Synthesis of Meprobamate (Miltown)
[ Back to the Chemistry Archive ]
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.
Preparation of 2,2-disubstituted 1,3-propanediols
2,2-dimethyl-, diethyl-, methyl-n-propyl-, and ethyl-n-butyl-1,3-propanediol 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 -10°C 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 -5°C to 0°C. 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 149-150°C 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. [...]
Reference: Journal of the American Chemical Society 73, 5779 (1951)