1-Nitroethylene → 2'H-Spiro[1-azabicyclo[2.2.2]octane-2,3'-pyrrolidin]-2'-one

The compounds of Formula 2, wherein u=1, v=2, w=1, x=0, y=2 and z=2, possess the spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine] core and can be prepared in a manner similar to that for the corresponding spiro[1-azabicyclo[2.2.1]heptane-2,3′-pyrrolidine], as seen in Scheme 11. Ethyl quinuclidine-2-carboxylate can be generated from (4-bromomethyl)tetrahydropyran by the procedures discussed previously for ethyl 1-azabicyclo[2.2.1]heptane-2-carboxylate. The requisite 4-(bromomethyl)tetrahydropyran can be prepared according to procedures found in Burger, et al., J. Am. Chem. Soc. 72:5512 (1950), Thomas, et al., J. Pharm. Pharmacol. 15:167 (1963) and J. Am. Chem. Soc. 115:8401 (1993). Ethyl quinuclidine-2-carboxylate is then deprotonated with lithium diisopropylamide and reacted with nitroethylene. Subsequent treatment with Raney nickel gives directly the spirolactam, spiro[azabicyclo[2.2.2]octane-2,3′-pyrrolidine]-2′-one, by reduction of the nitro group followed by spontaneous cyclization. This lactam is then reduced with lithium aluminum hydride to provide the desired spiro[1-azabicyclo[2.2.2]octane-2,3′-pyrrolidine], which is then arylated on the pyrrolidine nitrogen.

ORD record

ord-35fc12137c184ff599f9a898db49ed79

Source dataset

uspto-grants-2008_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07375110B2