Toluene → Ethyl 2-(diphenylmethyleneamino)acetate

Temperature

20 °C

To a 250 mL round bottom flask, was added 5.52 g of benzophenone (1 eq), 8.46 g of glycine ethyl ester hydrochloride (1, 2 eq), 67 mL of toluene, and a trace amount of BF3 Et2O. The slurry was heated to reflux (112˜113° C.). Tributylamine (11.2 g) was then added dropwise over 120 min. The reaction mixture was stirred at reflux (114-116° C.) until the area percent (AP) of benzophenone <9.0% by HPLC (22-29 h). The reaction mixture was cooled to 15-25° C. and water (35 mL) was added. After phase separation, the organic phase was concentrated to 50% (w/w) under reduced pressure at <40°. The concentrated solution was then cooled to 20° C., followed by addition of methanol (3 mL). The slurry was cooled to 10° C. and stirred for 30 min. The resultant slurry was filtered. The wet cake was washed with cold water/methanol (5:1 v/v, 2×20 mL), and dried under vacuum at 20° C. for 24 h to give N-(diphenylmethylene)glycine ethyl ester (2) as an off-white to yellow solid (5.5 g, 95% pure by HPLC, 65.6% isolated yield). 1H NMR (CDCl3): δ1.27 (t, J=7.25 Hz, 3H), 4.20 (s, 2H), 4.20 (q, J=7.07, 2H), 7.17-7.67 (m, 10H).

1. temperatureThe slurry was heated
2. temperatureto reflux (112˜113° C.)
3. customAfter phase separation
4. concentrationthe organic phase was concentrated to 50% (w/w) under reduced pressure at <40°
5. temperatureThe concentrated solution was then cooled to 20° C.
6. additionfollowed by addition of methanol (3 mL)
7. temperatureThe slurry was cooled to 10° C.
8. stirringstirred for 30 min
9. filtrationThe resultant slurry was filtered
10. washThe wet cake was washed with cold water/methanol (5:1 v/v, 2×20 mL)
11. customdried under vacuum at 20° C. for 24 h

ORD record

ord-288de55e628e47fea98eb23d765957f5

Source dataset

uspto-grants-2004_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06730809B2