Benzyl chloroformate → Benzyl 2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate

Temperature

-30 °C

4-methoxypyridine (796 g, 7.29 mole) was stirred in 8 L of anhydrous THF in a 20 L reactor. The reactor was cooled to −30° C., then methylmagnesium bromide (5.1 L, 7.29 mole) was added as a 1.4M solution in 3:1 toluene/THF was added via cannula one 800 mL bottle at a time with 800 mls added over a 5 min time period. After the addition was complete and the reaction temperature was −30° C., benzyl chloroformate (1244 g, 7.29 mole) was added dropwise over a 60 min period via addition funnel. The warmest temperature reached was 16° C. After addition was complete the reaction was warmed to 25° C. and stirred for 1.5 hrs. The reaction was cooled to 0° C. and quenched with 4.0 L of 2 N HCl. 4 L of MTBE and brine was added and the layers separated. The temperature was now 25° C. The aqueous phase was extracted with 2×2 L of MTBE. The combined organics were washed with brine and dried over Na2SO4, filtered and concentrated to give the crude oil. Chromatography using a Varian Metaflash 150 long (15 cm×60 cm long 5 kilo silica) and eluting with 10-35% EtOAc/Heptanes gave the product as an oil.

1. additionadded over a 5 min time period
2. additionAfter the addition
3. customwas −30° C.
4. customreached was 16° C
5. additionAfter addition
6. temperaturewas warmed to 25° C.
7. temperatureThe reaction was cooled to 0° C.
8. customquenched with 4.0 L of 2 N HCl
9. addition4 L of MTBE and brine was added
10. customthe layers separated
11. customwas now 25° C
12. extractionThe aqueous phase was extracted with 2×2 L of MTBE
13. washThe combined organics were washed with brine
14. dry with materialdried over Na2SO4
15. filtrationfiltered
16. concentrationconcentrated
17. customto give the crude oil
18. washeluting with 10-35% EtOAc/Heptanes

ORD record

ord-1e352103c9ff4a84a7c1fc80d06f3a97

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08211904B2