CH534681A - 4-benzoyl-3-phenyl-4-piperidinol derivs - with hypolipaemic properties - Google Patents
4-benzoyl-3-phenyl-4-piperidinol derivs - with hypolipaemic propertiesInfo
- Publication number
- CH534681A CH534681A CH202471A CH202471A CH534681A CH 534681 A CH534681 A CH 534681A CH 202471 A CH202471 A CH 202471A CH 202471 A CH202471 A CH 202471A CH 534681 A CH534681 A CH 534681A
- Authority
- CH
- Switzerland
- Prior art keywords
- benzoyl
- hydroxy
- phenylpiperidine
- acid
- formula
- Prior art date
Links
- NKEJNNRTXMYMTR-UHFFFAOYSA-N (4-hydroxy-3-phenylpiperidin-4-yl)-phenylmethanone Chemical compound C(C1=CC=CC=C1)(=O)C1(C(CNCC1)C1=CC=CC=C1)O NKEJNNRTXMYMTR-UHFFFAOYSA-N 0.000 title abstract description 5
- 230000000055 hyoplipidemic effect Effects 0.000 title abstract description 3
- 239000002253 acid Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 150000002148 esters Chemical class 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 11
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- LLSKXGRDUPMXLC-UHFFFAOYSA-N 1-phenylpiperidine Chemical class C1CCCCN1C1=CC=CC=C1 LLSKXGRDUPMXLC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229940051803 opioid analgesics phenylpiperidine derivative Drugs 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- -1 benzoyl-1-methyl-3-phenylpiperidine hydrobromide Chemical compound 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- GADCSODZDASQJN-UHFFFAOYSA-N (4-hydroxy-1-methyl-3-phenylpiperidin-4-yl)-phenylmethanone Chemical compound C(C1=CC=CC=C1)(=O)C1(C(CN(CC1)C)C1=CC=CC=C1)O GADCSODZDASQJN-UHFFFAOYSA-N 0.000 description 3
- VHHAMVPFHQZXNQ-UHFFFAOYSA-N ethyl 4-acetyloxy-4-benzoyl-3-phenylpiperidine-1-carboxylate Chemical compound CCOC(=O)N1CCC(OC(C)=O)(C(C1)C1=CC=CC=C1)C(=O)C1=CC=CC=C1 VHHAMVPFHQZXNQ-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- PYNBGTIFODDTRW-UHFFFAOYSA-N (4-benzoyl-1-methyl-3-phenylpiperidin-4-yl) acetate Chemical compound CN1CCC(OC(C)=O)(C(C1)C1=CC=CC=C1)C(=O)C1=CC=CC=C1 PYNBGTIFODDTRW-UHFFFAOYSA-N 0.000 description 2
- JUYSZZMOSLZFCF-UHFFFAOYSA-N (4-bromo-1-methyl-3-phenylpiperidin-4-yl)-phenylmethanone hydrobromide Chemical compound Br.C(C1=CC=CC=C1)(=O)C1(C(CN(CC1)C)C1=CC=CC=C1)Br JUYSZZMOSLZFCF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- BLAJMHVJUDNHAR-UHFFFAOYSA-N Cl.C(C1=CC=CC=C1)(=O)C1(C(CNCC1)C1=CC=CC=C1)O Chemical compound Cl.C(C1=CC=CC=C1)(=O)C1(C(CNCC1)C1=CC=CC=C1)O BLAJMHVJUDNHAR-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- AIUGCCRGGIRXQC-UHFFFAOYSA-N (1-methyl-3-phenylpiperidin-4-yl)-phenylmethanone Chemical compound C1N(C)CCC(C(=O)C=2C=CC=CC=2)C1C1=CC=CC=C1 AIUGCCRGGIRXQC-UHFFFAOYSA-N 0.000 description 1
- QZNMGHHMQOWYCW-UHFFFAOYSA-N (1-methyl-3-phenylpiperidin-4-yl)-phenylmethanone hydrobromide Chemical compound Br.C(C1=CC=CC=C1)(=O)C1C(CN(CC1)C)C1=CC=CC=C1 QZNMGHHMQOWYCW-UHFFFAOYSA-N 0.000 description 1
- OGWAWDBXBGRLEQ-UHFFFAOYSA-N (4-bromo-1-methyl-3-phenylpiperidin-4-yl)-phenylmethanone Chemical compound C(C1=CC=CC=C1)(=O)C1(C(CN(CC1)C)C1=CC=CC=C1)Br OGWAWDBXBGRLEQ-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- UZWXYEHTFDWCIS-UHFFFAOYSA-N 3-chloro-n-methylpropanamide Chemical compound CNC(=O)CCCl UZWXYEHTFDWCIS-UHFFFAOYSA-N 0.000 description 1
- QEYMMOKECZBKAC-UHFFFAOYSA-N 3-chloropropanoic acid Chemical compound OC(=O)CCCl QEYMMOKECZBKAC-UHFFFAOYSA-N 0.000 description 1
- IPLKGJHGWCVSOG-UHFFFAOYSA-N 4-chlorobutanoic acid Chemical compound OC(=O)CCCCl IPLKGJHGWCVSOG-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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007900 aqueous suspension Substances 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
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- GKMQAGZRPQBLHG-UHFFFAOYSA-N ethyl 1-methyl-3,6-dihydro-2h-pyridine-4-carboxylate Chemical compound CCOC(=O)C1=CCN(C)CC1 GKMQAGZRPQBLHG-UHFFFAOYSA-N 0.000 description 1
- ZCLGVXACCAZJOX-UHFFFAOYSA-N ethyl 3-chloropropanoate Chemical compound CCOC(=O)CCCl ZCLGVXACCAZJOX-UHFFFAOYSA-N 0.000 description 1
- OPXNFHAILOHHFO-UHFFFAOYSA-N ethyl 4-chlorobutanoate Chemical compound CCOC(=O)CCCCl OPXNFHAILOHHFO-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- 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
- C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/38—Halogen atoms or nitro radicals
-
- 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
- C07D211/30—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—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 doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen 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
- C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
- C07D211/50—Aroyl radical
-
- 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
- C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Title derivs of formula (I) (where n is 1,2,3 or 4 and R is OH, lower alkoxy NH2, or mono- or disubstd. amino) and their acid addn salts are prepd. by reacting 4-benzoyl-3-phenyl-4-piperidinol with a cpd. Y-(CH2)n-COR (where Y is the acid residue of a reactive ester gp) and opt. converting the prodt. into an acid addn salt. (I) have the same pharmacodynamic (esp. hypolipaemic) properties as the cpds. described in the parent patent.
Description
Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung neuer Phenylpiperidinderivate der Formel I, worin n eine ganze Zahl von 1-4 bedeutet und R für die Hydroxy-, eine niedere Alkoxygruppe, die Aminogruppe oder eine durch niedere Alkylgruppen mono- oder disubstituierte Aminogruppe steht, und ihrer Säureadditionssalze.
Die in dem Rest R enthaltenen niederen Alkylgruppen bestehen vorzugsweise aus 1-3 Kohlenstoffatomen und bedeuten insbesondere die Methylgruppe.
Erfindungsgemäss gelangt man zu den neuen Verbindungen der Formel I, indem man die Verbindung der Formel II, mit Verbindungen der Formel III, worin n und R obige Bedeutung besitzen und Y für den Säurerest eines reaktionsfähigen Esters steht, umsetzt und gewünschtenfalls die erhaltenen Verbindungen der Formel I in ihre Säureadditionssalze überführt.
Das Verfahren kann z. B. wie im Hauptpatent beschrieben, ausgeführt werden.
Auch die Ausgangsprodukte werden wie im Hauptpatentgesuch beschrieben erhalten. Weiters haben die Verbindungen der Formel I die gleichen pharmakodynamischen, insbesondere hypolipämischen Eigenschaften wie die im Hauptpatentgesuch beschriebenen Verbindungen der Formel I und können daher in gleicher Weise verwendet werden.
In den nachfolgenden Beispielen, die die Erfindung näher erläutern, ihren Umfang aber in keiner Weise einschränken sollen, erfolgen alle Temperaturangaben in Celsiusgraden.
Beispiel 1 5- (4-Benzoyl-4-hydroxy-3-phenylpiperidino) - essigsäuremethylester
Die Suspension von 15,8 g 4-Benzoyl-4-hydroxy-3-phenylpiperidinhydrochlorid und 17,3 g Kaliumcarbonat in 160 ml Dimethylformamid wird unter Rühren bei 600 tropfenweise mit der Lösung von 7,3 g Chloressigsäuremethylester in 20 ml Dimethylformamid versetzt. Man lässt 15 Stunden bei 1000 reagieren, verdünnt darauf mit 500 ml Benzol und extrahiert wiederholt mit Wasser. Die über Magnesiumsulfat getrocknete Benzolphase wird eingedampft und der Rückstand nach Lösen in Äthanol durch Zugabe der berechneten Menge äthanolischer Fumarsäurelösung in das Fumarat übergeführt. Nach einer Umkristallisation des ausfallenden Rohproduktes aus Aceton/Äther erhält man das reine Fumarat der Titelverbindung. Smp. 84-9Oo.
Das Ausgangsprodukt kann folgendermassen erhalten werden: a) 4-Benzoyl- 1-methyl-3 -phenylpiperidin
10,1 g Magnesium werden mit 20 ml abs. Tetrahydrofuran überschichtet und mit einigen Kristallen Jod und 0,5 ml Äthylenbromid abgeätzt. Dann tropft man eine Lösung von 65,0 g Brombenzol in 80 ml abs. Tetrahydrofuran so zu, dass die Reaktion im Gang bleibt. Das Reaktionsgemisch wird anschliessend noch 2 Stunden am Rückfluss gekocht, auf 5O abgekühlt und bei dieser Temperatur mit einer Lösung von 30,0 g 1-Methyl-1 ,2,3,6-tetrahydroisonicotinsäureäthylester in 50 ml abs. Tetrahydrofuran innerhalb von 15-20 Minuten versetzt. Man erwärmt das Gemisch 30 Minuten zum Sieden, kühlt es auf 100 ab und giesst es unter gutem Rühren in eine Lösung von 60 g Ammoniumchlorid in 400 ml Eiswasser.
Die erhaltene wässerige Suspension wird mehrmals mit Methylenchlorid extrahiert und das Extrakt mit 2N Salzsäurelösung ausgeschüttelt. Die sauren Lösungen werden unter Kühlen mit konz. Natronlauge alkalisch gestellt, mit Methylenchlorid extrahiert und die Extrakte über Kaliumkarbonat getrocknet und unter vermindertem Druck eingedampft. Der Rückstand wird am Hochvakuum destilliert, wobei zuerst 1-Methyl-3phenyl-isonipecotinsäure-äthylester vom Sdp. 100-1100/0,05 Torr als Vorlauf übergeht und dann das 4-Benzoyl-1-methyl3-phenylpiperidin bei etwa 165-180q0,05 mm Hg. Durch Zugabe von Bromwasserstoff zur freien Base erhält man 4 Benzoyl-1-methyl-3-phenylpiperidin-hydrobromid vom Smp.
243-2440 (Zers.).
b) 4-Benzoyl-4-brom- 1 -methyl-3-phenylpiperidin
Die Lösung von 165,7 g 4-Benzoyl-1-methyl-3-phenylpiperi- dinhydrobromid in 1700 ml Eisessig wird bei 100o innerhalb von 5 Stunden mit 147 g Brom versetzt, worauf man den Ansatz noch eine Stunde bei derselben Temperatur weiterrührt. Man lässt das Reaktionsgemisch über Nacht bei Raumtemperatur stehen, dampft es dann unter vermindertem Druck bei 600 ein und versetzt den Rückstand mit Aceton. Nach Auskristallisierenlassen im Kühlschrank erhält man das reine 4-Benzoyl-4-brom- 1-methyl 3-phenylpiperidin-hydrobromid vom Smp. 163-1640 (leichte Zers.).
c) 4-Benzoyl-4-hydroxy-1-methyl-3-phenylpiperidin
Eine Lösung von 23,3 g Natrium in 700 ml Methanol wird unter Eiskühlung portionenweise mit 148,4 g 4-Benzoyl-4 brom-1-methyl-3-phenylpiperidin-hydrobromid versetzt. Man lässt während 22 Stunden bei Raumtemperatur rühren und versetzt darauf das Reaktionsgemisch tropfenweise mit konzentrierter Salzsäure bis zur kongosauren Reaktion. Man rührt noch 15 Minuten weiter und dampft dann das Methanol unter vermindertem Druck bei 600 ab. Der Rückstand wird mit 20 %iger Kaliumkarbonatlösung versetzt, worauf man mehrmals mit Chloroform extrahiert. Die vereinigten Chloroformextrakte werden über Magnesiumsulfat getrocknet, filtriert und unter vermindertem Druck bis zur beginnenden Kristallisation eingeengt.
Man lässt über Nacht im Kühlschrank stehen und erhält das reine 4-Benzoyl-4-hydroxy- 1 -methyl-3-phenylpiperidin vom Smp. 1671690.
d) 4-Acetoxy-4-benzoyl- 1 -methyl-3-phenylpiperidin
197,4 g 4-Benzoyl-4-hydroxy-1 -methyl-3-phenylpiperidin werden in 2 000 ml Essigsäureanhydrid bei 90o gelöst und langsam auf 1600 erhitzt. Man kühlt das Reaktionsgemisch auf ca. 1000 ab und entfernt das überschüssige Essigsäureanhydrid durch Destillation im Wasserstrahlvakuum. Der verbleibende zähflüssige Rückstand wird in Chloroform aufgenommen und mit kalter verdünnter Natriumhydroxydlösung ausgeschüttelt.
Man trocknet die organische Schicht über Magnesiumsulfat, dampft das Lösungsmittel unter vermindertem Druck ab und kristallisiert den verbleibenden Rückstand einmal aus ca.
2 000 ml Äthanol um. Man erhält das reine 4-Acetoxy-4-benzoyl- 1 -methyl-3-phenylpiperidin vom Smp. 158-159o.
e) 4-Acetoxy-4-benzoyl-3 -phenylpiperidincarbon- säureäthylester
Eine Lösung von 206,7 g 4-Acetoxy-4-benzo-yl-1-methyl-3- phenylpiperidin in 2 000 ml abs. Benzol wird mit 392 ml Chlorameisensäureäthylester versetzt und das Reaktionsgemisch unter Rühren während 16 Stunden zum Sieden erhitzt.
Man extrahiert anschliessend 3 mal mit Wasser, trocknet die organische Phase über Magnesiumsulfat und dampft zur Trockne ein. Nach Kristallisation des Rückstandes aus Benzol erhält man den reinen 4-Acetoxy-4-benzoyl-3 - phenylpiperidincarbonsäureäthylester vom Smp. 125-1260.
f) 4-Benzoyl-4-hydroxy-3 -phenylpiperidin
216,1 g 4-Acetoxy-4-benzoyl-3phenylpiperidincarbonsäureäthylester werden in einem Gemisch von 1500 ml konzentrierter Salzsäure und 500 ml Wasser suspendiert und unter Rühren wäh rend 72 Stunden zum Sieden erhitzt. Man filtriert das nach dem Abkühlen des Reaktionsgemisches ausfallende Produkt ab, kristallisiert einmal aus Athanol um und erhält das reint 4-Benzoyl-4-hydroxy-3phenylpiperidin-hydrochlorid vom Smp. 236-2370.
Beispiel 2
4-(4-Benzoyl-4-hydroxy-3 phenylpiperidino)buttersäureäthylester 4-Benzoyl-4-hydroxy-3-phenylpiperidin-hydrochlorid wird mit 4-Chlorbuttersäureäthylester nach dem in Beispiel 1 beschriebenen Verfahren umgesetzt. Reaktionszeit 15 Stunden bei 100 . Smp. des Hydrogenfumarats der Titelverbindung 142-1440 (aus Aceton/Äther).
Beispiel 3
4-(4-Benzoyl-4-hydroxy-3 phenylpiperidino)buttersäure 4-Benzoyl-4-hydroxy-3-phenylpiperidin-hydrochlorid wird mit 4-Chlorbuttersäure nach dem in Beispiel 1 beschriebenen Verfahren umgesetzt. Reaktionszeit 15 Stunden bei 1000. Smp.
der Titelverbindung 216-2220 (aus Methanol/Wasser).
Beispiel 4
2-(4-Benzoyl-4-hydroxy-3 phenylpiperidino)essigsäure
4-Benzoyl-4-hydroxy-3-phenylpiperidin-hydrochlorid wird mit Chloressigsäure nach dem in Beispiel 1 beschriebenen Verfahren umgesetzt. Reaktionszeit 15 Stunden bei 1000. Smp.
2182210 (aus Methanol/Wasser).
Beispiel 5
2-(4-Benzoyl-4-hydroxy-3 phenylpiperidino) acetamid 4-Benzoyl-4-hydroxy-3 -phenylpiperidin-hydrochlorid wird mit Chloracetamid nach dem in Beispiel 1 beschriebenen Verfahren umgesetzt. Reaktionszeit 15 Stunden bei 1000. Smp.
der Titelverbindung 182-1850 (aus Methanol).
Beispiel 6
3 -(4-Benzoyl-4-hydroxy-3 phenylpiperidino)propionsäureäthylester
4-Benzoyl-4-hydroxy-3-phenylpiperidin wird mit 3-Chlorpropionsäureäthylester nach dem in Beispiel 1 beschriebenen Verfahren umgesetzt. Smp. des Hydrochlorids der Titelverbindung 205-2060 (aus Äthanol).
Beispiel 7
3-(4-Benzoyl-4-hydroxy-3 phenylpiperidinozpropionsäure
4-Benzoyl-4-hydroxy-3-phenylpiperidin wird mit 3-Chlorpropionsäure nach dem in Beispiel 1 beschriebenen Verfahren umgesetzt. Smp. des Hydrochlorids der Titelverbindung 178179,50 (aus Wasser).
Beispiel 8 3-(4-B enzoyl-4-hydroxy-3- phenylpiperidino) -N-methyl-propionamid
4-Benzoyl-4-hydroxy-3-phenylpiperidin wird mit 3-Chlorpropionsäure-N-methylamid nach dem in Beispiel 1 beschriebenen Verfahren umgesetzt. Smp. der Titelverbindung 1931960 (aus Methanol).
Beispiel 9
3-(4-Benzoyl-4-hydroxy-3 phenylpiperidino) -N-diäthylpropionamid
4-Benzoyl-4-hydroxy-3-phenylpiperidin wird mit 3-Chlorpropionsäure-N-diäthylamid nach dem in Beispiel 1 beschriebenen Verfahren umgesetzt. Smp. des Hydrochlorid-monohydrats der Titelverbindung 110-115o (aus Wasser).
EMI2.1
Y-(CH2)n-COR III
The present invention relates to a process for the preparation of new phenylpiperidine derivatives of the formula I in which n is an integer from 1-4 and R is the hydroxy, a lower alkoxy group, the amino group or an amino group mono- or disubstituted by lower alkyl groups, and their acid addition salts.
The lower alkyl groups contained in the radical R preferably consist of 1-3 carbon atoms and are in particular the methyl group.
According to the invention, the new compounds of the formula I are obtained by reacting the compound of the formula II with compounds of the formula III in which n and R have the above meaning and Y stands for the acid radical of a reactive ester, and if desired the compounds of the formula obtained I converted into their acid addition salts.
The method can e.g. B. as described in the main patent.
The starting products are also obtained as described in the main patent application. Furthermore, the compounds of the formula I have the same pharmacodynamic, in particular hypolipemic properties as the compounds of the formula I described in the main patent application and can therefore be used in the same way.
In the following examples, which explain the invention in greater detail but are not intended to limit its scope in any way, all temperatures are given in degrees Celsius.
Example 1 5- (4-Benzoyl-4-hydroxy-3-phenylpiperidino) -acetic acid methyl ester
The suspension of 15.8 g of 4-benzoyl-4-hydroxy-3-phenylpiperidine hydrochloride and 17.3 g of potassium carbonate in 160 ml of dimethylformamide is added dropwise with a solution of 7.3 g of methyl chloroacetate in 20 ml of dimethylformamide while stirring at 600. The mixture is left to react for 15 hours at 1000, then diluted with 500 ml of benzene and extracted repeatedly with water. The benzene phase, dried over magnesium sulfate, is evaporated and the residue, after dissolving in ethanol, is converted into the fumarate by adding the calculated amount of ethanolic fumaric acid solution. After recrystallization of the precipitating crude product from acetone / ether, the pure fumarate of the title compound is obtained. M.p. 84-90o.
The starting product can be obtained as follows: a) 4-Benzoyl-1-methyl-3-phenylpiperidine
10.1 g of magnesium are combined with 20 ml of abs. Tetrahydrofuran covered and etched with a few crystals of iodine and 0.5 ml of ethylene bromide. A solution of 65.0 g of bromobenzene in 80 ml of abs is then added dropwise. Tetrahydrofuran so that the reaction continues. The reaction mixture is then refluxed for a further 2 hours, cooled to 50 and at this temperature with a solution of 30.0 g of ethyl 1-methyl-1,2,3,6-tetrahydroisonicotinate in 50 ml of abs. Tetrahydrofuran is added within 15-20 minutes. The mixture is heated to boiling for 30 minutes, cooled to 100 and poured into a solution of 60 g of ammonium chloride in 400 ml of ice water with thorough stirring.
The aqueous suspension obtained is extracted several times with methylene chloride and the extract is extracted with 2N hydrochloric acid solution. The acidic solutions are cooled with conc. Sodium hydroxide solution made alkaline, extracted with methylene chloride and the extracts dried over potassium carbonate and evaporated under reduced pressure. The residue is distilled in a high vacuum, first 1-methyl-3-phenyl-isonipecotinic acid-ethyl ester with a bp. 05 mm Hg. By adding hydrogen bromide to the free base, 4 benzoyl-1-methyl-3-phenylpiperidine hydrobromide of melting point is obtained.
243-2440 (dec.).
b) 4-Benzoyl-4-bromo-1-methyl-3-phenylpiperidine
147 g of bromine are added to the solution of 165.7 g of 4-benzoyl-1-methyl-3-phenylpiperidine hydrobromide in 1700 ml of glacial acetic acid at 100 ° over the course of 5 hours, whereupon the batch is stirred for a further hour at the same temperature. The reaction mixture is left to stand overnight at room temperature, it is then evaporated under reduced pressure at 600 and the residue is treated with acetone. After allowing to crystallize in the refrigerator, pure 4-benzoyl-4-bromo-1-methyl-3-phenylpiperidine hydrobromide with a melting point of 163-1640 (slight decomposition) is obtained.
c) 4-Benzoyl-4-hydroxy-1-methyl-3-phenylpiperidine
A solution of 23.3 g of sodium in 700 ml of methanol is added in portions with 148.4 g of 4-benzoyl-4-bromo-1-methyl-3-phenylpiperidine hydrobromide while cooling with ice. The mixture is left to stir for 22 hours at room temperature and then concentrated hydrochloric acid is added dropwise to the reaction mixture until the reaction is Congo acidic. The mixture is stirred for a further 15 minutes and then the methanol is evaporated off at 600 ° under reduced pressure. The residue is mixed with 20% strength potassium carbonate solution, whereupon it is extracted several times with chloroform. The combined chloroform extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure until crystallization begins.
It is left to stand in the refrigerator overnight and pure 4-benzoyl-4-hydroxy-1-methyl-3-phenylpiperidine with a melting point of 1671690 is obtained.
d) 4-acetoxy-4-benzoyl-1-methyl-3-phenylpiperidine
197.4 g of 4-benzoyl-4-hydroxy-1-methyl-3-phenylpiperidine are dissolved in 2000 ml of acetic anhydride at 90 ° and slowly heated to 1600. The reaction mixture is cooled to about 1000 and the excess acetic anhydride is removed by distillation in a water-jet vacuum. The remaining viscous residue is taken up in chloroform and extracted with cold, dilute sodium hydroxide solution.
The organic layer is dried over magnesium sulfate, the solvent is evaporated off under reduced pressure and the remaining residue is crystallized once from approx.
2,000 ml of ethanol. Pure 4-acetoxy-4-benzoyl-1-methyl-3-phenylpiperidine with a melting point of 158-159o is obtained.
e) 4-Acetoxy-4-benzoyl-3-phenylpiperidinecarboxylic acid ethyl ester
A solution of 206.7 g of 4-acetoxy-4-benzo-yl-1-methyl-3-phenylpiperidine in 2,000 ml of abs. Benzene is mixed with 392 ml of ethyl chloroformate and the reaction mixture is heated to the boil for 16 hours while stirring.
It is then extracted 3 times with water, the organic phase is dried over magnesium sulfate and evaporated to dryness. After crystallization of the residue from benzene, the pure ethyl 4-acetoxy-4-benzoyl-3-phenylpiperidinecarboxylate with a melting point of 125-1260 is obtained.
f) 4-Benzoyl-4-hydroxy-3-phenylpiperidine
216.1 g of 4-acetoxy-4-benzoyl-3phenylpiperidinecarboxylic acid ethyl ester are suspended in a mixture of 1500 ml of concentrated hydrochloric acid and 500 ml of water and heated to boiling with stirring during 72 hours. The product which precipitates out after the reaction mixture has cooled is filtered off, recrystallized once from ethanol, and pure 4-benzoyl-4-hydroxy-3phenylpiperidine hydrochloride with a melting point of 236-2370 is obtained.
Example 2
4- (4-Benzoyl-4-hydroxy-3 phenylpiperidino) butyric acid ethyl ester 4-Benzoyl-4-hydroxy-3-phenylpiperidine hydrochloride is reacted with 4-chlorobutyric acid ethyl ester according to the method described in Example 1. Response time 15 hours at 100. M.p. of the hydrogen fumarate of the title compound 142-1440 (from acetone / ether).
Example 3
4- (4-Benzoyl-4-hydroxy-3 phenylpiperidino) butyric acid 4-Benzoyl-4-hydroxy-3-phenylpiperidine hydrochloride is reacted with 4-chlorobutyric acid according to the method described in Example 1. Reaction time 15 hours at 1000. m.p.
of the title compound 216-2220 (from methanol / water).
Example 4
2- (4-Benzoyl-4-hydroxy-3 phenylpiperidino) acetic acid
4-Benzoyl-4-hydroxy-3-phenylpiperidine hydrochloride is reacted with chloroacetic acid according to the method described in Example 1. Reaction time 15 hours at 1000. m.p.
2182210 (from methanol / water).
Example 5
2- (4-Benzoyl-4-hydroxy-3 phenylpiperidino) acetamide 4-Benzoyl-4-hydroxy-3-phenylpiperidine hydrochloride is reacted with chloroacetamide according to the method described in Example 1. Reaction time 15 hours at 1000. m.p.
the title compound 182-1850 (from methanol).
Example 6
3 - (4-Benzoyl-4-hydroxy-3 phenylpiperidino) propionic acid ethyl ester
4-Benzoyl-4-hydroxy-3-phenylpiperidine is reacted with ethyl 3-chloropropionate by the method described in Example 1. M.p. of the hydrochloride of the title compound 205-2060 (from ethanol).
Example 7
3- (4-Benzoyl-4-hydroxy-3 phenylpiperidinozpropionic acid
4-Benzoyl-4-hydroxy-3-phenylpiperidine is reacted with 3-chloropropionic acid by the method described in Example 1. M.p. of the hydrochloride of the title compound 178179.50 (from water).
Example 8 3- (4-Benzoyl-4-hydroxy-3-phenylpiperidino) -N-methyl-propionamide
4-Benzoyl-4-hydroxy-3-phenylpiperidine is reacted with 3-chloropropionic acid-N-methylamide according to the process described in Example 1. M.p. of the title compound 1931960 (from methanol).
Example 9
3- (4-Benzoyl-4-hydroxy-3 phenylpiperidino) -N-diethylpropionamide
4-Benzoyl-4-hydroxy-3-phenylpiperidine is reacted with 3-chloropropionic acid-N-diethylamide according to the method described in Example 1. Mp. Of the hydrochloride monohydrate of the title compound 110-115o (from water).
EMI2.1
Y- (CH2) n-COR III
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH202471A CH534681A (en) | 1971-02-11 | 1971-02-11 | 4-benzoyl-3-phenyl-4-piperidinol derivs - with hypolipaemic properties |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH202471A CH534681A (en) | 1971-02-11 | 1971-02-11 | 4-benzoyl-3-phenyl-4-piperidinol derivs - with hypolipaemic properties |
| CH516770A CH528506A (en) | 1972-03-30 | 1972-03-30 | Process for the preparation of new phenylpiperidine compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH534681A true CH534681A (en) | 1973-03-15 |
Family
ID=25689297
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH202471A CH534681A (en) | 1971-02-11 | 1971-02-11 | 4-benzoyl-3-phenyl-4-piperidinol derivs - with hypolipaemic properties |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH534681A (en) |
-
1971
- 1971-02-11 CH CH202471A patent/CH534681A/en unknown
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