Diisopropylethylamine → 5-Bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 923961Notes

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])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][C:24]1([OH:28])[CH2:27][NH:26][CH2:25]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:26]2[CH2:27][C:24]([OH:28])([CH3:23])[CH2:25]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])[F:18])=[CH:12][CH:11]=1)=[O:8]

Participants

Conditions

Temperature: 140 °C

Procedure

5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 1.38 g, 3.5 mmol) and 3-methyl-azetidin-3-ol (HCl salt, 519 mg, 4.2 mmol) were dissolved in iPrOH (3.5 mL). DIPEA (1.4 mL, 8 mmol) was added and the RM mixture was heated at 140° C. for 4 h in a pressure safe vial. After cooling at RT, the RM was dissolved in EtOAc, washed with 0.5 M. HCl and brine. The organic phase was dried over Na2SO4 and the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, n-hexane/EtOAc, from 50 to 100% EtOAc) to afford the title compound as a white crystalline solid. HPLC (Condition 4) tR=5.59 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=448.1 [M+H]+.

Workup

temperatureAfter cooling at RT
washwashed with 0.5 M
dry with materialThe organic phase was dried over Na2SO4
customthe mixture was evaporated to dryness under reduced pressure
customThe crude product was purified by flash chromatography (RediSep® Silica gel column, n-hexane/EtOAc, from 50 to 100% EtOAc)

Sources & evidence

ORD record: ord-84bf674ceb4843288520a768eb78792e
Source dataset: uspto-grants-2016_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09278981B2

Reaction notes

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