Water → N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3,3-difluoropyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide

HRID 525713Notes

Reaction equation

Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:19]1[C:38]([C:39]2[NH:43][N:42]=[CH:41][CH:40]=2)=[CH:37][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([Cl:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[O:24])=[CH:21][N:20]=1.O>CC(O)C>[Cl:36][C:33]([F:34])([F:35])[O:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:37]=[C:38]([C:39]3[NH:43][N:42]=[CH:41][CH:40]=3)[C:19]([N:5]3[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]3)=[N:20][CH:21]=2)=[CH:31][CH:30]=1

Participants

Conditions

Temperature: 140 °C

Procedure

3,3-Difluoropyrrolidine hydrochloride (69.8 mg, 0.486 mmol) and DIPEA (0.170 mL, 0.972 mmol) were added to 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 100 mg, 0.243 mmol) in iPrOH (0.5 mL) and stirred at 140° C. for 3 h. The RM was treated with water, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude material which was purified by crystallization from DCM/EtOAc to give the title product as a white solid. HPLC (Condition 7) tR=6.746 min, UPLC-MS (Condition 3) tR=1.11 min, m/z=470.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.32-2.45 (m, 2H) 3.42-3.51 (m, 2H) 3.56 (t, J=13.29 Hz, 2H) 6.48 (s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.73-7.88 (m, 3H) 8.13 (d, J=2.35 Hz, 1H) 8.79 (s, 1H) 10.30 (s, 1H) 13.01 (br.s, 1H).

Workup

extractionextracted with EtOAc
dry with materialThe combined extracts were dried over Na2SO4
customthe solvent was evaporated off under reduced pressure
customto give the crude material which
customwas purified by crystallization from DCM/EtOAc

Sources & evidence

ORD record: ord-f4f2f51b69584915a0e2659bca195ab1
Source dataset: uspto-grants-2016_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09340537B2

Reaction notes

Loading…