3-Pyridinecarboxaldehyde → HCID 22311394, compound

The manner in which 2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octanes, 2-(2-phenyl-1-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octanes and 2-(3-phenyl-1-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octanes of the present invention can be synthetically produced can vary. For example, pyridine-3-carboxaldehyde and quinuclidin-3-one hydrochloride (commercially available from Aldrich) are reacted together in the presence of methanolic potassium hydroxide as described in Neilsen and Houlihan, Org. React. 16: 14-38 (1968) to give the aldol condensation product, 2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one as a crystalline solid. 2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one can then be converted to 2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane-3-one by treatment with phenylmagnesium bromide in ethanol at −10° C. The ketone is then treated with sodium borohydride to yield the alcohol, 2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-ol. This intermediate is reacted with neat thionyl chloride at room temperature to give 3-chloro-2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane as a crystalline solid. Removal of the chlorine is accomplished by hydrogenation in the presence of Raney nickel as described by de Koning, Org. Prep. Proced Int. 7:31 (1975) to give the desired product, 2-(1-phenyl-1-(3-pyridyl)methyl)-1-azabicyclo[2.2.2]octane. The related compounds, 2-(2-phenyl-1-(3-pyridyl)ethyl)-1-azabicyclo[2.2.2]octane and 2-(3-phenyl-1-(3-pyridyl)propyl)-1-azabicyclo[2.2.2]octane can be prepared in a similar manner by replacing phenylmagnesium bromide with benzylmagnesium bromide or 2-phenethylmagnesium bromide, respectively, in the synthetic approach given above.

1. customReact
2. custom16: 14-38 (1968) to give

ORD record

ord-3476f329fa274539aec3d1835590314c

Source dataset

uspto-grants-2002_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06432975B1