3-Hydroxypiperidine → HCID 89907350, compound

HRID 923949Notes

Reaction equation

HRID 923949 reaction equation
[Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O[CH:29]1CCCNC1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[C:3]([N:22]2[CH2:26][CH2:29][CH2:25][CH:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=1)=[O:8]

Participants

5

Reactant 3

HCID 232933-HydroxypiperidineHCID 81531DiisopropylethylamineHCID 86702593(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 89907350HCID 89907350, compound

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35, 1 g, 2.53 mmol), 3-hydroxypiperidine (307 mg, 3.03 mmol) and DIPEA (883 μL, 5.06 mmol) in iPrOH (2528 μL) were added to a MW vial and subjected to MW irradiation at 140° C. for 60 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure, treated with 0.5 M HCl (25 mL) and extracted with EtOAc. The combined extracts were washed with HCl 0.5 M, brine, dried over MgSO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (Silica gel column, 24 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1)), from 15% to 60% EtOAc-EtOH+0.1% NH4OH (9:1)) to afford the title compound as a white foam. UPLC-MS (condition 1) tR=2.89 min, m/z=460.0-462.0 [M+H]+, m/z=458.0-460.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.45 (m, 1H) 1.46-1.66 (m, 1H) 1.73-1.87 (m, 1H) 1.89-2.01 (m, 1H) 2.74 (dd, J=12.23, 9.29 Hz, 1H) 2.92 (t, J=10.64 Hz, 1H) 3.56-3.70 (m, 1H) 3.70-3.81 (m, 1H) 3.91 (dd, J=12.10, 3.30 Hz, 1H) 4.87 (d, J=4.40 Hz, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.42 (d, J=1.96 Hz, 1H) 8.76 (d, J=1.96 Hz, 1H) 10.37 (s, 1H).

Workup

  1. customsubjected to MW irradiation at 140° C. for 60 min
  2. customthe RM was evaporated to dryness under reduced pressure
  3. additiontreated with 0.5 M HCl (25 mL)
  4. extractionextracted with EtOAc
  5. washThe combined extracts were washed with HCl 0.5 M, brine
  6. dry with materialdried over MgSO4
  7. customevaporated to dryness under reduced pressure
  8. customThe crude product was purified by flash chromatography (Silica gel column, 24 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1)), from 15% to 60% EtOAc-EtOH+0.1% NH4OH (9:1))

Sources & evidence

ORD record
ord-b7024b7e8445476681df71ceece47dcb
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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