SYNTHESIS OF NORNICOTINE ANALOGS TO USE AS HAPTENS FOR IMMUNOASSAYS

Analogs of N''-substituted nornicotines were synthesized with functional groups that can be covalently linked to macromolecules for antibody production. The key intermediate, trans-3''-(hydroxymethyl)nornicotine was prepared from 3-pyridinecarboxaldehyde by a 4-step synthesis. 5-Bromo-3-carboxypyridine, 5-bromonicotine and 5-bromo-N''-nitrosonornicotine were also obtained. As shown by 1H NMR and high-pressure liquid chromatography, the analogs of N''-nitrosonornicotine crystallize preferentially as the N''-nitroso E isomer. Several analogs of nornicotine with a N-substituted pyrrolidine ring are present in tobacco and tobacco smoke. These alkaloids are very likely derived from the major tobacco alkaloid nicotine. One of these, N''-nitrosonornicotine, is carcinogenic in rats, mice and hamsters.