Patent GB-587548-A (GB)
Title: New pyrimidine compounds
IPC: C07D239/46
Filed: 1944-09-25
Abstract: Pyrimidine compounds of the general formula <FORM:0587548/IV/1> wherein X represents hydrogen or a hydrocarbon radical, Y represents hydrogen or a neutral substituent such as a hydrocarbon radical or an alkoxy, aryloxy, alkylmercapto or cyano group, and also X and Y may be joined together to form an alkylene chain, and of Z and Z1 one represents a hydroxy group and the other a substituted amino group 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 aliphaticcarbocyclic linking group, which may be substituted by hydrocarbon radicals, hydroxy, alkoxy or dialkylaminoalkyl groups, and which, when wholly or partly an aliphatic chain, may be interrupted by oxygen, nitrogen or sulphur atoms, and NRR1 represents an amino or substituted amino group such as alkylamino or dialkylamino or piperidino or other strongly basic nitrogen-containing heterocyclic group, are manufactured by the interaction of a diamine NHR11-A-NRR1 with a 2- or 4-hydroxypyrimidine bearing the atoms or groups Y and X in the 5- and 6-positions respectively and in the 4- or 2-position an alkylmercapto or substituted alkylmercapto group.  Alternatively, when NRR1 is a primary amino group, this is protected by acylation and the acyl group is split off after condensation with the pyrimidine compound. The reaction is effected by heating the reagents together, optionally in the presence of a solvent or diluent, e.g. b -ethoxyethanol.  When the diamine is of the form NH2-A-NH2 it is preferably used in excess to suppress the side reaction wherein 1 mol. of the diamine combines with 2 mols. of the pyrimidine derivative.  The products form salts with mineral and organic acids, e.g. hydrochloric, picric and 3 : 5-dinitrobenzoic acid.  When the terminal amino group NRR1 is a primary amino group it can be alkylated or converted to a heterocyclic ring such as a piperidino radicle, e.g. by heating with an alkyl iodide, dimethyl sulphate or pentamethylene dibromide. Examples describe the preparation, from the appropriate diamines and the appropriate 2- or 4-hydroxy-4- or 2-methylmercaptopyrimidines of: 2-b -diethylaminoethylamino-, 2-g -diethyl-, -dimethyl- and -dibutyl-aminopropylamino-, 2 - d  - diethylaminobutylamino-, 2 - g - piperidinopropylamino-, 2 - d  - diethylamino - a  - methylbutylamino-, 2 - g  - butylaminopropylamino-, 2 - g  - (b 1 - diethylaminoethoxy) - propylamino-, 2 - g  - (N - methyl - N - b 1 - diethylaminoethyl)-aminopropylamino-, 2-(N-methyl-N - b  - diethylaminoethyl)-amino-, 2-(61-aminohexylamino)- and 2 - b  - aminoethylamino - 4 - hydroxy - 6 - methylpyrimidine; 2 - g  - diethyl- and -dibutyl-aminopropylamino-4-hydroxy-5-ethyl-6-methylpyrimidine; 4-b -diethylaminoethylamino-, 4 - g  - diethylaminopropylamino and 4 - d - diethylamino - a  - methylbutylamino-2 - hydroxy - 6 - methylpyrimidine; 2-g -dibutylaminopropylamino- and 2-b -diethylaminoethyl amino - 4 - hydroxy - 5 : 6 - dimethylpyrimidine; and 2-g -dibutylaminopropylamino-4-hydroxypyrimidine.  In a further example, 2-methylmercapto - 4 - hydroxy - 6 - methylpyrimidine is heated with monoacetylethylenediamine to produce 2-b -acetylaminoethylamino-4-hydroxy-6-methylpyrimidine, and the acetyl group is then removed by heating with dilute hydrochloric acid. Additional starting materials specified are, on the one hand, 2-dimethylaminoethylamine, 4-dimethyl- and -di-n-butyl-aminobutylamine, 5-dimethyl- and-diethyl-amino-n-amylamine, 3-diethylamino-1 : 2-dimethylpropylamine, 6 - dimethylaminohexylamine, 3 - diethylamino-2-hydroxypropylamine, 2-methylaminoethylamine, 3 - (b  - diethylaminoethylmercapto) - propylamine, 2 - pyrrolidinoethylamine, 1 : 3-bis-diethylamino-2-aminopropane, 2-piperidinoethylamine, 2-piperidino-2-methylethylamine, b -piperidino-iso-propylamine, p-diethylaminoethoxyaniline, p - diethylaminoethylmercaptoaniline and 3-diethylamino-2 : 2-dimethylpropylamine, and, on the other hand, 2-ethyl- and -benzyl-mercapto-4-hydroxy-6-methylpyrimidine, 2 - methylmercapto - 4 - hydroxy - 6 - ethyl- and - 6 - phenyl - pyrimidine, 2 - ethylmercapto - 4 - hydroxy - 5 - phenyl-, -5-methyl- and -5-phenoxy-pyrimidine, 2-ethylmercapto-4-hydroxy-5-benzyl-6-methylpyrimidine, 2-methylmercapto-4-hydroxy-5 : 6 : 7 : 8-tetrahydroquinazoline and 2-methylmercapto-4-hydroxy-5 : 6-trimethylenepyrimidine. Specification 587,550 is referred to.  2 - Alkylmercapto - 4 - hydroxypyrimidines are obtainable by interaction of appropriate alkyl isothioureas with formylacetic esters appropriately substituted, where necessary, on the a - and b -carbon atoms, or by direct S-alkylation of the 2 - mercapto - 4 - hydroxypyrimidines obtained from thiourea and formylacetic esters.  2 - Hydroxy - 4 - alkylmercaptopyrimidines are obtainable from the above-mentioned isomers by treatment with phosphorus oxychloride to convert the 4-hydroxy group to chlorine, replacement of this by a mercapto group by the action of sodium or potassium hydrosulphide, acid hydrolysis of the 2-alkylmercapto group and S-alkylation of the resulting 2-hydroxy-4-mercapto compound.  4-Di-n-butylaminobutylamine is obtainable by sodium and ethanol reduction of 4-di-n-butylaminobutyronitrile, which may be made by interaction of 4 - bromobutyronitrile with dibutylamine.  3 - Diethylamino - 1 : 2 - dimethylpropylamine is obtainable by reduction of the oxime of 4-diethylamino-3-methylbutan-2-one, which may be made by condensation of methyl ethyl ketone, formaldehyde and diethylamine. 2-Piperidino-2-methylethylamine is obtainable by reduction of a -piperidinopropionitrile, which may be made by the action of sodium cyanide on the condensation product of piperidine with acetaldehyde-sodium bisulphite.  N - Methyl - N - b  - diethylaminoethylpropylenediamine is obtainable by reduction of the condensation product of acrylonitrile with b -diethylaminoethylmethylamine.