Patent GB-715813-A (GB)
Title: Improvements in derivatives of pyrimidine
Filed: 1951-05-30
Abstract: The invention comprises compounds, having improved antimalarial properties, of the general formula <FORM:0715813/IV (b)/1> wherein Ar represents a 3- or 4-halophenyl, 3 : 4-dihalophenyl or 4-nitrophenyl radical, R represents a primary alkyl radical of 1-5 carbon atoms and X represents NH2, and their salts, and the manufacture of compounds of the said general formula wherein Ar represents any aryl radical, which may be substituted, R represents hydrogen, or an aryl or alkyl radical either of which may be substituted, and X represents hydrogen or an alkyl or aryl radical, or NH2 when R is other than hydrogen, by condensing a compound (guanidine or an amidine) of the formula X-C(: NH)NH2 with a b -alkoxy-a -arylacrylonitrile of the formula <FORM:0715813/IV (b)/2> (wherein R1 represents an alkyl or aralkyl radical).  The latter reactant is preferably prepared in situ from the corresponding b -hydroxy compound (tautomeric with an a -acyl-a -arylacetonitrile).  In examples: (1) a -acetyl-p-chlorophenylacetonitrile is treated with diazomethane in ether and the product is refluxed with guanidine in alcohol to produce 2 : 4-diamino - 5 - p - chlorophenyl - 6 - methylpyrimidine; the same compound is obtainable by condensing guanidine with b -ethoxy-b -methyl - a  - p - chlorophenylacrylonitrile; (2) a  - propionyl - p - chlorophenylacetonitrile is treated as in the first part of (1) to form 2 : 4-diamino - 5 - p - chlorophenyl - 6 - ethylpyrimidine; (3)-(5), (8)-(10) and (13) the corresponding 6 - n - propyl, 6 - isobutyl, 6-a -ethyl-n-propyl, 6-n-amyl, 6-n-undecyl, 6-b -phenethyl and 6-phenyl compounds are similarly prepared; (6) 2 : 4-diamino-5-phenyl - 6-methylpyrimidine is prepared similarly or from b  - methyl - b  - benzyloxy - a  - phenylacrylonitrile; (7) the product of (6) is nitrated in the para-position of the 5-phenyl group; (11), (12) (14), and (24)-(35) by the process of the first part of (1) are prepared 2 : 4-diamino-5-phenyl-6 - (N - methyl - N - phenylaminomethyl)-, -5-a -naphthyl-6-methyl-, -5 : 6-diphenyl-, -5-p-chlorophenyl-6-n-butyl-, -5-p-nitrophenyl-6-ethyl-, -5-p-bromophenyl-6-ethyl-, -5-m-fluorophenyl-6-methyl-, -5-m-chlorophenyl-6-methyl-, - 5 - m - bromophenyl - 6 - methyl -, - 5 - (31 : 41-dichlorophenyl) - 6 - methyl -, - 5 - (31 : 41-dichlorophenyl) - 6 - ethyl -, - 5 - (31 : 41 - dichlorophenyl) - 6 - n - propyl -, - 5 - (31 : 41-dichlorophenyl - 6 - n - butyl -, - 5 - (31 : 41-dibromophenyl) - 6 - ethyl - and - 5 - (31-bromo - 41 - chlorophenyl) - 6 - methyl - pyrimidine; (15)-(23) from the appropriate amidines and b -methoxy-a -arylacrylonitriles are prepared 4-amino-5-phenyl-, -6-methyl-5-phenyl -, - 5 - p - chlorophenyl - 6 - phenyl -, - 2 - methyl - 5 - p - chlorophenyl -, - 5 - p-chlorophenyl - 2 : 6 - dimethyl -, - 5 - p - chlorophenyl - 2 - methyl - 6 - phenyl -, - 5 - p - chlorophenyl - 2 - p - tolyl -, - 5 - p - chlorophenyl - 6-methyl - 2 - phenyl - and - 5 - p - chlorophenyl-6-phenyl-2-p-tolyl-pyrimidine.  a  - Acyl - a  - arylacetonitriles of the general formula <FORM:0715813/IV (b)/3> are obtainable by condensing, in the presence of an alkali metal alkoxide, arylacetonitriles with esters RCOO Alkyl, e.g. p-chlorophenylacetonitrile with ethyl propionate or ethyl benzoate, phenylacetonitrile with N-phenyl-N-methylglycine ester, or m-fluorophenylacetonitrile with ethyl acetate.  Arylacetonitriles are obtainable by reacting arylmethyl halides with alkali metal cyanides, e.g. m-fluorotoluene is refluxed with sulphuryl chloride in the presence of benzoyl peroxide and the product is refluxed with potassium cyanide in aqueous ethanol to produce m-fluorophenylacetonitrile.