Diisopropylethylamine → (R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

HRID 525672

Reaction equation

HRID 525672 reaction equation
[Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 2759337(R)-3-PyrrolidinolHCID 725460895-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 72545856(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

5-Bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 22.2, 206 mg, 0.5 mmol) and (R)-pyrrolidin-3-ol (52.3 mg, 0.6 mmol) were dissolved in iPrOH (1 mL). DIPEA (192 μL, 1.1 mmol) was added and the RM mixture was stirred at 140° C. for 1 h in a sealed vial. After cooling at RT, the RM was dissolved in EtOAc, washed with 0.5 M HCl and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc from 20% to 100% EtOAc). The resulting product was triturated under n-heptane, filtered and dried to afford the title compound as a white crystalline powder. HPLC (Condition 4) tR=5.68 min, UPLC-MS (Condition 3) tR=1.15 min, m/z=462.1 [M+H]+.

Workup

  1. temperatureAfter cooling at RT
  2. washwashed with 0.5 M HCl and brine
  3. dry with materialdried over Na2SO4
  4. customthe solvent was evaporated off under reduced pressure
  5. customto give a crude product which
  6. customwas purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc from 20% to 100% EtOAc)
  7. customThe resulting product was triturated under n-heptane
  8. filtrationfiltered
  9. customdried

Sources & evidence

ORD record
ord-6d1a51c7ff22406fba09269d7007b305
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Linked notes

Loading…