Dimethylformamide → 2-(1,1-Dimethylethyl)-1,2,3,4-tetrahydro-6-methoxy-2,7-naphthyridine

Temperature

-20 °C

To a stirred solution of 2,2,6,6-tetramethylpiperidine (9.0 mL, 60 mmol) in dry THF (300 mL) under argon at −20° C. was slowly added 1.6M n-BuLi in hexanes (40 mL, 60 mmol) while the temperature was kept at −20° C. After the addition was complete, stirring was continued at −20° C. for 40 min. Then a solution of tert-butyl-[(6-methoxy-4-methylpyridin-3-yl)methylene]amine (6.3 g, 30 mmol) in dry THF (100 mL) was added dropwise at −20° C. The mixture was stirred at −15 to −10° C. for 1.5 h and then cooled to −20° C. Anhydrous DMF (6.5 ml, 70 mmol) was added dropwise over five minutes and stirring continued at −10° C. for 1.5 h. Then glacial acetic acid (60 mL) in MeOH (250 ml) was added, followed by the portion-wise addition of sodium cyanoborohydride (2.3 g, 40 mmol) over five minutes. After stirring overnight, the solvent was evaporated and 20% potassium carbonate solution was added slowly to raise the pH to 9. The mixture was extracted four times with TBME. The combined organic phases were washed with brine, dried and concentrated to give a crude oil. Vacuum distillation gave 5.2 g (77%) of the title compound as a colourless oil, b.p. 105-106° C./0.5 mmHg.

1. customat −20° C.
2. customwas kept at −20° C
3. additionAfter the addition
4. stirringThe mixture was stirred at −15 to −10° C. for 1.5 h
5. stirringstirring
6. waitcontinued at −10° C. for 1.5 h
7. stirringAfter stirring overnight
8. customthe solvent was evaporated
9. addition20% potassium carbonate solution was added slowly
10. temperatureto raise the pH to 9
11. extractionThe mixture was extracted four times with TBME
12. washThe combined organic phases were washed with brine
13. customdried
14. concentrationconcentrated
15. customto give a crude oil
16. distillationVacuum distillation

ORD record

ord-ac59a9a15de54dc0aa4de7a6ce0ef178

Source dataset

uspto-grants-2010_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07655664B2