Crystalline forms of the 4-pyrimidinesulfamide derivative aprocitentan
A technology of sulfonamide and pyrimidine, applied in the field of crystal form of 4-pyrimidine sulfonamide derivatives, can solve problems such as increased side effects
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example 1
[0231] Example 1: Form A:
[0232] 1.1. Load 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine in a 3L double-jacketed reactor (100g, 0.213mol, 1eq. (WO2015 / 121397)), sulfonamide (40.9g, 0.425mol, 2.0eq.), K 2 CO 3 (147g, 1.06mol, 5eq.) and DMSO (500mL, 5vol.), mixed with water (2mL, 0.111mol, 0.5eq.). The heterogeneous mixture was heated to 70°C during about 3 hours, after which complete conversion was observed. After cooling to 20°C, most of the inorganic salt cargo was removed by filtration. The filter cake was washed with EtOAc / iPrOAc 1:1 (300 mL, 3 vol.). Celite (100 g, 1 wt.) topped with a layer of charcoal (20 g, 0.2 wt.) was preconditioned with EtOAc / iPrOAc 1:1 (500 mL, 5 vol.) (the filtrate was discarded). The reaction mixture was filtered on this filter cake and rinsed with EtOAc / iPrOAc 1:1 (300 mL, 3 vol.). Then IM aqueous NaOAc (500 mL, 0.5 mol, 2.3 eq, 5 vol.) was added while maintaining the temperature at 25 to 35 °C. The aqueou...
example 2
[0234] Example 2: Form B (DCM solvate of the compound):
[0235] Make 5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine (10.0g, 21.3mmol, 1.00eq.) , sulfonamide (4.1g, 42.5mmol, 2.0eq.) and K 2 CO 3 (14.7 g, 106 mmol, 5.0 eq.) was suspended in DMSO (50 mL, 5 vol.) and heated to 70° C. for 5 hours. The mixture was cooled to room temperature and EtOAc (40 mL, 4 vol.) was added followed by water (100 mL, 10 vol.). After the layers were separated (the organic phase was discarded), the aqueous phase was extracted with DCM (100 mL, 10 vol.). The DCM layer was acidified from pH 11.5 to pH 7.0 with concentrated AcOH (3 mL, 52 mmol, 2.5 eq.), resulting in crystallization of the product. The suspension was cooled to 0°C for 1 hour, then to -5°C for 15 minutes. The solid was filtered, washed with cold DCM (10 mL, 1 vol.) and dried to obtain {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidine- 2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfonamide in DCM solvate (9.8 g, 8...
example 3
[0236] Example 3: Form C:
[0237] 0.2 mL of {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidine dissolved in THF at 50 mg / mL -4-yl}-sulfonamide stock solution was divided into 3 vials. Purchased from Hettich AG ( Switzerland) in a Combidancer apparatus operated at 35° C. and 200 mbar for 90 minutes. Immediately thereafter, 0.015 mL of MeOH was added to the first vial, EtOH was added to the second vial and iPrOH was added to the third vial and the vials were allowed to sit sealed for 3 days. Each of these solvents afforded {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidine-4- base}-sulfonamide solid residue.
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