Dicyclohexylcarbodiimide → Benzimidazole

Temperature

50 °C

To reactor-1 was charged III (35 g, 140.95 mmol) in toluene (140 g). The mixture was heated to 50° C. to obtain a clear solution. To a second reactor was charged IV (36.4 g, 169.10 mmol) and toluene (300 g), followed by addition of a solution of dicyclohexyl carbodimide (11.6 g, in 50% toluene, 28.11 mmol) at 0-10° C. The mixture was stirred at the same temperature for 15 min, then charged in parallel with the content of reactor-1 and the solution of dicyclohexyl carbodimide (52.4 g, in 50% toluene, 126.98 mmol) within 1 hr while maintaining the batch temperature at 0-10° C. The mixture was agitated at the same temperature for 3 hrs, and warmed to 25° C. for another 1 hr. Once III was consumed, toluene (˜300 mL) was distilled off under reduced pressure at 70-80° C. n-Butanol (200 g) was added, followed by 3 M HCl solution in n-butanol (188 g) while maintaining the temperature at 70-80° C. (Gas evolution, product precipitates). After stirring for over 30 min at 70-80° C., the mixture was cooled to 20-30° C. over 1 hr. The precipitate was filtered and washed with acetone (172 g) and toluene (88 g). The wet cake was dried in vacuo at ˜60° C. to give V toluene solvate as off white solid (60-72 g, 85-95% yield). Compound V could be used directly for the next step or basified prior to next step to obtain the free base compound VI used in the next step.

1. customto obtain a clear solution
2. additioncharged in parallel with the content of reactor-1
3. stirringThe mixture was agitated at the same temperature for 3 hrs
4. temperaturewarmed to 25° C. for another 1 hr
5. customOnce III was consumed
6. distillationtoluene (˜300 mL) was distilled off under reduced pressure at 70-80° C. n-Butanol (200 g)
7. additionwas added
8. temperaturewhile maintaining the temperature at 70-80° C.
9. custom(Gas evolution, product precipitates)
10. stirringAfter stirring for over 30 min at 70-80° C.
11. temperaturethe mixture was cooled to 20-30° C. over 1 hr
12. filtrationThe precipitate was filtered
13. washwashed with acetone (172 g) and toluene (88 g)
14. customThe wet cake was dried in vacuo at ˜60° C.
15. customto give V toluene

ORD record

ord-f24914a57d8342e5b0844259246745f7

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08598183B2