Patent GB-781002-A (GB)
Title: Substituted azacycloalkanes and derivatives thereof
Filed: 1954-12-21
Abstract: The invention comprises compounds of the general formula <FORM:0781002/IV (a)/1> wherein <FORM:0781002/IV (a)/2> represents either <FORM:0781002/IV (a)/3> or <FORM:0781002/IV (a)/4> wherein A stands for an anion, R1 represents lower alkyl, R, R2 and R3 stand for either hydrogen or lower alkyl, R4 represents hydrogen, -O.CO. lower alkyl, -CONH2 or -COO. alkali metal, R5 represents naphthyl, benzhydryl, phenyl or substituted phenyl and n stands for a whole number from 1 to 6.  Substituents in the phenyl ring may be lower alkyl, lower alkoxy, halogen, nitro, hydroxy, aliphatic acyl and acyloxy, amino and mono- and dilower alkyl-substituted amino radicals ("lower" designating a group with 7 or less carbon atoms).  A 4-aryl-cyano-azacycloalkane is obtained by heating a 3-aryl-3-cyano-1-dialkylamino-omegahaloalkane or 1,2-alkyl derivative thereof to a temperature of from 200 DEG  to 250 DEG  C. in the presence of an inert solvent boiling at or above 200 DEG  C. to form a 4-aryl-4-cyano 1-methylazacycloalkane or a 2- or 3-alkyl derivative.  This cyano-derivative heated with an alkali metal amide at 50 DEG  to 150 DEG  C. in an inert solvent or with water and an alkali metal hydroxide at 250 DEG  to 300 DEG  C., gives a 4-aryl-1-methylazacycloheptane or 2- or 3-alkyl derivative thereof, which in turn, on heating with a lead salt of a lower aliphatic carboxylic acid in the presence of the corresponding carboxylic acid at a temperature of substantially 100 DEG  C. yields a 4-aryl-4-acyloxy-1-methylazacycloalkane or a 2- or 3-alkyl derivative.  The cyano-derivative heated with a higher alcohol and a base at substantially 160 DEG  C. yields 4-aryl-4-amido-1-methylazacycloalkane or a 2- or 3-alkyl derivative thereof.  At a temperature above 160 DEG  C. with a higher alcohol and an alkali metal hydroxide the cyano-compound gives the alkali metal salt of a 4-aryl-4-carboxy - 1 - methylazacycloalkane.  In examples: (1) 3 - phenyl - 3 - cyano - 1 - dimethylamino - 6 - chlorohexane (from the reaction 2 - phenyl - 4 - dimethylamino - n - butyronitrile and trimethylene chlorobromide at - 20 DEG  to - 25 DEG C. in the presence of sodamide) is refluxed in 2,6,8-trimethyl-nonanol-4 to give 4 - cyano - 1 - methyl - 4 - phenyl - azacycloheptane; (2) 3 - cyano - 3 - phenyl - 1 - methylazacyclo-octane its picrate are prepared similarly; (3) phenylacetonitrile and 1-dimethylamino-2-chloropropane are reacted in the presence of sodamide to give a mixture of 4-dimethylamino - 3 - and 4 - methyl - 2 - phenyl-n-butyronitriles, reaction of which with trimethylene chlorbromide in the presence of sodamide gives a mixture of 1-dimethylamino-1- and 2 - methyl - 3 - cyano - 3 - phenyl - 6 - chlorhexanes.  The mixture is cyclized by the method of the parent Specification by heating in nitrobenzene at 100 DEG  C. 4-Cyano-1,2-dimethyl - 4 - phenylazacycloheptane methochloride precipitates, is filtered off, and heated in undecanol to yield the tertiary base.  The filtrate from the cyclization, containing the 2-methyl chlorohexane unchanged, is extracted with acid and the recovered base is refluxed in undecanol (b.pt. 235 DEG  C.) to give 4-cyano-1,3-dimethyl - 4 -phenylazacycloheptane.  This compound is refluxed with sulphuric acid, alcohol is added and heating continued to give the 4-carbethoxy compound, which is purified as its hydrochloride. Similarly prepared is 4 - (m - hydroxyphenyl) - 4 - cyano - 1 - methyl - azacycloheptane azacycloheptane; (4) 4 - cyano - 1 - methyl-4-phenyl-azacycloheptane refluxed with sodamide in toluene yields 1-methyl-4-phenylazacycloheptane which is converted to its picrate, hydrochloride, methiodide and isopropiodide.  There may also be prepared the sulphate, hydrobromide, nitrate, phosphate, acetate, propionate and lactate and quaternary compounds with, e.g. lauryl bromide or chloride; (5) and (6) 4-cyano-1,2-dimethyl-4-phenylazacyloheptane and 1,2-dimethyl-4-phenylazacycloheptane and 4 - cyano - 1,3 - dimethyl - 4 - phenylazacycloheptane and 1,3-dimethyl-4-phenylazacycloheptane are prepared similarly; (7) 4-cyano - 4 - phenyl - 1 - methylazacycloheptane heated at 157-160 DEG  C. in heptanol-2 with potassium hydroxide gives 4-carbamyl-4-phenyl-1-methylazacycloheptane monohydrate; (8) the same cyano base heated in methanol at 200 DEG C. with potassium hydroxide yields 4-carboxy-4-phenyl-1-methylazacycloheptane; 4-phenyl-1-methylazacycloheptane heated with lead tetraacetate in acetic acid gives 4-acetoxy-4-phenyl-1-methylazacycloheptane, from which the picrate and methiodide are prepared; (10) and (12) 4 - acetoxy - 4 - phenyl - 1,2 - dimethylazacycloheptane and 4-acetoxy-4-phenyl-1,3-dimethylazacycloheptane and their methiodides are prepared analogously; (11) 4-phenyl-1,3-dimethylazacycloheptane heated in propionic acid with lead tetra-propionate gives 4-propionoxy - 4 - phenyl - 1,3 - dimethylazacycloheptane.