Patent GB-807826-A (GB)
Title: Derivatives of pyrimido[5,4-d] pyrimidine and production thereof
IPC: C07D487/04
Filed: 1956-03-14
Abstract: The invention comprises pyrimido [5,4-d] pyrimidines substituted in at least one of the 2-, 4-, 6- and 8-positions by one or more of the following atoms or groups: halogen (e.g. Cl, Br, I), amino, mono- or di-substituted amino (e.g. mono- or di-alkyl- or -aryl-amino), ether (e.g. alkoxy, aryloxy), thiol, thioether (e.g. alkylmercapto, carboxyalkylmercapto, arylmercapto), hydrazino, guanidino or heterocyclic groups, which groups may in turn be substituted; and the preparation of pyrimido [5,4-d] pyrimidine derivatives by reacting compounds of the general formula <FORM:0807826/IV (b)/1> (wherein at least one of the symbols R1-R4, which may be the same or different, represents a halogen atom and the remainder hydrogen, a substituted hydroxy group, an amino or thiol group or the residue of a heterocyclic ring) with compounds of the general formula H-R or MeI-R (wherein R represents bromine, iodine, a substituted hydroxy group, a free or substituted amino, thiol, guanidino or hydrazino group or the residue of a heterocyclic ring, and MeI represents an alkali metal atom).  The reaction is advantageously carried out at - 20 DEG  to 250 DEG  C. (if necessary under pressure) in an inert solvent and diluent and in the presence of an acid-binding agent (e.g. an alkali metal hydroxide or carbonate, a tertiary amine, or excess of the second reaction component when suitable) and/or a reaction accelerator (e.g. of the Friedel-Crafts type) and/or copper powder, copper salts or strong inorganic acids as catalysts. When the starting material has more than one halogen atom available for exchange, the reaction may be carried out stepwise. In some cases also, not only halogen but also other substituents (e.g. free or substituted hydroxy or amino groups) may be replaced by the residue R.  Suitable reactants H-R and MeI-R are alcohols, phenols, mercaptans, thiophenols, alkali metal alcoholates, phenolates, hydrosulphides and thiophenolates, ammonia, primary and secondary amines, guanidines, hydrazines, aminoalcohols, morpholine, piperidine and sodium iodide.  In examples: (1) 4:6:8-trichloropyrimidopyrimidine is reacted with 6 molecular proportions of sodium methoxide in methanol to produce 4:6:8-trimethoxypyrimidopyrimide; (2) tetrachloropyrimidopyrimidine is reacted in dioxan with 4 molecular proportions of ammonia and various amines to replace the chlorine atoms in the 4- and 8-positions by the residues of the amino compounds, viz. N-hydroxyethylanilino, morpholino, p-chloranilino, b -hydroxyethylamino, b -diethylaminoethylamino, methyldodecylamino, isoamylamino, benzylamino, p - dimethylaminoanilino, diallylamino, methylcyclohexylamino, b -chlorethylamino, butylethanolamino, benzylethanolamino, 2:3 - dihydroxypropylamino, amino and carbethoxymethylamino; (3) 2:4:6:8 - tetrachloropyrimidopyrimidine is boiled with sodium iodide in acetone to produce 2:6-dichloro - 4:8 - diiodopyrimidopyrimidine; (4) the product of (3) is reacted with 4 molecular proportions of aniline in dioxan and benzene to form 2:6 - dichloro - 4:8 - dianilinopyrimidopyrimidine; (5) 2:4:6:8 - tetrachloropyrimidopyrimidine is refluxed with excess of aniline to give 2:4:6:8 - tetra-anilinopyrimidopyrimidine; the starting material may be replaced by 2:6-dichloro-4:8-dianilino-, -diamino-, -dihydroxy- or -dipiperidino-pyrimidopyrimidine; (6) 6-chloro-4:8-diiodopyrimidopyrimidine is reacted with 2.3-molecular proportions of morpholine and 2 molecular proportions of triethylamine in dioxan to produce 6 - chloro - 4:8 - dimorpholinopyrimidopyrimidine; (7) various 6-chloro-4:8-diaminopyrimidopyrimidines are heated (where necessary under pressure) with various amines to form 6 - morpholino - 4:8 - bis - (diethylamino) -, 6 - methylamino- and 6-morpholino-4:8-bis-(ethylamino) -, 6 - morpholino - 4:8 - di - (ethylethanolamino) -, 6 - anilino -, 6 - dimethylamino - and 6 - morpholino - 4:8 - diamino -, 6 - diethanolamino - 4:8 - bis - (allylamino) -, 6 - diethanolamino - 4:8 - dipiperidino -, 6 - (b  - hydroxyethylamino) -, 6 - diisopropanolamino - and 6 - diethanolamino - 4:8 - dimorpholino -, 6 - methylethanolamino - 4:8 - bis - (methylamino) -, 6 - morpholino - 4:8 - di - (g  - methoxypropylamino) -, 6 - diethanolamino - 4:8 - di - (p - nitroanilino) - and 6 - piperidino - 4:8 - di - (b  - hydroxyethylamino) - pyrimidopyrimidine; (8) 2:4:6:8 - tetrachloropyrimidopyrimidine is reacted under vigorous conditions with excess of ammonia and various amines to replace all four chlorine atoms by dimethylamino, allylamino, methylethanolamino, b -hydroxyethylamino, piperidino, morpholino, p-chloranilino, amino and methylamino; (9) 4:6:8 - trichloropyrimidopyrimidine is reacted as in (2) to replace the chlorine atoms in the 4- and 8-positions by allylamino, methylethanolamino, diisopropylamino, methylamino, diethanolamino, p-nitroanilino, 3-methoxypropylamino, o-methoxyanilino, dibenzylamino, ethyleneimino and semicarbazido; (10) 2:6-dichloro - 4:8 - bis - (diethylamino) - pyrimidopyrimidine is refluxed with a solution of sodium in b -dimethylaminoethanol to produce 2:6-bis-(b  - diethylaminoethoxy) - 4:8 - bis - (diethylamino) - pyrimidopyrimidine; (11) 4:6:8 - trichloro - 2 - thiopyrimidopyrimidine is reacted with 4 molecular proportions of morpholine in dioxan to form 6-chloro-2-thio-4:8-dimorpholinopyrimidopyrimidine; (12) piperidine similarly yields the corresponding dipiperidino compound; (13) 6 - methylthio - 2:4 - dichloropyrimidopyrimidine is reacted with excess of morpholine to produce 6-methylthio-2:4-dimorpholinopyrimidopyrimidine; (14) 2:6-dichloro - 4:8 - bis - (b  - diethylaminoethylamino)-pyrimidopyrimidine is heated under pressure with sodium ethoxide in ethanol to replace the chlorine atoms by ethoxy groups; (15) 2:4:6:8-tetrachloropyrimidopyrimidine is heated with 4 molecular proportions of phenol and 2 of sodium carbonate to form 2:4:6:8-tetraphenoxypyrimidopyrimidine; (16) 2:4:6:8-tetrachloropyrimidopyrimidine is reacted with 4 molecular proportions each of thiophenol and sodium hydroxide in moist dioxan to give 2:4:6:8 - tetraphenylthiopyrimidopyrimidine; (17) 2:4:6:8-tetrachloropyrimidopyrimidine is refluxed with excess of sodium hydrosulphide in dimethylformamide to replace the chlorine atoms by thiol groups; (18) 2:4:6:8-tetrachloropyrimidopyrimidine is reacted with 6 molecular proportions of ethyl mercaptan and 2 of pyridine to produce 2:6-dichloro-4:8-diethylthiopyrimidopyrimidine; (19) 4:8 - dichloropyrimidopyrimidine is reacted as in (2) to replace the chlorine atoms by morpholino, piperidino, anilino, amino, methylamino, dimethylamino, hydrazino, N:N1-diphenylguanidino, b  - hydroxyethylamino and N-hydroxyethyl - p - nitroanilino; (20) 4:8-dichloropyrimidopyrimidine is reacted with potassium hydrosulphide in alcohol and dioxan to produce 4:8-dithiopyrimidopyrimidine; (21) the product of (18) is heated under pressure with morpholine in aqueous copper sulphate solution to form 2:6-dimorpholino-4:8-diethylthiopyrimidopyrimidine; (22) 2:4:6:8 - tetrachloropyrimidopyrimidine is heated with excess of ethyl mercaptan and pyridine in dioxan to give 2:4:6:8 - tetraethylthiopyrimidopyrimidine; (23) 6 - chloro - 4:8 - di - (carboxymethylthio) - pyrimidopyrimidine is heated with morpholine to produce 6 - morpholino - 4:8 - di - (carboxymethylthio) - pyrimidopyrimidine; (24) 4:6:8-trichloropyrimidopyrimidine is heated under pressure with excess of thioglycollic acid and pyridine to produce 4:6:8-tri-(carboxymethylthio) - pyrimidopyrimidine; (25) 6-chloro-4:8-di - (propylamino) - pyrimidopyrimidine similarly yields 6-carboxymethylthio-4:8-di-(propylamino) - pyrimidopyrimidine; (26) various 2:6 - dichloro - 4:8 - diaminopyrimidopyrimidines are heated with various amines to form 2:6 - bis - (diethanolamino) - 4:8 - dipiperidino-, -4:8-bis-(diethylamino)-, -4:8-dipyrrolidino-, -4:8-bis-(diallylamino)-, -4:8-bis-(dimethylamino)-, -4:8-bis-(dibutylamino)- and -4:8-dimorpholino-, 2:6 - di - (methylethanolamino) - 4:8-dipiperidino- and -4:8-di-(dodecylethanolamino)-, 2:6 - di - (propylethanolamino) - 4:8 - dimorpholino-, and 2:6 - bis - (diisopropylamino) - 4:8 - dipiperidino - pyrimidopyrimidine; (27) similarly prepared, but at higher temperatures under pressure, are 2:6-dimorpholino - 4:8 - di - (ethylethanolamino) -, 4:8 - di - (propylethanolamino) -, - 4:8 - di - (methylethanolamino) -, - 4:8 - bis - (diethanolamino) - and - 4:8 - bis - (dimethylamino) -, 2:6 - dipiperidino - 4:8 - bis - (diethanolamino) -, - 4:8-bis - (isoamylamino) -, - 4:8 - dipyrrolidino - and -4:8-di-(benzylethanolamino)-, and 2:6-bis - (diethylamino) - 4:8 - bis - (diethanolamino) - pyrimidopyrimidine; (28) 2:4:6 - trichloropyrimidopyrimidine is heated (in some cases under pressure and in the presence of copper salts) with excess of various amines to replace all three chlorine atoms by methylamino, ethylamino, propylamino, dimethylamino, b -hydroxyethylamino, morpholino, anilino, p-chloroanilino and o-methoxyanilino; (29) 6 - chloro - 4:8 - dimorpholinopyrimidopyrimidine is heated (if desired under pressure) with various sodium alkoxide solutions to replace the chlorine atom by ethoxy, butoxy, b -diethylaminoethoxy, b -ethoxyethoxy and b -propoxyethoxy; (30) 2:6-dichloro-4:8-di-(b -propoxyethoxy) - pyrimidopyrimidine is heated with morpholine under pressure to give 2:6-dimorpholino - 4:8 - di - (b  - propoxyethoxy) - pyrimidopyrimidine. Additional starting materials and products are listed.  Starting materials.  Halogen-substituted pyrimidopyrimidines are obtainable by (a) halogenation of the corresponding hydroxy compounds (e.g. the starting materials of Examples (1), (3), (5), (11), (13) and (19) are prepared by the action of PCl5 and/or POCl3 on, respectively, 4:6:8 - trihydroxy-, 3 - methyl - 2:6:8 - trihydroxy - 4 - oxo - 3:4 - dihydro -, 2:6 - dichloro - 4:8 - dihydroxy -, 4:6:8 - trihydroxy-2-thio-, 6-methylthio-2:4-dihydroxy-