Cyclobutanone → 4-[(1-Cyanocyclobutyl)amino]-2-fluoro-N-methylbenzamide
Reaction equation
[Si]([C:5]#[N:6])(C)(C)C.[NH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=1.[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1>C(O)(=O)C.O>[C:5]([C:19]1([NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)[CH2:22][CH2:21][CH2:20]1)#[N:6]Participants
Conditions
- Temperature
- 80 °C
Procedure
TMS-CN (29.7 g, 300 mmol) was added to a mixture of N-methyl-2-fluoro-4-aminobenzamide 4a (16.8 g, 100 mmol) and cyclobutanone (14 g, 200 mmol) in 90% acetic acid (200 mL). The reaction mixture was stirred at 80° C. for 24 h. The mixture was cooled and diluted with water (200 mL). The suspension was extracted with ethyl acetate (3×200 mL). Combined organic layers were washed with brine (4×100 mL), dried (MgSO4) and concentrated in vacuo to dryness. The residue was triturated with a mixed solvent of hexanes and ethylether (20 mL-20 mL) to remove cyclobutanone cyanohydrin. The solid was collected by filtration, affording the title compound 6a (20 g, 84% yield). MS (ES-API Negative): 246 (M−H)−. 1H NMR (CDCl3, 500 MHz): δ 7.92 (1H, dd, J=8.4, 8.4 Hz), 6.76 (1H, q, J=4.3 Hz), 6.48 (1H, dd, J=8.3, 1.9 Hz), 6.29 (1H, dd, J=14.3, 1.9 Hz), 4.72 (1H, br s), 2.97 (3H, d, J=4.4 Hz), 2.85-2.75 (2H, m), 2.4-2.35 (2H, m), 2.3-2.15 (1H, m), 1.95-1.85 (1H, m).
Workup
- temperatureThe mixture was cooled
- extractionThe suspension was extracted with ethyl acetate (3×200 mL)
- washCombined organic layers were washed with brine (4×100 mL)
- dry with materialdried (MgSO4)
- concentrationconcentrated in vacuo to dryness
- customThe residue was triturated with a mixed solvent of hexanes and ethylether (20 mL-20 mL)
- customto remove cyclobutanone cyanohydrin
- filtrationThe solid was collected by filtration
Sources & evidence
- ORD record
- ord-84dcd3e505114b39b185e80b06545549
- Source dataset
- uspto-grants-2014_08
- Patent number
- US08809550B2
Reaction notes
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