Patent GB-634072-A (GB)
Title: Process for the preparation of local anaesthetics
IPC: C07D295/14
Filed: 1944-08-10
Abstract: 2 : 6-Dimethylanilides of alkyl carboxylic acids containing a mono- or di-substituted amino group (especially an alkylamino, dialkylamino, allylamino, cyclohexylamino or piperidino group) are manufactured by reacting vic.-m-xylidine, or a hydrohalide thereof, with a halogen alkyl carboxylic acid or a derivative thereof, and treating the resulting halogen alkyl carboxylic acid xylidide with a primary or secondary amine.  The preparation of the halogen alkyl carboxylic acid xylidides may be effected by reacting the vic.-m-xylidine with the halogen alkyl carboxylic acid itself (e.g. chloracetic acid) in the presence or absence of thionyl chloride, phosphorus pentoxide or phosphorus halides, or with a halogen alkyl carboxylic acid halide (e.g. chloracetyl chloride, a -bromopropionyl bromide or b -chloropropionyl chloride), preferably in the presence of a solvent (e.g. glacial acetic acid, acetone, dioxane, ether, chloroform or benzene), in the presence or absence of water, or by heating a hydrohalide of vic.-m-xylidine with a halogen alkyl carboxylic acid amide (e.g. chloracetamide).  The subsequent treatment with a primary or secondary amine (e.g. diethylamine, methylamine, butylamine, piperidine or cyclohexylamine) is preferably carried out in an anhydrous organic solvent (e.g. benzene).  The products are useful as local an sthetics, particularly in the form of their salts with organic or inorganic acids, e.g. citric or especially hydrochloric acid.  Examples describe the preparation, from appropriate starting materials, of the 2 : 6-dimethylanilide of N-diethylamino- and N-cyclohexylamino-acetic and ja - and b -N-diethylamino- and a -piperidino-propionic acids.  The Specification as open to inspection under Sect. 91 comprises also: (i) the subject-matter of Specification 634,073; (ii) the manufacture of other anilides containing in the acyl radical at least one mono- or di-substituted amino group and in the nucleus at least two substitutents consisting of acyclic or cyclic hydrocarbon radicals or heterocyclic radicals, e.g. the 2 : 3 : 4-trimethylanilide of b -(N-diethylamino)-propionic acid, the 2 : 3 : 5-trimethylanilides of N - diethylaminoacetic acid, the 2 : 4 : 5 - trimethylanilide of ja -piperidinopropionic acid, and the 3 : 4 : 5 - trimethylanilide of N - cyclohexylaminoacetic acid; (iii) the following additional methods of preparation: (a) condensing an at least disubstituted phenyl halide with an aminocarboxylic acid amide, e.g. 2 : 3 : 5 : 6 - tetramethyl - 1 - bromobenzene with the sodium derivative of N-(b -phenylethyl)-aminoacetamide; (b) condensing an at least disubstituted phenylamine with a hydroxycarboxylic acid or anhydride, replacing the hydroxy group by a halogen atom and treating the product with a primary or secondary amine, e.g. heating 2 : 6-diethyl-4-methylaniline with glycollide, treating the resulting glycollic anilide with phosphorus oxychloride and pentachloride and the product with benzylamine.  Aniline, aminoquinolines and aminothiazoles are additionally specified as amines which may be reacted with the halogencarboxylic acid anilides, and xylene as a solvent in which this reaction may be effected.  This subject-matter does not appear in the Specification as accepted.