GB1122212A - Process for the preparation of substituted piperidine derivatives - Google Patents

Process for the preparation of substituted piperidine derivatives

Info

Publication number
GB1122212A
GB1122212A GB3485665A GB3485665A GB1122212A GB 1122212 A GB1122212 A GB 1122212A GB 3485665 A GB3485665 A GB 3485665A GB 3485665 A GB3485665 A GB 3485665A GB 1122212 A GB1122212 A GB 1122212A
Authority
GB
United Kingdom
Prior art keywords
dimethoxy
tetrahydro
isoquinolyl
acid
benzoyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
GB3485665A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck KGaA
Original Assignee
E Merck AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by E Merck AG filed Critical E Merck AG
Publication of GB1122212A publication Critical patent/GB1122212A/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • C07D455/08—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems having an isoquinolyl-1, a substituted isoquinolyl-1 or an alkylenedioxyisoquinolyl-1 radical linked through only one carbon atom, attached in position 2, e.g. emetine

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.
GB3485665A 1964-08-19 1965-08-13 Process for the preparation of substituted piperidine derivatives Expired GB1122212A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEM0062148 1964-08-19
DEM0062274 1964-09-01

Publications (1)

Publication Number Publication Date
GB1122212A true GB1122212A (en) 1968-07-31

Family

ID=25987592

Family Applications (1)

Application Number Title Priority Date Filing Date
GB3485665A Expired GB1122212A (en) 1964-08-19 1965-08-13 Process for the preparation of substituted piperidine derivatives

Country Status (3)

Country Link
CH (1) CH461496A (en)
DE (2) DE1470084A1 (en)
GB (1) GB1122212A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002010135A1 (en) * 2000-08-01 2002-02-07 Ono Pharmaceutical Co., Ltd. 3,4-dihydroisoquinoline derivative compounds and drugs containing these compounds as the active ingredient

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ191763A (en) * 1978-10-13 1984-05-31 Hoffmann La Roche 7-beta-phenyl-quinolidines, intermediates and pharmaceutical compositions
GB8615785D0 (en) * 1986-06-27 1986-08-06 Beecham Group Plc Compounds

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002010135A1 (en) * 2000-08-01 2002-02-07 Ono Pharmaceutical Co., Ltd. 3,4-dihydroisoquinoline derivative compounds and drugs containing these compounds as the active ingredient
US6956033B2 (en) 2000-08-01 2005-10-18 Ono Pharmaceutical Co., Ltd. 3,4-dihydroisoquinoline derivative compound and a pharmaceutical agent comprising it as active ingredient
JP4982937B2 (en) * 2000-08-01 2012-07-25 小野薬品工業株式会社 3,4-Dihydroisoquinoline derivative compound and drug containing the compound as an active ingredient

Also Published As

Publication number Publication date
CH461496A (en) 1968-08-31
DE1470084A1 (en) 1969-05-29
DE1470091A1 (en) 1969-05-08

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