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.
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
article in our Journal.