Patent GB-1510016-A (GB)
Title: Imidazole derivatives and process for their manufacture
IPC: C07D233/58
Filed: 1975-04-11
Abstract: 1510016 Imidazole derivatives SCHERING AG 11 April 1975 [11 April 1974 6 March 1975 7 March 1975] 15012/75 Heading C2C Novel compounds of the Formula I wherein Z is a direct bond or a group of the formula -(CH 2 ) n -CH(R 1 )-, in which n is 0, 1 or 2, and R 1  is hydrogen, C 1-6  alkyl or phenyl optionally substituted by one or more substitutents selected from halogen, C 1-6  alkyl or alkoxy or nitro the group -CHR 1 - being attached to the phenyl group shown in the Formula I; R 2  and R 3  each are hydrogen, C 1-10  alkyl, C 1-6  alkoxy or alkyl mercapto, halogen or nitro or R 2  and R 3  together are -CH=CH-CH=CH- attached to adjacent carbon atoms of the phenyl group shown in the Formula I; R 4  is C 3-6  alkenyl or alkynyl, a phenyl group optionally substituted with one or more substituents selected from halogen, nitro, trifluoromethyl, C 1-6  alkyl or alkoxy or a phenyl- (C 1-4 )-alkyl which is optionally substituted in the ring by one or more substitutents selected from halogen, nitro, trifluoromethyl, or C 1-6  alkyl or alkoxy, and, when n is zero may also be a C 1-6  alkyl, and X is 5, 0 or NH and physiologically acceptable salts thereof may be prepared by (1) when Z is a group -(CH 2 ) n - CHR 1 -, reacting a compound of the Formula II in which Y is halogen or a reactive ester, or when n is zero Y may also be hydroxyl, with imidazole or an alkali metal salt thereof, or (2) reacting a compound III or an alkali metal salt thereof with R 4 Q where Q is halogen or a reactive ester, and optionally forming acid addition salts of I. Various intermediates of the Formula II in which X is oxygen and Y is chloro are prepared by (1) reduction of a carboxylic ester to -CH 2 OH, (2) reduction of an aldehyde to CH 2 OH or (3) reaction of an aldehyde with a Grignard reagent to form a secondary alcohol all followed by chlorination of the hydroxy group formed. Various intermediates of the Formula III in which X is oxygen are prepared by reacting imidazole of a salt thereof with an appropriate hydroxy(alkyl)phenyl radical. 3 - (2,4 - Dichlorobenzyloxy)benzoic acid methyl ester is prepared by condensing 3-hydroxybenzoic acid methyl ester with 2,4-dichlorobenzyl chloride. 5-Bromosalicyl alcohol is prepared by reduction of the corresponding acid. 4 - 2,4 - Dichlorobenzyloxy) - 3 - nitrobenzaldehyde is prepared by condensing 4-hydroxy-3- nitrobenzaldehyde with 2,4 - dichlorobenzyl chloride. 4 - (2,4 - Dichlorobenzyloxy) - benzhydrol is prepared by condensing 4-hydroxybenzophenone and 2,4 - dichlorobenzylchloride followed by reduction of the 4-(2,4-dichlorobenzyloxy)- benzophenone so formed. 2 - Hydroxy - 2<SP>1</SP>,4,4<SP>1</SP> - trimethoxybenzophenone is prepared by reaction of 2,2<SP>1</SP>-dihydroxy- 4,4<SP>1</SP>-dimethoxy-benzophenone with 1 equivalent of diazomethane. 4 - (2,4 - Dichlorobenzyloxy) - acetophenone is prepared by condensing 4-hydroxyacetophenone with 2,4-dichlorobenzyl chloride. 5 - Chloro - 2 - hydroxy-benzhydrol is prepared by reduction of 5-chloro-2-hydroxy-benzophenone. 2 - (2,4 - Dichlorobenzyloxy) - benzaldehyde is prepared by condensing salicyl aldehyde with 2,4 - dichlorobenzyl chloride. 2 - (1 - Imidazolylmethyl) - aniline is prepared by condensing imidazole with 2-nitrobenzyl chloride to form 1-(2-nitrobenzyl)-imidazole followed by reduction of the nitro group. 2 - (1 - Imidazoyl) - 4 - nitrophenol is prepared by nitration of 1-(2-methoxyphenyl)- imidazole followed by demethylation of the methoxy group. 4 - Chloro - 2 - (1 - imidazolyl) - phenol is prepared by reduction of 1-(2-methoxy-5-nitrophenyl)-imidazole to the corresponding amine which is converted to chloro by a Sandmeyer reaction. 2- and 4 - (Imidazolyl)aniline are prepared by reduction of 1-(2- or 4- nitrophenyl)-imidazole. 4 - (1 - Imidazolyl) - thiophenol is prepared by diazotizing 4-(1-imidazoyl) aniline followed by treatment with potassium ethyl xanthate and then base. 2 - (1 - Imidazolyl) - thiophenol is prepared by reaction of 2-(1-imidazolyl)-phenol with dimethyl-thiocarbamoyl chloride to form the dimethyl thiocarbamate which is rearranged and hydrolysed to give the required compound. [4 - (# - Chlorethyl) - phenyl] - (2,4 - dichloro benzyl) ether is prepared by condensing 4-hydroxyphenethyl alcohol with 2,4-dichlorobenzyl alcohol to yield [4-(#-hydroxyethyl)-phenyl]-(2,4- dichlorobenzyl) ether which is chlorinated. 4 - [3 - (1 - Imidazolyl) - 1 - methylpropyl]- phenol is prepared by reacting 4-methoxy acetophenone with triethyl phosphonoacetate in strong base to yield ethyl 3-(4-methoxyphenyl)- crotonate which is hydrogenated to ethyl 3-(4- methoxyphenyl)butyrate then reduced to 3-(4- methoxyphenyl)-butanol, chlorinated to 3-(4- methoxyphenyl)-1-chlorobutane and condensed with imidazole to yield the required compound. 4 - [3 - (1 - Imidazolyl) - propyl] - aniline is prepared by condensing 3-(4-nitrophenyl)-1- chloropropane with imidazole to form 1-[3-(4- nitrophenyl)-propyl]-imidazole which is reduced to the aniline. 3 - [2 - Bromo - 4 - (2,4 - dichlorobenzyloxy)-5- methoxyphenyl]- -propionic acid ethyl ester is prepared by reacting vanillin with trimethyl phosphonoacetate in strong base to yield ethyl 3 - (4 - hydroxy - 3 - methoxyphenyl)acrylate which is hydrogenated to ethyl 3-(4- hydroxy-3- methoxyphenyl(-propionate which is condensed with 2,4-dichlorobenzyl chloride to yield ethyl- 3 - [4 - (2,4 - dichlorobenzyloxy) - 3- - methoxyphenyl] propionate which is brominated to the required compound. Pharmaceutical compositions of the compounds I with the usual excipients are active against dermatophytes, yeasts, protozoa and gram negative and gram positive bacteria and systemic fungal infections when administered topically or orally.