Pyridine → Methyl 3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-carboxylate

Temperature

25 °C

Methyl 2-oxo-2-((2-oxo-2-(pent-4-en-1-yloxy)ethyl)amino)acetate (42.5 g, 1 eq) and dichloromethane (DCM) (425 mL) were added to a vessel with stirring followed by the addition of pyridine (17.6 g, 1.2 eq). Tf2O (78.5 g, 1.5 eq) was added over 45 min to the mixture maintaining an internal temperature of ˜25° C. The mixture was stirred for 6 h at which point the reaction was carefully quenched by the addition of 20 wt % aqueous NaOAc (255 mL) to form a biphasic solution. The aqueous layer was extracted with DCM (85 mL). The combined organic layers were washed first with water (127.5 mL) and 10 wt % citric acid solution (170 mL). 6N HCl (127.5 mL) was added to the mixture to form a biphasic mixture. The two layers were separated and the organic layer was extracted with 6 N HCl (85 mL). The acidic aqueous layers were combined and DCM (127.5 mL) was added. While maintaining the temperature below 25° C., 28 wt % aqueous NH4OH was slowly added until the pH of the aqueous layer reached 3-5. The two layers were separated and the aqueous layer was extracted with DCM (85 mL). The combined organic layers were washed with water (85 mL). The organic solution was concentrated under reduced pressure to provide the title compound as an oil which solidified on standing. 1H NMR (400 MHz, CDCl3) δ ppm 8.17 (s, 1H), 7.80-7.86 (m, 1H), 4.26 (t, J=5.19 Hz, 2H), 3.92 (s, 3H), 2.79 (t, J=6.44 Hz, 2H), 1.97-2.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ ppm 165.11, 154.25, 138.95, 138.64, 130.06, 126.13, 65.55, 51.99, 23.57, 20.67; HRMS (M+Na) m/z, calcd for C10H11NO3Na, 216.0637; found, 216.0643.

1. stirringThe mixture was stirred for 6 h at which
2. customwas carefully quenched by the addition of 20 wt % aqueous NaOAc (255 mL)
3. customto form a biphasic solution
4. extractionThe aqueous layer was extracted with DCM (85 mL)
5. washThe combined organic layers were washed first with water (127.5 mL) and 10 wt % citric acid solution (170 mL)
6. addition6N HCl (127.5 mL) was added to the mixture
7. customto form a biphasic mixture
8. customThe two layers were separated
9. extractionthe organic layer was extracted with 6 N HCl (85 mL)
10. additionDCM (127.5 mL) was added
11. temperatureWhile maintaining the temperature below 25° C., 28 wt % aqueous NH4OH
12. additionwas slowly added until the pH of the aqueous layer
13. customThe two layers were separated
14. extractionthe aqueous layer was extracted with DCM (85 mL)
15. washThe combined organic layers were washed with water (85 mL)
16. concentrationThe organic solution was concentrated under reduced pressure

ORD record

ord-513eb40a50ca4208b987d002439e4a8c

Source dataset

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08759523B2