Patent GB-756686-A (GB)
Title: Improvements in or relating to cyclic compounds particularly useful for diuretics and antifungals
Inventor: CAMPEN MARCUS GEORGE VAN
IPC: C07D211/02
Filed: 1953-10-12
Abstract: The invention comprises compounds of formula <FORM:0756686/IV(a)/1> and acid addition and quaternary ammonium salts thereof, wherein R1 is hydrogen, methyl or ethyl; R2 is an alkyl group having 1 to 3 carbon atoms; R5 is hydrogen, phenyl or an alkyl group having 1 to 6 carbon atoms; R3 and R4 are independently hydrogen, alkyl groups having 2 to 11 carbon atoms, cycloalkyl and substituted cycloalkyl groups having not more than 9 carbon atoms and including endo-alkylene (e.g. endomethylene), phenyl, halo-phenyl, alkylphenyl and alkoxyphenyl having 1 to 6 carbon atoms in the alkyl or alkoxy group and monocyclic heterocyclic groups (e.g. pyridyl, piperidyl, thienyl or furyl), provided that when R1, R3 and R5 are hydrogen and R2 is methyl or ethyl, R4 is not aryl, and with the further requirement that the sum of the carbon atoms in R3 and R4 is at least 6, or, alternatively, the radical -CR3R4- represents a cyclic group having 9 to 13 carbon atoms comprising 9-fluor-enylidene, cyclohexylcyclohexylidene, bornyli-dene, fenchylidene and methoxyphenylcyclo-hexylidene.  The compounds are prepared (1) by reacting a piperidine compound <FORM:0756686/IV(a)/2> or a compound having the alternative grouping -CHR5COOX, where COOX is an ester group, with an R4-Grignard or R4-lithium compound or with a mixture of a lithium alkyl and an appropriate R4-halide; (2) by reacting a pyridinium compound <FORM:0756686/IV(a)/3> with an alkyl halide having 1 to 3 carbon atoms and hydrogenating the resulting quaternary pyridinium compound in presence of a hydrogenation catalyst; and (3) by hydrogenating the starting material of method (2) in presence of a hydrogenation catalyst and N-alkylating the resulting piperidine compound.  The N-alkylation of the piperidine intermediates resulting from method (3) is effected by reacting said compounds either with an alkyl halide having 1 to 3 carbon atoms or with an aldehyde to form the corresponding piperidine-oxazine compound which is then catalytically hydrogenated or reacted with the acid corresponding to the aldehyde.  Quaternary ammonium salts are prepared from the products of methods (1) to (3) by subsequent treatment with alkyl halides.  The examples describe the preparation of a  - phenyl - a  - para - tolyl - 1 - methyl -, a  - para - phenetyl - a  - phenyl - 1 - methyl -, a  - meta - chlorophenyl - a  - phenyl - 1 - methyl -, a : a  - di(para - chlorophenyl) - 1 - methyl -, a  - 41 - methylcyclohexyl - a  - phenyl - 1 - methyl -, a  - cyclopentyl - a - phenyl - 1 - methyl -, a  - (11-methyl - 31 - isopropylcyclopentyl) - a  - phenyl - 1 - methyl -, a  - n - hexyl - a  - phenyl - 1 - methyl -, a  - n - hexyl - a  - phenyl - 1 : 6 - di-methyl -, a  - n - hexyl - a  - phenyl - 1 - methyl - 5 - ethyl -, a : b  - diphenyl - 1 - methyl -, a  - para - tolyl - b  - phenyl - 1 - methyl -, a  : a - di-phenyl - 1 : b  - dimethyl -, a  : a  - diphenyl - b  - ethyl - 1 - methyl -, a  : a  - diphenyl - b  - amyl - 1 - methyl -, a  : a - diphenyl - b  - methyl - 1 - ethyl -, a  : a  - diphenyl - b  - methyl - 1 - propyl-, a  : a  - di - (ortho, meta or para-tolyl or methox-phenyl) - b  - (methyl, ethyl or amyl) - 1 - (methyl, ethyl or propyl)-, a -cyclohexyl-a -n-hexyl-1-methyl -, a  : a  - di - n - hexyl - 1 - methyl -, a  - (11 - phenylcyclohexyl) - 1 - methyl -, a : a  - diphenyl - 1 - methyl -, a  : a  - di - para - methoxyphenyl - 1 - methyl -, a  : a  - diphenyl - 1 - ethyl-, a  : a  - diphenyl - 1 - propyl -, a  : a  - diphenyl - 1 : 6 - dimethyl -, a  - phenyl - a - para - chlorophenyl - 1 - methyl -, a  : a  - di - para - tolyl - 1 - methyl -, a  - phenyl - a  - para - cumyl - 1 - methyl -, a  : a  - dicyclohexyl - 1 - methyl -, a  : a - dicyclohexyl - 1 - ethyl -, a : a  - dicyclohexyl - 1 - propyl -, a  - phenyl - a  - cyclohexyl - 1 - methyl-, a -phenyl-a -cyclohexyl-1-ethyl-, a -phenyl-a -cyclohexyl - 1 - propyl -, a  - phenyl - a  - cycloa  - (21 - pyridyl) - a  - phenyl hexyl - 1 : 6 - dimethyl -, a  - (21 - pyridyl) - a  - phenyl - 1 - methyl -, a  - (21 - piperidyl) - a  - phenyl - 1 - methyl -, a - (21 - thienyl) - a  - phenyl - methyl -, a  - phenyl - a  - isopropyl - 1 - methyl -, a  : a  - di - isobutyl - 1 - methyl -, a : a - di - tert. - butyl - 1 - methyl -, a  - phenyl - a  - n - amyl - 1 - methyl -, a  - phenyl - a  - n - octyl - 1 - methyl-, a -phenyl-a -n-undecyl-1-methyl-, a -phenyl - a  - (2 - bicyclo - [2:2:1] - heptyl) - 1 - methyl -, a  : a  - di - n - heptyl - 1 - methyl -, a  - ethyl - a  - n - octyl - 1 - methyl - and a  - cyclohexyl - 1 - methyl - 2 - piperidine-ethanols, and hydrochlorides and hydrobromides thereof; a  : a  - diphenyl - 1 - methyl - 2 - piperidine-ethanol methobromide; a  : a -diphenyl-1-methyl-3-piperidine-ethanol and the hydrobromide; a  : a -diphenyl - b  - butyl - 1 - methyl -, a  : a  - di - (ortho, meta or para-tolyl or methoxyphenyl)-b -butyl - 1 - methyl - and a  : a  - diphenyl - 1 - methyl - 4 - piperidine-ethanols and hydrobromides thereof; 9 - (a  - 1 - methyl - 2 - pipecolyl) - 9 - fluorenol and the hydrochloride; 1 - (a  - 1 - methyl - 2 - pipecolyl) - 2 - cyclohexylcyclohexanol and the hydrochloride; 1-(a -1-methyl - 2 - pipecolyl) - 2 - para - methoxyphenyl-1-cyclohexanol and the hydrochloride; a  - (a  - 1 - methyl - 2 - pipecolyl) - d - borneol and the hydrochloride; and a -(a -1-methyl-2-pipecolyl)-dl-fenchol and the hydrochloride.  Starting compounds of formula <FORM:0756686/IV(a)/4> are prepared (1) by reacting an acyclic or cyclic ketone of formula R3COR4 with an appropriate a -picolyl lithium, a -picolyl sodium or mixture of compounds yielding same, followed by decomposition of the reaction mixture with ammonium chloride solution; and (2) by hydrogenation of corresponding ketones having the grouping -CHR5-COR3 as a nuclear substituent using a platinum oxide catalyst.  2-Benzylpyridine is condensed with ethyl benzoate or ethyl para-toluate in presence of lithium to give a -phenyl-2-phenacylpyridine and a  - para - toluoyl - 2 - benzylpyridine respectively.  2-Ethylpyridine is condensed with ethyl benzoate in presence of lithium to give a -methyl-2-phenacylpyridine. The corresponding a -ethyl-, a -butyl- and a -amyl-compounds are similarly prepared.  a  - Methyl - 2 - phenacylpyridine yields the corresponding methobromide, ethobromide and propobromide by treatment with methyl, ethyl and propyl bromide respectively.  Hydrogenation of the methobromide, ethobromide and propobromide using a platinum oxide catalyst yields 1 : a -dimethyl-2-phenacylpiperidine, 1 - ethyl - a - methyl - 2 - phenacylpiperidine and 1 - propyl - a  - methyl-2-phenacylpiperidine respectively.  1 - Phenylcyclohexanecarboxylate is reacted with a -picolyl lithium to give 2-(11-phenylcyclohexacyl)-pyridine, which is hydrogenated using a platinum oxide catalyst to give 2-(11-phenylcyclohexacyl)-piperidine.  Benzonitrile is added to the Grignard reagent formed from para-methylcyclohexyl bromide and the intermediate ketimine is decomposed by refluxing the reaction mixture with hydrochloric acid to give 4-methylcyclohexyl phenyl ketone.  The 2 : 4 - dinitrophenylhydrazone of the latter compound is described. The product formed by reacting a -picoline with phenyl lithium is subjected to carbonation and the reaction mixture treated with methanol to give methyl 2-pyridineacetate.  The latter compound yields the corresponding methobromide when allowed to stand in contact with methanolic methyl bromide.  Hydrogenation of the methobromide using a platinum oxide catalyst yields methyl 1-methyl-2-piperidine-acetate.