Lithium Hydroxide → 1,1-Dimethylethyl 3-(5-bromo-1-isoquinolinyl)propanoate

Participants

Reaction Conditions

Reaction Steps

A solution of 5-bromo-2-(phenylcarbonyl)-1,2-dihydro-1-isoquinolinecarbonitrile (D10; 70 g, 206 mmol) and 1,1-dimethylethyl 3-bromopropanoate (Aldrich; 37.9 ml, 227 mmol) in dry, degassed DMF (250 ml) was added dropwise over 40 mins to a suspension of sodium hydride (60%; 24.76 g, 619 mmol) in dry, degassed DMF (750 ml) at −10° C. under nitrogen. The mixture was stirred at −10° C. for 10 mins, then allowed to warm to room temp over 3 h. Water (1500 ml) was cautiously added and the mixture extracted with ethyl acetate (3×500 ml). The combined organic extracts were washed with brine (5×500 ml) and dried (MgSO4). The solvent was evaporated to give a brown oil. The crude intermediate was dissolved in THF (700 ml) and lithium hydroxide (24.71 g, 1032 mmol) in water (100 ml) (note: not all soluble) was added. The mixture was vigorously stirred for 30 h, then stored in the fridge over the weekend. The mixture was partitioned between water (700 ml) and ethyl acetate (3×500 ml) and the combined organic extracts washed with brine (2×500 ml) and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica eluting with 5-15% ethyl acetate in isohexane gave the title compound (48.2 g)

Provenance & Evidence