Patent GB-712762-A (GB)
Title: Preparation of substituted benzoic acids
IPC: C07C233/12
Filed: 1951-08-14
Abstract: Compounds of the general formula <FORM:0712762/IV (b)/1> wherein R1 represents hydrogen or an alkyl, aryl, aralkyl or cycloalkyl radical, n is 0 or an interger from 1 to 7 inclusive, Z represents hydrogen or an arylsulphonyl, aralkylsulphonyl, alkylsulphonyl or cycloalkylsulphonyl radical, and R represents an alkyl, alkoxymethyl, aryloxymethyl, aralkoxymethyl, dialkoxymethyl or acyloxymethyl radical, are prepared by mixing a solution of a metal dichromate in an aqueous acid with a solution of a compound of the general formula <FORM:0712762/IV (b)/2> where R1, n, Z and R have the above significance, in a substantially water-immiscible organic liquid which is inert under the reaction conditions.  The reactants may be mixed, e.g. with vigorous agitation, at a temperature between about - 10 DEG  C. and about 30 DEG  C.  The organic liquid may be an aromatic or halo-aromatic hydrocarbon, e.g. benzene, toluene or chlorobenzene, or may be chloroform.  Acids which may be used are inorganic acids, e.g. sulphuric or phosphoric acid, and aliphatic acids, e.g. acetic, propionic or butyric acid, or mixtures of aliphatic acids, or mixtures of aliphatic and inorganic acids may be used. Metal dichromates which may be used in the reaction are the dichromates of the heavy metals and sodium, potassium, calcium and magnesium dichromate.  The reaction mixture may contain at least two equivalent weights of metal dichromate for each molar weight of hydroxy compound.  The aqueous solution of dichromate may contain from about 4 to about 9 mols. of metal dichromate per litre.  The ester residue may be a methyl, ethyl, n-propyl, n-butyl, t-butyl, amyl, lauryl, iso-propyl, dodecyl, phenyl, tolyl, xylyl, cyclohexyl or benzyl ester.  The esters prepared by the above method, i.e. when R1 represents an alkyl, aryl, aralkyl or cycloalkyl radical, can be converted to the free acids, i.e. when R1 represents hydrogen, by treatment with alkali. The radical Z may be an o or p-toluenesulphonyl, benzenesulphonyl, naphthalenesulphonyl, methanesulphonyl, alpha-toluenesulphonyl or cyclohexylsulphonyl radical.  The arylsulphonyl radicals may contain inert substituents, e.g chlorine or bromine or the nitro radical.  The arylsulphonyl radical may be split off to form the corresponding free amine by treatment with hydrogen bromide in an aliphatic acid medium and in the presence of a bromine acceptor by the method described in Specification 676,037.  The free amines can be converted to the arylsulphonyl compounds by reaction with arylsulphonyl halides in the presence of alkali.  In the examples, the following compounds are prepared: diethyl N1-(N-(3-acetoxy-2-ketopropyl) - N - (p - toluenesulphonyl) - p - aminobenzoyl) - l - glutamate, ethyl N - (3,3 - diethoxy - 2 - ketopropyl) - N - (p - nitrobenzenesulphonyl) - p - aminobenzoate, ethyl N-(3,3 - diethoxy - 2 - ketopropyl) - p - aminobenzoate, ethyl N - (3,3 - diethoxy - 2 - ketopropyl) - N - (p - toluenesulphonyl) - p - aminobenzoate, diethyl N1 - (N - (3,3 - diethoxy - 2-ketopropyl) - p - aminobenzoyl) - l - glutamate, diethyl - N1 - (N - (3,3 - diethoxy - 2 - ketopropyl) - N - (p - toluenesulphonyl) - p - aminobenzoyl) - l - glutamate and diamyl N1-(N - 3,3 - dibutoxy - 2 - ketopropyl) - N - (betanaphthalenesulphonyl) - p - aminobenzoyl - l-glutamate.  The Specification refers to a number of additional compounds which may be prepared by the process referred to above, and the starting compounds from which these additional compounds may be prepared. Specifications 671,532, 675,383 and 676,037 are referred to. Substituted amino-benzoate compounds of the general formula <FORM:0712762/IV (b)/3> wherein R represents an alkyl, aryl, aralkyl or or radical, R1 represents an alkyl radical and Z and n have the significance indicated above, are prepared by reacting a compound of the general formula <FORM:0712762/IV (b)/4> with a 1,2-epoxypropyl compound of the formula <FORM:0712762/IV (b)/5> tertiary amine. Compounds of the above general formula wherein R1 represents hydrogen may be prepared by hydrolysing the carboxylic ester groups.  Diethyl N1-(N-(3-acetoxy-2-hydroxypropyl) - N - (p - toluenesulphonyl)-p - aminobenzoyl - l - glutamate is prepared by reacting diethyl N1-(N-(p-tolyenesulphonyl)-p - aminobenzoyl - l - glutamate and glycidol in the presence of pyridine.  Substituted amino-benzoate compounds of the general formul  <FORM:0712762/IV (b)/6> wherein R and R1 represent alkyl radicals and n and Z have the significance indicated above, are prepared by reacting a compound of the general formula <FORM:0712762/IV (b)/7> with a 1,2-epoxyalkane of the formula <FORM:0712762/IV (b)/8> preferably in the presence of a tertiary amine.  Compounds of the above general formula wherein R1 represents hydrogen are prepared by hydrolysing the carboxylic ester groups. Diethyl N1 - (N - (p - toluenesulphonyl) - p-aminobenzoyl)-l-glutamate is prepared by reacting N - (p - toluenesulphonyl) - p - aminobenzoyl chloride and diethyl l-glutamate hydrochloride in the presence of triethylamine.  Ethyl N - (3,3 - diethoxy - 2 - hydroxypropyl)-N - (p - nitrobenzenesulphonyl) - p - aminobenzoate is prepared by reacting ethyl N-(p-nitrobenzenesulphonyl) p-aminobenzoate and 1,2 - epoxy - 3,3 - diethoxypropane in the presence of pyridine.  Ethyl N - (3,3 - diethoxy - 2 - hydroxypropyl)-p-aminobenzoate is prepared by reacting ethyl-p-aminobenzoate and the diethyl acetal of 2,3-oxidopropanol in the presence of pyridine.  Ethyl N - (3,3 - diethoxy - 2 - hydroxypropyl)-N - (p - toluenesulphonyl) - p - aminobenzoate is prepared by reacting ethyl p-aminobenzoate and the diethyl acetal of 2,3-oxidopropanol as above and then adding p-toluenesulphonyl chloride.  N - (3 - alkyl - 2,3 - diketopropyl) - N - (p-toluenesulphonyl) - p - aminobenzoate compounds are prepared by oxidizing the compounds of the general formula <FORM:0712762/IV (b)/9> wherein R represents an alkyl radical containing more than one carbon atom, Z represents the p-toluenesulphonyl radical and n and R1 have the significance indicated above, with selenium dioxide.  These compounds may be condensed with 2,4,5 - triamino - 6 - hydroxypyrimidine to form compounds related to folic acid having an alkyl substituent on the pterine nucleus.