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

HRID 525780

Reaction equation

HRID 525780 reaction equation
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

Participants

12

Reactant 6

HCID 8028TetrahydrofuranHCID 81531Diisopropylethylamine2×HCID 82029Methyl morpholine oxideHCID 4437323-Buten-1-amine2×HCID 516920Potassium bisulfateHCID 867026376-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

Product 1

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

Reagents, catalysts & solvents 5

HCID 30318Osmium TetroxideCatalystHCID 962WaterSolventHCID 3776IsopropanolSolvent2×HCID 6344DichloromethaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
130 °C

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-4a0650c423934afab0cd279642b2c7a9
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Linked notes

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