(3S)-pyrrolidin-3-ol → (S)-3-Bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

HRID 923828Notes

Reaction equation

HRID 923828 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 2733874(3S)-pyrrolidin-3-olHCID 867025923-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide

Product 1

HCID 118195171(S)-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 1.2, 100 mg, 0.264 mmol), (S)-pyrrolidin-3-ol (46.1 mg, 0.529 mmol) and TEA (147 μL, 1.058 mmol) in DMSO (200 μL) was stirred at 90° C. for 16 h. The RM was diluted with 30 mL of TBME/EtOAc (1:1), sequentially washed 5 times with 0.5 M HCl and brine then evaporated to dryness under reduced pressure. The crude product was purified by flash column chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 10% to 50% EtOAc-EtOH+0.1% NH4OH (9:1)) to afford the title compound as a white solid. UPLC-MS (condition 1) tR 2.83 min, m/z=444.9 [M+H]+, m/z=443.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.92 (m, 1H) 1.91-2.04 (m, 1H) 3.27 (d, J=10.76 Hz, 1H) 3.34-3.45 (m, 1H) 3.67 (dd, 1H) 3.81 (dd, J=10.39, 4.77 Hz, 1H) 4.30-4.42 (m, 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) 7.81-7.90 (m, 3H) 8.13 (d, J=2.20 Hz, 1H) 10.18 (s, 1H).

Workup

  1. washsequentially washed 5 times with 0.5 M HCl and brine
  2. customthen evaporated to dryness under reduced pressure
  3. customThe crude product was purified by flash column chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1), from 10% to 50% EtOAc-EtOH+0.1% NH4OH (9:1))

Sources & evidence

ORD record
ord-64cb0535689f4b94879f0ce40ed01cd1
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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