Patent GB-436200-A (GB)
Title: Process for the manufacture of new compounds of the hydrouracile series
Filed: 1934-01-02
Abstract: Compounds of the hydrouracil series are prepared by condensing b -amino acids substituted by two hydrocarbon radicles on the a  carbon atom, or their carboxylic derivatives such as esters, amides, or alkylamides, with carboxylic acids, their salts or esters, cyanamide, mustard oils, S-alkyl isothioureas, or carbonic acid derivatives such as chloroformic ester.  These compounds have the general formula <FORM:0436200/IV/1> where R1 and R2 are aliphatic, alicyclic or aromatic hydrocarbon radicles, and R3, R4, and R5 either hydrogen or hydrocarbon radicles.  The intermediate products first produced readily undergo change with ring closure, in some cases with the use of condensing agents.  Those derivatives containing a CS or C = NH instead of a CO group are converted by the use of a desulphurizing or saponifying agent.  The following examples are given: (1) the hydrochloride of the ethyl ester of b -amino-a -diethyl propionic acid, obtained by catalytic reduction of the ethyl ester of diethyl-cyanacetic acid, is heated with aqueous potassium cyanate. The ethyl ester of b -ureido-a -diethylpropionic acid precipitates. The ester is condensed with a solution of sodium in ethyl or other alcohol, the alcohol removed, the remaining sodium salt dissolved in water and neutralized with acid to precipitate 5-diethylhydrouracil which is purified by recrystallization from alcohol.  (2) The ethyl ester of b -methylamino-a -diethylpropionic acid, made by partial methylation of the ethyl ester of b -amino-a -diethylpropionic acid, is neutralized with hydrochloric acid and treated with potassium cyanate as in (1) to obtain a ureido ester, which is condensed with sodium ethylate to give 1-methyl-5-diethylhydrouracil.  (3) The hydrochloride of the methylamide of b  - amino - a  - diethylpropionic acid, made by catalytic reduction of the methylamide of diethylcyanacetic acid, is treated with caustic soda and the ethyl ester of chloroformic acid to give the methylamide of b -carbethoxyamino-a -diethylpropionic acid.  This is condensed with sodium ethylate to obtain 3-methyl-5-diethylhydrouracil.  (4) The ethyl ester of b -amino-a -diethylpropionic acid is treated with methyl isocyanate to give the ethyl ester of b -N<1>-methyl-ureido-a -diethylpropionic acid.  This with sodium ethylate gives the same product as (3).  (5) The procedure of (3) is followed, starting with the ethylamide of b -amino-a -diethylpropionic acid, to yield finally 3-ethyl-5-diethylhydrouracil.  (6) The ethyl ester of ethyl-n-butyl-cyanacetic acid is dissolved in alcohol, hydrochloric acid added, and the mixture shaken with hydrogen in the presence of platinum oxide at 70--75 DEG  C. and 40 atmospheres. The alcohol is distilled off, non-hydrogenated ester extracted with ether, and the ethyl ester of b -amino-a -ethyl-a -butylpropionic acid precipitated with caustic soda, taken up in ether, dried with KOH, and distilled after distilling off the ether.  The ester is converted into the ureido ester and finally into 5-ethyl-5-butylhydrouracil with potassium cyanate and sodium ethylate respectively as in (1).  (7) The ethyl ester of b -amino-a -ethyl-a -phenylpropionic acid is made by hydrogenation as in (6) and methylated to give the ester of b -methylamino-a -ethyl-a -phenylpropionic acid which is converted into the ureido ester and thence into 1-methyl-5-ethyl-5-phenyl-hydrouracil as in (1) and (6).  (8) The methylamide of phenylcyanacetic acid, made by treating the ethyl ester with aqueous methylamine, is reacted with ethyl bromide and sodium ethylate to give the methylamide of ethylphenylcyanacetic p acid which is hydrogenated in presence of platinum oxide to produce the hydrochloride of the methylamide of b -amino-a -ethyl - a  - phenylpropionic acid.  This is precipitated as ether insoluble sulphate and the methylamide treated as in (3) with chloroformic ester and the product condensed to 3-methyl-5-ethyl-5-phenylhydrouracil.  (9) The amide of b -amino-a -diethylpropionic, and diethyl carbonate are refluxed with sodium ethylate to yield 5-diethylhydrouracil.  (10) The methylamide replaces the amide of (9) to yield 3-methyl-5-diethylhydrouracil. (11) A solution of the ethyl ester of b -ureido-a -diethylpropionic acid in benzene is refluxed with sodium amide to yield 5-diethylhydrouracil.  (12) b -amino-a -diethylpropionic acid, made by catalytic reduction of diethylcyanacetic acid, is treated with potassium cyanate and the ureido acid refluxed with thionyl chloride to form the hydrochloride of b -ureido-a -diethylpropionic chloride which on heating at 200 DEG  C. yields 5-diethylhydrouracil.  (13) The ethyl ester of b -amino-a -diethylbutyric acid, made by reduction of the oxime of diethyl-acetoacetic ester, is converted into the ureido ester with potassium cyanate and this is condensed as in (1) to give 6-methyl-5-diethyl-hydrouracil.  (14) The ethyl ester of dimethylcyanacetic acid is hydrogenated in solution in deka-hydronaphthalene with a nickel catalyst at 130--150 DEG  C. and 120 atmospheres.  HCl is passed into the product to precipitate the hydrochloride of b -amino-a -dimethylpropionic acid ethyl ester, which on heating with potassium cyanate yields 5-dimethylhydrouracil. The mother liquor on extraction with ether yields the ethyl ester of b -ureido-a -dimethylpropionic acid.ALSO:The ethyl ester of b -amino-a -ethyl-a -butylpropionic acid is obtained by dissolving the ethyl ester of ethyl-n-butyl-cyanacetic acid in alcohol, adding hydrochloric acid and shaking with hydrogen in the presence of platinum oxide at 70--75 DEG  C., and 40 atmospheres.  The ethyl ester of b -amino-a -ethyl-a -phenylpropionic acid is made similarly. The methylamide of ethyl-phenylcyanacetic acid by hydrogenation in the presence of platinum oxide yields the methylamide of b -amino-a -ethyl-a -phenylpropionic acid.  The ethyl ester of dimethylcyanacetic acid is hydrogenated in solution in deka-hydro-naphthalene with a nickel catalyst at 130--150 DEG  C., and 120 atmospheres to give the ethyl ester of b -amino-a -dimethylpropionic acid.