(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one as well as enantiomerically pure forms of 1-azabicyclo[2.2.1]heptan-3-one and mixtures thereof have been shown to be useful in the preparation of compounds which are useful as pharmaceutical agents. See, e.g., U.S. Pat. No. 5,514,812, incorporated herein by reference. Certain compounds formed from enantiomerically pure forms of 1-azabicyclo[2.2.1]heptan-3-one are muscarinic agonists, rendering them useful as pharmaceutical agents in the area of cognition disorders, as disclosed, for example, in U.S. Pat. No. 5,346,911; European Published Applications EP 414,394 A2; EP 427,390 A2; EP 402,056 A2; EP 307,142 A1; and various publications, e.g. H. Tecle et al., BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, 5, 631-636, (1995) ; H. Tecle, et al., BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, 5, 637-642, (1995), all incorporated herein by reference.
In order to be commercially viable, an efficient and cost-effective, large scale process for preparing substantially enantiomerically pure forms of 1-azabicyclo[2.2.1]heptan-3-one isomers is needed. Jakob Boelsterli et al., HELV. CHIM. ACTA, 75, 507-12 (1992) prepared (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one by oxidation of (1S,3S,4R)-1-azabicyclo[2.2.1]heptan-3-ol. See also, U.S. Pat. No. 5,346,911. This route involves the formation of racemic 1-azabicyclo[2.2.1]heptan-3-exo-ol in four or more steps. The racemic alcohol is then resolved using D-tartaric acid (unnatural tartaric acid) by formation of a 1 to 1 salt. (1S,3S,4R)-1-azabicyclo[2.2.1]heptan-3-ol is then freed from the D-tartaric acid and recrystallized several times. The (1S,3S,4R)-1-azabicyclo[2.2.1]heptan-3-ol is then oxidized (Swern oxidation) at low temperatures (-60.degree. C.) to give (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. The crude (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one is then isolated as the hydrochloride salt and recrystallized. A similar reaction sequence is carried out using L-tartaric acid in order to obtain (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one.
Although the route disclosed by the prior art provides (1S,4R)- and (1R,4S)-azabicyclo[2.2.1]heptan-3-ones as the respective hydrochloride salts in high enantiomeric purity, the process is difficult to conduct on large-scale for the following reasons: 1) the process is long, involving at least five steps in addition to the resolution and free alcohol formation steps, 2) the process utilizes a low temperature oxidation step (-60.degree. C.) which requires specialized equipment on a manufacturing scale, and 3) the process relies upon a potentially hazardous oxidation step. In the latter respect, see, e.g., L. Bretherick, "Bretherick's Handbook of Reactive Chemical Hazards", Fourth Edition, Butterworths, Boston, Mass., pp. 299-300 (1990). The known potential alternative to the hazardous oxidation step, utilized in the formation of racemic 1-azabicyclo[2.2.1]heptan-3-one as reported by Spry et al., J. ORG. CHEM, 34, 3674 (1969), does not work as well, and utilizes chromic acid, a toxic and environmentally problematic substance and a known carcinogen. See, e.g., Budavari, S., Ed., THE MERCK INDEX, Twelfth Edition, p. 375, Merck, Whitehouse Station, N.J. (1996). It would be desirable to provide an efficient and economical process for obtaining substantially enantiomerically pure (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one and (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one. It would be further desirable to provide these substantially enantiomerically pure isomers in a stable, easily stored form.