Patent GB-587550-A (GB)
Title: New pyrimidine compounds
Filed: 1944-09-25
Abstract: Pyrimidine compounds, useful as chemotherapeutic agents and as intermediates therefor, of the general formula <FORM:0587550/IV/1> wherein X represents hydrogen or a hydrocarbon radicle, Y represents hydrogen or a neutral substituent such as a hydrocarbon radical or an alkoxy, aryloxy, alkylmercapto, cyano or nitro group, and also X and Y may be joined together to form an alkylene chain, and of Z and Z1 one represents an arylamino group, free from strongly acidic substituents (such as sulphonic, carboxylic, phosphoric, or arsonic acid or sulphuric ester groups) but optionally bearing one or more other nuclear substituents, e.g. feebly acidic groups such as phenolic hydroxy or mercapto groups, halogen atoms, nitro, cyano or esterified carboxyl groups or hydrocarbon radicals (which themselves may bear substituents and which may be attached to the acrylamino group directly or through an oxygen, nitrogen or sulphur atom or a carboxyl group), and the other represents a radical of the form -NR11-A-NRR1 wherein R11 represents hydrogen or an alkyl or substituted alkyl (e.g. alkoxyalkyl or dialkylaminoalkyl) group, A represents an aliphatic, alicyclic or aliphatic-carbocyclic linking group which may be substituted by hydrocarbon radicals, alkoxy groups or dialkylaminoalkyl groups, and which, when wholly or partly an aliphatic chain, may be interrupted by oxygen, sulphur or nitrogen atoms, and -NRR1 represents a substituted amino group such as alkylamino or dialkylamino, or piperidino or other strongly basic nitrogen-containing heterocyclic group, are manufactured by the interaction of an appropriate primary arylamine with an appropriate pyrimidine derivative bearing in the 2- or 4-position the group -NR11-A-NRR1, in the 5- and 6-position the atoms or groups Y and X respectively and in the 4- or 2-position a halogen atom.  The reaction may be affected by heating together the reagents, either of which may be in the form of a salt (e.g. the hydrochloride or acetate), optionally in the presence of a solvent or diluent (which may be an excess of the arylamine), or conveniently in an aqueous medium using one molecular proportion of each of the reagents and one or slightly more than one of a mineral acid.  The products form salts with mineral and organic acids, e.g. hydrogen halides, sulphuric, phosphoric, picric, acetic, lactic, tartaric, lower alkanesulphonic (e.g. methanesulphonic), methylene bis-2 : 3-hydroxynaphthoic and methylene bis-salicylic acids.  Examples describe the preparation, from the appropriate arylamines (or salts thereof) and the appropriate 2- or 4-chloropyrimidines (or salts thereof), of: 2-g -diethyl-, -dimethyl- or -dibutyl-aminopropylamino-, 2-b -diethylaminoethylamino-, 2 - d  - diethylaminobutylamino-, 2 - g  - piperidinopropylamino-2 - g  - butylaminopropylamino-, 2 - (N - methyl-N - b  - diethylaminoethyl) - amino -, 2 - d  - diethylamino - a  - methylbutylamino-, 2 - g  - (b 1-diethylaminoethoxy) - propylamino - and 2 - g -(N - methyl - N - b 1 - diethylaminoethylamino)-propylamino - 4 - p - chloroanilino - 6 - methyl-pyrimidine; 4-anilino-, 4-p-methyl-, methoxy-, -nitro- and -cyano-anilino-, 4-(31 : 41-dichloroanilino)- and 4-(61-bromo-21-naphthylamino)-2 - b  - diethylaminoethylamino - 6 - methyl-pyrimidine; 2-g -diethyl- and -dibutyl-amino propylamino - 4 - p - chloroanilino - 5 - ethyl - 6 - methylpyrimidine; 2-anilino-, 2-p-chlor-methoxy-, -methyl-, -methylmercapto-, hydroxy, and -ethoxy - anilino-, 2 - o - chloro-, -methoxy- and -methyl - anilino-, 2 - m - methyl-and -nitro-anilino-, 2-a - and -b -naphthylamino-, 2 - (61 - bromo- and -methoxy - 21 - naphthyl)-amino- and 2 - (41 - chloro - 11 - naphthyl)-amino - 4 - b  - diethylaminoethylamino - 6 - methylpyrimidine; 2-g -diethyl- and -dibutyl aminopropylamino-, (2 - g  - mono - n - butyl-aminopropylamino-, 2 - g  - piperidinopropylamino- and 2 - d  - diethylamino - a  - methyl-butylamino - 4 - (61 - bromo - 21 - naphthyl) - amino - 6 - methylpyrimidine; 4 - p - bromo -, -cyano-, -hydroxy- and -nitro-anilino-, 4-(21 : 41- and 31 : 41-dichloroanilino)- an 4-m-chloroanilino - 2 - g  - dibutylaminopropylamino-6-methylpyrimidine; 4-m- and p-nitro anilino- and 4-p-cyanoanilino-2-g -piperidinopropylamino-6-methylpyrimidine; 4-p-cyano-hydroxy- and -nitro - anilino - 2 - g  - diethyl-aminopropylamino - 4 - methylpyrimidine; 2-p-chloro-, -dimethylamino-, -bromo-, butyl-, -carbomethoxy-, -phenyl-, -nitro- and -cyanoanilino-, 2-o- and m-chloroanilino-, 2-(21 : 41-, 31-41, 31-41- and 21 : 51-dichloroanilino)-, 2-(21-methyl - 41 - chloroanilino)-, 2 - (31 - chloro - 41 - methylanilino)-, 2-(31 : 41- and 31 : 51-dimethylanilino)- 2-(31 : 51 - dibromoanilino)-, 2 - b  - naphthylamino- and 2 - (61 - bromo - 21 - naphthylamino) - 4 - g  - diethylaminopropylamino - 6 - methylpyrimidine; 2 - p - chloroanilino - 4 - g  - diethylaminopropylaminopyrimidine; 2 - o -, m- and p-chloroanilino-, 2-o- and p-methoxyanilino-, 2-p-bromoanilino- and 2-(33 : 41-dichloroanilino) - 4 - d  - diethylamino - a  - methyl-butylamino - 6 - methylpyrimidine; 4 - p cyano- and -nitro - anilino - 2 - d  - diethylamino - a  - methylbutylamino - 6 - methylpyrimidine; 4-p-nitro- and -cyano-anilino-2-g -diethylaminopropylamino - 5 - ethyl - 6 - methylpyrimidine; 2 - g  - dibutylaminopropylamino - 4 - p - nitro- and -chloro - anilinopyrimidine; 2-g -(b 1-diethylaminoethoxy)-propylamino-, 2 - g - butylaminopropylamino- and 2 - g  - dimethylaminopropylamino - 4 - p - nitro-anilino - 6 - methylpyrimidine; 4 - g  - diethylaminopropylamino- and 4 - b  - diethylaminoethylamino - 2 - p - chloroanilino - 5 - nitro - 6 - methylpyrimidine. Additional arylamines specified are o-bromoaniline, p-mercaptoaniline, p-dimethylaminosulphonylaniline and 6-hydroxy-2-naphthylamine.  4 - g - Diethylaminopropylamino- and 4 - b  - diethylaminoethylamino - 2 - chloro - 5 - nitro - 6 - methylpyrimidine hydrochlorides, which are the starting materials for the last two products named above, are obtainable by the interaction of 2 : 4-dichloro-5-nitro-6-methylpyrimidine in ethanol with an equimolecular proportion of g -diethylaminopropylamine and b -diethylaminoethylamine respectively.  Specifications 584,917, 587,548 and 587,549 are referred to.