg of macitentan in a 5 mL glass vial, add 0.5 mL of methanol to form a suspension, stir at room temperature for 7 days, precipitate white crystals, separate by filtration, wash with methanol for 3 times, and dry in vacuum at room temperature for 24 hours to obtain macitentan Tetan methanolate crystals, yield 48.1mg, yield 93%.
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