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          Journal of the American Chemical Society 73, 5779 (1951)

   [Contribution from the research division, Wallace Laboratories, Inc.]

          Some Anticonvulsant Agents Derived from 1,3-Propanediols

                      By B. J. Ludwig and E. C. Piech

        A number of mono- and dicarbamate esters of 2,2-disubstituted
1,3-propanediols have been prepared for evaluation as anticonvulsants. The
dicarbamate esters were synthesized by phosgenation of the substituted
propanediols followed by amidization of the bis-(chlorocarbonate)
derivatives. The monocarbamate esters were obtained by ammonolysis of the
cyclic carbonates prepared from the substituted propanediols.

        The anticonvulsant properties of 2,2-disubstituted
1,3-propanediols, a class of compounds bearing little sructural
relationships with the accepted anticonvulsants, have recently described.
Pharmacological studies on 2,2-diethyl-1,3-propanediol, one of the more
active members of this series, indicated that this compound had a powerful
but short anticonvulsant action. It was also found that the actions of
certain esters was of longer duration than resulting from the diol itself.
In an extension to this study, a number of mono- and dicarbamate esters of
2,2-disubstituted 1,3-propanediols have been prepared for pharmacological
evaluation as potential anticonvulsant agents. This paper describes the
synthesis and physical properties of these compounds. The results of the
pharmacological studies carried out on these compounds will be described
elsewhere.
        Of the variety of procedures which have appeared in the litterature
for the preparation of carbamates, we found the method described by Oesper,
Broker and Cook most suitable for the conversion of dihydric alcohols to
the corresponding dicarbamate derivatives. This method consists of low
temperature phosgenation of the substituted 1,3-propanediol in an intert
medium in the presence of a tertiary amine, followed by conversion of the
bis-(chlorocarbonate) derivative to the desired diamide. In our experience
antipyrine gave consistently higher over-all yields of pure carbamates than
the other tertiary amines used in the acylation reaction. Although the
substituted 1,3-propanediol bis-(chlorocarbonate) derivatives could be
readily isolated an purified by distillation, it was advantageous to
convert them directly to the diamide by direct ammoniation of the phosgene
reaction mixture.
        Monocarbamate derivatives of 1,3-propanediols could be prepared in
a similar manner, using an equimolar ratio of phosgene and diol, but this
reaction yielded, in addition to the desired monocarbamate derivative, a
considerable amount of unreacted diol and appreciable quantities of the
dicarbamate and cyclic carbamate derivatives. The difficulty of separating
these products could be avoided by forming the monocarbamates through
ammonolysis of the cyclic carbonate esters. The latter compounds were
prepared by the reaction of equimolar quantities of phosgene and
propanediol in the presence of antipyrin at a temperature somewhat higher
than that found most suitable for chlorocarbonate formation.
        The carbamate and carbonate esters prepared in this study were
white crystalline solids or high boiling liquids. Except for the lower
members of the monocarbamate series, which possess considerable water
solubility, these compounds are relatively insoluble in water.

                                Experimental

PREPARATION OF 2,2-DISUBSTITUTED 1,3-PROPANEDIOLS
2,2-dimethyl-, diethyl-, methyl-n-propyl-, and ethyl-n-butyl-1,3propanediol
were prepared by the conensation of formaldehyde with isobutyraldehyde.
2-ethylbutyraldehyde, 2-methylvaleraldehyde and 2-ethylhexylaldehyde,
respectively, following the procedure of [JACS 70, 946 (1948)]. The
remaining 1,3-propanediols were obtained by reduction of the corresponding
substituted malonic esters with lithium aluminum hydride.

PREPARATION OF 2,2-DISUBSTITUTED 1,3-PROPANEDIOL DICARBAMATES
The following procedure illustrates the method that was adopted for the
preparation of the dicarbamates listed in Table 1. To a solution of 20g
(0.2 mole) of phosgene in 200 ml of toluene at -10øC there was added with
stirring a cooled solution of 13.2 grams (0.1 mole) of 2,2-diethyl-1,3-
propanediol, and 38 g (0.2 mole) of antipyrine in 100 ml of chloroform, at
such a rate that the temperature of the reaction mixture was maintained at
-5øC to 0øC. The mixture was allowed to warm slowly to room temperature and
to remain at this temperature overnight. The antipyrine hydrochloride was
removed by filtration, and the chlorocarbonate was converted directly to
the amide by treating the filtrate with gaseous ammonia with moderate
cooling. The amide was separated by filtration, freed from ammonium
chloride by extracting with 250 ml of cold water and recryztallized from
hot water; 17.5 g. (80%) of 2,2-diethyl-1,3-propanediol dicarbamate, mp
149-150øC was obtained. [...]
        The dicarbamate esters of 1,3-propanediols substituted with higher
alkyl groups sometimes remained in solution following treatment with
ammonia. In these cases, the amide was obtained by evaporation of the
toluene-chloroform solvent under reduced pressure. All of the dicarbamates
prepared was crystallized from water, and over-all yields of 60-90%
purified compounds were obtained. [...]

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