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

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%).

1. customresulting in the formation of a clear solution, which
2. temperaturewas then cooled to −780 C
3. waitmin and subsequently at −22° C. for another 3 h
4. customThe resulting suspension was quenched after 16 h 45 min by addition of 200 mL saturated aqueous NH4Cl
5. extractionThe mixture was extracted three times with 150 mL
6. dry with materialThe combined organic phases were dried over 20 g Na2SO4 (30 min)
7. filtrationfiltered
8. washThe filter cake was washed with 40 mL dichloromethane
9. customAfter evaporation of solvent
10. customin a rotary evaporator (40° C./20 mbar)

ORD record

ord-6d4d3fa3fb494af49c3c758467a01e15

Source dataset

uspto-grants-2010_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07705155B2