Patent GB-776717-A (GB)
Title: Derivatives of mandelic acid and their salts and process for the preparation thereof
IPC: C07D295/08
Filed: 1955-08-05
Abstract: The invention comprises compounds of the formula <FORM:0776717/IV(b)/1> and acid addition and quaternary salts of the formula <FORM:0776717/IV(b)/2> in which E is a 2 : 5-endomethylene-D 3-cyclohexenyl or 2 : 5 - endomethylenecyclohexyl radical, R1 is hydrogen, an alkyl radical, preferably containing 1-6 carbon atoms, or an alkoxy radical, preferably containing 1-4 carbon atoms; R2 is hydrogen or an alkoxy radical preferably containing 1 or 2 carbon atoms; R3 and R4 are alkyl radicals, preferably containing 1-4 carbon atoms, or together with the nitrogen atom form a heterocyclic ring, which may contain further hetero atoms, such as pyrrolidine, piperidine or morpholine; R5 is hydrogen, an alkyl radical, preferably containing 1-10 carbon atoms, or an aralkyl radical; X is a straight or branched chain alkylene group, preferably containing from 1-4 carbon atoms; and Y is the anion of an inorganic or organic acid.  It comprises also the esters and acids of the formula <FORM:0776717/IV(b)/3> wherein R6 is a hydrogen atom or an alkyl radical.  The compounds are made by reacting an a -keto-carboxylic acid or its esters of the formula <FORM:0776717/IV(b)/4> in which R6 is hydrogen or an alkyl radical with an organo-metal compound of 2 : 5-endomethylene - D 3 - cyclohexene or 2 : 5 - endomethylenecyclohexane, such as an alkali metal compound or a magnesium halide, hydrolysing the reaction product to give the substituted mandelic acid or ester thereof of the formula III and reacting the acid of this formula (R6=H) with an aminoalkyl halide of the formula R3(R4)N-X-Halogen to give the basic ester. Alternatively, the acids or esters of the formula III are reacted with the amino alcohol R3(R4)N-X-OH.  Reaction of the organo-metal compound with the a -keto-carboxylic acid IV is carried out under anhydrous conditions, preferably in the presence of an inert solvent such as ether, benzene or tetrahydrofuran, and preferably at an elevated temperature, for example at the boiling temperature of the solvent.  Suitably the reaction is commenced at a low temperature and is completed by raising the temperature to the temperature of the solvent.  If the reaction product is obtained as an ester it may be converted into the free acid by saponification.  The reaction of the substituted mandelic acid III with the aminoalkyl halide is suitably carried out in an inert solvent such as isopropanol, at an elevated temperature, preferably at the boiling point of the solvent, and in the presence of a hydrogen halide binding agent.  Direct esterification of the substituted mandelic acid III with the amino alcohol may be carried out with or without esterification catalysts, or by removing the water formed during esterification by azeotropic distillation. Preferably, the reaction is effected in the presence of a basic substance such as an alkali metal or alkali metal alcoholate, at 110-130 DEG  C. in the presence or absence of solvents such as toluene or xylene.  The esters can be converted into acid addition or quaternary ammonium salts by reaction with a compound of the formula R5Y, suitably in a solvent such as ether, ethanol, acetone, ethyl acetate or benzene. The basic esters and their salts of formula I or II are used as therapeutic agents.  Examples describe the preparation of a -(2 : 5-endomethylene-D 3-cyclohexenyl) - mandelic acid and its ethyl, b -dimethylaminopropyl, b -dimethylaminoethyl, b  -(1 - piperidino) - ethyl, diethylamino - ethyl and pyrrolidinoethyl esters; the p-methyl-, p-isopropyl-, 3 : 4 - dimethoxy- and p - n - butoxy derivatives of a -(2 : 5-endomethylene-D 3-cyclohexenyl)-mandelic acid and the corresponding ethyl and diethylamino-ethyl esters; a -(2 : 5 -endomethyl - D 3 - cyclohexenyl) - p - methyl mandelic acid b  - morpholinoethyl and b -pyrrolidinoethyl esters; and a -(2 : 5-endomethylenecyclohexyl) mandelic acid and its ethyl and b -dimethylaminoethyl esters; the basic esters are isolated as acid addition salts and the preparation of corresponding quaternary salts is described.