Patent GB-698201-A (GB)
Title: Manufacture of new halogenaryl-pyridyl alkanones
Filed: 1951-03-01
Abstract: The invention comprises p-halogenphenylpyridyl-alkanones of the general formula <FORM:0698201/IV (b)/1> (where R represents a bivalent aliphatic hydrocarbon residue of 2-6 carbon atoms, D represents two alkyl residues, each containing 1-5 carbon atoms, or one such alkyl residue and a cycloalkyl residue, or with N an alkylene-imino group, and R1 represents an aliphatic hydrocarbon residue of 1-5 carbon atoms), and salts thereof (e.g. with hydrohalic acids, sulphuric, nitric, phosphoric, acetic, propionic, oxalic, malic, citric, benzoic, salicylic, p-aminosalicylic, methane- or ethane-sulphonic or p-toluenesulphonic acid).  These compounds, which are useful as antihistaminic agents, may be prepared by (a) treating a nitrile of the formula <FORM:0698201/IV (b)/2> with a metal organic compound, e.g. a Grignard reagent, and decomposing the resulting ketimide, e.g. with mineral acid, or (b) introducing the residue-R-N=D into a compound of the formula <FORM:0698201/IV (b)/3> (employed in the form of a metal derivative thereof or treated in the presence of an agent capable of converting it thereto, e.g. an alkali or alkaline-earth metal or an amide, hydride, hydrocarbon derivative or alcoholate thereof).  In examples: (1) o -dimethylamino-a -(p-chlorophenyl) - a  - (2 - pyridyl) - butyronitrile is treated with ethyl magnesium bromide in ether and the product decomposed with ice and hydrochloric acid to 1-dimethylamino-3-(p-(p-chlorphenyl) - 3 - (21 - pyridyl) - hexan - 4 - one, which may be converted into its hydrochloride by treatment with dry hydrogen chloride in ethyl acetate; (2) the corresponding diethylamino compound is similarly prepared, as also are (3) the N-methyl-N-cycloheptylamino compound, and (5) the pyrrolidino compound; (4) o  - (N - methyl - N - cyclopentylamino) - a  - (p - chlorophenyl) - a  - (2 - pyridyl) - butyronitrile and n-propyl magnesium bromide similarly yield 1-(N-methyl-N-cyclopentylamino)-3 - (p - chlorophenyl) - 3 - (21 - pyridyl) - heptan - 4-one and its hydrochloride; (6) o -piperidino-a -(p - chlorophenyl) - a  - (2 - pyridyl) - valeronitrile and methyl magnesium iodide similarly give 1 - piperidino - 4 - (p - chlorophenyl) - 4 - (21 - pyridyl) - hexan - 5 - one; (7) 1 - (p - chlorophenyl) - 1 - (21 - pyridyl) - butan - 2 - one is warmed with b -chlorethyldimethylamine in toluene in the presence of sodamide to give the same product as in (1).  Nitriles of the second general formula above, used as starting materials in examples (1)-(6) above, are obtainable by reacting p-chlorobenzyl cyanide in benzene in the presence of sodamide with (1) b -chlorethyldimethylamine; (2) b -chlorethyldiethylamine; (3) b  - chlorethyl - N - methyl - N - cycloheptylamine; (4) b  - chlorethyl - N - methyl - N - cyclopentylamine; (5) a b  - pyrrolidinoethyl halide; and (6) q  - chloropropylpiperidine, and in each case reacting the product similarly with 2-bromopyridine.  b  - Chlorethyl - N - methyl - N - cycloheptylamine is obtainable by condensation of suberone with ethanolamine with simultaneous catalytic hydrogenation of the Schiff's base, followed by N-methylation and treatment with thionyl chloride. p  1 - (p - Chlorophenyl) - 1 - (21 - pyridyl) - butan - 2-one is obtainable by treating (p-chlorophenyl)-(2-pyridyl)-acetonitrile in anisole with an ethereal solution of ethyl magnesium iodide and decomposing the product with ice and Rochelle salt.