DE1049377B - Process for the preparation of substituted vinyl piperidines - Google Patents
Process for the preparation of substituted vinyl piperidinesInfo
- Publication number
- DE1049377B DE1049377B DENDAT1049377D DE1049377DA DE1049377B DE 1049377 B DE1049377 B DE 1049377B DE NDAT1049377 D DENDAT1049377 D DE NDAT1049377D DE 1049377D A DE1049377D A DE 1049377DA DE 1049377 B DE1049377 B DE 1049377B
- Authority
- DE
- Germany
- Prior art keywords
- compound
- alkyl
- formula
- pipecolylcarbinol
- substituted
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 15
- LEWNYOKWUAYXPI-UHFFFAOYSA-N 1-ethenylpiperidine Chemical class C=CN1CCCCC1 LEWNYOKWUAYXPI-UHFFFAOYSA-N 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 17
- -1 vinylpiperidine compound Chemical class 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229940102396 methyl bromide Drugs 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 238000005932 reductive alkylation reaction Methods 0.000 claims description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims 1
- 150000001350 alkyl halides Chemical class 0.000 claims 1
- 150000003863 ammonium salts Chemical class 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 229920002554 vinyl polymer Polymers 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 230000008018 melting Effects 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 7
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 239000004305 biphenyl Substances 0.000 description 5
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 235000010290 biphenyl Nutrition 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 125000006267 biphenyl group Chemical group 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- APMOETXMGRRPIQ-UHFFFAOYSA-N 1,1-diphenyl-2-pyridin-4-ylethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)CC1=CC=NC=C1 APMOETXMGRRPIQ-UHFFFAOYSA-N 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000008098 formaldehyde solution Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 description 1
- RCWRYKSQLPUTOV-UHFFFAOYSA-N 2-ethenyl-1-methylpiperidine Chemical class CN1CCCCC1C=C RCWRYKSQLPUTOV-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 241000158147 Sator Species 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 241000009298 Trigla lyra Species 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000003298 dental enamel Anatomy 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- IZHPYHWMQGCRSU-UHFFFAOYSA-N methyl (4-methylphenyl) sulfate Chemical compound COS(=O)(=O)OC1=CC=C(C)C=C1 IZHPYHWMQGCRSU-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000563 toxic property Toxicity 0.000 description 1
- ORGHESHFQPYLAO-UHFFFAOYSA-N vinyl radical Chemical class C=[CH] ORGHESHFQPYLAO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Description
DEUTSCHESGERMAN
Die Erfindung betrifft ein Verfahren zur Herstellung von substituierten Vinylpiperidinen der allgemeinen FormelThe invention relates to a method for producing substituted vinyl piperidines of the general formula
X-Qx XQ x
_C = CH-|-_C = CH- | -
worin Q eine Phenylgruppe, Q1 eine Phenyl-, Pyridyl-, ίο Thienyl-, niedrige Alkyl- oder Cycloalkylgruppe ist oder die Gruppierungwherein Q is a phenyl group, Q 1 is a phenyl, pyridyl, ίο thienyl, lower alkyl or cycloalkyl group or the grouping
X =X =
den Fluorenylidenrest darstellt, X und X1 gleich oder verschieden sind und Wasserstoff- oder Halogenatome und R Wasserstoff oder eine niedere Alkylgruppe bedeuten. ·,.■■■represents the fluorenylidene radical, X and X 1 are identical or different and represent hydrogen or halogen atoms and R represents hydrogen or a lower alkyl group. · ,. ■■■
Zu ihrer Herstellung wird erfindungsgemäß folgendermaßen verfahren, wobei die einzelnen Verfahrensstufen nach an sich bekannten Methoden durchgeführt werden. Ein Keton der allgemeinen FormelTo produce them, the procedure according to the invention is as follows, with the individual process steps be carried out according to methods known per se. A ketone of the general formula
Verfahren zur Herstellung
von substituierten VinylpiperidinenMethod of manufacture
of substituted vinyl piperidines
Anmelder:Applicant:
Abbott Laboratories,
North Chicago, 111. (V. St. A.)Abbott Laboratories,
North Chicago, 111. (V. St. A.)
Vertreter:Representative:
Dr. G. W. Lotterhos und Dr.-Ing. H. W. Lotterhos,
Patentanwälte, Frankfurt/M., Lichtensteinstr. 3Dr. GW Lotterhos and Dr.-Ing. HW Lotterhos,
Patent attorneys, Frankfurt / M., Lichtensteinstr. 3
Beanspruchte Priorität:
V. St. v. Amerika vom 3. April 1952Claimed priority:
V. St. v. America April 3, 1952
Arthur W. Weston, Waukegan, 111. (V. St. Α.),
ist als Erfinder genannt wordenArthur W. Weston, Waukegan, 111. (V. St. Α.),
has been named as the inventor
X-QX-Q
:c =: c =
(-0(-0
worin Q und Q1 sowie X und X1 die oben angegebenen Bedeutungen haben, wird in bekannter Weise mit α-, β~ oder y-Picolin, vorzugsweise in Gegenwart von Natriumamid, kondensiert, das erhaltene Picolylcarbinol der Formelin which Q and Q 1 and X and X 1 have the meanings given above, the picolyl carbinol obtained of the formula is condensed in a known manner with α-, β- or γ-picoline, preferably in the presence of sodium amide
(Π)(Π)
zu dem entsprechenden Pipecolylcarbinol hydriert, dieses Pipecolylcarbinol oder eine hieraus durch reduktive Alkylierung erhaltene N-Alkylverbindung mit niedrigem Alkylrest unter wasserabspältenden Bedingungen umgesetzt, eine so gegebenenfalls erhaltene Verbindung der Formelhydrogenated to the corresponding pipecolylcarbinol, this pipecolylcarbinol or one of it by reductive Alkylation obtained N-alkyl compound with low Reacted alkyl radical under dehydrating conditions, an optionally obtained compound of formula
(III)(III)
gewünschtenfalls am Stickstoff unter Anwendung eines Reduktionsmittels durch einen niedrigen Alkylrest substituiert und gegebenenfalls eine Verbindung der Formel (III) oder das erhaltene N-Alkylderivat einer solchen Verbindung in ein Säureadditionssalz oder quaternäres Ammoniumsalz übergeführt.if desired substituted on the nitrogen by a lower alkyl radical using a reducing agent and optionally a compound of the formula (III) or the N-alkyl derivative thereof obtained Compound converted into an acid addition salt or quaternary ammonium salt.
Die Reduktion des Picolylcarbinols zu dem entsprechenden Pipecolylcarbinol wird vorzugsweise mit Wasserstoff in Gegenwart von Platin vorgenommen und die Wasserabspaltung aus dem Pipecolylcarbinol vorzugsweise mit konzentrierter Schwefelsäure durchgeführt.The reduction of the picolyl carbinol to the corresponding pipecolyl carbinol is preferably carried out with hydrogen made in the presence of platinum and the elimination of water from the pipecolylcarbinol is preferred carried out with concentrated sulfuric acid.
Die Einführung eines Methylrestes in die 1-Stellung des Piperidinkerns läßt sich in der Weise durchführen, daß man die Pipccolylcarbinole oder die Vinylpiperidine mit Formaldehyd in Gegenwart von Ameisensäure unter Rückfluß behandelt.The introduction of a methyl radical in the 1-position of the piperidine nucleus can be carried out in such a way that the pipccolylcarbinols or the vinylpiperidines treated with formaldehyde in the presence of formic acid under reflux.
An Hand folgender Beispiele soll das Verfahren der Erfindung näher erläutert werden.The process of the invention is to be explained in more detail with the aid of the following examples.
a) Diphenyl- (4-pipecolyl) -carbinola) Diphenyl- (4-pipecolyl) -carbinol
30 g Natriumamid werden in 60 g 4-Picolin suspendiert und 45 g Benzophenon, das in 40 g 4-Picolin gelöst ist, langsam zugefügt. Während der Zugabe findet eine Ammoniakentwicklung statt. Die Reaktionsmischung wird über Nacht bei Raumtemperatur gerührt, anschließend vorsichtig auf Eis gegossen, der dabei gebildete Nieder^ schlag abfiltriert, mit Wasser gewaschen und getrocknet.30 g of sodium amide are suspended in 60 g of 4-picoline and 45 g of benzophenone, which is dissolved in 40 g of 4-picoline, slowly added. During the addition there is an evolution of ammonia. The reaction mixture will Stirred overnight at room temperature, then carefully poured onto ice, the resulting lower ^ filtered off, washed with water and dried.
809 747/432809 747/432
Diphenyl- (4-picolyl)-carbinol wird durch Umkristalli- ' 'ätherischen Lösung von Oxalsäure in das entsprechende sieren aus absolutem Alkohol mit einem Schmelzpunkt Oxalat umwandelt, das einen Schmelzpunkt von 1350C von 1S9 bis 1600C in guter Ausbeute erhalten. Eine essig- besitzt.Diphenyl (4-picolyl) carbinol is Umkristalli- '' ethereal solution of oxalic acid into the corresponding Sieren from absolute alcohol with a melting point oxalate converts the obtained has a melting point of 135 0 C to 160 0 C of 1S9 in good yield. A vinegar-owns.
saure Lösung von 5 g Diphenyl-(4-picolyl)-carbinol wird : ■■ ■ . .acidic solution of 5 g of diphenyl- (4-picolyl) -carbinol is : ■■ ■ . .
in Gegenwart von; Platin unter einem Wasserstoffdruck, 5 : : b) 2-(^Diphenyl-vinyl)-l-methyl-piperidmvon 2,109 at (kg/cm2) reduziert, anschließend der Kataly- > hydrochlondin the presence of; Platinum under a hydrogen pressure, 5 :: b ) 2 - (^ Diphenyl-vinyl) -l-methyl-piperidm of 2.109 at (kg / cm 2 ) reduced, then the Kataly-> hydrochloride
sator abgetrennt und das Filtrat unter vermindertem Das nach vorstehendem erhaltene basische Carbinolsator separated and the filtrate under reduced The basic carbinol obtained according to the above
Druck eingeengt. Durch Zugabe von Wasser wird ein Teil wird analog der Un Abschnitt b) von Beispiel 2 beschrieder nicht reduzierten Picolylverbindurig ausgefällt und benen Arbeitsweise in das Hydrochlorid der entspredie wäßrige Lösung durch Zugabe von Natriumcarbonat io chenden Diphenylvinylverbindung übergeführt. Schmelzoder einem geeigneten Alkalihydroxyd alkalisch gemacht. punkt nach Umkristallisation: 192 bis 193° C. Das gewünschte Zwischenprodukt, nämlich das Diphenyl- ' R . . .Pressure restricted. By adding water, part of the non-reduced picolyl compound described in Section b) of Example 2 is precipitated and converted into the hydrochloride of the corresponding aqueous solution by adding sodium carbonate. Made alkaline enamel or a suitable alkali hydroxide. point after recrystallization: 192 to 193 ° C. The desired intermediate, namely the diphenyl- ' R. . .
(4-pipecolyl)-carbiriol, wird nach Umkristallisieren aus '. eispie(4-pipecolyl) -carbiriol, becomes after recrystallization from '. eispie
absolutem Alkohol als feste ..Substanz erhalten, die bei a) 4-(/3,JS-Diphenyl-vinyl)-l.-methyl-piperidinabsolute alcohol obtained as a solid .. substance, which in a ) 4 - (/ 3, J S-diphenyl-vinyl) -l.-methyl-piperidine
156 bis 157°C schmilzt. Das Hydrochlorid, das mit Salz- 15 4-(/^-Diphenyl-vinyl)-piperidin-hydrochlorid wird gesäure erhalten werden kann, weist einen Smp. von 247 maß Beispiel 1 hergestellt. Eine Lösung von 7,2 g dieserMelts from 156 to 157 ° C. The hydrochloride, which is mixed with salt 15 4 - (/ ^ - Diphenyl-vinyl) -piperidine hydrochloride, becomes acidic can be obtained has a m.p. of 247. Example 1 prepared. A solution of 7.2 g of this
bis 2480C (Zersetzung) auf. „ Verbindung, 40 g etwa 37%ige Formaldehydlösung undup to 248 0 C (decomposition). "Compound, 40 g of about 37% formaldehyde solution and
{-, ν,ΛΟΤΑ. , , · \V ■ "· τ V ι i'i' · 1 20g 90%ige Ameisensäure werden über Nacht unter{-, ν, ΛΟΤΑ . ,, · \ V ■ "· τ V ι I 'i' · 1 20g 90% formic acid overnight
b) 4-(^,^-Diphenyl-ymyl):PiPendin-hydrochlond Rückfluß erhitzt, verdünnte Salzsäure hi der Mischungb) 4 - (^, ^ - Diphenyl-ymyl) : P i P endin-hydrochloride heated to reflux, dilute hydrochloric acid hi the mixture
Eine Lösung von 1 g Diphenyl-(4-pipecolyl)-carbinol 2° hinzugefügt und anschließend unter vermindertem Druck in 20 ecm 85°/oiger Schwefelsäure erhitzt man 2 bis 3 Mi- ■ zur Trockne eingedampft. Das aus einem Gemisch von nuten im Wasserbad. Dalm gießt man die Mischung auf absolutem Alkohol· und Äther umkristaUisierte Produkt Eis, und das unlösliche Sulfat wird in der Kälte abfiltriert. hat einen Schmelzpunkt von 242 bis 243° C. Durch Be-Die feste Substanz schüttelt:man mit 4%iger Kalium- handlung des Hydrochlorides mit konzentrierter Kaliumhydroxydlösung und extrahiert das Öl mit ,einer Äther- 25 hydroxydlösung wird die freie Base erhalten, die sich Chloroform-Mischung. Die nach Entfernung des Sulfates "■' langsam verfestigt. Nach Umkristallisieren aus Essigerhaltene Base wird anschließend durch Behandlung mit ester besitzt sie einen Schmelzpunkt von 76 bis!77°C. Chlorwasserstoff in Äther in das Hydrochlorid überge- Die Ausbeute beträgt 60%. · ; '"Added a solution of 1 g of diphenyl (4-pipecolyl) carbinol 2 ° and then under reduced pressure in 20 cc of 85 ° / o sulfuric acid is heated for 2 to 3 micro ■ evaporated to dryness. That from a mixture of grooves in a water bath. The mixture is then poured onto ice, which has crystallized out in absolute alcohol and ether, and the insoluble sulfate is filtered off in the cold. has a melting point of 242 to 243 ° C. The solid substance is shaken by Be-Die: the hydrochloride is treated with 4% potassium with concentrated potassium hydroxide solution and the oil is extracted with an ether hydroxide solution, the free base is obtained Chloroform mixture. . The slowly solidified 'after removal of the sulphate "■ After recrystallization from ethyl resulting base is then removed by treatment with ester it has a melting point of 76 to 77 ° hydrochloric handed over in ether into the hydrochloride C The yield is 60% ·!..; '"
führt,-das aus einem Gemisch von absolutem Alkohol . .leads -that from a mixture of absolute alcohol. .
und Äther umkristaUisiert wird und danach einen Schmelz- 30 b) ^(^-Diphenyl-vmylH-methyl-piperidm-brompunkt von 223 bis 2240C besitzt. Die Ausbeute beträgt ^ methylatand ether is umkristaUisiert and then a melting 30 b) ^ (^ -. vmylH diphenyl-methyl-piperidm-brompunkt of 223 has to 224 0 C. The yield is ^ methylate
7O°/o. : ■'.-. hb .·.:. Eine Lösung von 4- (/5,/J-Diphenyl- vinyl) -1-methyl-piper-70 ° / o. : ■ '.-. hb. ·.:. A solution of 4- (/ 5, / J-diphenyl-vinyl) -1-methyl-piper-
v· Beispiel·^;1 i idin wird in trockenem Äther gelöst und mit. über-v · example · ^; 1 i idin is dissolved in dry ether and mixed with. above-
a) Diphenyl-(2-pipecolyl)-carbinol schüssigem, Methylbromid behandelt., pas dafe aus-a) Diphenyl- (2-pipecolyl) -carbinol Schüssigem, treated methyl bromide., pas dafe aus-
35 fällende quaternäre Brommethylat wird aus absolutem35 precipitated quaternary bromomethylate is converted from absolute
Analog dem-im Abschnitt~a) ■ von Beispiel! beschrie- ''■■ Alkohol umkristaUisiert und besitzt einen Schmelzpunkt
benen Verfahren erhält manvaus 2-Picolm und Benzo- von 287 bis 289°C (Zersetzung). Die Ausbeute beträgt
phenori Dipheriyl-(2-picolylj-carbinol, das nach der a. a. O. 85%, bezogen auf ursprünglich angewendetes Hydroangegebenen
Weise zu" dem entsprechenden Pipecolyl- chlorid.
derivat reduziert wird. Das" "Diphenyl-(2-pipecölyl)-cär- 40 . - Beispiel 5Analogous to that in section ~ a) ■ of example! Described '' ■■ Alcohol is recrystallized and has a melting point. Processes are obtained from 2-picolm and benzo from 287 to 289 ° C (decomposition). The yield is phenori Dipheriyl- (2-picolylj-carbinol, which according to the loc. Cit. 85%, based on the originally applied Hydrogen amount to "the corresponding pipecolyl chloride.
derivative is reduced. The "" diphenyl- (2-pipecölyl) -car- 40. - Example 5
binol hat einen Schmelzpunkt von 190 bis 1910C. . n,n„-^. , - ,* , , -·· -^- , ■,binol has a melting point of 190 to 191 0 C. n , n "- ^. , -, *, - ·· - ^ -, ■,
2-(p,p-Diphenyl-vinyl)-l-methyl-piperidin-hydro-2- (p, p-diphenyl-vinyl) -l-methyl-piperidine-hydro-
b) 2-(/S,/S-Diphenyl-vinyl).-piperidin-hydrochlorid chldridb) 2 - (/ S, / S-diphenyl-vinyl) .- piperidine hydrochloride chloride
... Eine Lösung von1 4,2 g Diphenyl-(2-pipecolyl)-carbinol Zunächst wird gemäß Beispiel 2 das 2-(/?,/?-Diphenyl-... A solution of 1 4.2 g of diphenyl (2-pipecolyl) carbinol First, according to Example 2, the 2 - (/?, /? - diphenyl
in 50 ecm 85%iger Schwefelsäure wird 3 bis 4 Stunden 45 viny^-piperidin-hydrochlorid'.. hergestellt. Analog der im auf einem Dampfbad erhitzt, die erhaltene" dunkelrote ,. Abschnitt a) von Beispiel 4 angegebenen Verfahrensweise Reaktionsmischung auf Eis gegossen und das Sulfat der wird aus dieser Verbindung das entsprechende 1 -Methyl-. Verbindung als eine braungelbe Substanz abgetrennt. derivat erhalten, das nach Umkristallisieren aus einem Durch Behandlung mit Kaliumhydroxydlösung führt Essigester-Alkohol-Gemisch einen Schmelzpunkt von 192 man dieses Salz in die freie Base über, die ihrerseits mit 50 bis 193° C besitzt-. Die Ausbeute beträgt 33%. -■ Äther extrahiert wird. Anschließend führt. man in die ; _ . . . , .:■·.·..in 50 ecm of 85% sulfuric acid, 45 viny ^ -piperidine hydrochloride is produced for 3 to 4 hours. Analogous to the im heated on a steam bath, the resulting "dark red,. Section a) of Example 4 specified procedure The reaction mixture is poured onto ice and the sulfate is converted into the corresponding 1 -methyl- from this compound. Compound separated as a brownish yellow substance. obtained derivative that after recrystallization from a Treatment with potassium hydroxide solution results in a mixture of ethyl acetate and alcohol having a melting point of 192 this salt is converted into the free base, which in turn has a temperature of 50 to 193 ° C. The yield is 33%. - ■ Ether is extracted. Subsequently leads. one in the; _. . . ,.: ■ ·. · ..
getrocknete Ätherlösung gasförmigen Chlorwasserstoff ,' eispie . ..;;dried ethereal solution, gaseous hydrogen chloride, 'eispie. .. ;;
ein, kristallisiert das gebildete; Hydrochlorid aus Essig- 2-(^,^-Diphenyl-vinyl)-l-methyl-piperidm-brom-a, crystallizes the formed; Hydrochloride from vinegar- 2 - (^, ^ - Diphenyl-vinyl) -l-methyl-piperidm-brom-
ester um, das anschließend'.', einen' Schmelzpunkt von . methylatester, followed by '.', a 'melting point of. methylate
1680C; aufweist. Eine Analyse ergab, daß das gebildete 55 Nach Beispiel 5 wird das Hydrochlorid-des 2-(/3,/3-Di- ^aIz ein Hemi-hydrat ist. Die Ausbeute beträgt 70%. '·. phenyl-vinyl)-1-methyl-piperidins und hieraus die freie •ι;;'-!·-: ..'. . ' -p '·■■'■··- 1.λ■ Base. hergesteUt Eine Lösung derselben in trockenem168 0 C; having. Analysis showed that the formed 55. According to Example 5, the hydrochloride-des 2 - (/ 3, / 3-di- ^ aIz is a hemihydrate. The yield is 70%. '·. Phenyl-vinyl) -1 -methyl-piperidins and from this the free • ι ;; '-! · -: ..'. . '-p' · ■■ '■ ·· - 1.λ ■ Base. A solution of the same in dry
" Äther wird mit überschüssigem Methylbromid behandelt.·"Ether is treated with excess methyl bromide. ·
D bd l hid ihD bd l hid ih
. . Das gebildete quaternäre: Brommethylat scheidet sich. . The quaternary : bromomethylate formed separates
Diphenyl-(2-pipecolyl).-carbinol wird gemäß' Ab- 60 langsam ab. Nach.Umkristallisieren aus einem Gemisch schnitt a) von Beispiel 2 hergestellt. Eine Lösung von von absolutem Alkohol und Äther schmilzt es bei einer 8 g Diphenyl-(2-pipecolyl)-carbinol in 30 g etwa 37%iger Temperatur von 214 bis 2150C unter Zersetzung. Die Formaldehydlösung und 18^g Ameisensäure wird über Ausbeute beträgt 57%, bezogen auf ursprünglich ange-N.acht unter Rückfluß erhitzt,.anschließend verdünnte wendetes Hydrochlorid. ,..Diphenyl- (2-pipecolyl) .- carbinol is slowly reduced according to 'Ab- 60. After recrystallization from a mixture cut a) from Example 2 produced. A solution of absolute alcohol and ether, it melts at a 8 g of diphenyl (2-pipecolyl) carbinol in 30 g of about 37% temperature 214-215 0 C with decomposition. The formaldehyde solution and 18 ^ g of formic acid are refluxed over a yield of 57%, based on the originally applied N., then diluted hydrochloride. , ..
Salzsäure zugegeben und die Lösung unter vermindertem 65 ' ; _ . ·■ ■{η Hydrochloric acid added and the solution under reduced 65 '; _. · ■ ■ {η
fJruck eingeengt. .Durch Zugabe von 40%iger Kalium- . " ·,fJruck narrowed. .By adding 40% potassium. "·,
hydroxydlösung zu dem dickflüssigen Rest wird die freie, 2-(/3,/S-Diphenyl-vinyl)-l-methyl-piperidin-]od-hydroxide solution to the viscous residue is the free, 2 - (/ 3, / S-diphenyl-vinyl) -l-methyl-piperidine-] or
Basei;erhalten, ■ die in einer.:Äther-Chloroform-Mischung methylatBase i; obtained, ■ the methylate in a.: ether-chloroform mixture
aufgenommen wird.Näch Verdampfen des Lösungsmittels 2-(/3,/3-Diphenyl^vinyl)-l-methyl-piperidin wird, wie imAfter evaporation of the solvent 2 - (/ 3, / 3-Diphenyl ^ vinyl) -l-methyl-piperidine, as in
erhält man die Base, die mau durch Behandeln mit einer 70 Beispiel 6 angegeben, hergestellt. Eine Lösung dieserthe base is obtained which is prepared by treating with an example 6. A solution to this
Base in trockenem Äther wird mit überschüssigem Methyljodid behandelt, wobei sich ein in Äther unlösliches quaternäres Jodmethylat bildet, das nach Umkristallisieren aus absolutem Alkohol einen Schmelzpunkt von 224 bis 2250C (Zersetzung) aufweist. Die Ausbeute beträgt 63°/0, bezogen auf ursprünglich angewendetes Hydrochlorid. .. ' ,' V ' . ..Base in dry ether is treated with excess methyl iodide, forming an insoluble in ether quaternary Jodmethylat, which has a melting point of 224-225 0 C (decomposition) after recrystallization from absolute alcohol. The yield is 63 ° / 0, based on originally-applied hydrochloride. .. ',' V '. ..
. ■'''Die substituierten Aryl-, Alkyl-, Cycloalkyl- und heterocyclischen Derivate der weiter oben bezeichneten Piper1 idinverbindungen sind in einfacher Weise durch Wasserabspaltung aus den symmetrischen oder unsymmetrischen substituierten Pipecolylcarbinolen nach dem im Beispiel l,b) beschriebenen Verfahren zu gewinnen. So können durch Behandeln von p-Chlorphenyl-phenyl-(4-pipecolyl)-carbinol, Di-(p-chlorphenyl)-(4-pipecolyl)-carbinol, (2-Thienyl)-phenyl-(4-pipecolyl)-carbinol, n-Butyl-phenyl - (4 - pipecolyl) - carbinol, Cyclohexyl - phenyl - (4 - pipecolyl) - carbinol und 9 - (4 - Pipecolyl) - 9 - fluorenol mit 85°/0iger Schwefelsäure die folgenden ungesättigten freien Basen 4 - [ß - (p - Chlorphenyl) -ß - phenyl - vinyl] - piperidin, 4-[^,^-Di-(p-chlorphenyl)-vinyl]-piperidin, 4-[β-(2-Thienyl) -/S-phenyl-vinyl] -piperidin, 4- [β- (η-Butyl) -/5-phenylvinyl] -piperidin, 4- (^-Cyclohexyl-jff-phenyl-vinyl)-piperidin und 4-(9-Fluorenyliden-methyl)-piperidin in guter Ausbeute erhalten werden.. ■ '''The substituted aryl, alkyl, cycloalkyl and heterocyclic derivatives of the piper 1 idine compounds identified above can be obtained in a simple manner by splitting off water from the symmetrical or asymmetrical substituted pipecolyl carbinols by the method described in Example 1, b). By treating p-chlorophenyl-phenyl- (4-pipecolyl) -carbinol, di- (p-chlorophenyl) - (4-pipecolyl) -carbinol, (2-thienyl) -phenyl- (4-pipecolyl) -carbinol , n-butyl-phenyl - (4 - pipecolyl) - carbinol, cyclohexyl - phenyl - (4 - pipecolyl) - carbinol and 9 - (4 - pipecolyl) - 9 - fluorenol with 85 ° / 0 sulfuric acid the following unsaturated free bases 4 - [ß - (p - chlorophenyl) -ß - phenyl - vinyl] - piperidine, 4 - [^, ^ - di- (p-chlorophenyl) vinyl] piperidine, 4- [β- (2-thienyl) - / S-phenyl-vinyl] -piperidine, 4- [β- (η-butyl) - / 5-phenylvinyl] -piperidine, 4- (^ -Cyclohexyl-jff-phenyl-vinyl) -piperidine and 4- (9 -Fluorenylidenemethyl) piperidine can be obtained in good yield.
Diese ungesättigten Basen können in einfacher Weise am N-Atom methyliert werden, indem man ihre Hydrochloride mit etwa 37°/0iger Formaldehydlösung und Ameisensäure analog der im Abschnitt a) von Beispiel 4 angegebenen Weise behandelt und in die N-Methylderivate, nämlich 4-[/?-(p-Chlorphenyl)-/?-phenyl-vinyl]-l-methyl - piperidin, 4-[ß,ß-Di-(p- chlorphenyl) - vinyl] -1 - methyl-piperidin, 4-[/?-(2-Thienyl)-β-phenyl-vinyl]-1 -methyl-piperidin, 4-[^-(n-Butyl)-jS-phenyl-vinyl]-l-methylpiperidin, 4 - [ß - Cyclohexyl -β- phenyl - vinyl] -1 - methylpiperidin und 4-(Fluorenyliden-methyl)-l-methyl-piperidin, überführt.These unsaturated bases may be methylated by analogous their hydrochlorides with about 37 ° / 0 solution of formaldehyde and formic acid of the manner specified in paragraph a) of Example 4 treated and in a simple manner at the N atom in the N-methyl derivatives, namely 4- [/? - (p-chlorophenyl) - /? - phenyl-vinyl] -l-methyl-piperidine, 4- [ß, ß-di- (p- chlorophenyl) - vinyl] -1 - methyl-piperidine, 4- [/? - (2-Thienyl) -β-phenyl-vinyl] -1-methyl-piperidine, 4 - [^ - (n-Butyl) -jS-phenyl-vinyl] -l-methylpiperidine, 4 - [ß - Cyclohexyl- β- phenyl-vinyl] -1-methylpiperidine and 4- (fluorenylidene-methyl) -l-methyl-piperidine, transferred.
Die 2- und 3-Isomeren dieser disubstituierten Vinylpiperidine sowie die disubstituierten Vinyl-1-methylpiperidine werden in analoger Weise wie die 4-Isomeren aus den entsprechenden 2- bzw. 3-Isomeren hergestellt.The 2- and 3-isomers of these disubstituted vinyl piperidines and the disubstituted vinyl-1-methylpiperidines are prepared in a manner analogous to the 4-isomers from the corresponding 2- or 3-isomers.
Die quaternären Ammoniumsalze der 2-, 3- und 4-Isomeren der disubstituierten Piperidine werden entweder analog dem in den Beispielen 4, 6 oder 7 angegebenen Verfahren oder nach irgendeiner anderen üblichen Methode gebildet.The quaternary ammonium salts of the 2-, 3- and 4-isomers the disubstituted piperidines are given either analogously to that in Examples 4, 6 or 7 Process or any other conventional method.
Die nach dem Verfahren der Erfindung hergestellten Verbindungen weisen wertvolle j£asmojyjtische__ Eigenschaften bei Spasmen der glatten Muskulatur auf. Als besonders wirksam haben sich die Verbindungen erwiesen, die in 2- oder 4-Stellung des Piperidinkerns den substituierten Vinylrest tragen. Diese Verbindungen — unter ihnen insbesondere das l,l-Dimethyl-4-(/?,/J-diphenylvinyl)-piperidinium.bromid — stellen starke ^Anticholinr ergjca mit starker selektiver Einwirkung auf die motorischen und sekretorischen Funktionen des gastrointestinalen Traktes dar, worin sie den l-Alkyl-3-benzhydryliden-piperidinen überlegen sind. Im Gegensatz zu letzteren Verbindungen üben die Erzeugnisse des erfindungsgemäßen Verfahrens bei intravenöser Applikation auf die Herzfrequenz keine Nebenwirkungen aus.The compounds prepared by the process of the invention have valuable jasmojyjtische__ properties in spasms of the smooth muscles. The compounds which have the substituted vinyl radical in the 2- or 4-position of the piperidine nucleus have proven to be particularly effective. These compounds - among them in particular the l, l-dimethyl-4 - (/?, / J-diphenylvinyl) -piperidinium.bromid - represent strong anticholine r ergjca with a strong selective effect on the motor and secretory functions of the gastrointestinal tract, in which they are superior to the 1-alkyl-3-benzhydrylidenepiperidines. In contrast to the latter compounds, the products of the method according to the invention have no side effects on the heart rate when administered intravenously.
Es wurde gefunden, daß die gemäß Erfindung hergestellten Verbindungen in Form ihrer Salze, d. h. ihrer Säureadditionssalze und quaternären Salze, in Wasser gewöhnlich mehr löslich sind als die freien Basen. Daher ist eine Applikation in Salzform besonders geeignet, wenn eine schnelle Wirksamkeit erwünscht ist. Jede Säure, die zur Bildung wasserlöslicher Salze befähigt ist und die toxischen Eigenschaften nicht wesentlich erhöht, kann zur Salzherstellung verwendet werden. Die wenig löslichen Salze sowie die freien Basen werden gewöhnlich dann angewandt, wenn der gewünschte' pharmakologische Effekt langsam eintreten und verhältnismäßig lang sein soll; Die Verbindungen können auch in üblicher Weise in die entsprechenden quaternären Ammoniumsalze, wie ihre Brom- und Jodmethylate, übergeführt werden. An Stelle von Methylbromid und Methyl] odid kann auch zur Bildung der quaternären Ammoniumsalze Methylsulfat, Methyl-p-tolyl-sulfat, Behzylbromid oder Äthyl-ίο chlorid verwendet werden. Es wurde gefunden, daß die quaternären Ammoniumsalze der oben bezeichneten substituierten Vinylpiperidine eine sehr starke Aktivität besitzen und im allgemeinen wirksamer als die entsprechenden tertiären Amine sind.It has been found that the compounds prepared according to the invention in the form of their salts, i.e. H. of their Acid addition salts and quaternary salts, are usually more soluble in water than the free bases. Therefore application in salt form is particularly suitable when rapid effectiveness is desired. Any acid that is capable of forming water-soluble salts and does not significantly increase the toxic properties used to make salt. The sparingly soluble salts as well as the free bases are usually then used when the desired 'pharmacological effect occurs slowly and be relatively long target; The compounds can also be converted into the corresponding quaternary ammonium salts, such as their bromine and iodine methylates are converted. Instead of methyl bromide and methyl] odide can also for the formation of the quaternary ammonium salts methyl sulfate, methyl p-tolyl sulfate, behzyl bromide or ethyl ίο chloride can be used. The quaternary ammonium salts were found to be substituted for those identified above Vinylpiperidines have a very strong activity and are generally more effective than their counterparts tertiary amines are.
Claims (2)
Xi-Q/x-Qx
Xi-Q /
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1188403XA | 1952-04-03 | 1952-04-03 |
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| Publication Number | Publication Date |
|---|---|
| DE1049377B true DE1049377B (en) | 1959-01-29 |
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ID=22381039
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DENDAT1049377D Pending DE1049377B (en) | 1952-04-03 | Process for the preparation of substituted vinyl piperidines |
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| FR (1) | FR1188403A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2168851A1 (en) * | 1972-01-24 | 1973-09-07 | Synthelabo | 2-substituted propyl-1-methyl piperidines - bronchodilators and spasmolytics |
| GB9000305D0 (en) * | 1990-01-06 | 1990-03-07 | Pfizer Ltd | Anticholinergic agents |
| NZ249040A (en) * | 1992-02-06 | 1997-06-24 | Merrell Dow Pharma | Triphenyl azacycloalkane derivatives; treatment of drug resistance |
| KR100377280B1 (en) * | 1993-01-21 | 2003-07-18 | 메렐 파마슈티칼스 인크. | Multi-drug resistant tumor therapeutic efficacy-enhancing pharmaceutical composition containing diarylalkylpiperidine |
| US5670521A (en) * | 1994-08-05 | 1997-09-23 | Merrell Pharmaceuticals Inc. | Reversal of multi-drug resistance by triphenyl-azacycloalkane derivatives |
-
0
- DE DENDAT1049377D patent/DE1049377B/en active Pending
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