Succinic Acid → cevipabulin succinate anhydrous

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A mixture of 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine (9.00 g, 19.4 mmol) and succinic acid (2.75 g, 23.3 mmol) in water (90 mL) is stirred for about 15-20 min and then heated to about 65-75° C. The solution is filtered and the filtrate is cooled to about 0-5° C. over about 1 h. The mixture is stirred for about 1 h and then filtered and the collected solid washed with cold water (2×9 mL) and cold isopropanol (9 mL). The solid is dried under vacuum at about 40° C./10 mmHg for about 20 h to give a white solid in anhydrous form (6.6 g, 73%). A portion of the compound is placed in a drying dish at 80-100% relative humidity (RH) and room temperature for about 24 h. The compound absorbed 5.8% water forming a dihydrate which is stable at room temperature and at 5-100% relative humidity (RH). 1H NMR (CDCl3): δ 10.2 (bs, 1H), 8.26 (s, 1H), 6.80 (d, 2H, J=10.5 Hz), 5.79 (m, 1H), 4.13 (t, 2H, J=6.3 Hz), 3.03 (t, 2H, J=7.2 Hz), 2.57 (s, 3H), 2.35 (s, 4H), 2.07 (m, 2H), 1.27 (d, J=6.0, 3H). This compound absorbs two mole waters at 5%-100% RH to become its dihydrate, 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine succinate salt dihydrate.

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