Patent GB-833573-A (GB)
Title: Improvements in the production of ammonium compounds
Filed: 1957-03-27
Abstract: Quaternary ammonium compounds of the tetrahydrofuran series of the general formula <FORM:0833573/IV (b)/1> (wherein Rn is hydrogen or one or more, identical or different, methyl, ethyl, hydroxy, halogenated alkenyl, hydroxyalkyl, alkoxyalkyl or aryl radicals or is acyloxyalkyl, benzyloxyalkyl, tetrahydropyranyloxyalkyl, alkylidenedioxyalkyl, or alkanoyl radicals convertible by hydrolysis and/or reduction or hydrogenolysis to hydroxyalkyl radicals, R1 is an aliphatic, araliphatic or aromatic hydrocarbon radical, R2 is an aliphatic hydrocarbon radical, or -NR1R2 is a pyrrolidino, piperidino or morpholino radical, R3 is an alkyl, alkenyl, carbalkoxyalkyl or aroylalkyl radical or an aralkyl radical which may be halogen, alkyl or alkoxy substituted and An \s8 is a monovalent anion or a normal equivalent of a polyvalent anion) are prepared by (1) reacting a tertiary base of the general formula <FORM:0833573/IV (b)/2> with a compound R3-An1 (An1 being the aci radical corresponding to the anion of a halogen hydracid an alkyl sulphuric acid or an aryl sulphonic acid) and then, if desired, replacing the anion An1- by another anion; or (2) reacting an appropriate 3-halogeno-tetrahydrofuran with the amine NR1R2R3 and then, if desired, replacing the halide ion by another anion; or (3) ring closing a compound of the formula <FORM:0833573/IV (b)/3> during which process the anion An \s8 may be replaced by the anion of the acid, e.g. phosphoric acid, sulphuric acid, or HBr, used to close the ring.  Compounds (I) wherein one or more of R, R1, R2 and R3 are unsaturated may be reduced to the corresponding saturated compounds.  Anion exchange may be effected by double decomposition or by liberation of the free base and neutralization with the desired acid.  Products containing acyloxyalkyl substituents may be subsequently hydrolysed with alkali and those containing tetrahydropyranyloxyalkyl or alkylidenedioxyalkyl substituents with acid, benzyloxyalkyl groups may be hydrogenolized at any stage and keto groups in a side chain may be reduced, to obtain the corresponding free hydroxyalkyl compounds.  Mixtures of stereoisomeric pairs and single stereoisomers may be separated by known methods, or if optically active starting materials, e.g. aspartic acid esters, are used optically active products may be obtained direct. Examples describe the preparation of tetrahydrofurans of the formula (I) wherein Rn is variously hydrogen, 5-ethyl, 2 : 2 : 5 : 5-tetramethyl and -tetraethyl, 5-methyl, 5-phenyl, 5-bromovinyl, 2-ethyl, 2 : 5-dimethyl, 5 - (alpha - hydroxyethyl), 2 : 5 - dimethyl - 2 : 5-diethyl, hydroxymethyl and acetoxymethyl and the 3-substituent is variously trimethylammonium iodide, bromide, chloride, hydroxide and methosulphate, benzyl-dimethylammonium chloride, allyl-dimethylammonium bromide, methyl - diethylammonium iodide, methyl - piperidinium iodide, n - butyl - dimethyl-ammonium iodide and methyl-morpholinium iodide, some products being isolated as their tetrachloraurates. A list of further starting materials is also given, wherein R3 has the additional values of other lower alkyl and alkenyl groups, alkoxycarbonylmethyl groups, p-chloro-, p-methoxy- and p-methyl-benzyl groups, beta-phenylethyl and acetonyl, X- has the additional value of a p-toluenesulphonate ion, and -NR1R2 may also be pyrrolidine. Compounds of the formula (II) are prepared (1) by reacting a metal compound of propargyltetrahydropyranyl ether with a carboxylic anhydride to form a (gamma-acyl-propargyl)-tetrahydropyranyl ether, adding the amine NHR1R2 thereto to form a (gamma-acyl-beta-NR1R2 - allyl) - tetrahydropyranyl ether, reducing this to a delta-substituted-(delta-hydroxybeta-NR1R2-butyl) -tetrahydropyranyl ether and then treating this with, for example, phosphoric acid to give a 5-substituted-3-NR1R2-tetra-hydrofuran; (2) hydrogenating an R-substituted4 : 5 - dihydrofuran - 3 - carboxylic acid alkyl ester to give the corresponding tetrahydro compound, converting this to the 3-amide or 3-hydrazide, degrading this directly to the 3-amino compound or indirectly via the azide and the 3-carbobenzyloxy compound and conversion of the -NH2 group to an -NR1R2 group; the 3-amino compounds may also be prepared by reduction of aspartic acid esters which may be C-substituted to 2-amino-butane-1 : 4-diols or reaction of the esters with Grignard reagents to give 1 : 1 : 4 : 4 - tetrasubstituted 2 - amino - butane - 1 : 4 - diols, the diols then being ring closed, e.g. with sulphuric acid, to the 3-amino-tetrahydrofurans; (3) using N : N-di-substituted aspartic acid esters in the reactions described in (2) to give 3-tertiary-amino-tetrahydrofurans direct; (4) for compounds (II) containing a hydroxyalkyl radical or a radical convertible thereto, by condensing benyl glycidyl ethers or homologues thereof with acetoacetic acid esters to form alpha-acetyl-gamma-benzyloxyalkyl-butyrolactones, reacting these with benzene diazonium chloride to form phenyl hydrazones of alpha-oxo-gamma-benzyloxyalkyl-butyrolactones, reducing these to form alpha-formylamino - gamma - benzyloxyalkyl - butyrolactones, converting these to alpha-tertiaryamino - gamma - benzyloxyalkylbutyrolactones, reducing these to the corresponding diols and ring closing these, e.g. with H2SO4 or HBr, to obtain, depending on the reaction conditions, either 3 - tertiary - amino - 5 - benzyloxyalkyltetrahydrofurans or the 5-hydroxyalkyl compounds direct; and (5) reacting 3-halogenofurans with amines NHR1R2. 3-Halogeno-tetrahydrofurans are prepared (1) by reacting allyl or substituted allyl magnesium halides with aldehydes or ketones to form allyl or substituted allyl carbinols, adding halogen to these to form substituted or unsubstituted 3 : 4-dihalogen butanols and reacting these with alkalies, benzyloxyalkyl substituted tetrahydrofurans being obtained by the use of benzyloxy-alkanals; (2) by brominating 4 : 4diethoxy-1-butene (from allyl magnesium bromide and ethyl orthoformate) to give 4 : 4-diethoxy1 : 2-dibromo-butane, treating this with for example sulphuric acid to give 3 : 4-dibromobutyraldehyde (identified as a 2 : 4-dinitrophenylhydrazone), conversion of this to the sodium bisulphite addition compound, treatment of this with KCN to give 3-bromo-5-cyanotetrahydrofuran, reaction of this with alkyl magnesium halides to form 3-bromo-5-acyltetrahydrofurans (the 5-acetyl compound is identified as a 2 : 4-dinitrophenylhydrazone) and, if desired, reduction of these to 3-bromo-5(alpha - hydroxy - alkyl) - tetrahydrofurans; (3) by reacting 2 : 3-dichlorotetrahydrofuran with Grignard compounds to form 2-substituted-3chloro - tetrahydrofurans; (4) reacting 3 : 4epoxy-tetrahydrofurans with Grignard compounds to form 3-hydroxy-4-substituted-tetrahydrofurans and reacting these with inorganic acid halides.  Compounds of the general formula (III) are prepared by reacting tertiary 2amino - butane - 1 : 4 - diols with compounds R3-An1.  N - [21 : 51 - dihydroxy - hexyl - (31)] - N : N : N-trimethylammonium iodide is prepared from methyl iodide and the appropriate tertiary amine.  5 - (Alpha - hydroxyethyl) - tetrahydrofuran-3-carboxylic acid methyl ester is prepared by heating methyl furan-3-carboxylate with acetic anhydride in presence of BF3 to give methyl 5 - acetyl - furan - 3 - carboxylate and then catalytically reducing this, and is converted to 3 - dimethylamino - 5 - (alpha - hydroxyethyl) - tetrahydrofuran by the first method detailed under (2) above; the lastnamed compound is converted to the methochloride (via the methiodide) and this on heating with methyl iodide and silver oxide in methanol gives the corresponding hydroxide and N - [5 - (alpha - methoxyethyl) - tetrahydrofuryl - (3) -] - N : N : N - trimethyl ammonium hydroxide.  2 : 5 - Dimethyl - 2 : 5 - diethyl - 3 - dimethyl-aminotetrahydrofuran is prepared by heating 2 : 5 - dimethyl - 2 : 5 - diethyl - tetrahydrofuranone-(3) with dimethyl formamide and formic acid.  Benzyloxyacetaldehyde is prepared by oxidation of glycerine-alpha-benzyl ether with lead tetra-acetate or periodic acid.  3 - Dimethylamino - 5 - hydroxymethyl - tetrahydrofuran (prepared by hydrogenolysis of the 5-benzyloxy compound and identified as a perchlorate) with acetic anhydride gives the 5-acetoxymethyl compound, the methiodide of which can also be obtained from the methiodide of the 5-hydroxy compound and acetic anhydride.