Patent GB-825563-A (GB)
Title: -a--a-diaryl-2-substituted pyrrolidyl alkyl compounds
Filed: 1956-07-13
Abstract: The invention comprises compounds of the formula  <FORM:0825563/IV (b)/1> where Aryl represents phenyl or chloro-substituted phenyl, m is 1 or 2, n is 2 to 6 inclusive, -CnH2nis an alkylene group containing at least two carbon atoms between the valences, R1 and R11 are hydrogen or methyl, Z is a cyano or a carbomoyl (-CONR111R1111) radical where R111 and R1111 each represent hydrogen or a lower alkyl group containing 1 to 8 carbon atoms inclusive together with acid addition salts, quaternary ammonium salts, amine oxides and amine oxide acid addition salts thereof; and a process for their manufacture wherein (a) an a ,a -disubstituted compound of the formula  <FORM:0825563/IV (b)/2> is condensed with a compound of the formula <FORM:0825563/IV (b)/3> wherein X is a halogen atom in an inert medium in the presence of an alkaline condensing agent; (b) a compound of the formula (I) in which Z is cyano is hydrolysed to convert the -CN radical into a -CONH2 radical; and (c) a compound of the general formula I wherein Z is -CONH2 is alkylated with an alkyl halide to convert the -CONH2 radical into -CON(Alkyl)(R11111), wherein Alkyl is a lower alkyl group of 1 to 8 carbon atoms inclusive and R11111 is hydrogen or a lower alkyl group of 1 to 8 carbon atoms. As an example of (a) diphenyl acetonitrile is condensed with b -spiro - (cyclohexane - 1,21 - pyrrolidyl-11)-ethyl chloride in dry toluene in the presence of lithium amide to form a ,a -di-phenyl - g  - (spiro - [cyclohexane - 1,21 - pyrro-lidyl-11])-butyronitrile, its hydrochloride, and hydrochloride dihydrate.  Similarly are prepared a - (p - chlorophenyl) - a  - phenyl - g  - (spiro - [cyclohexane - 1,21 - pyrrolidyl - 11]) - butyronitrile and its hydrochloride and a ,a -diphenyl - g  - (spiro - [cyclohexane - 1,21 pyrrolidyl - 11]) - N,N - dimethylbutyramide (the starting material (II) being diphenyl-N,N-dimethyl acetamide and the condensing agent sodium amide) its hydrobromide, by reaction of the base with hydrobromic acid, and its methobromide by reaction of the base with cold methyl bromide.  In an example of (b) a ,a -diphenyl-g -(spiro - [cyclohexane - 1,21 - pyrrolidyl - 11])-butyronitrile is hydrolysed with sulphuric acid to form first the sulphate of and then, by the addition of ammonia, the base a ,a -diphenyl-g -(spiro - [cyclohexane - 1,21 - pyrrolidyl - 11]) - butyramide; the hydrochloride and methobromide are also prepared.  Likewise is prepared a  - (p - chlorophenyl) - a  - phenyl - g  - (spiro - [cyclohexane - 1,21 - pyrrolidyl - 11]) - butyramide.  Further as an example of (c) a ,a -diphenyl - g  - (spiro - [cyclohexane - 1,21 - pyrro-lidyl-11])-butyramide is reacted with methyl bromide in the presence of sodium amide and dry toluene to form a ,a -diphenyl-g -(spiro-[cyclo-hexane - 1,21 - pyrrolidyl - 11]) - N - methyl-butyramide and its hydrochloride; and similarly is prepared a ,a -diphenyl-g -(spiro-[cyclo-hexane - 1,21 - pyrrolidyl - 11]) - N,N - dimethyl-butyramide, using the corresponding N-methyl-butyramide as starting material.  It is also disclosed that by reacting an a ,a -diaryl-pyrroli-dylalkano-amide or nitrile of the general formula (I), preferably in the form of the free base, in an inert reaction medium with hydrogen peroxide the amine oxide is produced.  Reacting the amine oxide in an inert medium with an acid, e.g. hydrochloric, hydrobromic, hydiodic, sulphuric, phosphoric, acetic, propionic, benzoic, citric, succinic, lactic, nitric or p-toluene-sulphonic acid the amine oxide acid addition salts are produced.  Specification 825,564 is referred to.