Iodine → HCID 11644438, compound

3-Bromobenzotrifluoride (1.46 g, 6.5 mmol) was added over 5-10 minutes as a solution in diethyl ether (5 mL) dropwise to magnesium turnings (0.145 g, 5.9 mmol) in diethyl ether (2 mL), under an atmosphere of nitrogen with iodine (1 crystal) to initial reaction. The dropping funnel was washed with diethyl ether (3 mL total). The reaction was allowed to reach reflux during the addition of the bromide and then allowed to cool to room temperature and stirred for a further 1 hr. Copper (I) iodide (103 mg, 0.54 mmol) was added in one portion and the reaction mixture cooled to 0° C. over 10 minutes. (S)-epichlorohydrin (0.5 g, 5.4 mmol) was added as a solution in diethyl ether (3 mL) over 10 minutes and the reaction allowed to warm to room temperature. After 2 hrs methanol (10 mL) was added and the resulting suspension stirred vigorously. Then sodium hydroxide (1.73 g, 43 mmol) was added as a solution in water (2.7 mL), followed by more methanol (4 mL) to try to loosen the precipitate formed, and 2-aminoethane hydrogen sulfate (3.05 g, 21.6 mmol) was added. The mixture was warmed to 42° C. (bath temperature) for 2 hrs, then toluene (10 mL) and sodium hydroxide (1.35 g, crushed, 33.8 mmol) added and the resulting green paste heated at 70° C. (bath temperature) for 18 hrs. The reaction was allowed to cool to room temperature, poured into water (40 mL) and extracted with toluene (20 mL) and ethyl acetate (20 mL×2). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; triethylamine/ethanol/ethyl acetate, 1/20/79 ratio) to yield the desired morpholine. The morpholine (0.27 g) was dissolved in diethyl ether (3 mL total) and added to a solution of fumaric acid (0.119 g, 1.03 mmol) in IPA (2 mL) at 40° C. and the solution allowed to cool to room temperature. The precipitate was filtered out and washed with diethyl ether and dried in vacuo to yield the desired morpholine 74 as a fumarate salt as a white powder (0.284 g).

1. customreaction
2. washThe dropping funnel was washed with diethyl ether (3 mL total)
3. temperatureto reach reflux during the addition of the bromide
4. temperaturethe reaction mixture cooled to 0° C. over 10 minutes
5. temperatureto warm to room temperature
6. stirringthe resulting suspension stirred vigorously
7. customformed
8. temperatureThe mixture was warmed to 42° C. (bath temperature) for 2 hrs
9. temperaturethe resulting green paste heated at 70° C. (bath temperature) for 18 hrs
10. temperatureto cool to room temperature
11. extractionextracted with toluene (20 mL) and ethyl acetate (20 mL×2)
12. washThe combined organic layers were washed with brine (10 mL)
13. dry with materialdried (MgSO4)
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customThe residue was purified by column chromatography (silica; triethylamine/ethanol/ethyl acetate, 1/20/79 ratio)

ORD record

ord-65a76ddcecad4776a85805c540211a90

Source dataset

uspto-grants-2008_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07323466B2