Patent GB-675383-A (GB)
Title: The synthesis of compounds of the folic acid group and intermediates therefor
Inventor: WEISBLAT DAVID IRWIN
IPC: C07D475/04
Filed: 1950-01-24
Abstract: Compounds of the general formula <FORM:0675383/IV (b)/1> where R represents hydrogen or an alkyl, cycloalkyl, aralkyl or aryl radical, n is zero or a positive integer up to 7 (preferably 1) and Z represents an arylsulphonyl, alkylsulphonyl or cycloalkylsulphonyl radical (the arylsulphonyl radical optionally carrying substituents such as chlorine, bromine or a nitro group), are manufactured by reacting an N-(2-ketopropyl)-p-aminobenzoate compound of the general formula <FORM:0675383/IV (b)/2> (wherein R represents chlorine, bromine or iodine or a hydroxy, alkoxy, aryloxy, aralkoxy or acyloxy radical) with 2 : 4 : 5-triamino-6-hydroxypyrimidine (or its dihydrochloride), advantageously at room temperature in a liquid reaction medium (e.g. glacial acetic acid).  Subsequently, if desired, the group Z may be split off (e.g. by treatment with hydrogen bromide and a bromine acceptor, such as phenol, in an aliphatic medium) and/or any ester groups present may be hydrolysed to free carboxyl groups.  Examples describe the condensation of 2 : 4 : 5-triamino-6-hydroxypyrimidine (or its dihydrochloride) with diethyl N1-[N-(3-chloro-, 3-formoxy-, 3-hydroxy-, 3-methoxy- and 3-phenoxy-2-ketopropyl)-p1-toluenesulphonyl - p - aminobenzoyl] - glutamate, ethyl N-(3-benzoyloxy-, 3-formoxy-, 3-acetoxy-, 3-hydroxy- and 3 - methoxy - 2 - ketopropyl) - p1 - toluenesulphonyl-p-aminobenzoate, and N-(3-hydroxy-2-ketopropyl) -p1-toluenesulphonyl-p-aminobenzoic acid.  Lists of additional radicals which may be represented by R1 and Z are given.  N - (2 - Ketopropyl) - p - aminobenzoate compounds of the second general formula above (wherein Z represents hydrogen or an arylsulphonyl radical) are obtainable by oxidation, with chromic anhydride, of the corresponding 2-hydroxy compounds, which are prepared as follows: (a) when R represents chlorine, bromine or iodine, by condensing a p-aminobenzoate compound of the general formula <FORM:0675383/IV (b)/3> with epichlorhydrin, epibromhydrin or epiiodohydrin; (b) when R represents a hydroxy, alkoxy, aralkoxy, aryloxy or acyloxy radical, by treating the foregoing 3-halo-2-hydroxy compounds with alkali to form a 2 : 3-epoxy compound, and reacting this with water, an alcohol, a phenol or a carboxylic acid.  The 3-hydroxy-2-keto compounds are alternatively obtainable by alkaline hydrolysis of the 3-halo-2-keto compounds or alcoholysis of the 3-acyloxy-2-keto compounds.  Diethyl N1-[N-(3-phenoxy - 2 - hydroxypropyl) -p1-toluenesulphonyl-p-aminobenzoyl]-l-glutamate is alternatively prepared by heating diethyl N1 - (p1 - toluenesulphonyl - p - aminobenzoyl) - l - glutamate with 1 : 2 - epoxy - 3 - phenoxypropane in the presence of pyridine.  The preparation of certain of the starting materials of the examples, and intermediates therefor, is described in detail.  p-Aminobenzoate compounds of the general formula immediately above are obtainable as follows: (i) when n=1-7, by treating a glutamic acid compound of the general formula <FORM:0675383/IV (b)/4> with a p-nitrobenzoyl halide, then reducing the nitro group catalytically with hydrogen to an amino group, and, if desired, reacting the product with an arylsulphonyl halide in the presence of a hydrogen halide acceptor (e.g. pyridine in the case of esters or a dilute alkali in the case of acids); (ii) when n is zero, R1 is alkyl or hydrogen, and Z is arylsulphonyl, by treating p-aminobenzoic acid or an alkyl ester thereof with an arylsulphonyl halide as in (i); (iii) diethyl N1-(p1-toluenesulphonyl-p-aminobenzoyl)-l-glutamate is alternatively prepared by treating diethyl l(+)-glutamate hydrochloride with p1-toluenesulphonyl-p-aminobenzoyl chloride in ethylene dichloride in the presence of triethylamine or in aqueous ethylene dichloride in the presence of magnesium oxide.