Patent GB-815801-A (GB)
Title: Substituted amides
IPC: C07D295/14
Filed: 1956-06-12
Abstract: The invention comprises compounds of the formula <FORM:0815801/IV (b)/1> (wherein n is 2, 3, 4, 5 or 6, Y is a tertiary amino radical and R and R1 are hydrocarbon radicals which may be substituted by halogen, hydroxy, alkoxy or dialkylamino radicals, the last named including saturated nitrogen containing heterocyclic radicals, the total number of carbon atoms in R and R1, separately, being at most 8) and acid-addition salts, quaternary ammonium compounds, amine oxides and amine oxide-acid addition salts formed therefrom; and their preparation either by partial hydrolysis of a nitrile of the formula <FORM:0815801/IV (b)/2> to the corresponding amide which is then reacted with the appropriate halide RHal in the presence of an alkali metal or a hydride, alkoxide or amide thereof, or by complete hydrolysis of the nitrile to the corresponding acid, reaction of this with a halide of phosphorus or thionyl chloride to form the acid halide and reaction of this with the appropriate primary amine RNH2. The last step of each of these processes is advantageously performed in an inert solvent.  In examples: (1) 4-dimethylamino-2 : 2-diphenylvaleronitrile is hydrolysed with sulphuric acid at 150 DEG C. to 4-dimethylamino-2 : 2-diphenylvaleric acid acid sulphate, this with thionyl chloride gives the acid sulphate of 4-dimethylamino-2 : 2-diphenylvaleryl chloride and this on heating with isopropylamine in benzene gives, on working up, 4-dimethylamino-N-isopropyl - 2 : 2 - diphenylvaleramide, the hydrochloride and methobromide of which are also prepared; (2) to (5) the corresponding N-methyl, N - cyclohexyl, N - ethyl, N - allyl and N-n-butyl compounds are similarly prepared; (7) 4 - diethylamino - 2 : 2 - diphenylbutyramide is reacted with methyl bromide in toluene with sodium amide to give the N-methyl derivative, the hydrochloride and methobromide of which are also prepared; (8) 4-(21 : 21-dimethyl-11-pyrrolidinyl) - 2 : 2 - diphenyl - N - methylbutyramide and its hydrochloride, methobromide and methiodide are similarly prepared; (9) 5 - (11 - pyrrolidinyl) - 2 : 2 - diphenylvaleronitrile is hydrolysed as in (1) to the acid sulphate of 5 - (11 - pyrrolidinyl) - 2 : 2 - diphenylvaleric acid, this with SOCl2 in benzene gives the acid sulphate of 5-(11-pyrrolidinyl-2 : 2-diphenylvaleryl chloride and this with methylamine in benzene gives, on working up, 5-(11-pyrrolidinyl) - 2 : 2 - diphenyl - N - methylvaleramide, the hydrochloride and methobromide of which are also prepared; (10) 4-diisopropylamino - N - methyl - 2 : 2 - diphenyl butyramide and its hydrochloride are prepared by the method of (7); (11) and (12) 4-(21-methyl - 11 - pyrrolidinyl) - 2 : 2 - diphenyl - N-methylbutyramide and 4-dimethylamino-3-methyl - 2 : 2 - diphenyl - N - methyl - butyramide, and their hydrochlorides, are similarly prepared; (13) 5 - diethylamino - 2 : 2 - diphenylvaleronitrile is hydrolysed as in (1) to the acid sulphate of 5-diethylamino-2 : 2-diphenyl valeric acid, this with thionyl chloride gives the acid sulphate of 5-diethylamino-2 : 2-diphenyl-valeryl chloride and this with methylamine in benzene gives, on working up, 5-diethylamino-N-methyl-2 : 2-diphenylvaleramide, the hydrochloride and methobromide of which are also prepared; (14) the acid sulphate of 4-dimethylamino-2 : 2-diphenylvaleryl chloride and aniline in benzene give 4 - dimethylamino - 2 : 2 - diphenylvaleranilide, the hydrochloride of which is also prepared; (15) and (16) the optical enantiomorphs of the compounds of (1) are prepared by the method of (1) from, respectively, l- and d-4-dimethylamino - 2 : 2 - diphenylvaleronitrile; (17) the acid sulphate of 4-dimethylamino-2 : 2-diphenylvaleryl chloride with ethanolamine in benzene gives 4-dimethylamino-N-(21-hydroxyethyl) - 2 : 2 - diphenylvaleramide, the hydrochloride and methobromide of which are also prepared; (18) 4-dimethylamino-N-methyl-2 : 2-diphenylvaleramide with H2O2 in methanol gives the corresponding N-oxide, the conversion of which to its hydrochloride and hydrobromide is also referred to; (19) 4-(21 : 21-dimethyl-11 pyrrolidinyl) - 2 - phneyl - 2 - (p - chlorophenyl)-N-methyl butyramide is prepared by the method of (7); and (20) the acid sulphate of 4-dimethylamino - 2 : 2 - diphenyl - valeryl chloride and 2-pyrrolidino-ethylamine in benzene give, on working up, 4-dimethylamino-2 : 2-diphenyl - N - (21 - pyrrolidinoethyl) - valeramide, the hydrochloride of which is also prepared.  Reference is also made to the use of 4-piperidino2 : 2 - diphenylbutyronitrile, 4 - dimethylamino-2 : 2 - diphenylvaleronitrile, 4 - piperidino-2 : 2 - diphenylvaleronitrile, 4 - piperidino - 3-methyl - 2 : 2 - diphenylbutyronitrile, 4 - morpholino - 2 : 2 - diphenylvaleronitrile, 4 - morpholino - 3 - methyl - 2 : 2 - diphenylbutyronitrile and 5 - piperidino - 2 - (p - chlorophenyl)-2-phenylvaleronitrile to prepare compounds of the invention and a further list of values which the radicals R, R1, CnH2n and Y can assume is also given, including, for R and R1, alkyl, alkneyl, cycloaliphatic, aralkyl and further aryl radicals and, for Y, further dilower alkyl and saturated nitrogen containing heterocyclic radicals.  Compounds of the formula II are prepared by the process <FORM:0815801/IV (b)/3> <FORM:0815801/IV (b)/4> or by the action of a compound YH on a compound of the formula <FORM:0815801/IV (b)/5> this last compound being prepared either by the reaction of compound III with a compound ClCnH2nCl in the presence of a condensing agent such as LiNH2 or by conversion of compound III to a compound of the formula <FORM:0815801/IV (b)/6> by the action of ClCnH2nOH in the presence of a condensing agent such as LiNH2 and chlorination of compound V with SOCl2.