Patent GB-590706-A (GB)
Title: New pyrimidine compounds
Filed: 1945-02-27
Abstract: Pyrimidine compounds, useful as chemotherapeutic agents and as intermediates therefor, of the general formula <FORM:0590706/IV/1> wherein X and X1 each represents hydrogen or a hydrocarbon radical, Y represents hydrogen or a hydrocarbon radical which may bear one or more non-acidic substituents, 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 or hydroxy, alkoxy or dialkylaminoalkyl groups, and, when wholly or partly an aliphatic chain, may be interrupted by oxygen, nitrogen or sulphur atoms, and NRR1 represents a strongly basic amino or substituted amino group such as alkylamino, dialkylamino or piperidino or other strongly basic nitrogen-containing heterocyclic group, are manufactured by the interaction of a diamine R11NH-A-NRR1 with an appropriate 6-aminopyrimidine derivative bearing the atoms or groups X and X1 in the 2- and 5-positions and in the 4-position a labile substituent, such as a halogen atom or a hydrocarbon radical attached by an ether or thioether linkage, e.g. an alkoxy, aryloxy or alkylmercapto group.  The reaction may be effected by heating the reagents together, optionally in the presence of a solvent or diluent.  One or other of the reagents may be employed in the form of a salt, e.g. hydrochloride, or acetate, and an acid-binding agent such as sodium hydroxide may be present.  When R1 represents hydrogen, the diamine may be replaced by its acyl derivative R11NH-A-NR-Ac, where R represents hydrogen or a hydrocarbon radical and Ac an acyl group which is subsequently removed by hydrolysis.  A further modification consists in introducing the basic 4-substituent in stages by reacting the pyrimidine starting material with an amino compound R11NH-A1-B where A1 represents the whole or part of the linking group A, and B represents a reactive group which is then converted directly or indirectly, by methods involving reaction with ammonia or an amino compound, into the group NRR1 or into a group A11-NRR1 such that A1 and A11 together constitute the linking group A. The terminal amino group, when unsubstituted, may be subsequently modified, e.g. by alkylation, conversion to a heterocyclic group such as piperidino or by reaction with a halogeno-amine Hal-A111-NRRR1 so as to extend the linking group A to A-NH-A111.  The products form salts with inorganic and organic acids, e.g. hydrogen halides or sulphuric, phosphoric, acetic, lactic, tartaric, lower alkanesulphonic (e.g. p  methanesulphonic), picric, 3 : 5-dinitrobenzoic methylene bis-2 : 3-hydroxynaphthoic and methylene bis-salicyclic acids.  In examples, the following products are made from the appropriate diamines and 4-chloropyrimidines : 4-g -dimethyl- and -diethyl-aminopropylamino- and 4 - b  - diethylaminoethylamino - 6 - amino -2 : 5-dimethylpyrimidine; 4 - d - diethylamino - a  - methylbutylamino-, 4 - b  - diethylaminoethylamino- and 4 - g  - diethylaminopropylamino-6-amino - 2 - methylpyrimidine; 4 - b  - diethylaminoethylamino- 4 g  - diethyl- and -di-n-butyl - aminopropylamino-, 4 - g  - piperidino-propylamino-, 4 - d  - diethylamino - a  - methylbutylamino- and 4 - g  - (b 1 - diethylaminoethoxy) - propylamino - 6 - p - chloroanilino - 2 - methylpyrimidine; 4 - b  - diethylaminoethylamino-, 4 - g  - diethylaminopropylamino- and 4 - g - diethylamino - a  - methylbutylamino - 6 - p - methoxyanilino - 2 - methylpyrimidine; 4 - b  - diethylaminoethylamino - and 4 - g  - dimethyl- and -dibutyl - aminopropylamino - 6 - p - nitroanilino - 2 - methylpyrimidine; 4 - b  - diethylaminoethylamino-, 4 - g  - diethyl-, -dimethyl- and -dibutyl-aminopropylamino- and 4 - a  - diethylamino - a  - methylbutylamino - 6 - (61 - bromo - 21 - naphthylamino) - 2 - methylpyrimidine; 4 - b  - diethylaminoethylamino - 6 - p - methoxyanilino - 2 : 5 - dimethylpyrimidine; 4 - b  - diethylaminoethylamino -, 4 - g  - diethyl- and -dimethyl-aminopropylamino- and 4 - [d  - diethylamino - a  - methylbutylamino-6-p-chloroanilino-2 : 5-dimethylpyrimidine; 4-b -diethylaminoethylamino- and 4-g -dimethyl- and -diethyl - aminopropylamino - 6 - p - chloroanilino - 2 - methyl - 5 - ethylpyrimidine; 4-b -diethylaminoethylamino - and 4 - g  - dimethylaminopropylamino - 6 - p - methoxyanilino - 2 - methyl - 5 - ethylpyrimidine; 4 - b  - diethylaminoethylamino- and 4 - g  - diethylaminopropylamino - 6 - amino - 5 - methylpyrimidine; 4 : 6 - bis - (d  - diethylamino - a  - methylbutylamino) - 2 - methylpyrimidine; 4 - b  - diethylaminoethylamino - 6 - p - nitroanilino - 2 : 5 - dimethylpyrimidine; 4 - b  - diethylaminoethylamino - 6 - p - chloroanilino - 2 - phenylpyrimidine; and 4 - g  - diethylaminopropylamino - 6 - p - chloroanilino - 2 - methyl - 5 - phenylpyrimidine.  Additional starting materials specified are, on the one hand, 4-bromo-, 4-ethoxy-, 4-phenoxy- and 4-methylmercaptopyrimidines, and on the other hand, ethylenediamine, 2 - dimethylaminoethylamine, 4 - diethylaminobutylamine, 3 - diethylamino - 1 : 2 - dimethylpropylamine, 3 - diethylamino - 2 - hydroxypropylamine, 2 - methylaminoethylamine, 3 - n - butylaminopropylamine, 3 - (b  - diethylaminoethylmercapto) - propylamine, 5-diethylamino - 1 - aminopentane, 2 - pyrrolidinoethylamine, 1 : 3 - bis - diethylamino - 2 - aminopropane, N - ethyl - N b  - diethylaminoethyl - ethylenediamine, 2 - piperidinoethylamine, p - dimethyl - and - diethyl - aminoethoxyaniline, p - diethylaminoethylmercaptoaniline, 3 - diethylamino - 2 : 2 - dimethylpropylamine, N - methyl - N - b  - diethylaminoethyl - 1 : 3 - propylenediamine, b  - piperidino - b  - methylethylamine, N-methyl and N-ethyl-N1-diethyl-ethylenediamine and bis-(b -diethylaminoethyl)-amine.  Specification 584,917 is referred to.  4 - Halogeno - 6 - aminopyrimidine derivatives of the kind employed as starting materials are obtained by interaction of an amino-compound Y-NH2, e.g. p-chloroaniline, p-anisidine, p-nitroaniline or 6-bromo-2-naphthylamine, with the appropriate 4 : 6-dihalogenopyrimidine, e.g. 2 - methyl -, 2 : 5 - dimethyl -, 2 - methyl - 5 - ethyl- or 2 - methyl - 5 - phenyl - 4 : 6 - dichloropyrimidine, which dihalogeno-compounds are obtained by the action of phosphorus oxychloride or oxybromide on the corresponding 4 : 6-dihydroxy-compounds.  The corresponding pyrimidines containing ether or thioether groups in the 4-position are obtainable by reaction of the 4-halogeno-derivatives with the appropriate hydroxy or mercapto compounds or their alkali metal derivatives.  4 - Chloro - 6 - (g  - diethylamino - a  - methylbutylamino) - 2 - methylpyrimidine is obtainable is obtainable by heating 4-chloro-6-hydroxy-2-methylpyrimidine with d  - diethylamino - a  - methylbutylamine and phosphorus oxychloride,