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

HRID 1475181노트

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HRID 1475181 반응식
C(O)(=O)CCC(O)=O.[CH3:9][CH:10]([CH3:34])[CH2:11][NH:12][C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1.C(#N)C.[C:38](=[O:41])([O-])[O-].[K+].[K+].[CH3:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][N:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1C(Cl)(Cl)Cl>C1(C)C=CC=CC=1.O.CS(C)=O>[CH3:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][N:50]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:51]1[C:38]([N:12]([CH2:11][CH:10]([CH3:34])[CH3:9])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:14]1)=[O:41]

참가 물질

8

반응물 4

HCID 6342AcetonitrileHCID 11430Potassium CarbonateHCID 67025978HCID 67025978, 화합물HCID 86680827HCID 86680827, 화합물

생성물 1

HCID 58355127tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate수율 18,548.199%

시약·촉매·용매 3

HCID 679Dimethyl Sulfoxide용매HCID 962Water용매2회HCID 1140Toluene용매

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온도
40 °C

실험 절차

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%).

후처리

  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.

출처 및 근거

ORD 기록
ord-8933a1157037431d9a8dd287c45239fe
출처 데이터셋
uspto-grants-2015_04
특허 번호
US09018374B2

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