Patent GB-799177-A (GB)
Title: Improvements in or relating to the preparation of new derivatives of 7,9-pyrimidino pyrimidine-(1,3)
Filed: 1955-01-17
Abstract: The invention comprises homopurine compounds of the general formula (including tautomeric forms thereof): <FORM:0799177/IV (b)/1> wherein R3 is a hydrogen atom or an alkyl, alkenyl, aryl, aralkyl, heterocyclic or -CONH2 group; R4 is a hydrogen atom or an alkyl or aralkyl group, or, where R7 is hydrogen or alkyl, is simply a bond with the carbon atom at position 8; R5 is a hydrogen atom or an alkyl, alkylthio, alkenylthio, aralkylthio, aryl or aralkyl group; R6 is a hydrogen atom or a hydroxyl group and R7 is a hydrogen, oxygen or sulphur atom or an alkyl group, there being a double bond between the carbon atom at position 8 and R7 when the latter is an oxygen or sulphur atom; and wherein when R7 is oxygen, R6 is hydrogen and R5 is not hydrogen.  They may be prepared by condensing a pyrimidine 4-carboxylic acid (or a functional derivative thereof such as an ester, halide, amide or nitrile) substituted in the 5-position with a halogen atom or a substituted or unsubstituted amino group, ammonia or a compound producing ammonia under the reaction conditions being added when the 5-substituent is a halogen atom and preferably also when the 5-substituent is an amino or substituted amino group, with a compound R-(C = X)-Y, where R, X and Y are groups corresponding to the nature of the desired product, examples of such compounds being: (1) amides, thioamides, carbamates, thiocarbamates, ureas, thioureas and like compounds of the formul  R-(C = O)-NHR1 and R-(C = S)-NHR1, wherein R is hydrogen or unsubstituted or substituted alkyl, aryl, aralkyl, hydroxyl, mercapto or amino and R1 is hydrogen, alkyl, aryl, aralkyl, heterocyclic or acyl; (2) amidines, guanidines and like compounds of the formula R-(C = NR2)-NHR1, wherein R2 may be hydrogen, alkyl, aralkyl, aryl, heterocyclic or acyl; and (3) nitriles, cyanates, isocyanates, cyanamides, thiocyanates and like compounds of the formula R-C ­ N.  The compounds R-(C = X)-Y may also be formed, from compounds of simpler constitution, in the reaction mixture, e.g. ammonium formate may replace formamide, formic acid and aniline may replace formanilide, phosgene and amines or isocyanates and water may replace ureas, ortho-formic acid esters and aniline or formic acid and aniline may replace N : N1-diphenyl formamidine and benzimino ethers and ammonia may replace benzamidine.  The reaction is preferably carried out at elevated temperature, with or without conventional solvents and with the compound R-(C = X)-Y preferably in substantial excess and advantageously in some cases in the presence of accelerators such as copper sulphate or copper powder and/or water-removing agents, e.g. acetic anhydride, hydrochloric acid and alkali metal hydroxides.  The compounds of the invention may be alkylated, acylated or aralkylated by conventional methods. In examples: (1) 2-methyl-5-amino pyrimidine carboxylic acid-(4) (hereinafter called compound A) is heated with urea to give 2-methyl-8 : 10 - dihydroxyhomopurine; (2) the product of (1) is prepared by heating 2-methyl-5-bromo pyrimidine carboxylic acid-(4) with urea in presence of concentrated ammonium hydroxide and copper sulphate; (3) the ammonium hydroxide of (2) is replaced by sodium hydroxide in methanol, the product being as in (1); (4) 2-phenyl-5-amino pyrimidine carboxylic acid-(4) and urea yield 2-phenyl-8 : 10-dihydroxyhomopurine, a by-product being 2-phenyl-5-amino pyrimidine carboxylic acid-(4) amide; (5) 2-benzyl - 5 - amino pyrimidine carboxylic acid-(4) (prepared from the 5-bromo compound and ammonia) and urea yield 2-benzyl-8 : 10-dihydroxyhomopurine; (6) compound A and N : N1-diphenyl formamidine are heated together to give 2-methyl-9-phenyl-10-oxo-9 : 10-dihydrohomopurine; (7) 2-phenyl-5-amino pyrimidine carboxylic acid-(4) and N : N1-dimethyl formamidine yield 2-phenyl-9-methyl-10-oxo-9 : 10 - dihydrohomopurine; (8) 2 - methyl - 5-methylamino pyrimidine carboxylic acid-(4) and urea yield 2 : 7 - dimethyl - 8 : 10 - dioxo-7 : 8 : 9 : 10 - tetrahydrohomopurine; (9) compound A is heated with ethyl orthoformate and aniline to yield the product of (6); (10) compound A, sodium cyanate and ammonium chloride are heated in water to yield the product of (1); (11) compound A, sodium cyanate and hydrochloric acid give, at room temperature, 2-methyl - 5 - ureido pyrimidine carboxylic acid-(4) which on heating with either sodium hydroxide, acetic anhydride or hydrochloric acid yields the product of (1); (12) the process of (11) is repeated without isolation of the intermediate, sodium hydroxide being used to effect ring closure; (13) the product of (1) is methylated both with diazomethane and, separately, dimethylsulphate yielding in both cases 2 : 7 : 9-trimethyl - 8 : 10 - dioxo - 7 : 8 : 9 : 10 - tetrahydrohomopurine; (14) 2 - methyl - 5 - amino pyrimidine carboxylic acid-(4) amide (obtained from the 5-bromo compound and ammonia) is heated with urea to give the product of (1); (15) compound A and aqueous cyanogen bromide are reacted at room temperature and the product is evaporated to dryness and heated with sodium hydroxide to yield the product of (1); (16) 2-methylthio - 5 - amino pyrimidine carboxylic acid-(4) (hereinafter called compound B) and urea are heated to yield 2-methylthio-8 : 10-dihydroxyhomopurine; (17) 2-ethylthio-5-amino pyrimidine carboxylic acid - (4), prepared from the 5-bromo compound and ammonia, similarly yields 2 - ethylthio - 8 : 10 - dihydroxy homopurine; (18) and (19) 2 - allylthio and 2-benzylthio - 5 - amino pyrimidine carboxylic acids-(4), prepared from the 5-bromo compounds and ammonia, similarly yield 2-allylthio- and 2 - benzylthio - 8 : 10 - dihydroxyhomopurines; (20) 2 - methylthio - 5 - butylamino pyrimidine carboxylic acid-(4) and urea yield 2-methylthio-7 - butyl - 8 : 10 - dioxo - 7 : 8 : 9 : 10 - tetrahydrohomopurine; (21) compound B and N : N1-dimethyl urea yield 2-methylthio-9-methyl-8 : 10 - dioxo - 7 : 8 : 9 : 10 - tetrahydrohomopurine and, as a by-product, 2-methylthio-5-amino-pyrimidine carboxylic acid-(4) amide; (22) compound (B) and N : N1-dimethyl formamidine yield 2 - methylthio - 9 - methyl - 10 - oxo-9 : 10 - dihydrohomopurine; (23) compound (B) and formamide are heated in formic acid to yield 2 - methylthio - 10 - hydroxyhomopurine; (24) compound B is heated with acetamide and acetic anhydride to yield 2-methylthio-8-methyl - 10 - hydroxyhomapurine; (25) compound (B) is heated with ammonium thiocyanate to yield 2-methylthio-8-thio-10-hydroxyhomopurine; (26) compound B is heated with monoformyl urea to yield 2-methylthio-10-oxo - 9 : 10 - dihydrohomopurine - 9 - carboxylic acid amide; (27) the product of (1) is benzylated with benzyl chloride giving 2-methyl-7 or 9-benzyl-8 : 10-dioxo-7 : 8 : 9 : 10-tetrahydrohomopurine; (28) 2-methylthio-5-bromo-pyrimidine carboxylic acid-(4) is heated with formamide, ammonia and copper sulphate solution to give the product of (23); (29) compound B and N : N1-dibenzylformamidine give 2 - methylthio - 9 - benzyl - 10 - oxo - 9 : 10 - dihydrohomopurine; (30) compound B and N : N1-di - (a  - pyridyl) - formamidine give 2 - methylthio - 9 - (a  - pyridyl) - 10 - oxo - 9 : 10 - dihydrohomopurine; (31) compound B and N-phenyl thiourea give 2-methylthio-8-thio-9-phenyl-10-oxo - 9 : 10 - dihydrohomopurine; (32) compound B, phenyl mustard oil and caustic soda give the product of (31); (33) compound B and allyl mustard oil are heated in dimethylformamide to give 2-methylthio-8-thio-9-allyl-10 - oxo - 9 : 10 - dihydrohomopurine; (34) compound B and diethyl cyanamide give the product of (16); (35) compound B and morpholine carboxylic acid-(4) amide give the product of (16); (36) 5-amino-6-hydroxy-pyrimidine carboxylic acid-(4)-amide, formamide and formic acid are heated to give 6 : 10-dihydroxyhomopurine; and (37) 5-amino-6-hydroxy-pyrimidine carboxylic acid-(4) methyl ester, acetamide and acetic anhydride are heated to give 8-methyl-6 : 10-dihydroxyhomopurine.  Reference is also made to the methylation of the product of (5) to yield 2 - benzyl - 8 : 10 - dioxo - 7 : 9 - dimethyl-7 : 8 : 9 : 10-tetrahydrohomopurine.