反应详情

温度

24 °C

Heat a mixture of 6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (120 g, 0.4629 mol) and toluene (14.4 L) to 70° C. for 45 min until most of the starting material is dissolved. Add diisobutylamine (1.197 g, 1.62 mL, 9.26 mmol) followed by addition of sulfuryl chloride (62.48 g, 37.19 mL, 0.463 mol) in toluene (360 mL) over 20 min. Stir the reaction mixture for 50 min and then add additional sulfuryl chloride (4.536 g, 2.70 mL, 0.0336 mol) neat and stir the reaction mixture for 15 min at 70° C. Cool the reaction mixture to 24° C. over 30 min and then add 1N hydrochloric acid (2.00 L). Separate, wash the organic layer with saturated aqueous NaHCO3 (2.00 L), brine (2.00 L) and then dry over Na2SO4. Filter and remove the solvent with a rotary evaporator at 70° C. until about 672.5 g remains using the minimum effective vacuum in order to maintain a vapor phase sufficient to prevent drying above the solvent line and self-seeding, thus preventing crystallization under these conditions. Using toluene heated to 70° C., transfer the light-yellow solution to a preheated (70° C.) 3-neck flask equipped with a mechanical stirrer. Lower the temperature to 58° C. over 1 h. If available, seed the solution with crystals of 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine from a prior synthesis to enhance crystallization. After 30 min, reduce the temperature further to 55° C. and observe the initiation of the crystallization process. Hold the temperature at 55° C. for 2 h. followed by 4 h. at 45° C., then turn off the heat allowing the mixture to slowly reach 24° C. (ambient temperature). After stirring for 8 h. with the heat off, cool the mixture to 0° C. for 2 h. followed by 2 h. at −10° C. Collect the resulting dense, white, granular crystals by vacuum filtration at −10° C. Rinse the crystals twice with cold (−10° C.) toluene and vacuum dry at 50° C., 5 Torr, for 12 h., to obtain the desired intermediate as a white solid (120.7 g, 99.5% purity, 88.8%): mp 133-134° C. MS (ES+) m/z 294 (M+H)+. Anal. Calc'd for C12H11ClF3NO2: C, 49.08; H, 3.78; N, 4.77; Cl, 12.07. Found: C, 49.01; H, 3.63; N, 4.72; Cl, 12.32.

1. temperatureHeat
2. dissolutionis dissolved
3. stirringstir the reaction mixture for 15 min at 70° C
4. customSeparate
5. washwash the organic layer with saturated aqueous NaHCO3 (2.00 L), brine (2.00 L)
6. dry with materialdry over Na2SO4
7. filtrationFilter
8. customremove the solvent
9. customwith a rotary evaporator at 70° C. until about 672.5 g
10. temperatureto maintain a vapor phase sufficient
11. customto prevent drying above the solvent line and self-seeding
12. customcrystallization under these conditions
13. temperatureUsing toluene heated to 70° C.
14. customto a preheated (70° C.) 3-neck flask
15. customequipped with a mechanical stirrer
16. waitLower the temperature to 58° C. over 1 h
17. customIf available, seed the solution with crystals of 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine from a prior synthesis
18. customcrystallization
19. waitAfter 30 min
20. customfurther to 55° C.
21. customat 55° C.
22. customfor 2 h.
23. waitfollowed by 4 h. at 45° C.
24. customto slowly reach 24° C. (ambient temperature)
25. stirringAfter stirring for 8 h. with the
26. temperatureheat off
27. temperaturecool the mixture to 0° C. for 2 h.
28. waitfollowed by 2 h. at −10° C
29. customCollect the resulting dense, white, granular crystals
30. filtrationby vacuum filtration at −10° C
31. washRinse the crystals twice with cold (−10° C.) toluene and vacuum
32. customdry at 50° C.
33. wait5 Torr, for 12 h.