Patent GB-532943-A (GB)
Title: Manufacture of alkamine esters and quaternary salts thereof
IPC: C07D295/088
Filed: 1939-08-01
Abstract: 532,943. Alkamine esters of disubstituted fatty acids. SOC. OF CHEMICAL INDUSTRY IN BASLE. Aug. 1, 1939, Nos. 22277 and 22278. Convention dates, Aug. 5, 1938 and June 20, 1939. [Class 2 (iii)] Di-alicyclic- or aryl-alicyclic-fatty acids are converted into their esters with amino-alcohols substituted in the amino group. Thus, the fatty acid or a reactive derivative thereof such as a halide, ester, anhydride or ketene, is reacted with the amino-alcohol ; or a reactive ester of the amino-alcohol is reacted with the fatty acid or salt thereof ; or the fatty acid or its reactive derivative may be combined with an alcohol containing a substituent, e.g. halogen, which is then replaced, on interaction with an amine by a substituted amino group. The products, which are useful therapeutically, may be converted into their quaternary salts. According to the examples, (1) dicyclohexylacetic acid 2-diethylamino-ethanol ester is prepared by reacting the acid chloride, prepared from the acid by means of thionyl chloride, with the amino-alcohol; its bromethylate is formed by heating with alkyl bromide and its bromomethylate, bromethylate and bromobenzylate are similarly prepared ; (2) phenyl-cyclohexylacetic acid is heated with chlorethyldiethylamine in the presence or absence of potassium carbonate to give the diethylamino-ethanol ester, which may be converted into its bromomethylate by treatment with methyl bromide ; the same esters of phenyl-cyclohexyl-propionic, phenyl - cyclohexyl - butyric, dicyclopentyl acetic, phenyl-cyclopentyl-acetic, phenyl-#<SP>1</SP>- or #<SP>2</SP>-cyclohexamyl-acetic and phenyl-#<SP>1</SP>- or # <SP>2</SP>-cyclopentenyl-acetic acids are similarly obtained ; also the piperidine-ethanol, diethylamino-n-butanol, diethylamino-ethanol, morpholino - ethanol, ethyl - acetoxyethylaminoethanol, ethyl-hydroxypropylamino-ethanol, methyl-propylamino-ethanol and m-dimethylaminocyclohexanol esters of phenyl-cyclohexylacetic acid. The following additional esters are referred to :-dicyclohexyl-acetic acid tropine ester, α:α<SP>1</SP>-dicyclohexyl-α-hydroxyacetic acid diethylamino-ethanol ester, α-phenyl-α-cyclohexyl-α-hydroxyacetic acid diethylamino-ethanol ester, the phenyl-cyclohexyl-acetic acid esters of ecgonine methyl ester and phenyldimethylaminocyclohexyl-acetic acid diethylamino-ethanol ester. The Specification as open to inspection under Sect. 91 also describes the manufacture of alkamine esters of mono-alicyclic-fatty acids. Thus, cyclohexyl-acetic acid, prepared by reduction of phenylacetic acid with hydrogen in presence of platinum, is converted into its chloride by means of thionyl chloride and reacted with diethylamino-ethanol to give cyclohexylacetic acid diethylamino-ethanol ester. In analogous manner are prepared α-cyclohexylhydracrylic acid tropine and scopine esters (the acid is prepared by reduction of tropic acid with hydrogen in presence of platinum), α-cyclohexyl-α-propyl-acetic acid diethylaminoetbanol ester (the acid is obtained by hydrogenation of α-phenyl-α-propyl-acetic acid in presence of platinum), and cyclohexyl-diethylaminoethyl-acetic acid diethylamino-ethanol ester (the acid being prepared by reaction of phenylacetonitrile with diethylaminoethyl chloride in presence of sodamide, saponification of the nitrile and reduction of the product). Other acids that may be used are cyclohexenyl-fatty acids and hydronaphthalene-fatty acids. This subject-matter does not appear in the Specification as accepted. Di-alicyclic- and aryl-alicyclic-fatty acids. Phenyl-cyclohexyl-acetic acid is obtained by reaction of phenylacetonitrile with cyclohexyl bromide in presence of sodamide and saponification of the product. Similarly, by reaction of phenylacetonitrile with A  , - or A 2-cyclohexenyl bromide, #<SP>1</SP>- or # <SP>2</SP>-cyclopentenyl bromide or dimethylaminocyclohexyl bromide, followed by saponification, the corresponding disubstituted acetic acids are obtained. Phenyl-cyclohexylpropionic and -butyric acids are prepared by reduction of an ester of diphenyl-propionic or - butyric acid with hydrogen in presence of a nickel catalyst, followed by saponification of the ester. Phenyl-cyclopentyl-acetic acid is obtained from a phenyl-cyclopentenyl-acetic acid by the action of mild reducing agents. α:α-Dicyclohexyl-α-hydroxyacetic acid results from the catalytic reduction of benzilic acid. α - Phenyl - x - cyclohexyl - α - hydroxyacetic acid is made by reacting a benzoyl-formic acid ester with cyclohexyl-magnesium bromide and saponifying the product. Di-alicyclic- and aryl-alicyclic-fatty acid anhydrides and -ketenes. The anhydrides are prepared by reacting an alkali metal salt of the acid with the corresponding acid halide, whilst the ketenes are formed when a di-alicyclic- or aryl-alicyclic-α-chlorofatty acid chloride, prepared by reacting the corresponding α-hydroxy acid with phosphorus pentachloride, is treated with zinc.