Tetrahydrofuran → N-(4-(Chlorodifluoromethoxy)phenyl)-6-((3,4-dihydroxybutyl)amino)-5-(1H-pyrazol-5-yl)nicotinamide

HRID 525780노트

반응식

HRID 525780 반응식
Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.C(N)CC=C.CCN(C(C)C)C(C)C.C[N+:48]1([O-])[CH2:53][CH2:52]OCC1.[OH:55]S([O-])(=O)=O.[K+].[CH2:61]1[CH2:65][O:64]CC1>[Cl-].[Na+].O.C(Cl)Cl.[Os](=O)(=O)(=O)=O.O.CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([NH:48][CH2:53][CH2:52][CH:61]([OH:55])[CH2:65][OH:64])=[N:3][CH:4]=2)=[CH:10][CH:11]=1

참가 물질

12

반응물 6

HCID 8028TetrahydrofuranHCID 81531Diisopropylethylamine2회HCID 82029Methyl morpholine oxideHCID 4437323-Buten-1-amine2회HCID 516920Potassium bisulfateHCID 867026376-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

생성물 1

HCID 89907837N-(4-(Chlorodifluoromethoxy)phenyl)-6-((3,4-dihydroxybutyl)amino)-5-(1H-pyrazol-5-yl)nicotinamide

시약·촉매·용매 5

HCID 30318Osmium Tetroxide촉매HCID 962Water용매HCID 3776Isopropanol용매2회HCID 6344Dichloromethane용매HCID 57417360Sodium chloride; water용매

반응 조건

온도
130 °C

실험 절차

6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2, 200 mg, 0.414 mmol), 3-buten-1-amine (50.5 μl, 0.497 mmol), DIPEA (145 μL, 0.828 mmol) and iPrOH (414 μL) were added to MW vial, which was sealed, purged with argon, and the RM was stirred at 130° C. for 5 h. iPrOH (1.5 μL) was added and the RM was stirred at 130° C. for 30 min. DIPEA (36.1 μL, 0.207 mmol), 3-buten-1-amine (16.83 μL, 0.166 mmol), and iPrOH (0.1 mL) were added and the RM was stirred at 130° C. for 2 h. The cooled RM was treated with brine and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 40 g, n-heptane/EtOAc from 20% to 50% EtOAc). N-Methylmorpholin-N-oxide (9.50 mg, 0.081 mmol) and then osmium tetroxide EnCat™ (5.17 mg, 1.545 mmol) were then added to a stirred solution of the aforementioned intermediate (40 mg, 0.077 mmol) in THF (1 mL)/water (0.1 mL) and the RM was stirred at 50° C. for 26 h under an argon atmosphere A 10% aq. solution of KHSO4 was then added and the mixture was extracted with EtOAc. The combined extracts were washed with water, sat. aq. NH4Cl and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was suspended in DCM, sonicated, filtered and dried to afford the title product as a white solid. UPLC-MS (Condition 8) tR=0.92 min, m/z=468.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.65 (m, 1H) 1.78-1.94 (m, 1H) 3.22-3.47 (m, 2H) 3.50-3.67 (m, 2H) 3.67-3.79 (m, 1H) 4.49-4.58 (m, 1H) 4.60-4.68 (m, 1H) 6.91-7.04 (m, 1H) 7.28-7.43 (m, 2H) 7.84-7.99 (m, 3H) 8.37-8.46 (m, 1H) 8.62-8.73 (m, 1H) 8.80-8.96 (m, 1H) 10.16-10.27 (m, 1H) 13.11-13.29 (m, 1H).

후처리

  1. customwas sealed
  2. custompurged with argon
  3. additionwas added
  4. stirringthe RM was stirred at 130° C. for 30 min
  5. stirringthe RM was stirred at 130° C. for 2 h
  6. extractionextracted with EtOAc
  7. dry with materialThe combined extracts were dried over Na2SO4
  8. customthe solvent was evaporated off under reduced pressure
  9. customto give a residue which
  10. customwas purified by flash chromatography (Silica gel column, 40 g, n-heptane/EtOAc from 20% to 50% EtOAc)
  11. additionwas then added
  12. extractionthe mixture was extracted with EtOAc
  13. washThe combined extracts were washed with water, sat. aq. NH4Cl and brine
  14. dry with materialdried over Na2SO4
  15. customthe solvent was evaporated off under reduced pressure
  16. customto give a crude product which
  17. customsonicated
  18. filtrationfiltered
  19. customdried

출처 및 근거

ORD 기록
ord-4a0650c423934afab0cd279642b2c7a9
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09340537B2

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