Isopropanol → 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 525702Notes

Reaction equation

CC[N:3]([CH:7]([CH3:9])C)[CH:4](C)C.[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17].C[CH:33]([OH:35])C>CCOC(C)=O>[Br:10][C:11]1[C:12]([N:3]2[CH2:4][CH:9]([CH2:33][OH:35])[CH2:7]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17]

Participants

Conditions

Temperature: 140 °C

Procedure

DIPEA (0.115 mL, 0.660 mmol) was added to a solution of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 119 mg, 0.3 mmol) and azetidin-3-yl-methanol, HCl salt (44.5 mg, 0.36 mmol) in iPrOH (0.3 mL) in a vial, which was sealed and the RM mixture stirred at 140° C. for 5 h. 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 (Silica gel column, n-hexane/EtOAc from 50% to 100% EtOAc) and crystallized from n-pentane/EtOAc to afford the title product as white crystals. HPLC (Condition 4) tR=5.33 min, UPLC-MS (Condition 3) tR=1.06 min, m/z=446.2 [M+H]+.

Workup

customwas sealed
temperatureAfter cooling at RT
washwashed with 0.5 M HCl and brine
dry with materialdried over Na2SO4
customthe solvent was evaporated off under reduced pressure
customto give a crude product which
customwas purified by flash chromatography (Silica gel column, n-hexane/EtOAc from 50% to 100% EtOAc)
customcrystallized from n-pentane/EtOAc

Sources & evidence

ORD record: ord-bcf1609e15f943efbb08adee780be6a1
Source dataset: uspto-grants-2016_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09340537B2

Reaction notes

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