Patent GB-1122212-A (GB)
Title: Process for the preparation of substituted piperidine derivatives
IPC: C07D455/02
Filed: 1965-08-13
Abstract: Compounds of the general formula <FORM:1122212/C2/1> some of which are stated to be novel, where R1 is alkyl, cycloalkyl, aryl or aralkyl of up to 11 carbon atoms in which the aromatic ring, when present, is optionally substituted by 1, 2 or 3 methoxy radicals or alkyl radicals or a methylenedioxy group, or is the radical <FORM:1122212/C2/2> R2 is alkyl, aryl or aralkyl of up to 8 C atoms where the aromatic ring, when present, is optionally substituted by 1, 2 or 3 Cl atoms, methoxy or alkyl groups or a methylenedioxy group; R3 and R4, same or different, are -(CH3)3- or -(CH3)4- which may be substituted by one or more C1- 6 alkyl radicals and/ or phenyl radicals, or the radical <FORM:1122212/C2/3> which latter is optionally substituted in the phenyl ring by 1, 2 or 3 alkyl or methoxy radicals, or a methylenedioxy group; R5 is H, acyl up to 9 C atoms, carbobenzoxy, carbalkoxy, alkyl or aralkyl radical containing up to 9 carbon atoms, and acid addition salts thereof are prepared by condensing a cyclic b -amino ketone of the formula <FORM:1122212/C2/4> where R6 is C1- 11 alkyl, cycloalkyl, aryl or aralkyl, in which the aromatic ring is optionally substituted by 1, 2 or 3 methoxy or C1- 2 alkyl radicals or a methylenedioxy group or is the radical <FORM:1122212/C2/5> where R7 is C1- 9 acyl or a carbobenzoxy o lower carbalkoxy radical or an acid addition salt thereof, with an aldehyde of the formula O=CH-CH2R2 in the presence of water and/or a water-miscible organic solvent to obtain a mixture of a compound of the first general formula above where R1 is R6 and a corresponding pyridinium salt of the formula <FORM:1122212/C2/6> where X(-) is an anion, reducing the mixed reaction products and, if desired, separating the resulting desired product into its diastereoisomeric forms and/or converting it into an acid addition salt.  The reduction is advantageously carried out with sodium borohydride in methanol.  1 - (N - benzoyl - 1,2,3,4 - tetrahydro - 6,7-dimethoxy - isoquinolyl - 1) - 2 - (1,2,3,4 - tetrahydro - 6,7 - dimethoxy - isoquinolyl - 1) - acetone is prepared by treating g -(1,2,3,4-tetrahydro-6,7 - dimethoxyisoquinolyl - 1) - b  - oxobutyric acid with benzoyl chloride and reacting the resulting corresponding N - benzoyl compound with 3,4 - dihydro - 6,7 - dimethoxy - isoquinoline (the product may be further benzoylated to 1,3 - bis - (N - benzoyl - 1,2,3,4 - tetrahydro-6,7-dimethoxy - isoquinolyl - 1) - acetone; perchlorate salts of all those compounds are mentioned.  1 - (N - carbobenzoxy - 1,2,3,4 - tetrahydro-6,7-dimethoxy - isoquinolyl - 1) - 3 - (1 - 1,2,3,4-tetrahydro - 6,7 - dimethoxy - isoquinolyl - 1)-acetone is prepared by reacting g -(1,2,3,4-tetrahydro-6,7 - dimethoxy - isoquinolyl - 1) - b  - oxobutyric acid with carbobenzoxychloride; the resulting corresponding N-carbobenzoxy compound loses CO2 on prolonged standing to form N-carbobenzoxy - 1 - acetonyl - 6,7 - dimethoxy - 1,2,3,4-tetrahydroisoquinoline and reacting this compound with 3,4 - dihydro - 6,7 - dimethoxy - isoquinoline (the product may be further reacted with carbobenzoxy chloride to form 1,3-bis-(N-carbobenzoxy - 6,7 - dimethoxy - 1,2,3,4 - tetrahydro - isoquinolyl - 1) - acetone which is also obtainable by direct reaction between 1,3-bis-(6,7 - dimethoxy - 1,2,3,4 - tetrahydro - isoquinolyl-1)-acetone and carbobenzoxy chloride).  1 - (N - benzoyl - 1,2,3,4 - tetrahydro - 6,7-methylenedioxy - isoquinolyl - 1) - 3 - (1,2,3,4-tetrahydro - 6,7 - methylenedioxy - isoquinolyl-1)-acetone is prepared by reacting acetone dicarboxylic acid and 6,7-methylenedioxy-3,4-dihydro-isoquinoline to form g (1,2,3,4-tetrahydro - 6,7 - methylenedioxy - isoquinolyl - 1)-b -oxobutyric acid which on standing loses CO2 to form bis - (6,7 - methylenedioxy - 1,2,3,4-tetrahydro - isoquinolyl - 1) - acetone, reacting this compound with benzoyl chloride and reacting the resulting corresponding N-benzoyl compound with 6,7 - methylenedioxy - 3,4 - dihydroisoquinoline.  Cyclohexyl - (6,7 - dimethoxy - 1,2,3,4 - tetrahydro - isoquinolyl - 1 - methyl) - ketone is prepared by reacting hexahydrobenzoic acid chloride with sodium acetoacetic ester, acid cleaving the resulting hexahydro-benzoyl-acetoacetic ester with sodium methylate in methanol to form hexahydrobenzoyl acetic acid methyl ester, saponifying this ester to the corresponding free carboxylic acid, and reacting this acid with 3,4 - dihydro - 6,7 - dimethoxy - isoquinoline. 1 - (2 - oxo - 4 - phenylbutyl) - 6,7 - dimethoxy-1,2,3, 4 - tetrahydroisoquinoline is prepared from hydrocinnamic acid chloride by a similar method.  3 - (2 - Benzoyl - 6,7 - dimethoxy - 1,2,3,4-tetrahydroisoquinolyl - 1) - acetone is prepared by reacting a -tripiperideine and the N-benzoyl compound of g  - (6,7 - dimethoxy - 1,2,3,4-tetrahydro - isoquinolyl - 1) - b  - oxobutyric acid and allowing the mixture to stand.  1 - (2 - p - Methoxyphenyl - 2 - oxo - ethyl)-6,7-dimethoxy - 1,2,3,4 - tetrahydroisoquinoline is prepared by saponification of p-methoxybenzoyl ethyl acetate with alkali at room temperature and condensation of the resulting b -keto acid.  Pharmaceutical compositions having e.g. amoebicidal or trichomonadocidal activity comprise a compound of the first general formula above or a pharmaceutically acceptable salt thereof together with an inert physiologically acceptable carrier. They may be administered parenterally or enterally and may be formulated as solutions, suspensions, emulsions, implantates, tablets, lozenges, creams or ointments.