Patent GB-765881-A (GB)
Title: Improvements in or relating to 2-butylamines and intermediates therefor
Filed: 1954-05-18
Abstract: Disubstituted butanones of the general formula: <FORM:0765881/IV(b)/1> (wherein Ar1 represents a p-hydroxyphenyl and Ar2 a phenyl radical, which radicals may be further substituted by at least one hydroxy, methoxy, alkyl, halo, amino or methylenedioxy substituent) are manufactured by condensing a mono-substituted a  : b -unsaturated butenone Ar2-CH = CH-CO-CH3 with a phenol Ar1H by heating the reactants together, first in the presence of an organic peroxide type catalyst at 80-90 DEG  C., then in the presence of a Friedel-Crafts type catalyst at substantially 100 DEG  C., and finally above 110 DEG  C.  The desired product may be separated by fractional distillation followed by crystallization, and may be converted by amination to the corresponding butylamine of the general formula  <FORM:0765881/IV(b)/2> When Ar2 in this product contains a p-methoxy group, this may be subsequently demethylated, and the resulting diphenolic butylamine may be isolated by fractional precipitation with a caustic alkali solution (e.g. in an amount sufficient to adjust the pH of the reaction mixture to 6.6-8.6), and may be converted to its hydrohalide by treatment under substantially dry conditions with a dry gaseous hydrogen halide.  The diphenolic butylamines are useful as hypotensive agents, and some of their monomethyl ethers as anti-extrasystolic agents.  In examples: (1) benzoyl peroxide is added to anisalacetone and o-cresol in toluene at 80-90 DEG  C., the temperature is raised to 100 DEG  C. and sulphuric acid added, and finally the mixture is boiled and then poured into sodium carbonate solution, and the toluene layer is separated and fractionally distilled to isolate 4-(41-methoxyphenyl) - 4 - (411 - hydroxy - 311 - methylphenyl)-butanone - 2 (recrystallized from a mixture of benzene and cyclohexane) and some 4-(41-methoxyphenyl) - - (211 - hydroxy - 311 - methylphenyl) - butanone - 2; (2) benzalacetone similarly yields 4 - phenyl - 4 - (41 - hydroxy-31 - methylphenyl) - butanone - 2; (3) 4 - (p-methoxyphenyl) - 4 - (p - hydroxyphenyl)-butanone-2 is similarly prepared from anisalacetone and phenol, 4-(21-chlorophenyl)-4-(411-hydroxy - 311 - methylphenyl) - butanone - 2 from o - chlorobenzalacetone and o - cresol, 4-(41 - hydroxy - 31 - methoxyphenyl) - 4 - (411-hydroxy - 311 - methylphenyl) - butanone - 2 from vanillalacetone and o - cresol, 4 - (31 : 41-dimethoxyphenyl) - 4 - (411 - hydroxy - 311-methoxyphenyl) - butanone - 2 from veratrylideneacetone and o - cresol, and 4 - (31 : 41-methylenedioxyphenyl) - 4 - (411 - hydroxy - 311-methylphenyl) - butanone - 2 from piperonalacetone and o - cresol; (4) 4 - (41 - methoxyphenyl) - 4 - (411 - hydroxy - 311 - methylphenyl)-butanone - 2 is heated with ammonium formate with subsequent hydrolysis of the resulting formylamino compound, to produce 4-(41-methoxyphenyl) - 4 - (411 - hydroxy - 311 - methylphenyl) - butylamine - 2; the products of (2) and (3) are similarly converted to the corresponding amines; (5) the first product of (4) is heated under pressure with conc.HCl and the reaction mixture is fractionally precipitated with caustic soda solution to isolate 4-(41-hydroxyphenyl) - 4 - (411 - hydroxy - 311 - methylphenyl) - butylamine - 2, which is converted into its hydrochloride by reacting dry HCl gas with the dry amine; other methoxy-containing products of (4) similarly yield 4 : 4-bis-(p-hydroxyphenyl) - butylamine - 2.  Reference is also made to the condensation of p-dimethylaminobenzalacetone with o-cresol, to hydrogen fluoride, boron fluoride and aluminium chloride as Friedel-Crafts catalysts, and to the use of ammonia and hydrogen and of formamide for the amination step.