DE1470350C - 5,6-Dihydro-morphanthridines and process for their preparation - Google Patents
5,6-Dihydro-morphanthridines and process for their preparationInfo
- Publication number
- DE1470350C DE1470350C DE1470350C DE 1470350 C DE1470350 C DE 1470350C DE 1470350 C DE1470350 C DE 1470350C
- Authority
- DE
- Germany
- Prior art keywords
- general formula
- dihydro
- preparation
- acid
- addition salts
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims description 5
- 238000000034 method Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 14
- -1 piperidylidene ring Chemical group 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 5
- 238000007792 addition Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 claims description 4
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical group [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 2
- 239000003638 reducing agent Substances 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K Aluminium chloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RZVHIXYEVGDQDX-UHFFFAOYSA-N Anthraquinone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C(=O)C2=C1 RZVHIXYEVGDQDX-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Description
Die Erfindung betrifft 5,6-Dihydro-morphanthridine der allgemeinen FormelThe invention relates to 5,6-dihydro-morphanthridines of the general formula
R1 R 1
C /CH3 C / CH 3
XCH2 --CH2-N X CH 2 --CH 2 -N
/CH,/ CH,
CH, -CH7-NCH, -CH 7 -N
mit komplexen Metallhydriden erhalten. Vorzugsweise erfolgt die Reduktion mittels Lithiumaluminiumhydrid in einem inerten wasserfreien Lösungsmittel bei mäßig erhöhten Temperaturen, vorteilhaft bei der Siedetemperatur des verwendeten Lösungsmittels. Als wasserfreies Lösungsmittel können Äther, Tetrahydrofuran oder Dioxan verwendet werden; ist die Verbindung der allgemeinen Formel II in dem betreffenden Lösungsmittel schwer löslich, so kann sie aus einer üblichen Extraktionsapparatur in das Reaktionsgefäß extrahiert werden.obtained with complex metal hydrides. The reduction is preferably carried out by means of lithium aluminum hydride in an inert anhydrous solvent at moderately elevated temperatures, advantageously at the boiling point of the solvent used. Ether, tetrahydrofuran or dioxane can be used as anhydrous solvent; if the compound of the general formula II is sparingly soluble in the solvent in question, it can be extracted from a conventional extraction apparatus into the reaction vessel.
Die erhaltenen Verbindungen der allgemeinen Formel I können gewünschtenfalls nach an sich bekannten Methoden in ihre Säureadditionssalze übergeführt werden. Als Säure kommen physiologisch verträgliche anorganische oder organische Säuren, wie Salzsäure, i Schwefelsäure, Phosphorsäure, Zitro- nensäure, Maleinsäure, Fumarsäure, Weinsäure u. dgl. in Betracht, j The resulting compounds of the general formula I can, if desired, be converted into their acid addition salts by methods known per se. Physiologically compatible inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, maleic acid, fumaric acid, tartaric acid and the like come into consideration as the acid
Für die Herstellung der als Ausgangsstoffe ver wendeten Verbindungen der allgemeinen Formel II kann von einem Anthrachinon ausgegangen werden, welches mit girier Aminoalkylmetallverbindung der allgemeinen Formel For the preparation of the compounds of the general formula II used as starting materials , one can start from an anthraquinone which has a girier aminoalkyl metal compound of the general formula
in der Ri und R2 wie eingangs definiert sind und Hai ein Halogenatom bedeutet, umgesetzt und anschließend mit Hydroxylamin zu einem Oxim der allgemeinen Formelin which Ri and R 2 are as defined at the outset and Hai is a halogen atom, reacted and then reacted with hydroxylamine to give an oxime of the general formula
in der R1 ein Wasserstoffatom und R2 eine Methylgruppe oder R1 und R2 zusammen mit dem Stickstoffatom und den dazwischenliegenden Kohlenstoffatomen einen Piperidyliden-Ring bedeuten, sowie deren Säureadditionssalze und ein Verfahren zu ihrer Herstellung.in which R 1 denotes a hydrogen atom and R 2 denotes a methyl group or R 1 and R 2 together with the nitrogen atom and the carbon atoms in between denote a piperidylidene ring, as well as their acid addition salts and a process for their preparation.
Die neuen Verbindungen werden erfindungsgemäß durch Reduktion von Verbindungen der allgemeinen FormelAccording to the invention, the new compounds are obtained by reducing compounds of the general formula
/CH,/ CH,
ί
\ί
\
IIIIII
R2 R 2
/CH3 / CH 3
— CH2 — CH2 —- CH 2 - CH 2 -
umgewandelt wird.is converted.
Diese Oxime lassen sich z. B. mit Polyphosphorsäure, Polyphosphorsäureester, Aluminiumchlorid, Schwefelsäure oder einem aromatischen Sulfonsäur.echlorid bei erhöhten Temperaturen zu einer Verbindung der allgemeinen Formel II unter gleichzeitiger Dehydratisierung umlagern. Eine andere Methode zur Herstellung der Verbindungen der allgemeinen Formel II besteht darin, daß ein entsprechendes 5,6-Dihydro-morphanthridin mit einem Aminoalkylmagnesiumchlorid der allgemeinen Formel III zu einer Verbindung der allgemeinen FormelThese oximes can be z. B. with polyphosphoric acid, polyphosphoric acid ester, aluminum chloride, Sulfuric acid or an aromatic sulfonic acid chloride at elevated temperatures to form a compound of the general formula II rearrange with simultaneous dehydration. Another method for the preparation of the compounds of general formula II consists in that a corresponding 5,6-dihydro-morphanthridine with an aminoalkylmagnesium chloride of the general formula III a compound of the general formula
CO)CO)
HO'HO '
-CH2-CH2-N-CH 2 -CH 2 -N
R1 R 1
V
-CH3 V
-CH 3
R2R2
umgesetzt und anschließend diese dabei entstandene Verbindung der allgemeinen Formel V in an sich bekannter Weise mit einem wasserabspaltenden Mittel behandelt wird.implemented and then this resulting compound of general formula V in itself is treated in a known manner with a dehydrating agent.
Die neuen Verbindungen sowie ihre Salze besitzen wertvolle therapeutische Eigenschaften, insbesondere weisen sie als Psychopharmaca eine gute antidepres^The new compounds as well as their salts have valuable therapeutic properties, in particular Assign them as Psychopharmaca a good antidepres ^
sive und anticonvulsive Wirkung auf, des weiteren sind sie histaminolytisch wirksam.They have an active and anticonvulsive effect, and they are also histaminolytically effective.
• B e i s ρ i e 1 1• B e i s ρ i e 1 1
l-(y-Dimethylaminopropyjiden)-5,6-dihydromorphanthridin 1- (γ-Dimethylaminopropyjiden) -5,6-dihydromorphanthridine
14,6 g 11 - (γ - Dimethylaminopropyliden) - 5,6 - dihydro-morphanthridin-6-on in 100 ml absolutem Tetrahydrofuran werden innerhalb 30 Minuten zu einer Suspension von 5,7 g Lithiumaluminiumhydrid in 200 ml absolutem Tetrahydrofuran getropft und anschließend unter Rühren 4 Stunden am Rückflußkühler gekocht. Anschließend wird unter guter Kühlung mit 25 ml Wasser durch tropfenweise Zugabe zersetzt, von den ausgefallenen Metallhydroxyden abgesaugt, der Filterkuchen 2mal mit je 100 ml Tetrahydrofuran extrahiert und die vereinigten organischen Lösungen . eingeengt. Das Reaktionsprodukt wird14.6 g of 11 - (γ - dimethylaminopropylidene) - 5,6 - dihydro-morphanthridin-6-one in 100 ml of absolute tetrahydrofuran are added dropwise within 30 minutes to a suspension of 5.7 g of lithium aluminum hydride in 200 ml of absolute tetrahydrofuran and then added under Stirring boiled for 4 hours on the reflux condenser. Then, with good cooling with 25 ml of water, it is decomposed by dropwise addition, the precipitated metal hydroxides are filtered off with suction, the filter cake is extracted twice with 100 ml of tetrahydrofuran each time and the combined organic solutions. constricted. The reaction product will
IOIO
durch Destillation gereinigt. Man erhält 11,7g 11 -(y-Dimethylaminopropyliden)-5-,6-dihydro-morphanthridin.
Kp.o,o5mm = 176 bis 178°C.
• Das Monomaleinat erhält man durch Ausfällung aus ätherischer Lösung mit in Äther gelöster Maleinsäure
und anschließender Umkristallisation aus Aceton. Diese Verbindung hat den Schmelzpunkt
168 bis 169° C.purified by distillation. 11.7 g of 11- (γ-dimethylaminopropylidene) -5-, 6-dihydro-morphanthridine are obtained. Kp. O , o 5mm = 176 to 178 ° C.
• The monomaleinate is obtained by precipitation from ethereal solution with maleic acid dissolved in ether and subsequent recrystallization from acetone. This compound has a melting point of 168 to 169 ° C.
B e i s ρ i e 1 2B e i s ρ i e 1 2
11 -(N-Methyl-4-piperidyliden)-5,6-dihydromorphanthridin 11 - (N-methyl-4-piperidylidene) -5,6-dihydromorphanthridine
5 g ll-(N-Methyl-4-piperidyliden)-5,6-'dihydromorphanthridin-6-on werden wie im Beispiel 1 mit 3 g Lithiumaluminiumhydrid in Tetrahydrofuran reduziert und nach Isolierung der Base (F. 190° C, Ausbeute: 4,3 g entspricht 90% der Theorie), in das Maleinat des ll-(N-Methyl-4-piperidyliden)-5,6-dihydromorphanthridins verwandelt. Diese Verbindung hat den Schmelzpunkt 1850C.5 g of II- (N-methyl-4-piperidylidene) -5,6-'dihydromorphanthridin-6-one are reduced as in Example 1 with 3 g of lithium aluminum hydride in tetrahydrofuran and, after isolation of the base (mp 190 ° C., yield: 4.3 g corresponds to 90% of theory), converted into the maleate of II- (N-methyl-4-piperidylidene) -5,6-dihydromorphanthridine. This compound has a melting point of 185 ° C.
Claims (4)
Family
ID=
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