Acetonitrile → tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate

Temperature

40 °C

tert-Butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate succinate (30.3 g, 62.2 mmol), acetonitrile (60.0 mL) and water (40.0 mL) were charged. Then, potassium carbonate (34.4 g, 0.249 mmol) was added, and the mixture was stirred for 10 min. 1-(4-Methoxybutyl)-2-trichloromethyl-1H-benzimidazole (20.0 g, 62.2 mmol) was added, and the mixture was stirred at 70-80° C. for 2 hr. Dimethyl sulfoxide (15.0 mL) was added, and the mixture was stirred at 70-80° C. for 6 hr. The reaction mixture was allowed to cool to 20-30° C. water (120 mL) and toluene (240 mL) were added, and the mixture was partitioned. The organic layer was washed successively with 10 w/v % brine (100 mL), 10 w/v % aqueous citric acid solution (100 mL) and 10 w/v % brine (100 mL). To the organic layer was added activated carbon Shirasagi A (1.0 g), and the mixture was stirred at 20-30° C. for 30 min. The activated carbon was filtered off and washed with toluene (40.0 mL), and the filtrate was concentrated under reduced pressure to 110 mL. After heating to 35-45° C., heptane (280 mL) was added dropwise tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate as crystals (10 mg) was added at 35-45° C., and the mixture was stirred at the same temperature for 1 hr. Heptane (140 mL) was added dropwise at 35-45° C., and the mixture was stirred for 30 min. The mixture was allowed to cool to 20-30° C. and stirred for 2 hr. The precipitated crystals were collected by filtration, washed with toluene-heptane (1:5, 40.0 mL), and dried under reduced pressure at 50° C. to give tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate as a pale yellowish white crystalline powder (27.7 g, yield 74.2%).

1. stirringthe mixture was stirred at 70-80° C. for 2 hr
2. stirringthe mixture was stirred at 70-80° C. for 6 hr
3. additionwere added
4. customthe mixture was partitioned
5. washThe organic layer was washed successively with 10 w/v % brine (100 mL), 10 w/v % aqueous citric acid solution (100 mL) and 10 w/v % brine (100 mL)
6. additionTo the organic layer was added
7. stirringthe mixture was stirred at 20-30° C. for 30 min
8. filtrationThe activated carbon was filtered off
9. washwashed with toluene (40.0 mL)
10. concentrationthe filtrate was concentrated under reduced pressure to 110 mL
11. additionheptane (280 mL) was added dropwise tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate as crystals (10 mg)
12. additionwas added at 35-45° C.
13. stirringthe mixture was stirred at the same temperature for 1 hr
14. additionHeptane (140 mL) was added dropwise at 35-45° C.
15. stirringthe mixture was stirred for 30 min
16. temperatureto cool to 20-30° C.
17. stirringstirred for 2 hr
18. filtrationThe precipitated crystals were collected by filtration
19. washwashed with toluene-heptane (1:5, 40.0 mL)
20. customdried under reduced pressure at 50° C.

ORD record

ord-8933a1157037431d9a8dd287c45239fe

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09018374B2