Patent GB-577634-A (GB)
Title: Manufacture of basic esters of ª‡-alkyl- or ª‡-cycloalkyl-aryl carbinols and of quaternary ammonium compounds formed therefrom
Filed: 1943-09-22
Abstract: a -Alkyl-, or a -cycloalkyl-aryl carbin esters of aliphatic aminocarboxylic acids disubstituted in the amino group, having neurotropic, musculotropic, an sthetic and bactericidal action, are obtained by treating (a) an a -alkyl-, or a -cycloalkyl-aryl carbinol with an aliphatic aminocarboxylic acid, disubstituted in p  the amino group; (b) such a carbinol, or a metal alcoholate thereof, with a reactive acid derivative of such acid, e.g. a halide or ester, or with an anhydride; (c) a reactive ester of an a -alkyl-or a -cycloalkyl-aryl carbinol, e.g. with a halogen hydracid or an arylsulphonic acid, with a salt of such acid; (d) such a carbinol, or a metal alcoholate thereof, with an aliphatic carboxylic acid carrying a replaceable substituent, e.g. a halogen atom or a hydroxy, or acylhydroxy group, and interacting the resultant ester with a secondary amine; an aminocarboxylic acid derivative unsubstituted or monosubstituted in the amino group, or an acyl derivative thereof, may be used as an alternative starting-material, and the desired N-substitution may be effected by reaction with a reactive ester, e.g. a halogen hydracid ester of an aliphatic alcohol.  Quaternary ammonium compounds having similar therapeutic action are obtained from the products by additive reactions with alkyl halides, alkenyl halides, e.g. allyl bromide, aryl sulphonic acid esters, dialkyl sulphates or aralkyl halides.  In examples: (1) silver b -diethylaminopropionate is heated under reflux with a -bromo-n-butyl benzene in absolute alcohol; (2) b -bromopropionyl chloride is heated with a mixture of n-propyl-p-methylphenyl-carbinol and absolute pyridine in absolute ether, and the resulting b  - bromopropionic acid - (n - propyl - p - methyl - phenyl-carbin)-ester is heated with diethylamine and the base is isolated by treatment with potash; (3) b - bromopropionic acid - (n - propyl - 3 : 4 - dimethylphenyl - carbin) - ester is heated with diethylamine for 2 hours and the base isolated as in (2).  Alkylation of the product may be effected to the quaternary stage by reaction with ammonia or ethylamine, and subsequently ethylating, e.g. with diethyl sulphate; (4) b -bromopropionic acid-(n-propyl-a  - naphthyl - carbin) - ester (prepared from b  - bromopropionyl chloride and n-propyl-a -naphthyl-carbinol under the conditions of example (2)); and (5) b -bromopropionic acid-(n-propyl-p - chlorophenyl - carbin) - ester (from b  - bromo - propionyl chloride and n-propyl-p-chlorophenyl-carbinol) are respectively treated with diethylamine for 2 hours at 60-70 DEG  C.; (6) b -bromopropionyl chloride is added to iso-butyl-phenyl-carbinol as in example (2), completing the reaction by heating at 40 DEG  C. for 1 hour and refluxing for 1 hour with diethylamine; (7) iso-butyl-phenyl-carbin-chloracetate is obtained by the reaction of chloracetyl chloride on iso-butyl-phenyl-carbinol as in (6) and is then interacted with diethylamine by heating for 1 hour at 70-80 DEG C.; (8) the crude bromo-derivative from the interaction of iso-butyl-3 : 4-dimethyl-phenyl-carbinol and b -bromopropionyl chloride is treated as in (7) with dimethylamine and the product is isolated in the customary manner; similarly, a b -diethylamino-propionic acid ester is obtained from b -bromopropionic acid-(n-butyl-3 : 4-dimethylphenyl-carbin)-ester and diethylamine; (9) the crude ether residue from reaction of cyclohexyl-phenyl-carbinol and b -bromopropionyl chloride is added dropwise at 20 DEG  C. to a solution of diethylamine in absolute ether and refluxed for 3 hours on the steam-bath; the basified aqueous solution is extracted with benzene and the residue treated with 2N-hydrochloric acid so as to isolate a crystalline hydrochloride; the corresponding b -diethylamino-propionic acid ester is similarly obtained from cyclohexyl-p-methylphenyl-carbinol. n-Propyl-p-methylphenyl-carbinol is obtained by the action of p-toluyl aldehyde on n-propyl-magnesium bromide in absolute ether. iso-Butyl-3 : 4-dimethylphenyl-carbinol is obtained by the action of 3 : 4-dimethyl benzaldehyde (1 mol.) on iso-butyl-magnesium bromide (1 mol.) in ether.  n-Butyl-3 : 4-dimethylphenyl-carbinol is obtained by reaction of n-butyl-magnesium bromide with 3 : 4-dimethyl benzaldehyde.  Cyclohexyl-p-methylphenyl-carbinol is derived by a Grignard reaction of p-toluyl aldehyde with cyclohexyl-magnesium bromide.  The Specification as open to inspection under Sect. 91 of the Acts comprises in general terms the manufacture of basic esters of a -substituted aralkyl alcohols.  This subject-matter does not appear in the Specification as accepted.