Copyright © 1996, 1997, 2001 by Galen Daryl Knight and VitaleTherapeutics, Inc.

VitaleThine is not a Trivial Synthesis.

Hydrogen Bromide Salts

One researcher has reported foul odors coming from his attempts to synthesize vitalethine through the phosgenation of ß-alethine. More than likely this results from his use of the hydrogen bromide salt (or that which is incompletely converted to the hydrogen chloride salt). The hydrogen bromide salt will cause the production of dimethyl sulfide from the dimethyl sulfoxide in this reaction mixture and generate bromine which can brominate the amines of ß-alethine. Logically, ß-alethine must be completely converted from the hydrogen bromide to the the hydrogen chloride salt to produce any vitalethine from the phosgenation reaction.

Mixing of the Reaction

Theoretically, the best phosgenation reaction will occur at the interface between 1) all of the reagents (except phosgene) that were stirred and frozen at crushed dry ice temperatures (not dry ice bath temperatures) and 2) the phosgene in toluene that is added last without stirring. This allows very high concentrations of phosgene relative to ß-alethine at the interface and ensures that the disulfide will react with two equivalents of phosgene, and not just one, as the reaction propagates through the melting solid phase. The ZnO used is so flocculent that it floats on this mixture instead of sinking to the bottom, so it is concentrated at the interface to help neutralize the reaction where it is occurring. Also, the vent to the NaOH trap remains open during the reaction to allow any excess HCl and phosgene to escape. It seems only prudent for safety reasons to prevent the build-up of excessive pressure from the exothermic reaction in a glass reaction vessel containing a chemical warfare agent in this manner. Neutralization of phosgene and HCl through this vent is probably accompanied by a gentle back-hydration of the reaction products with water vapor which likely stabilizes the vitalethine produced, as its carbonimidic tautomer. After blowing out the volatilized phosgene with nitrogen and pouring off the liquid portion of the finished reaction, it is important to rinse the remaining dense precipitate on the glass walls with acetonitrile to remove as much of the phosgene, HCl, and zinc chloride as possible before resuspending in a small volume of pure water neutralized with a small excess of ZnO (remaining solid); resuspending in deuterated instead of protonated water at this point facilitates NMR spectral analysis and may produce some beneficial isotopic stabilization of the carbamate/imidocarbonate bond. There are strong indications from the carbon NMR that the vitaletheine modulators prefer the carbonimidate tautomer in aqueous solution.

Zinc Oxide

The zinc oxide preparation used in the reported synthesis is no longer available from the reported supplier. It is a highly flocculent dentifrice-grade ZnO. If not finely divided (wispy, easily-blown-away powder) the zinc oxide may not dissolve fast enough to neutralize the reaction, thereby resulting in acid-catalyzed hydrolysis of the carbamate/imidocarbonate bonds as they are formed.

There is little need to worry about excess zinc ions in the preparation of vitalethine since the pH of aqueous solutions of zinc oxide rarely exceeds 7.0, since zinc chloride appears to be soluble in acetonitrile, and since excess ZnO, being practically insoluble in water, can be filtered out of aqueous solutions prior to precipitation with acetonitrile. Make sure the reaction is neutralized by ZnO by adding excess.

Sublimation of zinc oxide from zinc salts of the vitaletheine modulators under reduced pressure can be problematic, essentially dehydrating these salts under anhydrous conditions which sometimes can rehydrate to different products. Handling and storage of the hydrated zinc salts at ambient pressure (or even hyperbaric pressures of ZnO) are therefore preferred until other handling and storage strategies can be devised.

Concentration Factors in NMR

NMR specta of vitalethine reported in this Web Page were obtained on a 100 mg sample. Since a variety of reaction products from attempts to synthesize the vitaletheine modulators have aggregated solvents to form inclusion complexes, it seems possible that the abundance of any particular tautomer may be a function of the concentration of vitalethine in the carbon NMR sample. Comparable concentrations for NMR spectral analysis of vitalethine are encouraged to see the peak at about 100 ppm.

In Depth Chemical Discussion

Particulars about the syntheses and characterizations of the vitaletheine modulators are discussed extensively in the first article in our Journal.


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