Dimethylformamide → 3-Hydroxy-2-isopropyl-4-methoxy-2,3-dihydro-pyrrolo[3,4-c]pyridin-1-one

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Reaction Steps

To a stirred suspension of 10.00 g N-isopropyl-2-methoxy-isonicotinamide (51.40 mmol), as obtainable from example 13, in 300 mL TBME were added at room temperature 17.2 mL TMEDA (113.3 mmol, 2.2 eq) resulting in the formation of a clear solution, which was then cooled to −780 C. Subsequently 102.8 mL n-butyllithium in hexane (1.5 M, 154.4 mmol, 3.0 eq) were then added over 35 min and stirring was continued at the same temperature for additional 3 h min and subsequently at −22° C. for another 3 h. To the slightly brown suspension, 13.9 mL DMF (180.0 mmol, 3.5 eq) were added at −28° C. The resulting suspension was quenched after 16 h 45 min by addition of 200 mL saturated aqueous NH4Cl. The mixture was extracted three times with 150 mL, in total 450 mL dichloromethane. The combined organic phases were dried over 20 g Na2SO4 (30 min) and filtered. The filter cake was washed with 40 mL dichloromethane. After evaporation of solvent in a rotary evaporator (40° C./20 mbar), the crude product (19.400 g, 170% w/w, regioselectivity: 11.68:1, as determined by 1H-NMR) was obtained as a brown oil (HPLC purity 77.6%).

Provenance & Evidence