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With hydrogenchloride; water; In methanol; at 30 - 50℃; for 0.75h;Product distribution / selectivity; |
Example 16[0080] A l L, 4-neck, round-bottom flask equipped with a mechanical stirrer, a thermometer, heating/cooling capacity, and an addition funnel was charged in sequence with 4-methyl-N- [3 -(4-methyl-imidazol- 1 -yl)-5 -trifluoromethyl-phenyl] -3 -(4-pyridin-3 -yl-pyrimidin-2- ylamino)-benzamide free base (10 g), methanol (250 mL), and 37% hydrochloric acid (1.85 g) under nitrogen purge. The mixture was heated to 42-5O0C and stirred for an additional 15 minutes. The resulting solution was filtered through a polypropylene pad, while maintaining the batch temperature above 4O0C. The clear solution was transferred under nitrogen atmosphere to another 1 L, 4-neck, round-bottom flask equipped with a mechanical stirrer, a thermometer, and heating/cooling capacity. The batch was stirred and cooled to 3O0C over a period of 30 minutes. Seeds (20 mg) were added at this temperature, and the batch was cooled to 230C over a period of 45 minutes. The batch was stirred for an additional 3 hours to obtain a thick white suspension. The suspension was cooled to -1O0C over a period of 1.5 hours and stirred for an additional 30 minutes. Any solid was collected by filtration and rinsed with cold (-1O0C) methanol (20 mL). The solid was dried at 50-55C/10-20 torr for 8-16 hours to obtain 4-methyl-N-[3v(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrirnidin-2-ylamino)-benzamide monohydrochloride monohydrate salt form B (9.8 g) as a white solid.[0081] 1H NMR 300 MHz, DMSO-d6), delta 10.9 (s, IH), 9.58 (s, IH), 9.29 (s, IH), 9.20 (s, IH), 8.70 (d, IH), 8.63 (s, IH), 8.55 (d, IH), 8.49 (d, IH), 8.32 (d, 2H), 8.00 (s, IH), 7.91 (s, IH), 7.84 (d, IH), 7.56-7.44 (m, 3H), 2.50 (s, 3H), 2.35 (s, 3H); x-ray diffraction pattern showing maxima at 2Theta = 7.4, 9.4, 11.6, 12.1, 15.8, 19.3, 19.6, 22.1, 24.1, 25.7. |
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With hydrogenchloride; water; In methanol; at 23 - 50℃; for 4.5h; |
Example 1 Preparation of Monohydrochloride M onohydrate SaltAMN107 AMN107 HCI H2O salt[0035] A l L, 4-neck, round-bottom flask equipped with a mechanical stirrer, a thermometer, heating/cooling capacity, and an addition funnel was charged in sequence with 4-methyl-N- [3-(4-methyl-imidazol-l-yl)-5-t?fluoiOmethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2- ylamino)-benzamide free base (10 g), methanol (250 mL), and 37% hydrochloric acid (1.85 g) under nitrogen purge. The mixture was heated to 42-5O0C and stirred for an additional 15 minutes. The resulting solution was filtered through a polypropylene pad, while maintaining the batch temperature above 400C. The clear solution was transferred under nitrogen EPO <DP n="12"/>atmosphere to another 1 L, 4-neck, and round-bottom flask equipped with a mechanical stirrer, a thermometer, and heating/cooling capacity. The batch was stirred and cooled to 300C over a period of 30 minutes. Seeds (20 mg) were added at this temperature, and the batch was cooled to 23C over a period of 45 minutes. The batch was stirred for an additional 3 hours to obtain a thick white suspension. The suspension was cooled to -1O0C over a period of 1.5 hours and stirred for an additional 30 minutes. Any solid was collected by filtration and rinsed with cold (-100C) methanol (20 mL). The solid was dried at 50-55C/10-20 torr for 8-16 hours to obtain 4-methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4- pyridin-3-yl-pyrimidin-2-ylamino)-benzamide monohydrochloride monohydrate salt (9.8 g) as a white solid.[0036] 1H NMR 300 MHz, DMSO-d6), delta 10.9 (s, IH), 9.58 (s, IH), 9.29 (s, IH), 9.20 (s, IH), 8.70 (d, IH), 8.63 (s, IH), 8.55 (d, IH), 8.49 (d, IH), 8.32 (d, 2H), 8.00 (s, IH), 7.91 (s, IH), 7.84 (d, IH), 7.56-7.44 (m, 3H), 2.50 (s, 3H), 2.35 (s, 3H); x-ray diffraction pattern showing maxima at 2Theta = 7.4, 9.4, 11.6, 12.1, 15.8, 19.3, 19.6, 22.1, 24.1, 25.7. |
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With hydrogenchloride; water; In methanol; at -10 - 64℃; for 2.5h;Product distribution / selectivity; |
Example 20[0087] 4-Methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl- pyrimidin-2-ylamino)-benzamide hydrochloride form B is prepared by suspending free base in methanol at room temperature or at 5O0C. 1.06 equivalent of 37% aqueous hydrochloric acid is added, and the mixture is heated to reflux (640C) to give a solution that is clarified by filtration. The clarified solution is then cooled to 420C and seeded with 0.1% seeds per base. The seeds are suspended in a mixture of 99% methanol and 1% water. The suspension is stirred at 420C for 2.5 hours and afterwards cooled down to -1O0C according to a slow cooling profile. At 2O0C, the cooling is interrupted for four hours in order to let a potentially formed methanol solvate transform to the desired monohydrate.[0088] The suspension is filtered and washed with two portions of methanol/water mixture (99% methanol/1% water). The filter cake is dried in an oven at 7O0C under a vacuum below 10 mbar overnight. The water content after filtration was found to be below the theoretical value of 3.05% for 50 g scale and above. To assure the correct water content, a second drying stage is added where water is evaporated in a stirred vessel and transported to the dryer by a vacuum pump. The conditions in the dryer are changed to 6O0C and 30 mbar in order to assure adequate conditions for the desired water content. The water is added until the saturation capacity is reached. With the described method, a water content of 3.5-3.6% was obtained with two lab scale (1 L) paddle dryer experiments. |
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