Patent GB-919126-A (GB)
Title: Quaternary ammonium compounds and their preparation
Inventor: COPP FREDERICK CHARLES
Filed: 1958-07-01
Abstract: The invention comprises quaternary ammonium compounds containing a cation of the formula <FORM:0919126/IV (b)/1> (wherein R7 and R8 are methyl, ethyl or 2-hydroxyethyl groups, R9 is an acetyl, phenacetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, acetamido or propionamido group when E is an ethylene radical, L and M are hydrogen or halogen atoms or methyl, ethyl or methoxy groups, and Z is a hydrogen atom, or R9 is a benzoyl, halobenzoyl, C1-4 alkylbenzoyl, C1-4 alkoxybenzoyl, nitro-benzoyl or aminobenzoyl radical when E is an ethylene, trimethylene, or 1- or 2-methylethylene radical, L and M have the values given above and Z is a hydrogen atom or a hydroxy group) and their preparation by reacting a tertiary amine (which may be formed in situ) with a reactive ester of a hydroxy derivative of the substituted-phenoxyalkyl, R7, R8 or methyl group, the aminobenzoyl compounds being prepared by subsequent reduction of the nitrobenzoyl compounds.  Anions may be exchanged by metathesis.  Reactive esters referred to are halides and p-toluenesulphonates, and these may be reacted either directly with the tertiary amine or with a suitable primary or secondary amine to form first the tertiary amine and then the quaternary derivative.  Detailed examples are provided. p 2-L-4-R9-5-Z-6-M-phenoxyalkyl substituted secondary and tertiary amine starting materials wherein the other substituent or substituents on the nitrogen atom is or are one or two of the groups R7, R8 and CH3 are prepared from corresponding haloalkyl substituted secondary and tertiary amines and 2-L-4-R9-5-Z-6-M-phenols or from appropriate primary or secondary amines containing one or two of the groups R7, R8 and CH3 and 2-L-4-R9-5-Z-6-M-phenoxyalkyl halides, which in turn are prepared either from 2-L-4-R9-5-Z-6-M-phenols and alkylene dihalides or, when R9 is a benzoyl or substituted benzoyl group, from 2-L-5-Z-6-M-phenoxyalkyl halides and benzoyl or substituted benzoyl halides.  2-(21,61-Dimethylphenoxy)-propan-1-ol is prepared by reduction of ethyl a -(2,6-dimethylphenoxy)-propionate, in turn prepared from 2,6-dimethylphenol and ethyl a -bromopropionate.  3 - Bromo-4-hydroxy-5-methyl-benzophenone is prepared by bromination of 4-hydroxy-3-methyl-benzophenone. 3-Ethyl-4-hydroxy-5-methyl-benzophenone is prepared by heating aluminium chloride with 2-ethyl-6-methyl-phenyl benzoate, in turn prepared from 2 - ethyl - 6 - methyl - phenol and benzoyl chloride. 4 - hydroxy - 3,5 - dimethyldeoxybenzoin and the intermediate 2,6-dimethylphenyl phenacetate are prepared similarly.  The compounds of the invention, which are stated to depress the peripheral sympathetic nervous system, may be formulated as pharmaceutical preparation with suitable carriers.  Powders (which may contain dispersing and surface-active agents and which may be presented in a draught in water or in a syrup), capsules, or cachets (in the dry state or in nonaqueous suspension, which may contain a suspending agent), tablets, suspensions (which may contain flavouring, preserving, suspending, thickening or emulsifying agents), aqueous injection solutions (which may contain anti-oxidants, buffers, bacteriostats, solubilizing agents and salts to render the solutions isotonic), suppositories and pessaries are referred to.  The first Provisional Specification describes quaternary ammonium compound containing a cation of the formula <FORM:0919126/IV (b)/2> wherein R1 and R2 are methyl or ethyl, A has the values of E detailed above, the a and b rings may be substituted by alkyl, alkenyl or alkoxy groups or halogen atoms, and the b ring may, in addition, be substituted by a nitro, amino or acylamino group.  In the third Provisional Specification quaternary ammonium compounds containing a cation of the formula II wherein Z may additionally be a methoxy group, R6 may additionally be isobutyryl, R when benzoyl may additionally be substituted by acylamino groups and R6 when phenacetyl may additionally be substituted by acylamino, alkyl, alkoxy, nitro or amino groups or halogen atoms, are described.  Specification 765,850 is referred to.