(R)-3-Pyrrolidinol → (R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

HRID 73727

Reaction equation

HRID 73727 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>CS(C)=O.CC(OC)(C)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]

Participants

5

Reactant 2

HCID 2759337(R)-3-PyrrolidinolHCID 867025923-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide

Product 1

HCID 86702591(R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 18176222EtOAc MTBESolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.3, 100 mg, 0.264 mmol), (R)-pyrrolidin-3-ol (46.1 mg, 0.529 mmol) and TEA (147 μL, 1.058 mmol) in DMSO (199 μL) was stirred at 90° C. for 16 h. The RM was diluted with TBME/EtOAc (1:1) (30 mL), washed with 0.5 M HCl (3×5 mL) and brine (5 mL) and the solvent was evaporated off under reduced pressure to give a crude product that was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 30% to 80% EtOAc-EtOH+0.1% NH4OH (8:2)) to yield the title compound as an off-white solid. UPLC-MS (Condition 1) tR=2.83 min, m/z=444.9/446.9 [M+H]+, m/z=443.0/445.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.80-1.92 (m, 1H) 1.92-2.04 (m, 1H) 3.24-3.30 (m, 1H). 3.36-3.46 (m, 1H) 3.60-3.72 (m, 1H) 3.81 (dd, J=10.51, 4.65 Hz, 1H) 4.36 (d, J=2.69 Hz, 1H) 4.97 (d, J=3.42 Hz, 1H) 6.93 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.80-7.90 (m, 3H) 8.14 (d, J=1.96 Hz, 1H) 10.19 (s, 1H).

Workup

  1. washwashed with 0.5 M HCl (3×5 mL) and brine (5 mL)
  2. customthe solvent was evaporated off under reduced pressure
  3. customto give a crude product that
  4. customwas purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 30% to 80% EtOAc-EtOH+0.1% NH4OH (8:2))

Sources & evidence

ORD record
ord-351bd0c558ac47e08fd83f4ac574e2f6
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Linked notes

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