Patent GB-677342-A (GB)
Title: New pyrimidine derivatives and their use in the manufacture of pteridin derivatives
Inventor: BOON WILLIAM ROBERT
IPC: C07D475/02
Filed: 1949-08-19
Abstract: Pyrimidine derivatives of the general formula <FORM:0677342/IV (b)/1> (wherein A represents a hydroxy, amino or alkylamino group, B represents a hydroxy, thiol, alkylthio, amino or mono- or di-substituted amino group, Ar represents an aryl radical which may contain substituents, R and R1 represent hydrogen or hydrocarbon or substituted hydrocarbon radicals, or one only of them may represent -COR11, and R11 represents hydrogen, a hydrocarbon radical which may contain substituents, a hydrocarbon-oxy radical, or an amino or mono-substituted amino group) are converted into dihydropteridine derivatives by reducing the -N=N-Aryl group to -NH2 and allowing or causing the product to undergo ring closure to a compound of the formula <FORM:0677342/IV (b)/2> (the former being formed when R11 is hydrogen or a hydrocarbon radical and the latter when R11 is a hydrocarbon-oxy, amino or monosubstituted amino group).  The ring closure may occur spontaneously or may be brought about by heating, and the products, if at least one of R and R1 is hydrogen, may, if desired, be oxidized to the corresponding pteridines.  Examples describe the preparation of: (1) 2-amino - 6 - hydroxy - 8 - methyl - 9 : 10-dihydropteridine (in the form of its hydrochloride monohydrate), and the corresponding pteridine; (2) 9 : 10-dihydroxanthopterine sulphate; (5) 2 : 6-diamino-8-hydroxy-9 : 10-dihydropteridine sulphate; (7) 2 : 6 : 8-trihydroxy - 9 : 10 - dihydropteridine; (9) 2-amino - 6 - mercapto - 8 - hydroxy - 9 : 10-dihydropteridine; (10) 2 - amino - 6 - diethylamino - 8 - hydroxy - 9 : 10 - dihydropteridine; (11) 2 - amino - 6 - methylamino - 8 - hydroxy-9 : 10-dihydropteridines.  1 - Phthalimido - 3 - phenoxypropanone - 2 is prepared by heating glycidyl phenyl ether with phthalimide, and oxidizing the resulting 1 - phthalimido - 3 - phenoxy - 2 - propanol with chromic anhydride in glacial acetic acid.ALSO:The invention comprises pyrimidine derivatives of the general formula <FORM:0677342/IV (c)/1> (wherein A represents a hydroxy, amino or alkylamino group, B represents a hydroxy, thiol, alkylthio, amino or mono- or di-substituted amino group, Ar represents an aryl radical which may contain substituents, R and R1 represent hydrogen or hydrocarbon or substituted hydrocarbon radicals, or one only of them may represent -COR11, and R11 represents hydrogen, a hydrocarbon radical which may contain substituents, a hydrocarbon-oxy radical, or an amino or mono-substituted amino group), and the manufacture thereof by (a) treating a pyrimidine derivative of the formula <FORM:0677342/IV (c)/2> (wherein X represents a halogen atom) with reagents capable of replacing an active halogen substituent by a hydroxy, thio, alkylthio, amino or mono- or di-substituted amino group, or (b) (when B is a hydroxy, thiol, amino or alkylamino group) reacting a pyrimidine derivative of the formula <FORM:0677342/IV (c)/3> (wherein X represents a halogen atom and Y a hydroxy, thiol, amino or alkylamino group) with an a -amino-aldehyde, -ketone or -carboxylic ester or amide NH2-CRR1-COR11, or with a functional derivative (e.g. acetal, oxime or semicarbazone) of the aldehyde or ketone with subsequent hydrolysis.  The reagents in process (a) may be alkali metal hydroxides, hydrogen sulphide, alkali metal hydrosulphides or mercaptides, ammonia or primary or secondary amines, and when a primary amine is employed it may simultaneously replace a hydrocarbonoxy radical, if present as R11, by a monosubstituted amino group.  In examples, the following starting materials and reagents are employed: (1)-(4) 2 - amino - 4 - hydroxy - 5 - benzeneazo - 6 - chloropyrimidine and aminoacetone semicarbazone, glycine ethyl or isopropyl ester, or alanine ethyl ester; (5) 2 : 4-diamino-6-chloro - 5-p-chlorobenzeneazopyrimidine and glycine ethyl ester; (6) 2-amino-4-hydroxy-5-benzeneazo-6-chloropyrimidine and 1-amino-3-phenoxypropanone-2-semicarbazone; (7) and (8) 4-chloro-2 : 6-dihydroxy- or 6-amino-4-chloro- 2 - hydroxy - 5 - p - tolueneazopyrimidine and glycine methyl ester; (9)-(11) ethyl 2 - amino - 4 - chloro - 5 - p - chlorobenzeneazo - 6 - pyrimidylaminoacetate and sodium hydrosulphide, diethylamine or methylamine; (12) ethyl 4-chloro-2-methylamino-5-p-chlorbenzeneazo - 6 - pyrimidylacetate and sodium ethylmercaptide; (13) 2-amino-4-hydroxy-6-chloro-5-p-chlorobenzeneazopyrimidine and diethyl aminomalonate.  2 - Amino - 4 - hydroxy - 5 - benzeneazo - 6 - chloropyrimidine is prepared by coupling benzenediazonium chloride with 2-amino-4-hydroxy-6-chloropyrimidine.  2 : 4 - Diamino - 6 - chloro - 5 - p - chlorobenzeneazopyrimidine is prepared by coupling p-chlorobenzenediazonium chloride with 2 : 4-diamino-6-chloropyrimidine.  4 - Chloro - 2 : 6 - dihydroxy- and 6 - amino-4-chloro - 2 - hydroxy - 5 - p - tolueneazopyrimidine are prepared by coupling p-toluenediazonium chloride with 4-chloro-2 : 6-dihydroxypyrimidine and 4-chlorocytosine respectively.  Ethyl 2-amino- and 2-methylamino-4-chloro-5-p-chlorobenzeneazo-6 -pyrimidylaminoacetate are prepared by coupling p-chlorobenzenediazonium chloride with ethyl 2-amino- and 2-methylamino - 4 - chloro - 6 - pyrimidylaminoacetate respectively.