反应详情

温度

40 °C

5 mL of MTBE was added to 213.9 mg of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide amorphous free-base (0.500 mMol.). The mixture was heated to 40° C. with magnetic stirring for 1 hour. A solution of 4M HCl in 1,4-dioxane (1 eq; 125.1 uL) was added in four equal portions. After addition of the first portion (0.25 eq), the mixture was heated to 42° C. and 1 mL of acetonitrile was added to dissolve all of the solid material. After the remainder of the HCl solution was added, some solid material appeared. The slurry was stirred at 42° C. for 4 hours, then was cooled slowly to 22° C. overnight with 90 minute holds at 35° C., 30° C., and 25° C. The white solid material was filtered and dried at 50° C. under vacuum with a slow nitrogen bleed overnight. The yield was 73.6% (0.3685 mmol; 170.90 mg) of the HCl salt. The solid was found to be 1:1 stoichiometric HCl salt by ion chromatography, and to be crystalline by the Powder X-Ray Diffraction (PXRD) pattern depicted in FIG. 2 and as characterized by diffraction peaks below, and to have a melting point of 211° C.

1. additionAfter addition of the first portion (0.25 eq)
2. temperaturethe mixture was heated to 42° C.
3. dissolutionto dissolve all of the solid material
4. stirringThe slurry was stirred at 42° C. for 4 hours
5. temperaturewas cooled slowly to 22° C. overnight with 90 minute
6. customholds at 35° C., 30° C.
7. custom25° C
8. filtrationThe white solid material was filtered
9. customdried at 50° C. under vacuum with a slow nitrogen
10. waitbleed overnight