Patent GB-1109307-A (GB)
Title: Heterocyclic alkanoic acids
IPC: C07D307/42
Filed: 1965-12-21
Abstract: The invention comprises compounds of the formulae <FORM:1109307/C2/1> <FORM:1109307/C2/2> where n is 0, 1 or 2, M is a hydrogen atom or a C1- 5 alkyl, C2- 5 alkenyl, C2- 5 alkynyl, C1- 5 cycloalkyl, phenyl, C1- 6 alkanoyl, aminophenyl, carboxyphenyl, carboxamidophenyl, (C1- 5 alkoxy)-alkyl, poly-(C1- 5 alkoxy) C1- 5 alkyl, polyhydroxy hydroxy C1- 5 alkyl, or di-(C1- 5 alkyl) amino C1- 5 alkyl radical, or a cation, R4 is a halogen atom or a C1- 5 alkyl radical, Y is an oxygen or sulphur atom, R11 is a hydrogen atom or a C1- 5 alkyl radical, R1 is a C1- 5 alkylidene radical and R3 is a <FORM:1109307/C2/3> radical where R10 is a hydrogen atom or a hydroxy, C1- 5 alkoxy or benzyloxy radical with the proviso that R3 is not adjacent to the <FORM:1109307/C2/4> or <FORM:1109307/C2/5> group and that when Y is oxygen the R3 and <FORM:1109307/C2/6> or <FORM:1109307/C2/7> groups are not in a 2,4-position to each other; the process that comprises (a) admixing a 2-cyclohexyl heterocyclic compound of the formula <FORM:1109307/C2/8> with hydrogen cyanide in an inert solvent which is saturated or nearly saturated with a hydrohalide, at temperatures below ambient temperatures, subsequently mixing the resulting mixture with water, ice or ice-water and heating at elevated temperatures to form a 5-cyclohexyl-2-heterocyclic aldehyde compound; (b) oxidizing said aldehyde compound in an inert solvent containing an alkali metal or alkaline earth metal hydroxide to form a 5-cyclohexyl-2-heterocyclic carboxylic acid compound and (c) admixing said 5-cyclohexyl-2-heterocyclic carboxylic acid compound with an inorganic acid halide to form the corresponding carboxylic acid halide; reacting said carboxylic acid halide with diazomethane in an inert solvent to form the corresponding diazoketone compound, and admixing the latter with silver oxide in water to produce a compound of the formula <FORM:1109307/C2/9> wherein Y, R4 and n are as defined above; the process that comprises (a) admixing a compound of the formula <FORM:1109307/C2/10> with mercuric chloride in the presence of aqueous alkali or alkaline earth metal acetate to form a 2-cyclohexyl-5-chloromercuri compound; (b) admixing said 2-cyclohexyl-5-chloromercuri compound with a C1- 6 alkanoic acid halid in an inert solvent to form a 2-cyclohexyl-5-C1- 6 alkanoyl compound; (c) admixing said 2-cyclohexyl-5-C1- 6 alkanoyl compound with an inorganic cyanide with or without a solvent to form a 5-cyclohexyl-2-cyanohydrin compound; (d) admixing said 5-cyclohexyl-2-cyanohydrin with a mineral acid to form a 5 - cyclohexyl - 2 - (a  - hydroxy) - amide compound; (e) admixing said 5-cyclohexyl-2-(a -hydroxy)-amide compound with aqueous alkali metal or alkaline earth metal hydroxide, or a non-aqueous alkali metal or alkaline earth metal hydroxide in an inert solvent, aqueous ammonium hydroxide or a C1- 5 aliphatic amine with or without a solvent to form a 5-cyclohexyl-2-(a -hydroxy) acid compound and (f) admixing said 5-cyclohexyl-2-(a -hydroxy) acid compound with a strong acid in an inert solvent at elevated temperatures to produce a compound of the formula <FORM:1109307/C2/110> where Y, R4 and n are as defined above, and R1 and R2 taken together form a C2- 5 alkylidene group and (g) if desired, reducing said a -C2- 5 alkylidene compound over a catalyst in an inert solvent to form an a -C2- 5 alkyl compound in which R1 is hydrogen and R2 is C2- 5 alkyl and the process that comprises admixing a cyclohexyl thiophene compound of the formula <FORM:1109307/C2/121> with an aqueous concentrated hydrochloric acid formaldehyde solution to produce a cyclohexyl2-thiophene chloromethyl compound; (b) admixing said chloromethyl compound with an alkali metal or alkaline earth metal cyanide in an inert solvent at an elevated temperature to produce a cyclohexyl-2-thiophenecyanomethyl compound and (c) admixing said cyanomethyl compound with an aqueous alkali metal or alkaline earth metal hydroxide at elevated temperatures and subsequently acidifying the reaction mixture to produce a compound of the formula <FORM:1109307/C2/132> wherein R4 and n are as defined above and the CH2COOH group is other than joined to the <FORM:1109307/C2/143> group.  Pharmaceutical compositions having anti-inflammatory activity and containing the above compounds are administered orally.