Patent GB-760078-A (GB)
Title: Production of derivatives of cyclo-octane having strong cholagogic activity
IPC: C07C61/10
Filed: 1954-08-16
Abstract: A compound of the general formula <FORM:0760078/IV(b)/1> wherein two adjacent X's represent a double linkage and the remaining X represents hydrogen, R is an alkyl or alkenyl group, X is hydrogen and X2 is a carboxylic group is prepared by subjecting a compound of the above general formula wherein the X's and R have the meanings defined above, X1 is hydrogen or a carboxylic amide or ester group and X2 is a carboxylic ester, carboxylic amide or cyano group to a saponification treatment and, when X1 in the general formula of the starting materials is a carboxylic acid or ester group, effecting a partial decarboxylation during or after the saponification or at an intermediate stage thereof if it is effected stepwise.  The invention also comprises the subjection of an ester, amide or nitrile of an acid of the general formula <FORM:0760078/IV(b)/2> where R has the above-defined meanings, to a saponification treatment and during this treatment or in any sequence splitting off water by known methods to form a double bond.  The acids derived from either of the above processes may then be converted into salts with, for example, sodium hydroxide, magnesium carbonate, calcium carbonate, ammonia, diethylamine, ethanolamine, triethanolamine, morpholine, pyrrolidine, hexylamine or piperidine.  The saponification is preferably carried out in alkaline solution in water or organic solvents at 80-200 DEG C.  Reagents such as phosphorus tribromide, potassium bisulphate, acetic anhydride or para-toluene sulphonic acid may be used for the splitting off of water, or this can be achieved simultaneously with saponification under energetic conditions, e.g. with concentrated sulphuric acid.  The unsaturated acids wherein the double bonds are attached to the C1 atom of the cyclo-octane ring are stated to be mixtures of isomers in which the double bond is either attached to a C2 atom of the ring or to the a -carbon atom of the side-chain.  In examples: (1) D 1-cyclo-octenyl-ethyl-cyano-acetic acid ethyl ester is heated at 160-170 DEG  C. with potassium hydroxide in alcohol and, after working-up the resulting solution, the product is vacuum distilled to give D 1-cyclo-octenylethyl-acetic acid; the corresponding D 1-cyclo-octenyl - methyl -, n - propyl, butyl and allyl-acetic acids are prepared similarly; (2) D 2-cyclo-octenyl-ethyl malonic acid diethyl ester is saponified with potassium hydroxide in aqueous alcohol at reflux temperature to give D 2-cyclo-octenyl-ethyl-malonic acid monoethyl ester which on heating in a slight vacuum at 180 DEG  C. followed by high vacuum distillation yields D 2-cyclo-octenyl-ethyl-acetic acid ethyl ester which is then saponified to the free acid by refluxing with potassium hydroxide in aqueous methanol; the sodium, magnesium, calcium and zinc salts of the product are referred to; (3) (1-hydroxy-cyclo-octyl-(1)-)-ethyl acetic acid ethyl ester is heated with potassium bisulphate at 180 DEG  C. to give D 1-cyclo-octenyl-ethyl-acetic acid ethyl ester which is saponified to the free acid with potassium hydroxide in methanol at reflux temperature; alternatively the ester can be converted to the amide and this saponified; and (4) D 1-cyclo-octenyl-propyl-acetonitrile with potassium hydroxide in aqueous methanol at 180 DEG  C. gives D 1-cyclo-octenyl-propyl-acetic acid.  The products have cholagogic activity.  Starting materials.  Cyclo-octenyl-alkyl- or alkenyl-malonic acid esters and -cyanoacetic acid esters are obtained by splitting off water from the hydroxycarboxylic acid esters obtainable by the Reformatski reaction between cyclo-octanone and a -bromo-fatty acid esters or by condensation of cyclo-octyl magnesium halides with functional derivatives of pyruvic acid or alpha-keto butyric acid.  Esters, amides and nitriles of cyclo-octenyl-alkyl- or -alkenyl-malonic acids are obtained by condensing cyclo-octanone with functional derivatives of malonic acid and reacting the reaction products with alkyl or alkenyl halides, or with dimethyl or diethyl sulphate.  In the examples, D 2-cyclo-octenyl-ethyl-malonic acid diethyl ester is prepared from 1,2-dibromo cyclo-octane and monoethyl-malonic acid diethyl ester, D 1-cyclo-octenyl-propylacetonitrile is prepared by hydrolysis and decarboxylation of D 1 - cyclo - octenyl - propyl - cyanoacetic acid ethyl ester, (1-hydroxy-cyclo-octyl - (1) - ) - ethyl - acetic acid ethyl ester is prepared from cyclo-octanone and a -bromo-butyric acid ethyl ester by the Reformatski reaction, and D 1-cyclo-octenyl-methyl- and ethyl-cyano-acetic acid ethyl esters are prepared from cyclo-octylidene-cyano-acetic acid ethyl ester and dimethyl or diethyl sulphate.