Patent GB-587519-A (GB)
Title: Improvements in or relating barbituric acid derivatives and salts thereof and to methods of producing same
Filed: 1943-05-10
Abstract: 5 : 5-Disubstituted barbituric acids or derivatives thereof having hypnotic and sedative unaccompanied by harmful effects are obtained by condensing a disubstituted malonic ester or a disubstituted cyanoacetic ester having the formula:  <FORM:0587519/IV/1> wherein R and R1 represent alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups each containing not more than six carbon atoms, the number of carbon atoms in R and R1 together not exceeding ten, Z represents a cyano group or a COOR11 group and R11 represents an alkyl group containing not more than six carbon atoms, with urea or N-methyl urea in an organic solvent in the presence of sodium ethylate.  Advantageously when the cyano acetic ester is used the resulting iminobarbiturate is hydrolysed to the corresponding barbituric acid.  Salts of the barbituric acids may be obtained by neutralising the acid with an alkali, ammonia, a primary or secondary alkylamine, an alkylolamine or an alkylene diamine; and the alkali metal salts may be treated with alkaline earth metal salts to obtain the corresponding alkaline earth metal barbituric acid salt.  Preferred R or R1 groups are primary alkyl groups.  Specified R or R1 groups are: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, n-amyl, isoamyl, 2-ethylbutyl, allyl, 2-methylallyl, n-hexyl, secondary and tertiary butyl, -methyl butyl; cyclohexyl D  1-cyclohexenyl. Examples relate to the preparation of: (1) 5-n-butyl-5-ethylthiomethylene barbituric acid by the reaction of ethylthiomethylene-n-butyl malonic ester with urea in the presence of sodium and absolute alcohol; (2) 5-ethyl-5-n-amylthiomethylene barbituric acid by the similar reaction of n-amylthiomethylene ethyl malonic ester with urea; (3) 5-ethyl-5-allylthiomethylene barbituric acid by the similar reaction of allythiomethylene ethyl malonic ester with urea; (4) 5-ethyl-5-cyclohexylthiomethylene barbituric acid by the similar reaction of cyclohexylthiomethylene ethyl malonic ester with urea; (5) 5-ethyl-5-tert.-butylthiomethylene barbituric acid by the similar reaction of tert.-butylthiomethylene ethyl malonic ester with urea; (6) 5-n-butyl-n-butylthiomethylene barbituric acid by the similar reaction of n-butylthiomethylene-n-butyl cyanoacetic ester with urea followed by hydrolysis of the imino barbiturate with hydrochloric acid; (7) 1-nethyl-5-ethyltho methylene-5-methyl barbituric acid by the similar reaction of ethylthiomethylene methyl malonic ester with N-methylurea; (8) 1-methyl-5-ethylthiomethylene-5-isopropyl barbituric acid by the similar reaction of ethylthiomethylene isopropyl malonic ester with N-methyl urea; (9) 1-methyl-5-isopropylthiomethylene-5-ethyl barbituric acid by the similar reaction of isopropylthiomethylene ethyl malonic ester with N-methyl urea; (10) 1-methyl-5-n-butylthiomethylene-5-methyl barbituric acid by the similar reaction of n-butylthiomethylene methyl malonic ester with N-methyl urea.  The preparation of the sodium, calcium, ammonium, alkylamine and alkylolamine salts is described.  Disubstituted malonic esters and cyano acetic esters for use as starting materials may be obtained by treating a halomethyl sulphide of the general formula RS.CH2.Hal with an alkali metal derivative of a malonic or cyanoacetic ester having the general formul  <FORM:0587519/IV/2> respectively, wherein the symbols have the meanings defined above and M represents an alkali metal, in an organic solvent such as toluene or anhydrous ethanol.  In an example diethyl ethyl allylthiomethylene malonate is obtained by treating diethyl ethyl malonate with sodium in alcohol, removing the alcohol, adding toluene, and treating the solution with allyl chloromethyl sulphide.  The esters used in the above examples are obtained similarly.  In the Specification as open to inspection under Sect. 91 the invention comprises the use of 5,5 substituents wherein R and R1 are specified as hydrocarbon groups in general but such that each contains not more than six and together they contain not more than ten carbon atoms.  This subject-matter does not appear in the Specification as accepted.