Hydrochloric Acid → (E)-5-(2-(7-azabicyclo[2.2.1]hept-2-yl)ethenyl)isoxazole

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Reaction Steps

The manner in which arylethenyl- and arylethynyl-substituted 7-azabicyclo[2.2.1]heptane compounds of the present invention are synthetically produced can vary. Ethyl 7-aza-2-formylbicyclo[2.2.1]heptane-7-carboxylate can be utilized as a key intermediate in the synthetic pathway. Treatment of tropinone with ethyl chloroformate provides ethyl 8-aza-3-oxobicyclo[3.2.1]octane-8-carboxylate which is readily converted to ethyl 8-aza-2-bromo-3-oxobicyclo[3.2.1]octane-8-carboxylate upon treatment with bromine and 30% hydrogen bromide in acetic acid. Subsequent Favorski ring contraction using freshly prepared sodium ethoxide in ethanol provides ethyl 7-aza-2-(ethoxycarbonyl)bicyclo[2.2.1]heptane-7-carboxylate, as reported by Daly et al. Eur. J. Pharmacol. 321: 189-194 (1997). Di-isobutylaluminum hydride reduction of the ester functionality provides ethyl 7-aza-2-formylbicyclo[2.2.1]heptane-7-carboxylate in modest overall yield. Horner-Wadsworth-Emmons reaction between diethyl (5-isoxazolylmethyl)phosphonate and ethyl 7-aza-2-formylbicyclo[2.2.1]heptane-7-carboxylate provides a mixture of ethyl (E)-5-(2-(7-azabicyclo[2.2.1]hept-2-yl)ethenyl)isoxazole carboxylate and ethyl (Z)-5-(2-(7-azabicyclo[2.2.1]hept-2-yl)ethenyl)isoxazole carboxylate. The two isomers are readily separated by chromatography. Diethyl (5-isoxazolylmethyl)phosphonate is prepared according to the method described in Deshong et. al. J. Org. Chem. 53: 1356-1364 (1988). Deprotection of the amine functionality of ethyl (E)-5-(2-(7-azabicyclo[2.2.1]hept-2-yl)ethenyl)isoxazole carboxylate using hydrochloric acid affords (E)-5-(2-(7-azabicyclo[2.2.1]hept-2-yl)ethenyl)isoxazole. The synthesis of this compound is described as Example 1. Alternatively, the treatment of ethyl 7-aza-2-formylbicyclo[2.2.1]heptane-7-carboxylate with 5-(lithiomethyl)isoxazole and dehydration of the resulting alcohol as described in U.S. Pat. No. 6,022,868 to Olesen et. al. followed by removal of the ethyl carbamate protecting group will provide (E)- and (Z)-5-(2-(7-azabicyclo[2.2.1]hept-2-yl)ethenyl)isoxazole.

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