Cesium carbonate → HCID 66883198, compound

Participants

Reaction Conditions

Reaction Steps

To a solution of 8-chloro-2-(2,4-difluorobenzyl)-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one, a compound of formula (Id), (54 mg, 0.13 mmol) in N,N-dimethylformamide (1.0 mL), was added powdered Cs2CO3 (89 mg, 0.27 mmol), followed by 2-chloronicotinonitrile (33 mg, 0.23 mmol). The resulting suspension was stirred and heated in a 105° C. oil bath. After stirring for 64 h at 105° C., HPLC analysis of the reaction mixture showed no 8-chloro-2-(2,4-difluorobenzyl)-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one, nor 2-chloronicotinonitrile remaining. The reaction was allowed to cool to ambient temperature and was diluted with H2O (15 mL), and Et2O (50 mL). The layers were separated, the organic layer was washed with H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a yellow liquid. The crude product was purified by silica gel column chromatography by adsorbing the material onto silica gel from a CH2Cl2 solution, loading the resulting solid onto the column and eluting with a gradient from 10% to 40% EtOAc/hexane. The product peak was collected to afford 2-{4-[8-chloro-2-(2,4-difluorobenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl]phenoxy}nicotinonitrile, a compound of formula (Id), (36 mg, 57% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.35 (1H, dd, J=5.0, 2.0 Hz), 8.05 (1H, dd, J=7.6, 1.8 Hz), 7.54-7.51 (2H, m), 7.42-7.38 (1 H, m), 7.27-7.24 (2H, m), 7.22-7.18 (2H, m), 7.15 (1H, dd, J=7.6, 5.0 Hz), 7.08-7.00 (1H, m), 6.80-6.74 (1H, m), 6.71-6.65 (1H, m), 6.46 (1H, s), 5.22 (2H, s).

Provenance & Evidence