Epichlorohydrin → 3-(Chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine

Temperature

170 °C

A solution of (3R)-morpholin-3-ylmethanol (4.21 g, 36.0 mmol) in 2-(chloromethyl)oxirane (28.2 mL, 0.360 mol) was heated to 40° C. for 3 h and then the solution was concentrated in vacuo. The intermediate was cooled in an ice bath and treated with 30.0 mL of concentrated sulfuric acid. The mixture was heated to 170° C. for 2 h and then allowed to cool to room temperature. The mixture was poured into ice-water and solid sodium bicarbonate was carefully added until the solution was basic. 10% methanol in ethyl acetate was added and the biphasic mixture was filtered. The layers were separated and the aqueous layer was extracted (3×100 mL 10% methanol in ethyl acetate). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (SiO2, 2:5 hexanes:ethyl acetate) provided 3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine 2.44 g (35%) as two separated diastereomers. (3R,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine: (0.886 g, 13% yield): 1H NMR (400 MHz, CDCl3): 3.91 (m, 3H), 3.82 (m, 1H), 3.68 (dt, 1H), 3.61 (dd, 1H), 3.47 (dd, 1H), 3.35 (t, 1H), 3.19 (t, 1H), 2.80 (d, 1H), 2.54 (m, 2H), 2.40 (m, 2H); MS (EI) for C8H14NO2Cl: 192 (MH+). (3S,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine: (1.55 g, 22% yield): 1H NMR (400 MHz, CDCl3): 3.85 (m, 2H), 3.73 (m, 3H), 3.50 (m, 2H), 3.29 (t, 1H), 3.18 (t, 1H), 2.85 (dd, 1H), 2.64 (dd, 1H), 2.40 (m, 2H), 2.17 (t, 1H); MS (EI) for C8H14NO2CI: 192 (MH+).

1. concentrationthe solution was concentrated in vacuo
2. temperatureThe intermediate was cooled in an ice bath
3. additiontreated with 30.0 mL of concentrated sulfuric acid
4. temperatureto cool to room temperature
5. additionThe mixture was poured into ice-water and solid sodium bicarbonate
6. additionwas carefully added until the solution
7. addition10% methanol in ethyl acetate was added
8. filtrationthe biphasic mixture was filtered
9. customThe layers were separated
10. extractionthe aqueous layer was extracted (3×100 mL 10% methanol in ethyl acetate)
11. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo

ORD record

ord-62eb1da46d404dbf9ee600f14d12395d

Source dataset

uspto-grants-2009_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07579473B2