CH498839A - Analgesic indenopyridine derivs - Google Patents
Analgesic indenopyridine derivsInfo
- Publication number
- CH498839A CH498839A CH757369A CH757369A CH498839A CH 498839 A CH498839 A CH 498839A CH 757369 A CH757369 A CH 757369A CH 757369 A CH757369 A CH 757369A CH 498839 A CH498839 A CH 498839A
- Authority
- CH
- Switzerland
- Prior art keywords
- formula
- methyl
- indenopyridine
- new
- indeno
- Prior art date
Links
- AYJJTPLDSZAGGA-UHFFFAOYSA-N 2-ethyl-7-methyl-5-(4-methylphenyl)-1,3,4,4a,5,9b-hexahydroindeno[1,2-c]pyridine Chemical compound C1N(CC)CCC2C1C1=CC=C(C)C=C1C2C1=CC=C(C)C=C1 AYJJTPLDSZAGGA-UHFFFAOYSA-N 0.000 title 1
- 230000000202 analgesic effect Effects 0.000 title 1
- PFWJFKBTIBAASX-UHFFFAOYSA-N 9h-indeno[2,1-b]pyridine Chemical class C1=CN=C2CC3=CC=CC=C3C2=C1 PFWJFKBTIBAASX-UHFFFAOYSA-N 0.000 claims abstract description 9
- -1 benzyl- Chemical group 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims abstract description 3
- 150000008046 alkali metal hydrides Chemical class 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 229930194542 Keto Natural products 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 5
- 150000002576 ketones Chemical class 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 3
- 239000012280 lithium aluminium hydride Substances 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract description 2
- VXUQEYKVQIRONS-UHFFFAOYSA-N 1,9-dihydroindeno[2,1-b]pyridin-2-one Chemical compound C1=CC=C2C3=CC=C(O)N=C3CC2=C1 VXUQEYKVQIRONS-UHFFFAOYSA-N 0.000 abstract 1
- ICIGINUFPQUGPM-UHFFFAOYSA-N 2-methyl-1,3,4,4a,5,9b-hexahydroindeno[1,2-c]pyridin-5-ol Chemical compound CN1CC2C(CC1)C(C1=CC=CC=C12)O ICIGINUFPQUGPM-UHFFFAOYSA-N 0.000 abstract 1
- MSNNVXHRVQRZMN-UHFFFAOYSA-N 2-methyl-1,3,4,9b-tetrahydroindeno[1,2-c]pyridine Chemical compound CN1CC2C(CC1)=CC1=CC=CC=C12 MSNNVXHRVQRZMN-UHFFFAOYSA-N 0.000 abstract 1
- 208000001953 Hypotension Diseases 0.000 abstract 1
- 125000000304 alkynyl group Chemical group 0.000 abstract 1
- 229940035676 analgesics Drugs 0.000 abstract 1
- 239000000730 antalgic agent Substances 0.000 abstract 1
- 238000010531 catalytic reduction reaction Methods 0.000 abstract 1
- 230000018044 dehydration Effects 0.000 abstract 1
- 238000006297 dehydration reaction Methods 0.000 abstract 1
- 208000021822 hypotensive Diseases 0.000 abstract 1
- 230000001077 hypotensive effect Effects 0.000 abstract 1
- 229940125723 sedative agent Drugs 0.000 abstract 1
- 239000000932 sedative agent Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- SWJPEBQEEAHIGZ-UHFFFAOYSA-N 1,4-dibromobenzene Chemical compound BrC1=CC=C(Br)C=C1 SWJPEBQEEAHIGZ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- PFVFXDVOCHMQDU-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine-4-carboxylic acid Chemical compound OC(=O)C1CCNC=C1 PFVFXDVOCHMQDU-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 1
- ADEKJVNFIQUGRR-UHFFFAOYSA-N 4h-pyridin-3-one Chemical compound O=C1CC=CN=C1 ADEKJVNFIQUGRR-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- HZBOQOXQPRQKTF-UHFFFAOYSA-N bis(4-methylphenyl) 2,3-dihydroxybutanedioate Chemical compound C1=CC(C)=CC=C1OC(=O)C(O)C(O)C(=O)OC1=CC=C(C)C=C1 HZBOQOXQPRQKTF-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
-
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
(a) Indenopyridines of general formula (I) and their salts:- R1 = H-, low alkyl-, alkenyl- or alkynyl-, benzyl-, phenylethyl- R2 = H-, Cl-, Br-, lower alkyl- e.g. 2-methyl-1, 3, 4, 9b-tetrahydro-2H-indeno(1, 2-c) pyridine (b) Hydroxyindenopyridine intermediates (II):- e.g. 2-methyl 1, 2, 3, 4, 4a, 9b-hexahydro-5H-indeno-(1,2-c) pyridin-5-ol. Analgesics, sedatives, hypotensives. (a) Dehydration of hydroxy-cpd. (II) with strong acid (II) (I) (b) Catalytic reduction of ketone (III) using a complex alkali metal hydride, e.g. lithium aluminium hydride.
Description
Verfahren zur Herstellung neuer Indenopyridinderivate
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung neuer Indenopyridinderivate der Formel I (siehe Formelblatt), worin R1 Wasserstoff, niederes Alkyl oder Benzyl und R2 Brom bedeuten, dadurch gekennzeichnet, dass man eine Ketoverbindung der Formel II, worin R1 und R2 die obige Bedeutung besitzen, in einem unter den Reaktionsbedingungen inerten Lösungsmittel reduziert, sowie die Verwendung der neuen Indenopyridinderivate der Formel Ia zur Herstellung der neuen Indenopyridinderivate der Formel Ib, dadurch gekennzeichnet, dass man die Benzylgruppe hydrogenolytisch abspaltet.
Die Reduktion kann z. B. mittels komplexer Alkalimetallhydride, wie Natriumborhydrid, in einem unter den Reaktionsbedingungen inerten Lösungsmittel, zum Beispiel in einem Alkohol, wie Äthanol, oder in einem Gemisch eines Alkohols mit Wasser, wie Äthanol/Wasser, oder mittels Lithiumaluminiumhydrid in einem unter den Reaktionsbedingungen inerten Lösungsmittel, z. B. in einem cyclischen oder offenkettigen Äther, wie Tetrahydrofuran oder Dioxan, oder mittels katalytischer Hydrierung, wie gasförmiger Wasserstoff, in Gegenwart eines Hydrierungskatalysators, wie Platin oder Raney Nickel, beispielsweise in Äthanol ausgeführt werden.
Optisch aktive Verbindungen der Formel I werden erhalten, indem man die entsprechenden racemischen Verbindungen durch Umsetzung mit optisch aktiven Säuren, z.B. Di-p-tolyl-weinsäure, in diastereoisomere Salze überführt, diese durch fraktionierte Kristallisation trennt und anschliessend die Basen mittels Alkali freisetzt.
Die Verbindungen der Formel I sind neu und dienen als wertvolle Zwischenprodukte bei der Herstellung von Heilmitteln der Indenopyridinreihe.
Die Ketone der Formel II sind nur zum Teil bekannt und können folgendermassen hergestellt werden:
Man setzt niedere Alkylester der Isonicotinsäure mit Verbindungen der Formel VI, worin R1, für niederes Alkyl oder Benzyl und X für Brom oder Jod stehen, zu den entsprechenden 4-Alkoxycarbonyl-1-R1'-pyridinium- halogeniden um, z. B. durch mehrstündiges Erhitzen der Komponenten in Äthanol. Daraus erhält man mittels Natriumborhydrid Tetrahydroisonicotinsäureester der Formel III, worin R1, obige Bedeutung besitzt; man setzt diese mit Magnesiumverbindungen der Formel IV, worin R2 obige Bedeutung besitzt, um und hydrolysiert die entstandenen Produkte zu Verbindungen der Formel V, worin R1, und R2 obige Bedeutung besitzen.
Hieraus gewinnt man Ketone der Formel IIc, worin R1, und R2 obige Bedeutung besitzen, entweder durch Erhitzen mit Polyphosporsäure oder durch Hydrolyse zu den freien Carbonsäuren, Herstellung der Säurechloride und Behandlung der letzteren mit wasserfreiem Aluminiumchlorid. Am Stickstoff unsubstituierte Ketone der Formel IIa, worin R2 obige Bedeutung besitzt, erhält man aus Verbindungen der Formel IIb, worin R2 obige Bedeutung besitzt, und R5 für die Methyl- oder Benzylgruppe steht, durch Erhitzen mit einem niederen Alkylester der Chlorameisensäure und anschliessende Hydrolyse der entstandenen Urethane, z. B. mittels Salzsäure.
Im nachfolgenden Beispiel, welches die Ausführung des Verfahrens erläutert, den Umfang der Erfindung aber in keiner Weise einschränken soll, erfolgen alle Temperaturangaben in Celciusgraden; die Schmelz- und Siedepunkte sind unkorrigiert.
Beispiel
7-Brom-2-methyl-1 ,2,3,4,4a,9b-hexahydro-SH-indeno- [1,2-c]pyridin-5-ol
Zu einer Lösung von 20,0 g 7-Brom-2-methyl-l,2,3,4,- 4a,9b-hexahydro-5H-indeno[1,2-c]pyridin-5-on in 20 ml Äthanol wird innerhalb von 10 Min. unter gutem Rühren eine Lösung von 5,45 g Natriumborhydrid in einer Mischung von 0,5 ml 40% Natronlauge und 12 ml Wasser getropft, wobei die Temperatur 400 nicht übersteigen darf. Man rührt noch 1 Std. bei 400, dann 2 Std. unter Rückfluss und tropft anschliessend 15 ml Methanol zu.
Nach einer weiteren Std. wird abgekühlt, der Niederschlag abfiltriert und das Filtrat vollständig eingedampft.
Der Filterrückstand wird zusammen mit dem Eindampfrückstand des Filtrats mit Wasser und Chloroform geschüttelt, bis sich alles gelöst hat, und die wässrige Phase noch zweimal mit Chloroform extrahiert. Man trocknet die organische Phase über Magnesiumsulfat, dampft ein und kristallisiert den Rückstand mehrmals aus Isopropanol um. Smp. 165 bis 1670. Aus der Mutterlauge erhält man eine grössere Fraktion, die bei ca. 142 bis 1510 schmilzt und aus einem Stereoisomerengemisch besteht, das aber ohne weiteres für die nächste Stufe verwendet werden kann.
Das als Ausgangsprodukt benötigte 7-Brom-2-methyl - 1,2,3,4, 4a, 9b-hexahydro - 5H-indenof l,2-c]pyridin-5-on kann folgendermassen hergestellt werden: a) 1-Methyl-3-(4- bromphenyl)-isonipecotinsäuremethyl ester (Isomerengemisch)
14,0 g Magnesiumspäne werden mit 50 ml abs. Äther überschichtet und nach Zugabe von 0,2 g Jod mit 30,0 g p-Dibrombenzol versetzt, wobei eine heftige Reaktion einsetzt. Hierauf lässt man unter Rühren eine Lösung von 88,0 g p-Dibrombenzol in 200 ml abs. Äther so zutropfen, dass das Gemisch beständig siedet. Nach zweistündigem Rühren bei Siedetemperatur am Rückfluss lässt man abkühlen und gibt bei -150 innerhalb von 2 Std. tropfenweise eine Lösung von 35,6g l-Methyl -1,2*5,6-tetrahydro-isonicotinsäuremethylester in 45 ml abs. Toluol zu.
Das Reaktionsgemisch wird noch während 1 Std. bei -150 gerührt und anschliessend in eine Lösung von 150g Ammoniumchlorid in 600ml Wasser gegossen. Man schüttelt mehrmals mit Äther aus, extrahiert die organische Phase mit 1N Salzsäure und stellt die wässrige saure Lösung mit konz. Natronlauge stark alkalisch. Hierauf extrahiert man mit Methylenchlorid und trocknet die mit Wasser gewaschenen organischen Auszüge über Magnesiumsulfat. Nach Abdampfen des Lösungsmittels wird der Rückstand im Hochvakuum destilliert, wobei der 1 -Methyl-3-(4-bromphenyl)-isonipecotinsäuremethylester (Isomerengemisch) bei 146 bis 1480/ 0,06 Torr übergeht.
b) 7-Brom-2-methyl-1,2,3,4,4a,9b-hexakydro-5H-indeno- [1 ,2-c]pyridin-5-on
Ein Gemisch von 55,0g 1-Methyl-3-(4-bromphenyl) -isonipecotinsäuremethylester und 550 g Polyphosphorsäure wird 4 Std. bei 1800 gerührt, auf ca. 900 abgekühlt und dann unter starkem Rühren in 1,51 Wasser gegossen. Bei einer Temperatur von 10 bis 200 versetzt man die erhaltene trübe Lösung bis zur schwach alkalischen Reaktion (pH=8) langsam mit 40% Natronlauge, extrahiert das abgeschiedene Öl mehrmals mit Methylenchlorid, trocknet die organischen Extrakte über Kaliumcarbonat und dampft das Lösungsmittel vollständig ab.
Der Rückstand wird im Hochvakuum destilliert, wobei das 7-Brom-2-methyl-1,2,3,4,4a,9b-hexahydro-SH-indeno- [1,2-c]pyridin-5-on bei 170 bis 1850/0,1 Torr übergeht.
EMI2.1
Process for the preparation of new indenopyridine derivatives
The present invention relates to a process for the preparation of new indenopyridine derivatives of the formula I (see formula sheet), in which R1 is hydrogen, lower alkyl or benzyl and R2 is bromine, characterized in that a keto compound of the formula II in which R1 and R2 are as defined above , reduced in a solvent inert under the reaction conditions, and the use of the new indenopyridine derivatives of the formula Ia for the preparation of the new indenopyridine derivatives of the formula Ib, characterized in that the benzyl group is split off hydrogenolytically.
The reduction can e.g. B. by means of complex alkali metal hydrides, such as sodium borohydride, in a solvent which is inert under the reaction conditions, for example in an alcohol such as ethanol, or in a mixture of an alcohol with water, such as ethanol / water, or by means of lithium aluminum hydride in a solvent which is inert under the reaction conditions , e.g. B. in a cyclic or open-chain ether, such as tetrahydrofuran or dioxane, or by means of catalytic hydrogenation, such as gaseous hydrogen, in the presence of a hydrogenation catalyst such as platinum or Raney nickel, for example in ethanol.
Optically active compounds of formula I are obtained by reacting the corresponding racemic compounds with optically active acids, e.g. Di-p-tolyl-tartaric acid, converted into diastereoisomeric salts, these separated by fractional crystallization and then the bases released by means of alkali.
The compounds of the formula I are new and serve as valuable intermediates in the manufacture of medicinal products from the indenopyridine series.
The ketones of the formula II are only partially known and can be produced as follows:
Lower alkyl esters of isonicotinic acid are used with compounds of the formula VI, in which R1 is lower alkyl or benzyl and X is bromine or iodine, to give the corresponding 4-alkoxycarbonyl-1-R1'-pyridinium halides, e.g. B. by heating the components in ethanol for several hours. From this, by means of sodium borohydride, tetrahydroisonicotinic acid ester of the formula III is obtained, in which R1 has the above meaning; they are reacted with magnesium compounds of the formula IV, in which R2 has the above meaning, and the resulting products are hydrolyzed to give compounds of the formula V in which R1 and R2 have the above meaning.
From this, ketones of the formula IIc are obtained, where R1 and R2 have the above meaning, either by heating with polyphosphoric acid or by hydrolysis to give the free carboxylic acids, preparation of the acid chlorides and treatment of the latter with anhydrous aluminum chloride. Ketones of the formula IIa unsubstituted on nitrogen, in which R2 has the above meaning, are obtained from compounds of the formula IIb in which R2 has the above meaning and R5 stands for the methyl or benzyl group, by heating with a lower alkyl ester of chloroformic acid and subsequent hydrolysis of the resulting urethanes, e.g. B. by means of hydrochloric acid.
In the following example, which explains the implementation of the method but is not intended to restrict the scope of the invention in any way, all temperatures are given in degrees Celsius; the melting and boiling points are uncorrected.
example
7-Bromo-2-methyl-1, 2,3,4,4a, 9b-hexahydro-SH-indeno [1,2-c] pyridin-5-ol
To a solution of 20.0 g of 7-bromo-2-methyl-1,2,3,4, - 4a, 9b-hexahydro-5H-indeno [1,2-c] pyridin-5-one in 20 ml of ethanol a solution of 5.45 g of sodium borohydride in a mixture of 0.5 ml of 40% sodium hydroxide solution and 12 ml of water is added dropwise within 10 minutes with thorough stirring, the temperature not exceeding 400. The mixture is stirred for a further 1 hour at 400, then for 2 hours under reflux and then 15 ml of methanol are added dropwise.
After a further hour, the mixture is cooled, the precipitate is filtered off and the filtrate is completely evaporated.
The filter residue is shaken together with the evaporation residue of the filtrate with water and chloroform until everything has dissolved, and the aqueous phase is extracted twice more with chloroform. The organic phase is dried over magnesium sulphate and evaporated, and the residue is recrystallized several times from isopropanol. Melting point 165 to 1670. A larger fraction is obtained from the mother liquor, which melts at about 142 to 1510 and consists of a mixture of stereoisomers, which can, however, be used for the next stage without further ado.
The 7-bromo-2-methyl-1,2,3,4, 4a, 9b-hexahydro-5H-indenofl, 2-c] pyridin-5-one required as the starting product can be prepared as follows: a) 1-methyl -3- (4- bromophenyl) -isonipecotinic acid methyl ester (mixture of isomers)
14.0 g of magnesium shavings are mixed with 50 ml of abs. Covered with ether and after adding 0.2 g of iodine, 30.0 g of p-dibromobenzene were added, causing a violent reaction. A solution of 88.0 g of p-dibromobenzene in 200 ml of abs is then left with stirring. Add ether dropwise so that the mixture boils constantly. After stirring for two hours at the reflux temperature, the mixture is allowed to cool and a solution of 35.6 g of methyl l-methyl -1,2 * 5,6-tetrahydro-isonicotinic acid in 45 ml of abs is added dropwise at -150 within 2 hours. Toluene too.
The reaction mixture is stirred for a further 1 hour at -150 and then poured into a solution of 150 g of ammonium chloride in 600 ml of water. It is extracted several times with ether, the organic phase is extracted with 1N hydrochloric acid and the aqueous acidic solution is made with conc. Sodium hydroxide solution, strongly alkaline. It is then extracted with methylene chloride and the organic extracts washed with water are dried over magnesium sulfate. After evaporation of the solvent, the residue is distilled in a high vacuum, the 1-methyl-3- (4-bromophenyl) -isonipecotinic acid methyl ester (mixture of isomers) passing over at 146 to 1480 / 0.06 torr.
b) 7-Bromo-2-methyl-1,2,3,4,4a, 9b-hexakydro-5H-indeno- [1,2-c] pyridin-5-one
A mixture of 55.0 g of 1-methyl-3- (4-bromophenyl) -isonipecotinic acid methyl ester and 550 g of polyphosphoric acid is stirred for 4 hours at 1800, cooled to about 900 and then poured into 1.5 liters of water with vigorous stirring. At a temperature of 10 to 200, the cloudy solution obtained is slowly mixed with 40% sodium hydroxide solution until a weakly alkaline reaction (pH = 8), the separated oil is extracted several times with methylene chloride, the organic extracts are dried over potassium carbonate and the solvent is completely evaporated off.
The residue is distilled in a high vacuum, the 7-bromo-2-methyl-1,2,3,4,4a, 9b-hexahydro-SH-indeno [1,2-c] pyridin-5-one at 170 to 1850 / 0.1 Torr passes.
EMI2.1
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH757369A CH498839A (en) | 1966-06-21 | 1967-03-06 | Analgesic indenopyridine derivs |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH898466A CH491920A (en) | 1966-06-21 | 1966-06-21 | Process for the preparation of new indenopyridine derivatives |
| CH757369A CH498839A (en) | 1966-06-21 | 1967-03-06 | Analgesic indenopyridine derivs |
| CH324467A CH503027A (en) | 1966-06-21 | 1967-03-06 | Analgesic indenopyridine derivs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH498839A true CH498839A (en) | 1970-11-15 |
Family
ID=27174218
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH757369A CH498839A (en) | 1966-06-21 | 1967-03-06 | Analgesic indenopyridine derivs |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH498839A (en) |
-
1967
- 1967-03-06 CH CH757369A patent/CH498839A/en unknown
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| PLZ | Patent of addition ceased |