4-Methylmorpholine → (+/-)5-(2-Fluoromethyl-1,3-oxazol-5-yl)-1-azabicyclo [3.2.1]octane

Temperature

-15 °C

Sodium monofluoroacetate (110mg, 1.1 mmole) was dissolved in dry, distilled N,N-dimethylformamide (20ml), the solution cooled to -15° C., and N-methylmorpholine (0.114ml, 1.0 mmole) added, followed by isobutylchloroformate (0.176ml, 1.1 mmole). The resulting white suspension was stirred for 2-3 minutes. 5-(2-Aminoacetyl)-1-azabicyclo[3.2.1]octane dihydrochloride salt (D24A) (250mg, 1.0 mmol) was suspended in dry N,N-dimethylformamide (20ml) and N-methylmorpholine (0.228ml, 2.0 mmol) added. The resulting suspension was added immediately to the reaction mixture, the suspension stirred for 15-30 min and then allowed to warm to room temperature and stirred for 90 min. The reaction mixture was evaporated to dryness under reduced pressure and polyphosphoric acid (20g) added. The mixture was heated with stirring at 160° C. for 30 minutes and the warm syrup was then poured carefully onto a mixture of solid potassium carbonate and ice. The resulting aqueous solution was saturated with solid potassium carbonate and extracted with ethyl acetate (3×250ml) and chloroform (2×250ml). The organic extracts were dried (Na2SO4), filtered, combined and evaporated to dryness under reduced pressure. The resulting brown oil which was purified by column chromatography (basic alumina eluting with diethyl ether) to yield a pale yellow oil (37mg, 18%), which was converted into the hydrochloride salt m.p. 138°-141° C. (ethyl acetate).

1. customin dry
2. distillationdistilled N,N-dimethylformamide (20ml)
3. additionThe resulting suspension was added immediately to the reaction mixture
4. stirringthe suspension stirred for 15-30 min
5. temperatureto warm to room temperature
6. stirringstirred for 90 min
7. customThe reaction mixture was evaporated to dryness under reduced pressure and polyphosphoric acid (20g)
8. additionadded
9. temperatureThe mixture was heated
10. stirringwith stirring at 160° C. for 30 minutes
11. additionthe warm syrup was then poured carefully onto a mixture of solid potassium carbonate and ice
12. extractionextracted with ethyl acetate (3×250ml) and chloroform (2×250ml)
13. dry with materialThe organic extracts were dried (Na2SO4)
14. filtrationfiltered
15. customevaporated to dryness under reduced pressure
16. customThe resulting brown oil which was purified by column chromatography (basic alumina eluting with diethyl ether)

ORD record

ord-9222c7cab5704084a2b1d85a28c976c2

Source dataset

uspto-grants-1992_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05166357