Methanol → 4-(2,3-Epoxypropyl)morpholine

Temperatur

250 °C

To 1 L 3-neck round bottom flask, fitted with mechanical stirring, thermocouple and addition funnel, was charged morpholine (91.5 g, 91.5 ml, 1.05 mole, 1.0 eq.) and 200 ml of methanol. The solution was stirred rapidly while adding R-epichlorohydrin (100 g, 84.5 ml, 1.08 mole, 1.03 eq.) from the addition funnel over about 30 minutes. The temperature was monitored and when the pot temperature reached 27° C., the reaction was cooled with an ice water bath. The clear solution was stirred for 18 hours. The reaction was assayed by GC (dilute 5 drops of reaction mixture into 1 ml of ethanol and inject onto a 15 m DB-5 capillary GC column with the following run parameters, Injector 250° C., detector 250° C., initial oven temperature 28° C. warming to 250° C. at 10° C. per minute.) The reaction was complete with less than 3% morpholine remaining. The solution was cooled to 10° C. and a 25 wt. % solution of sodium methoxide in methanol (233 g, 1.08 mole, 247 ml) was added dropwise keeping the temperature less than 15° C. The resulting white slurry was stirred at 10-15° C. for 2 hours and checked by GC using the above conditions. None of the chlorohydrin could be observed. The mixture was concentrated on the rotoevaporator using 50° C. bath and full house vacuum. The resulting mixture was diluted with water (500 ml) and methylene chloride. The phases were separated and the aqueous phase washed with methylene chloride (500 ml). The combined organic layers were dried over sodium sulfate and concentrated to a clear, colorless oil. This provided 145 g, 97% yield of 1,2-epoxy-3-morpholin-4-ylpropane. 1H NMR (400 MHz, DMSO-d6) δ 3.3 (dd, 4H), 3.1 (m, 1H), 2.6 (dd, 1H), 2.5 (dd, 1H), 2.4 (m, 4H), 2.2 (dd, 2H); 13C NMR (100 MHz, DMSO-d6) δ 65.4, 60.1, 53.1, 48.9, 43.4.

1. customTo 1 L 3-neck round bottom flask, fitted with mechanical stirring
2. additionthermocouple and addition funnel
3. customreached 27° C.
4. temperaturethe reaction was cooled with an ice water bath
5. stirringThe clear solution was stirred for 18 hours
6. additiondilute
7. customwith the following run parameters, Injector 250° C.
8. customdetector 250° C.
9. temperatureThe solution was cooled to 10° C.
10. customthe temperature less than 15° C
11. stirringThe resulting white slurry was stirred at 10-15° C. for 2 hours
12. concentrationThe mixture was concentrated on the rotoevaporator
13. customusing 50° C.
14. additionThe resulting mixture was diluted with water (500 ml) and methylene chloride
15. customThe phases were separated
16. washthe aqueous phase washed with methylene chloride (500 ml)
17. dry with materialThe combined organic layers were dried over sodium sulfate
18. concentrationconcentrated to a clear, colorless oil

ORD-Eintrag

ord-db05c6fd466b4352a4d8e2401f6d36c8

Quelldatensatz

uspto-grants-2009_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07582756B2