Ethylene → (R)-6-(3-Hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide

HRID 73767Notes

Reaction equation

HRID 73767 reaction equation
[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:28]([C:29]3[N:33](COCC[Si](C)(C)C)[N:32]=[CH:31][CH:30]=3)=[CH:27][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.C=C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:28]([C:29]3[NH:33][N:32]=[CH:31][CH:30]=3)=[CH:27][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:26])([F:25])[C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1

Participants

5

Reactant 4

HCID 6325EthyleneHCID 8028TetrahydrofuranHCID 2724141Tetrabutylammonium FluorideHCID 86702612(R)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)nicotinamide

Product 1

HCID 72544891(R)-6-(3-Hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide

Conditions

Temperature
80 °C

Procedure

A mixture of (R)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)nicotinamide (Stage 16.1, 68 mg, 0.114 mmol) and ethylene damien (38.4 μL, 0.569 mmol) in a MW vial and sealed under an argon atmosphere 1 M TBAF in THF (1.707 mL, 1.707 mmol) was added and the RM was stirred at 80° C. for 20 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc (40 mL), washed 3 times with sat. aq. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column Diol, isocratic 27% in 9 min) to afford the title compound as an off-white solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=468.2 [M+H]+, m/z=466.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.78 (m, 1H) 1.83 (dd, J=8.80, 4.40 Hz, 1H) 2.96 (d, J=11.74 Hz, 1H) 3.19-3.29 (m, 2H) 3.40-3.50 (m, 1H) 4.20 (br. s, 1H) 4.83 (br. s, 1H) 6.39 (d, J=1.96 Hz, 1H) 7.65 (d, J=8.80 Hz, 2H) 7.77 (br. s, 1H) 8.02 (d, J=9.05 Hz, 2H) 8.05 (d, J=2.45 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.33 (s, 1H) 12.91 (br. s, 1H).

Workup

  1. additionwas added
  2. customThe solvent was evaporated off under reduced pressure
  3. dissolutionthe residue was dissolved in EtOAc (40 mL)
  4. washwashed 3 times with sat. aq. NaHCO3 and brine
  5. dry with materialdried over Na2SO4
  6. customthe solvent was evaporated off under reduced pressure
  7. customto give a residue which
  8. customwas purified by preparative SFC (Column Diol, isocratic 27% in 9 min)

Sources & evidence

ORD record
ord-e9c0ee8f974b4e2ea6087a94355fa587
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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