Patent GB-701242-A (GB)
Title: Improvements in or relating to disubstituted 6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinediones and methods of preparing the same
Filed: 1951-11-08
Abstract: The invention comprises 6-amino-1:2:3:4-tetrahydropyrimidine - 2:4 - dione derivatives of the general formula <FORM:0701242/IV (b)/1> (wherein one R represents an alkenyl radical and the other an alkyl, hydroxyalkyl, aralkyl or aryl radical), and the preparation thereof by cyanoacetylating a urea derivative of the formula Alkenyl-NH-CO-NH-R (wherein R has the second of the meanings given above) by treatment with acetic anhydride and cyanoacetic acid (e.g. at 50-100 DEG C.), and cyclizing the resulting cyanoacetyl derivative by treatment with alkali (e.g. at 40-100 DEG C.) yielding a mixture of isomers in which the one with the larger substituent in the 1-position predominates, or by the alternative processes described in the examples for obtaining one or other isomer in a pure state.  The products are therapeutically active (e.g. some of them improve renal functions and those of the cardiovascular system) whilst some of them are useful as parasiticides; they are also useful as intermediates in chemical syntheses.  In examples: (1) monoallylurea is warmed with acetic anhydride and cyanoacetic acid, the product is warmed with aqueous caustic soda, and the resulting 1-allyl-6-amino-1:2:3:4-tetrahydropyrimidine-2:4-dione is methylated in the 3-position by means of dimethyl sulphate or methyl iodide; (2), (5) and (6) the methylating agents in (1) are replaced by diethyl sulphate, n-propyl iodide and n-butyl iodide; (3) ethyl cyanoacetate is warmed with allylamine and the resulting N-allylcyanoacetamide is refluxed with ethyl isocyanate in toluene to produce N-allyl-N-cyanoacetyl-N1-ethylurea, which is cyclized with caustic soda to 1-ethyl-3 - allyl - 6 - amino - 1:2:3:4 - tetrahydropyrimidine - 2:4 - dione; (4) N - ethyl - N1 - allylurea is warmed with acetic anhydride, glacial acetic acid and cyanoacetic acid, and the product is warmed with aqueous caustic soda, giving a mixture of 1-allyl-3-ethyl- and some 1-ethyl-3-allyl - 6 - amino - 1:2:3:4 - tetrahydropyrimidine - 2:4 - dione; (7) isobutylamine is stirred with allyl isocyanate in benzene, and the resulting N-allyl-N1-isobutylurea is treated as in (6) (but omitting the glacial acetic acid) to produce a mixture of 1-allyl-3-isobutyl- and 1-isobutyl-3-allyl-6-amino-1:2:3:4 - tetrahydro - pyrimidine - 2:4 - dione; (8) n - hexylamine similarly yields 1 - hexyl - 3 - allyl - and some 1 - allyl - 3 - hexyl - 6 - amino - 1:2:3:4 - tetra - hydropyrimidine - 2:4 - dione; (9) phenyl isocyanate is stirred with allylamine in benzene and the resulting N-allyl-N1-phenylurea is treated as in (7) to produce 1-phenyl-3-allyl- and some 1-allyl-3-phenyl-6-amino-1:2:3:4-tetrahydropyrimidine - 2:4 - dione; (10) the isobutylamine in (7) is replaced by benzylamine, giving 1-benzyl-3-allyl- and some 1-allyl-3-benzyl - 6 - amino - 1:2:3:4 - tetrahydropyrimidine - 2:4 - dione; (11) crotyl isocyanate is stirred with b -aminoethanol in benzene and the resulting N-(b -hydroxyethyl)-N1-crotylurea is treated as in (7) to produce 1-crotyl-3-(b -hydroxyethyl)-and some 1-(b -hydroxyethyl)-3-crotyl-6-amino - 1:2:3:4 - tetrahydropyrimidone-2:4-dione; (12) ethyl isocyanate and methallylamine similarly yield 1-methallyl-3-ethyl- and 1-ethyl-3-methallyl-6-amino-1:2:3:4 -tetrahydropyrimidine - 2:4 - dione.  Xanthines.-Some of the products described above may be nitrosated in the 5-position, the nitroso group reduced, the resulting 5:6-diamino compound monoformylated in the 5-position and the product cyclized by short heating with alkali to form 1-alkyl-3-alkenyl- and 1-alkenyl-3-alkyl-xanthines.  Thus the product of (4) above yields ethylallylxanthine.  Reference is also made to the 3-allylxanthine obtainable from 1-allyl-6-amino-1:2:3:4-tetrahydropyrimidine-2:4-dione.