Patent GB-749765-A (GB)
Title: Azacycloalkanes and the method of preparation thereof
Filed: 1953-05-22
Abstract: The invention comprises compounds of the formula <FORM:0749765/IV(a)/1> wherein X represents an <FORM:0749765/IV(a)/2> group or an <FORM:0749765/IV(a)/3> group and wherein R1 represents a lower alkyl group, R2 represents a hydrogen atom or a lower alkyl group, A represents an anion, R represents a substituted or unsubstituted aryl or aralkyl radical, R3 and R4 each represent a hydrogen atom or a methyl or ethyl group, R5 represents a -CN, -COO lower alkyl or a -CO- lower alkyl group, and n is an integer from 1 to 6.  The term "lower" signifies groups having 7 or less carbon atoms.  Quaternary compounds of the above formula where R5 represents -CN are obtained by a cyclization process comprising heating a tertiary aminohaloalkanonitrile of the formula <FORM:0749765/IV(a)/4> or corresponding toluenesulphonic or methanesulphonic ester to a temperature of from about 70 DEG  to 120 DEG  C. in the presence of a highly polar solvent having a dipole moment of from 2.5 to about 4.5 debye units at 20 DEG  C., a dielectric constant above 10 and a boiling point above 70 DEG  C. and precipitating the cyclic quaternary ammonium compound formed.  The quaternary compounds can then be decomposed to release alkyl halide and form a polysubstituted azacycloalkanenitrile which may be hydrolysed to give the corresponding carboxylic acid which is then esterified, or the nitrile may be reacted with an alkyl lithium or alkyl Grignard compound and the product hydrolysed.  The radical represented by R may be a substituted or unsubstituted phenyl, naphthyl or benzhydryl radical.  The preferred substituents which may be from one to three in number, comprise lower alkyl, lower alkoxy, halogen, nitro, hydroxy, aliphatic acyl and acyloxy, amino and mono-and di-lower alkyl substituted amino radicals.  As polar solvents are specified nitrobenzene, o-nitrotoluene, benzonitrile, 2-nitropropane or ketones, such as methyl isobutyl ketone, diisopropyl ketone and acetophenone.  In addition a solvent which will make the product less soluble in the polar solvent, e.g. heptane, benzene, toluene or xylene may be added.  The aminohalonitrile is employed in a concentration of at least 0.001 mols. preferably 0.1 to 5.0 mols. per litre of polar solvent.  The decomposition of the quaternary halides is effected by heating at about 200 DEG  to 250 DEG  C. if desired in a solvent such as tetrahydro-naphthalene, higher alcohols or nitrobenzene.  For the hydrolysis of the nitrile group of the azacycloalkane nitrile, acids such as phosphoric or hydrobromic acid, or alkalis such as potassium hydroxide in ethylene glycol can be used.  The acid is esterified with a lower aliphatic alcohol, preferably one having no more than three carbon atoms.  Reaction of the nitriles with alkyl lithium or alkyl Grignard compounds and hydrolysis of the intermediate imino compound gives an acyl azacycloalkane.  The polysubstituted cyano-di-lower alkyl-amino-haloalkanes or corresponding toluenesulphonic or methanesulphonic acid ester used as starting materials can be prepared by reacting a dialkylaminobutyronitrile R-CH(CN)-CH(R3)-CHR4-NR1R2 with a polymethylene disulphonic ester or halide R6-CH2-(CH2)n -CH2-R7 in which R6 and R7 represent a chlorine, bromine or iodine atom or a p-toluene sulphonic acid ester group or a methane sulphonic acid group and n is an integer from 1 to 6 in the presence of a reagent capable of displacing active hydrogen such as sodium, potassium, lithium amide, phenyl-sodium, phenyl lithium or butyl-lithium in a solvent such as ether, benzene, xylene or toluene, and preferably under anhydrous conditions and in an inert atmosphere, at a temperature of -10 DEG  to 50 DEG  C., preferably 10 DEG  to 35 DEG  C.  In examples (1) 4 - phenyl - 4 - cyano - N - methyl azacycloheptane methobromide is prepared by heating 1 - dimethylamino - 3 - cyano - 3 - phenyl - 6-bromohexane in nitrobenzene; (2) the corresponding methochloride is prepared analogously using o-nitrotoluene or undecanol as reaction medium; (3) and (4) 4-phenyl-4-cyano-N-methyl azacycloheptane is prepared by refluxing the product of example (1) in tetrahydronaphthalene and 5-ethyl-nonanol-2 respectively.  n-Decyl alcohol and trimethyl nonanol may be used similarly; (5) 4-phenyl-4-cyano-N-methyl azocycloheptane is heated with sulphuric acid, and the product then esterified with alcohol to form 4-phenyl-4-carbethoxy-N-methyl azacycloheptane; (6) the product of example (5) is converted to the hydrochloride by treatment with ethanolic hydrochloric acid.  The hydrobromide, hydriodide, sulphate, acid sulphate, phosphate, maleate, malate, tartrate, citrate, succinate, acetate, propionate and acetyl salicylate can be prepared similarly.  Products in which the aryl radical is hydroxy-substituted are obtained by using the corresponding alkoxyaryl substituted starting materials, treating the alkoxy-aryl-cyano-azacycloalkane with 48 per cent hydrobromic acid, and esterifying the product by heating with alcohol and sulphuric acid.  Additional compounds of the first formula above are described, R1 being selected from methyl and ethyl, R from phenyl, 2- or 3-hydroxy phenyl benzhydryl, b -naphthyl and p-tolyl, R5 from carbethoxy, propionyl and butyryl, and n having various values from 1 to 6.  The products may be resolved into optically active isomers, using optically active acids.  The quaternary compounds of the invention, or such as are obtained by reacting the cycloalkanes with aliphatic halides having 8 to 18 carbon atoms are useful as wetting agents.  The products are also useful in forming salts of penicillin, for purifying the latter or for therapeutic purposes.  The free bases or salts of the azacycloheptanes also have an analgesic action.  1 - Dimethylamino - 3 - cyano - 3 - phenyl - 6-bromohexane is prepared by reacting 2-phenyl-4-dimethylaminobutyronitrile and trimethylene bromide in the presence of sodamide.  The corresponding 6-chloro-derivative is prepared using trimethylene chlorobromide as a starting material.  Other nitriles mentioned in place of the above butyronitrile are those containing o-or m-anisyl, m-nitrophenyl, benzhydryl, b -naphthyl, p-tolyl and p-chlorophenyl groups in the 4-position and ethyl and n-butyl radicals as N-substituents.  Other tri-, tetra-, penta-, hexa-, hepta- and octamethylene derivatives are also mentioned.ALSO:Compounds of the formula <FORM:0749765/VI/1> wherein X represents an > N - R1 group or an <FORM:0749765/VI/2> group and wherein R1 represents a lower alkyl group, R2 represents a hydrogen atom or a lower alkyl group, A represents an anion, R represents a substituted or unsubstituted aryl or aralkyl radical, R3 and R4 each represent a hydrogen atom or a methyl or ethyl group, R5 represents a -CN, -COO lower alkyl or a -CO lower alkyl group and n is an integer from 1 to 6 (the term lower signifying groups having 7 or less carbon atoms), which possess therapeutic, more particularly analgesic properties are employed in medicines.  They may be incorporated in the form of an elixir or other liquid form with excipients, suspending and flavouring agents, or in dry form with binding agents, sugars and other excipients in capsules or tablets. The compounds form salts with penicillin.  The preparation of a number of compounds of the above formula is given (see Group IV(b)).