Hydrochloric Acid → (R)-3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide

HRID 924117Notes

Reaction equation

HRID 924117 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]([Cl: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.Cl>CS(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]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 2759337(R)-3-PyrrolidinolHCID 867026223-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide

Product 1

HCID 86702621(R)-3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (1 g, 2.53 mmol), (R)-pyrrolidin-3-ol (0.331 g, 3.80 mmol) in TEA (0.706 mL, 5.07 mmol) and DMSO (2.53 mL) was stirred at 90° C. for 20 h. The RM was treated with 0.5 M HCl (50 mL) and extracted with EtOAc. The combined extracts were washed with 0.5 M HCl, sat. aq. NaHCO3 and brine, and dried over Na2SO4. The solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 1% to 4.5% EtOAc). The residue was suspended in cyclohexane. The solid was filtered-off and dried to yield the title product as a white amorphous solid. UPLC-MS (Condition 3) tR=1.15 min, m/z=462.9 [M+H]+, m/z=460.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.90 (m, 1H) 1.92-2.03 (m, 1H) 3.27 (dd, J=10.39, 1.10 Hz, 1H) 3.36-3.44 (m, 1H) 3.62-3.71 (m, 1H) 3.81 (dd, J=10.45, 4.71 Hz, 1H) 4.32-4.40 (m, 1H) 4.99 (d, J=3.42 Hz, 1H) 6.93 (d, J=8.80 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.82-7.91 (m, 3H) 8.14 (d, J=2.20 Hz, 1H) 10.21 (s, 1H).

Workup

  1. extractionextracted with EtOAc
  2. washThe combined extracts were washed with 0.5 M HCl, sat. aq. NaHCO3 and brine
  3. dry with materialdried over Na2SO4
  4. customThe solvent was evaporated off under reduced pressure
  5. customto give the crude product which
  6. customwas purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 1% to 4.5% EtOAc)
  7. customdried

Sources & evidence

ORD record
ord-6047e92018cd4ed39ccad556d9189498
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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