Patent GB-676653-A (GB)
Title: The production of intermediates for compounds of the folic acid series
IPC: H02P9/42
Filed: 1949-12-02
Abstract: Compounds of the general formula <FORM:0676653/IV (b)/1> wherein R1 represents hydrogen or an alkyl radical and n is zero or a positive integer up to 7 (preferably 0 or 1), are manufactured by reacting a keto aldehyd of the general formula <FORM:0676653/IV (b)/2> with 2 : 4 : 5 - triamino - 6 - hydroxypyrimidine (preferably in the form of its dihydrochloride), e.g. by mixing the reactants (preferably together with anhydrous sodium acetate) in glacial acetic acid solution and allowing the mixture to stand or stirring it under an inert atmosphere.  The aryl radical of the arylsulphonyl group may carry substituents not reactive under the reaction conditions (e.g. chlorine, bromine or a methoxy, phenoxy or nitro group), whilst, according to a modification of the invention, it may be replaced by an alkyl, cycloalkyl or aralkyl group.  When the starting material is an ester (R1=alkyl), the ester group or groups may be hydrolysed to -COOH before or after the condensation.  Examples describe the preparation of N-([2-amino-4-hydroxy-6-pteridyl] - methyl) - N - p1 - toluenesulphonyl - p - aminobenzoic acid or its ethyl ester from N - (2 - formyl - 2 - ketoethyl) - N - p1 - toluenesulphonyl-p-aminobenzoic acid or its ethyl ester, and of N1 - (N - [(2 - amino - 4 - hydroxy - 6 - pteridyl) - methyl] - N - p1 - toluenesulphonyl-p-aminobenzoyl)-l-glutamic acid or its diethyl ester from N1-(N-[2-formyl-2-ketoethyl]-N-p1-toluenesulphonyl - p - aminobenzoyl) - l - glutamic acid or its diethyl ester.  A list of additional starting materials is given.  The products may be converted to compounds of the folic acid series as described in Specification 671,532. Keto aldehydes of the second general formula above are manufactured by acid hydrolysis of the corresponding compounds acetalized at the aldehyde group (obtainable as in Specification 671,532), or by oxidation (e.g. with chromic acetate or, in the first two cases, with cupric acetate) of the corresponding compounds containing a -CHOH- group in place of the keto group (obtained by acid hydrolysis of their acetals, likewise obtainable as in Specification 671,532) or those containing a hydroxymethyl or methoxymethyl group in place of the aldehyde group.  The hydroxymethyl compounds are obtainable by reacting an N-arylsulphonyl-p-aminobenzoate compound of the general formula <FORM:0676653/IV (b)/3> with an epihalohydrin or an epoxypropyl aliphatic ester (e.g. 2 : 3-epoxypropyl acetate) to form the N-(3-halo- or 3-acyloxy-2-hydroxy-propyl) compound, oxidizing this (e.g. with chromic oxide) to the N-(3-halo- or 3-acyloxy-2-ketopropyl) compound, and then replacing the halogen atom or the acyloxy group by a hydroxy group by, respectively, carful hydrolysis with aqueous alkali or ester interchange with an alkanol. The methoxymethyl compounds are obtainable by carefully treating the foregoing N - (3 - halo - 2 - hydroxypropyl) compound with aqueous alkali to form an N-(2 : 3-epoxypropyl) compound, treating this with sodium methylate, and oxidizing the resulting N-(3-methoxy-2-hydroxypropyl) compound (e.g. with chromic oxide). Hydrolysis of ester groups -COOR1 (where R1=alkyl) to -COOH may be effected at various stages in the foregoing reaction scheme.  Diethyl N1-(N-[3-methoxy - 2 - hydroxypropyl) - N - p1 - toluenesulphonyl - p - aminobenzoyl) - l - glutamate is alternatively prepared directly by reacting diethyl N1 - (N - p1 - toluenesuphonyl - p - aminobenzoyl) - l - glutamate with 1 : 2 - epoxy-3 - methoxypropane.  The preparation, by several methods, of the starting materials of the examples above is described in detail, and lists of additional starting materials and intermediates are given.  N - Arylsulphonyl - p - aminobenzoate compounds of the general formula immediately above are obtainable by reacting a p-aminobenzoate compound of the general formula <FORM:0676653/IV (b)/4> with an arylsulphonyl halide. Diethyl N1-(N - p1 - toluenesulphonyl - p - aminobenzoyl) - l - glutamate is alternatively prepared by reacting N - p - toluenesulphonyl - p - aminobenzoyl chloride with diethyl l(+)-glutamate hydrochloride.  2 : 3-Epoxypropyl acetate is prepared by refluxing epichlorhydrin with anhydrous potassium acetate and potassium carbonate.  The Specification as open to inspection under Sect. 91 comprises also references to the reaction of ethyl N-(p1-toluenesulphonyl)-p-aminobenzoate with 1 : 2-epoxy-3-methoxypropane to form ethyl N - (3 - methoxy - 2 - hydroxypropyl) - N - (p1 - toluenesulphonyl) - p - aminobenzoate; the oxidation of the latter compound to N-(3-methoxy-2-ketopropyl)-N-(p1-toluenesulphonyl) -p-aminobenzoate and of this product to ethyl N - (2 - formyl - 2 - ketoethyl) - N - (p1 - toluenesulphonyl)-p-aminobenzoate; and the preparation of N-(3-methoxy-2-ketopropyl)- and N-(2-formyl - 2 - ketoethyl) - N - (p1 - toluenesullhonyl)-p-aminobenzoic acid and of N1-(N-[3-methoxy-2-ketopropyl]- and -[2 formyl-2-ketoethyl] - N - [p1 - toluenesulphonyl] - p - aminobenzoyl)-l-glutamic acid by saponification of their ethyl esters, and of the second and fourth compounds by oxidation of the first and third.  Examples are given of the hydrolysis of and splitting off the p-toluenesulphonyl radical from ethyl N - ([2 - amino - 4 - hydroxy - 6 - pteridyl]-methyl) - N - (p1 - toluenesulphonyl) - p - aminobenzoate and diethyl N1 - (N - [(2 - amino - 4 - hydroxy - 6 - pteridyl) - methyl] - N - (p1 - toluenesulphonyl) - p - aminobenzoyl) - l - glutamate.  This subject-matter does not appear in the Specification as accepted.