Epichlorohydrin → HCID 53630914, compound

Temperature

40 °C

(S)-(+)-Prolinol (6.00 g, 59.3 mmol) was added to epichlorohydrin (47 mL, 600 mmol) at 0° C. The solution was stirred at 40° C. for 0.5 h and then concentrated in vacuo. The residual oil was cooled in an ice bath and concentrated sulfuric acid (18 mL) was added dropwise with stirring. The mixture was heated at 170-180° C. for 1.5 h, poured into ice (300 mL) and then basified with sodium carbonate to pH˜8. The mixture was partitioned with ethyl acetate/hexanes and filtered. The filtrate was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford oil that was purified by column chromatography (ethyl acetate for less polar product and then 30% methanol in ethyl acetate). (3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (less polar product) (1.87 g, 10.7 mmol, 18% yield): 1H NMR (400 MHz, CDCl3): 4.06 (dd, 1H), 3.79-3.71 (m, 1H), 3.60-3.48 (m, 2H), 3.36 (dd, 1H), 3.15 (dd, 1H), 3.13-3.06 (m, 1H), 2.21-2.01 (m, 3H), 1.90-1.68 (m, 3H), 1.39-1.24 (m, 1H); MS (EI) for C8H14NOCl: 176 (MH+). (3R,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (1.54 g, 8.77 mmol, 15% yield): 1H NMR (400 MHz, CDCl3): 3.94-3.77 (m, 4H), 3.55 (dd, 1H), 3.02-2.93 (m, 2H), 2.45 (dd, 1H), 2.29-2.15 (m, 2H), 1.88-1.64 (m, 3H), 1.49-1.38 (m, 1H); MS (EI) for C8H14NOCl: 176 (MH+).

1. concentrationconcentrated in vacuo
2. temperatureThe residual oil was cooled in an ice bath
3. additionconcentrated sulfuric acid (18 mL) was added dropwise
4. stirringwith stirring
5. temperatureThe mixture was heated at 170-180° C. for 1.5 h
6. additionpoured into ice (300 mL)
7. customThe mixture was partitioned with ethyl acetate/hexanes
8. filtrationfiltered
9. customThe filtrate was separated
10. extractionthe aqueous portion was extracted twice with ethyl acetate
11. dry with materialThe combined organic portion was dried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customto afford oil that
15. customwas purified by column chromatography (ethyl acetate for less polar product

ORD record

ord-00b74661d92e4d0aa2beddda544a0c4d

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08178532B2