Diisopropylethylamine → 6-(3-Hydroxy-3-methylazetidin-1-yl)-5-(1H-imidazol-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 525736Notes

Reaction equation

HRID 525736 reaction equation
CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[NH:32][CH:33]=[CH:34][N:35]=2)=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.Cl.[CH3:37][C:38]1([OH:42])[CH2:41][NH:40][CH2:39]1>CC(O)C>[OH:42][C:38]1([CH3:37])[CH2:41][N:40]([C:11]2[C:30]([C:31]3[NH:32][CH:33]=[CH:34][N:35]=3)=[CH:29][C:14]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=3)=[O:16])=[CH:13][N:12]=2)[CH2:39]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 115427813-methylazetidin-3-ol HydrochlorideHCID 722014366-Chloro-5-(1H-imidazol-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 1180448706-(3-Hydroxy-3-methylazetidin-1-yl)-5-(1H-imidazol-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
140 °C

Procedure

DIPEA (0.139 mL, 0.794 mmol) was added to a mixture of 6-chloro-5-(1H-imidazol-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 69.1, 76 mg, 0.199 mmol) and 3-methylazetidin-3-ol HCl (27 mg, 0.218 mmol) in iPrOH (1 mL) and the RM was stirred at 140° C. 4.5 h. The solvent was evaporated off under reduced pressure and the residue was treated with water, extracted with EtOAc and the combined extracts were washed with water and brine, dried over MgSO4/charcoal and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 15 g, EtOAc/EtOH from 95:5 to 9:1) and crystallized from n-hexane/EtOAc to give the title product as white crystals. UPLC-MS (Condition 3) tR=0.7 min, m/z=434.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.32 (s, 3H) 3.54-3.67 (m, 4H) 5.47 (s, 1H) 7.05 (s, 1H) 7.26 (s, 1H) 7.35 (d, J=8.66 Hz, 2H) 7.87 (d, J=9.03 Hz, 2H) 8.15 (d, J=2.07 Hz, 1H) 8.76 (d, J=2.07 Hz, 1H) 10.25 (s, 1H) 12.39 (br. s, 1H).

Workup

  1. custom4.5 h
  2. customThe solvent was evaporated off under reduced pressure
  3. additionthe residue was treated with water
  4. extractionextracted with EtOAc
  5. washthe combined extracts were washed with water and brine
  6. dry with materialdried over MgSO4/charcoal
  7. customthe solvent was evaporated off under reduced pressure
  8. customThe residue was purified by flash chromatography (Silica gel column, 15 g, EtOAc/EtOH from 95:5 to 9:1)
  9. customcrystallized from n-hexane/EtOAc

Sources & evidence

ORD record
ord-d09ecaf63349473ea3edf08d049dbec9
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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