Tobacco Documents Online

CHARGE NUMBER: 2500 PROJECT TITLE: Synthesis of Tobacco Additives PROJECT LEADER: Jeffrey I. Seeman PERIOD COVERED: July 1- 31, 1981 DATE OF REPORT: August 10, 1981 I. Flavor Chemistry We are in the process of preparing a series of 2,6-dialkylpyridines for odor/flavor evaiuati.on. These compounds will be of significant interest because the additi'on of bulky substituents near the pyrfidine nitrogen has been observed to significantliy effect odor, e.g_., for hilghly substituted pyridines, there remains very little "pyridine-like" odor. 2-siec-Butyl-6- methylpyri.dine was obtained by alkylating 2,6-lutidine with isopropyl bromide/ phenyllithium. Purification of the materi.al was achieved by a combination of careful fractional distillation and Chromatotron chromotography. We are in the process of synthesizing additional compounds in this series.' A draft of a patent application for a process of preparing acylpyrazines has been completed.2'3 II. Nicotine Chemistry cis- and trans-4' -Methyinicotines have been purified by careful Chromatotron chromotography.," thereby completing the isolation of the series of monomethylnicotines. These compounds, which are currently undergoing pharmacological testing, have been examined by NMR spectroscopys at high .. magnettc field C36Q MHz and 400 MHz). Spectral data-amenable to line shape analysis, is_now in hand, thereby allowing a goa1of establishing the pyrrolidine ring conformations of these isomeric compounds. This structural information is important in that conformation has been related to pharmaco- logical activity for numerous compounds. Zn collaboration with Ron Bassfield, a procedure has been developed which quantitates the optical purity of nicotine. This lanthanide shift technique has been applied to 5-methyl and 6-methylnicotines. Characterization of optical purity is essential in evaluating the pharmacological activiti.es of chi.ral compounds, in that enantiomers and diastereomers usually have quiite different activity profiles." One_of the.important aspects of pharmacology is the i,solation, identi- fication and characterization of the pertinent receptor(s). For nicotine receptor isolation, the preparation of high specific labeled nicotine would be a significant asset. We have begun to evaluate a number of possible

-2- C r. syntheses of optically pure, "hot" 1-nicotine. Samples of 5'-cyanonicotine have'been successfully reduced to nicotine with both hydrogen gas and deuterium gas in the presence of Pd/C as catalyst. We are currently re- fining and improving these procedures which will eventually be used with carrier-free triti.um (under contract).6 To elucidate the ring-ring conformational features of nicotine, we have been examining the rotational properties of nicotine analogues with Jan Wooten. cis-3`-Methylnicotine-l'-ds, 2,4-dimethylnicotine-l`-d3 and 2,4-dimethylnicoti.ne have been synthesized for these studies.s We have completed the syntheses of optically pure 6-isopropyl-and 6-ethylnlcotine via the free radial alkylation routes and have obtained high optiical' rotat ns for these compaunds.1 We are continuing to have success in the preparation of additional bridged nicotinoids. 3-Cyanoacetamide-2-cyclohexenone was cyclized to 2,3,5,6,7,8-hexahydro-3, 8-dfoxo-4-isoquinoline carbonitrile (74% yield) and decyanated with 48% HBr (42%'yield) to 2,3,5,6,7,8-hexahydro-3,8- di'oxoisoquinoline, a precursor of the quinolone required.° III. RPLC Applications A series of substituted pyridines was run on HPLC and their relative retention volumes correlated excellently with their rate constants of iodomethylation. This novel reactivity-HPLC relationship will assist us in developing additional separation schemes for heteroaromatic compounds in both the nicotine and flavor/odor fields.' Six nicotine reaction mixtures were purified by HPLC and optical rotations were obtained for all the isolated analogues. These studies now serve both as the state-of-the-art models for nicotine purification and also provide us the data for understanding the mechanism of these nicotine reactions.' 1. Clawson, L. 7659 2. Southwick, R. 7447 3. With D. Williams 4. Chavdarian, C. 7594 5. With D. Cox 6. Secor, H. V. 7566 7. Howe, D. 7575