Patent GB-1076531-A (GB)
Title: 4-substituted-n-(substituted-allyl)-piperidines
IPC: C07D211/64
Filed: 1965-01-15
Abstract: Compounds of the formula <FORM:1076531/C2/1> wherein R1 is hydrogen or methyl; R2, R3 and R4 are hydrogen, chlorine, bromine or methyl; R5 is hydrogen or a methyl group orientated in the a - or b -position relative to the plane of the ring; R6 is hydrogen, chlorine or methyl; R7 is hydrogen, fluorine, chlorine, bromine, methyl, hydroxy, methoxy or acetoxy; R8 is methyl, ethyl, propyl, methoxy, ethoxy or propoxy and at least one of R2, R3 and R5 being halogen or methyl and non-toxic acid addition salts thereof and preparation thereof by reacting a compound of the formula <FORM:1076531/C2/2> wherein R5, R6, R7 and R8 are as defined above, with one or more molecular equivalents of a compound of the formula <FORM:1076531/C2/3> wherein R1, R2, R3 and R4 are as above and Z represents halogen or toluene-p-sulphonyloxy, in organic solvents such as alcohols or a mixture of dimethylformamide and tetrahydrofuran in the presence of a weak base such as sodium bicarbonate at temperatures between 50 DEG and 150 DEG  C.; by reacting a 4-cyano-piperidine of the formula <FORM:1076531/C2/4> wherein R1 to R7 inclusive have the above-mentioned significance, with an appropriate Grignard reagent and hydrolysing the ketimine intermediate to give a 4-alkanoyl-piperidine corresponding to the first general formula above; or by hydrolysing compounds of the fourth general formula above with an acid or a base and then esterifying the resulting carboxylic acid to yield a 4-alkoxy-carbonyl-piperidine corresponding to the first general formula above. Cis and trans isomeric forms of compounds of the first general formula above arise when R3 and R4 are different, due to geometrical isomerism about the allylic double bond, and are prepared either by fractional crystallization of the cis/trans mixture or by synthesis starting with the appropriate pure isomer of compounds of the third general formula above. 4-Cyanopiperidines of the fourth general formula above are obtained by reacting a di-(b -haloethyl)-amine of the formula <FORM:1076531/C2/5> wherein R1 to R5 inclusive are as defined above and Hal represents halogen, with a benzyl cyanide of the formula <FORM:1076531/C2/6> wherein R6 and R7 have the above significance, in toluene solution in the presence of sodamide at a temperature between 40 DEG  and 200 DEG  C.  The preparation of 4-alkoxy-carbonyl, e.g. methoxy-, ethoxy- or propoxy-carbonyl, or 4-alkanoyl-, e.g. acetyl-, propionyl- or butyryl-substituted derivatives of 4-(3-methylphenyl)-(145, 146), 4-(4-chlorophenyl)- (156) and 4-(2- or 3-hydroxyphenyl)- (187 to 189) substituted 1-(1-methylallyl)-piperidines; 4-phenyl- (192, 195), 4-(2-, 3- or 4-methylphenyl)- (117 to 126), 4-(3,4-dimethylphenyl)-(127 to 129), 4-(3- or 4-bromophenyl) - (130 to 132), 4-(2-, 3- or 4-chlorophenyl) - (133 to 141), 4-(3,4-dichlorophenyl) - (142, 143), 4-(3-fluorophenyl)- (144), 4-(2-, 3- or 4-hydroxyphenyl)- (174 to 176, 180 to 182, 184 and 186) substituted 1-(2-methyl-allyl)-piperidines; 4-(3-methylphenyl)- (149, 150), 4-(3- or 4-chlorophenyl)- (152 to 155), 4-(3-fluorophenyl) - (151), 4-(2-, 3- or 4-hydroxyphenyl) - (171 to 173, 177 to 179, 183 and 185) substituted 1-crotylpiperidines; 4-phenyl- (169, 170, 193 and 194), 4-(2- or 3- or 4-methylphenyl)-(91 to 100), 4-(3,4-dimethylphenyl)- (101 to 103), 4-(2-, 3- or 4-chlorophenyl)- (90, 104 to 112), 4(3,4-dichlorophenyl)- (113 to 115), 4-(2,4-dichlorophenyl)- (116), 4-(3-fluorophenyl)- (147, 148), 4-(2-, 3- or 4-hydroxyphenyl)- (157 to 162, 165 and 166), 4-(3-methoxyphenyl)- (163, 164) substituted 1-(3,3-dimethylallyl)- piperidines; 4-(2-, 3- or 4-methylphenyl)- (36 to 41), 4-(3- or 4-chlorophenyl)- (42 to 45), 4-(3-hydroxyphenyl)- (80 to 83) substituted 1-(2-bromoallyl)-piperidines; 4-(3-hydroxyphenyl)- (76 to 79) substituted 1-(3-bromoallyl)-piperidines; 4-(3-chlorophenyl)- (49), 4-(3-hydroxyphenyl) - (84 to 87) substituted 1-(3,3-dibromoallyl) -piperidines; 4-(3-hydroxyphenyl)- (64 to 67) substituted 1-(2-chloroallyl)-piperidines; 4-(2-, 3- or 4-methylphenyl)- (1, 8 to 17), 4-(3,4-dimethylphenyl) - (18 to 20), 4-(2-, 3- or 4-chlorophenyl) - (21 to 30 and 35), 4-(2,4-dichlorophenyl) - (34), 4-(3,4-dichlorophenyl)- (31 to 33), 4-(2-, 3- or 4-hydroxyphenyl)- (2 to 5, 51 to 53, 57, 58, 88 and 89), 4-(3-methoxyphenyl)- (6, 54, 55) and 4-(3-acetoxyphenyl)- (7, 56) substituted 1-(3-chloroallyl)-piperidines; 4-(3-methylphenyl) - (46, 47), 4-(3-chlorophenyl)- (48) and 4-(3-hydroxyphenyl)- (68 to 71) substituted 1 - (3,3 - dichloroallyl) - piperidines; 4 - (3-chlorophenyl) - (50) and 4-(3-hydroxyphenyl)- (72 to 75) substituted 1-(2,3-dichloroallyl)-piperidines; 3-a -methyl- (59 to 61) and 3-b -methyl - (62, 63) substituted 4-(3-hydroxyphenyl)-1 - (3 - chloroallyl) - piperidines; 3 - a  - methyl-(167, 168) substituted 4-(3-hydroxyphenyl)-1-(3,3 - dimethylallyl) - piperidines; and 3 - b -methyl - (190, 191) substituted 4-phenyl-1-(2-methylallyl) -piperidines is described.  trans - 1 - (3 - Chloroallyl) - 4 - (3 - hydroxyphenyl-4-carboxy-piperidine is obtained by hydrolysis of trans - 1 - (3 - chloroallyl) - 4 - (3-methoxyphenyl)-4-cyano-piperidine. trans - 1 - (3 - Chloroallyl) - 4 - (3 - methoxyphenyl) -4-cyano-piperidine is prepared by condensing trans - N - (3 - chloroallyl) - bis - (2 chloroethyl)amine with 3 - methoxy - benzyl cyanide.  trans - N - (3 - Choroallyl) - di - (b  - chloroethyl)amine hydrochloride is prepared by treating trans - N - (3 - chloroallyl) - diethanolamine, obtained from diethanolamine and trans-1,3-dichloro-propene, with thionyl chloride in chloroform.ALSO:Pharmaceutical compositions suitable for oral, parenteral or rectal administration, which have analgesic and morphine antagonistic activity, contain at least one compound of the formula:  <FORM:1076531/A5-A6/1> where R1 is hydrogen or methyl; R2, R3 and R1 are hydrogen, chlorine, bromine or methyl; R5 is hydrogen or a methyl group orientated in the a - or b - position relative to the plane of the ring; R6 is hydrogen, chlorine or methyl; R7 is hydrogen, fluorine, chlorine, bromine methyl, hydroxy, methoxy or acetoxy; R8 is methyl, ethyl, propyl, methoxy, ethoxy or propoxy and at least one of R2, R3 and R5 being halogen or methyl; or specified non-toxic acid addition salts thereof optionally in association with a pharmaceutical carrier or excipient and/or a habit-forming analgesic such as morphine, pethidine or ketobemidone.