Sodium Bicarbonate → 1-Benzhydryl-3-cyclopropyl-3-fluoroazetidine hydrochloride

Temperature

0 °C

Saturated NaHCO3 (100 ml) was added to a suspension of 1-Benzhydryl-3-cyclopropylazetidin-3-ol hydrochloride (7.78 g, 24.50 mmol) in ethyl acetate (100 ml). The mixture was transferred to a separating funnel and shaken vigorously until all of the solid had dissolved. The organic layer was separated and the aqueous extracted further with ethyl acetate (50 ml). The combined organic extracts were dried (Na2SO4) and concentrated an oil. The oil was dissolved in dichloromethane (100 ml) and cooled to −78° C. [bis(2-methoxyethyl)amino]sulfur trifluoride (5.98 g, 27.05 mmol, 5.0 ml) was added dropwise and the solution stirred for 30 mins at −78° C. and then warmed to 0° C. and stirred for a further 1 hr. Reaction was quenched with Saturated NaHCO3 (50 ml) and brine (50 ml) and the aqueous layer extracted with dichloromethane (50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give a yellow oil. The crude was purified on silica gel, eluting with 5% ethyl acetate/petrol. The resulting alcohol was dissolved in ether (100 ml) and the solution cooled to 0° C. A solution of HCl in ether (2M, 25 ml) was then added dropwise over 5 minutes. The HCl salt precipitated from solution. The resulting slurry was stirred at 0° C. for an additional 10 minutes then filtered. The filter cake washed with ether (20 ml) and the solid dried under vacuum. This furnished the product as a white solid (4.71 g, 61%). 1H NMR d4-MeOH δ 0.30-0.52 (4H, m), 1.22 (1H, brs), 4.01-4.23 (4H, m), 5.50-5.60 (1H, brs), 7.13-7.46 (10H, m); ES+ 282.

1. customThe mixture was transferred to a separating funnel
2. dissolutionhad dissolved
3. customThe organic layer was separated
4. extractionthe aqueous extracted further with ethyl acetate (50 ml)
5. dry with materialThe combined organic extracts were dried (Na2SO4)
6. concentrationconcentrated an oil
7. dissolutionThe oil was dissolved in dichloromethane (100 ml)
8. additionwas added dropwise
9. stirringthe solution stirred for 30 mins at −78° C.
10. stirringstirred for a further 1 hr
11. customReaction
12. customwas quenched with Saturated NaHCO3 (50 ml) and brine (50 ml)
13. extractionthe aqueous layer extracted with dichloromethane (50 ml)
14. dry with materialThe combined organic extracts were dried (Na2SO4)
15. concentrationconcentrated
16. customto give a yellow oil
17. customThe crude was purified on silica gel
18. washeluting with 5% ethyl acetate/petrol
19. dissolutionThe resulting alcohol was dissolved in ether (100 ml)
20. temperaturethe solution cooled to 0° C
21. additionA solution of HCl in ether (2M, 25 ml) was then added dropwise over 5 minutes
22. customThe HCl salt precipitated from solution
23. stirringThe resulting slurry was stirred at 0° C. for an additional 10 minutes
24. filtrationthen filtered
25. washThe filter cake washed with ether (20 ml)
26. customthe solid dried under vacuum

ORD record

ord-5b60ff1ce43642388b8d6f9505c18b0b

Source dataset

uspto-grants-2009_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07528142B2