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

HRID 73780Notes

Reaction equation

HRID 73780 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), 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, dried over Na2SO4 and 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 fractions containing the pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was triturated under cyclohexane 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. additionThe fractions containing the pure product
  8. customthe solvent was evaporated off under reduced pressure
  9. customto give a residue which
  10. customwas triturated under cyclohexane

Sources & evidence

ORD record
ord-8aada78891874d25a9addad864c23ab3
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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