Verfahren zur Herstellung von neuen Piperidinderivaten

摘要

1,141,664. Piperidine derivatives. JANSSEN PHARMACEUTICA N.V. 7 Dec., 1966 [8 Dec., 1965; 23 Sept., 1966], Nos. 52125/65 and 42589/66. Heading C2C. Novel piperidine derivatives having the general formula wherein Y is Ar or Ar3 and Z is Ar1 or Ar2 , Ar being phenyl, halophenyl or lower alkoxy phenyl, Ar1 being dihalophenyl, trihalophenyl, lower alkyl-halophenyl or trifluoromethyl-halophenyl, Ar2 being halophenyl and Ar3 being dihalophenyl or lower alkyl-halophenyl, with the proviso that when Y is Ar then Z is Ar1 and when Y is Ar3 then Z is Ar2, and their pharmaceutically acceptable acid addition salts and quaternary ammonium compounds may be prepared either by condensing a reactive ester of a compound of the formula with a compound of the formula (IV) in a suitable solvent or by reacting a reactive ester of a compound of the formula with a compound of Formula IV to prepare a compound of the formula which is then reacted under Grignard conditions with a compound Y-Mg-Halogen. Compounds of the Formula IV are prepared either by condensing a compound of Formula V wherein R is benzyl or alkoxy-carbonyl with a compound ZLi to give a compound of formula which is converted by water to the corresponding hydroxy compound after which the protecting group R is removed or reacting a compound of Formula V with Z-Mg-Halogen under Grignard conditions to give the hydroxy compound as above from which the protecting group R is then removed. Removal of R is by hydrogenation if R is benzyl or by treatment with alkali if R is alkoxy carbonyl. Intermediates prepared in examples are 1 - (3 - cyanopropyl) - 4 - hydroxy - 4 - (4 - chlorophenyl) piperidine, 1 - (ethoxycarbonyl) - 4 - hydroxy - 4 - (3 - chloro - 4 - methylphenyl) - piperidine. 1 - (ethoxy carbonyl) - 4 - hydroxy - 4 - (3 ,4 - dichlorophenyl) - -piperidine, 1 - (ethoxy - carbonyl) - 4 - hydroxy - 4 - (3 - methyl - 4 - chlorophenyl) - piperidine, 1 - (ethoxycarbonyl) - 4 - hydroxy - 4 - (3 - trifluoromethyl - 4 - chlorophenyl) - piperidine and 4 - hydroxy - 4 - (3 - trifluoro - methyl - 4 - chlorophenyl) - piperidine and 1 - (ethoxycarbonyl) - 4 - hydroxy - 4 - (3,4,5 - trichlorophenyl) - piperidine and 4 - hydroicy - 4 - (3,4,5 - trichlorophenyl) - piperidine. In one example 3,4,5 - trichlorobromobenzene is prepared by the action of Cu 2 Br 2 /HBr on diazotized trichlorobromoaniline in order to obtain 3,4,5 - trichlorophenyl magnesium bromide. Attention is directed in pursuance of Section 9, sub-section (1) of the Patents Act 1949 to Specification 881,893 and to Specification 895,309.