methyl 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxylate synthesis

Yield:-

Reaction Conditions:

with pyridine;trifluoromethylsulfonic anhydride in dichloromethane at 25; for 6 h;

Steps:

1.b

Example 1; Methyl 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxylate (b) The Title CompoundMethyl 2-oxo-2-((2-oxo-2-(pent-4-en-l-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). Tf₂0 (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 HC1 (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 HC1 (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. ^XH NMR (400 MHz, CDCI₃) ?pm 8.17 (s, 1 H), 7.80-7.86 (m, 1 H), 4.26 (t, J=5.19 Hz, 2 H), 3.92 (s, 3 H), 2.79 (t, J=6.44 Hz, 2 H), 1.97-2.09 (m, 2 H); ¹³C NMR (75 MHz, CDCI₃) δ ppm 165.1 1, 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 CioH_uN0₃Na, 216.0637; found, 216.0643.

References:

WO2012/12391,2012,A2 Location in patent:Page/Page column 10