Citric Acid → (R)-5-Bromo-N-(4-(1,1-difluoroethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

HRID 73796Notes

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]([F:20])([F:19])[CH3:18])=[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.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.CC(O)C>[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]([F:20])([F:19])[CH3:18])=[CH:12][CH:11]=1)=[O:8]

Participants

Conditions

Temperature: 120 °C

Procedure

A mixture of 5-bromo-6-chloro-N-(4-(1,1-difluoroethoxy)phenyl)nicotinamide (Stage 30.2, 700 mg, 1.752 mmol), (R)-pyrrolidin-3-ol (0.170 mL, 2.102 mmol) and DIPEA (0.673 mL, 3.85 mmol) and iPrOH (2 mL) in a sealed vial was heated to 120° C. for 1 h. The RM was diluted with EtOAc (80 mL), treated with citric acid 10% (40 mL; ˜pH4) and extracted with EtOAc. The combined extracts were washed with brine (2×40 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was washed with Et2O and n-hexane and the crystals were dried to give the title product as a beige solid. HPLC (Condition 5) tR=6.4 min, UPLC-MS (Condition 3) tR=1.02 min, m/z=442.1/444.0 [M+H]+.

Workup

extractionextracted with EtOAc
washThe combined extracts were washed with brine (2×40 mL)
dry with materialdried over Na2SO4
customthe solvent was evaporated off under reduced pressure
customto give a residue which
washwas washed with Et2O and n-hexane
customthe crystals were dried

Sources & evidence

ORD record: ord-d57b632ecede46cf91925a15e352eaa2
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08829195B2

Reaction notes

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