Patent GB-775370-A (GB)
Title: New pyrimidine derivatives and processes for their preparation
Inventor: JACOB ROBERT MICHEL
IPC: C07D239/52
Filed: 1954-06-30
Abstract: The invention comprises: (a) pyrimidien derivatives of the general formula: <FORM:0775370/IV(b)/1> wherein A represents a straight or branched chain aliphatic hydrocarbon group of 2 to 12 (preferably 6 to 10) carbon atoms, R represents an amino or mercapto group, and R1 represents a halogen atom, a hydroxy, lower (1-4 C) alkoxy, mercapto or primary, secondary or tertiary amino group, or (when R is amino) a hydrogen atom, and their acid addition salts; (b) the manufacture of the compounds in which R1 is a hydroxy group by condensing a di-(ethoxycarbonylformylmethoxy)-alkane of the formula: <FORM:0775370/IV(b)/2> with thiourea or guanidine; (c) manufacture of compounds in which R1 has the other specified meanings in accordance with the examples below.  The process may be effected by heating the reactants (the first of which may be prepared in situ and used in the form of its sodium derivative) in ethanol under reflux in the presence of sodium or potassium ethoxide, and may be followed by replacement of the hydroxy group (R1) by halogen (optionally after acetylation when R is NH2) and, if desired, reaction of the halogen derivative with ammonia, a primary or secondary amine or an alkali metal alcoholate or hydrosulphide.  The products have bactericidal and anthelmintic (schistosomicidal) properties.  In examples: (1) a mixture of 1 : 6-di-(ethoxycarbonylmethoxy)-hexane and ethyl formate is run into a suspension of sodium in ether, the precipitated 1 : 6 - di - (ethoxycarbonylformylmethoxy) - hexane (sodium derivative) is dissolved in alcohol and the solution refluxed with guanidine and potassium ethoxide to produce 1 : 6 - di - (21 - amino - 41 - hydroxypyrimidyl - 51-oxy)-hexane, the hydrochloride of which is described; (2) 1 : 10 - di - (ethoxycarbonylmethoxy)-decane similarly yields 1 : 10-di-(21-amino41 - hydroxypyrimidyl - 51 - oxy) - decane and its hydrochloride; (3) the product of (1) is acetylated with acetic anhydride and pyridine, the diacetyl derivative is treated with POCl3 and the product is hydrolysed with aqueous caustic soda to 1 : 6-di-(21-amino-41-chloropyrimidyl - 51 - oxy) - hexane, which is purified by conversion to its hydrochloride; (4) the product of (2) is similarly converted to 1 : 10-di-(21-acetylamino - 41 - chloropyrimidyl - 51 - oxy)-decane, which is heated with alcoholic ammonia to form 1 : 10 - di - (21 : 41 - diaminopyrimidyl-51 - oxy) - decane; (5) 1 : 6 - di - (21 - acetylamino - 41 - chloropyrimidyl - 51 - oxy) - hexane is heated with alcoholic ammonia to give 1 : 6-di-(21 : 41 - diaminopyrimidyl - 51 - oxy) - hexane the ammonia may be replaced by (6) dimethylamine; and (7) di-n-butylamine; (8) the ammonia in (4) is replaced by di-n-butylamine; (9) the guanidine in (1) is replaced by thiourea, producing 1 : 6 - di - (21 - mercapto - 41 - hydroxypyrimidyl - 51 - oxy) - hexane; (10) the product of (3) is heated with a solution of sodium in butanol to form 1 : 6-di-(21-amino-41-butoxypyrimidyl - 51 - oxy) - hexane; (11) the product of (3) is hydrogenated in aqueous ethanol in the presence of a palladium on calcium carbonate catalyst to give 1 : 6-di-(21-aminopyrimidyl - 51 - oxy) - hexane; (12) the product of (3) is heated with potassium hydrosulphide in ethanol to produce 1 : 6-di-(21 amino-41-mercaptopyrimidyl-51-oxy)-hexane.  Starting materials.  1 : 6-Di-(ethoxycarbonylmethoxy) hexane is obtained by the action of ethanol in acidic medium on 1 : 6-di(cyanomethoxy) hexane, itself obtained by the action of cuprous cyanide on hexane-1 : 6-diol di-chloromethyl ether.  The analogous decane derivatives are obtained similarly.  The chloromethyl diether of decane-1 : 10-diol is obtained by reacting paraformaldehyde and anhydrous hydrogen chloride with decane-1 : 10-diol.