DE1286045B - Process for the preparation of N-substituted 3-methoxy-6-oxo-14-hydroxy-morphinan derivatives - Google Patents
Process for the preparation of N-substituted 3-methoxy-6-oxo-14-hydroxy-morphinan derivativesInfo
- Publication number
- DE1286045B DE1286045B DE1963S0084596 DES0084596A DE1286045B DE 1286045 B DE1286045 B DE 1286045B DE 1963S0084596 DE1963S0084596 DE 1963S0084596 DE S0084596 A DES0084596 A DE S0084596A DE 1286045 B DE1286045 B DE 1286045B
- Authority
- DE
- Germany
- Prior art keywords
- methoxy
- oxo
- hydroxy
- morphinan
- cis
- 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 11
- -1 N-substituted 3-methoxy-6-oxo-14-hydroxy-morphinan Chemical class 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 4
- 229940051807 opiod analgesics morphinan derivative Drugs 0.000 title claims description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 4
- ONOALYIFHHYDNL-BRWVUGGUSA-N 3-methoxy-14-hydroxy-6-ketomorphinan Chemical compound C1C(=O)CC[C@@]2(O)[C@]3([H])NCC[C@@]21C1=CC(OC)=CC=C1C3 ONOALYIFHHYDNL-BRWVUGGUSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000468 ketone group Chemical group 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000004927 clay Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- IAKFGFQVHBKCAS-UHFFFAOYSA-N 2-phenylacetyl bromide Chemical compound BrC(=O)CC1=CC=CC=C1 IAKFGFQVHBKCAS-UHFFFAOYSA-N 0.000 description 1
- 102220501443 Cytosolic iron-sulfur assembly component 3_C27N_mutation Human genes 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- ASGJEMPQQVNTGO-UHFFFAOYSA-N benzene chloroform Chemical compound C(Cl)(Cl)Cl.C1=CC=CC=C1.C1=CC=CC=C1 ASGJEMPQQVNTGO-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000005907 ketalization reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- ACNHBCIZLNNLRS-UBGQALKQSA-N paxilline Chemical compound N1C2=CC=CC=C2C2=C1[C@]1(C)[C@@]3(C)CC[C@@H]4O[C@H](C(C)(O)C)C(=O)C=C4[C@]3(O)CC[C@H]1C2 ACNHBCIZLNNLRS-UBGQALKQSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- MCSOAHVAIJXNDN-ZTFGCOKTSA-N ram-322 Chemical compound C1C(=O)CC[C@@]2(O)[C@H]3CC4=CC=C(OC)C(O)=C4[C@]21CCN3C MCSOAHVAIJXNDN-ZTFGCOKTSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 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
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von N-substituierten 3-Methoxy-6-oxo-1 4-hydroxy-morphinan-Derivaten der allgemeinen Fonnel I worin R eine niedermolekulare Alkylgruppe oder eine phenyl-niedermolekulare Alkylgruppe bedeutet.The invention relates to a process for the preparation of N-substituted 3-methoxy-6-oxo-1 4-hydroxymorphinan derivatives of the general formula I. where R is a low molecular weight alkyl group or a phenyl low molecular weight alkyl group.
Dieses Verfahren ist dadurch gekennzeichnet, daß man 3-Methoxy-6-oxo-14-hydroxy-morphinan mit einem Säurederivat der allgemeinen Formel II worin Z ein Halogenatom oder den Rest bedeutet und R die oben angegebene Bedeutung hat, falls erforderlich, in Gegenwart eines inerten organischen Lösungsmittels und/oder unter Erhitzen unter Rückfluß, gewünschtenfalls in Gegenwart eines basischen Kondensationsmittels umsetzt, das so erhaltene 3-Methoxy-6-oxo-14-hydroxy-N-acyl-morphinan in an sich bekannter Weise durch Behandlung mit einem Glykol und einer Säure in ein Ketal umwandelt, die N-Acylgruppe in an sich bekannter Weise mit einem Metallhydridkomplex reduziert und danach in an sich bekannter Weise durch Erhitzen mit einer verdünnten Mineralsäure die Ketalgiuppe in die Ketogruppe zurückverwandelt.This process is characterized in that 3-methoxy-6-oxo-14-hydroxymorphinan is mixed with an acid derivative of the general formula II wherein Z is a halogen atom or the residue and R has the meaning given above, if necessary, in the presence of an inert organic solvent and / or with heating under reflux, if desired in the presence of a basic condensing agent, to convert the 3-methoxy-6-oxo-14-hydroxy-N thus obtained -acyl-morphinan is converted into a ketal in a manner known per se by treatment with a glycol and an acid, the N-acyl group is reduced in a manner known per se with a metal hydride complex and then the ketalg group in a manner known per se by heating with a dilute mineral acid converted back to the keto group.
Die Acylierung kann so durchgeführt werden, daß man das 3-Methoxy-6-oxo-14-hydroxy-morphinan mit dem genannten Säurederivat bei Zimmertemperatur, d. h. bei 15 bis 30°C, oder unter Erhitzen behandelt. Als Säureanhydrid kann z. B. Essigsäureanhydrid, Propionsäureanhydrid und Buttersäureanhydrid verwendet werden. Als Säurehalogenide können eingesetzt werden Acetylchlorid, Propionylchlorid, Butyrylchlorid, Benzoylchlorid, Phenacetylchlorid und Phenacetylbromid. Falls notwendig wird ein inertes organisches Lösungsmittel, z. B. Benzol, Toluol, Aceton, Dioxan, Tetrahydrofuran, vervJendet. The acylation can be carried out in such a way that the 3-methoxy-6-oxo-14-hydroxymorphinan is used with said acid derivative at room temperature, d. H. at 15 to 30 ° C, or below Heating treated. As the acid anhydride, for. B. acetic anhydride, propionic anhydride and butyric anhydride can be used. Can be used as acid halides be acetyl chloride, propionyl chloride, butyryl chloride, benzoyl chloride, phenacetyl chloride and phenacetyl bromide. If necessary, an inert organic solvent, z. B. benzene, toluene, acetone, dioxane, tetrahydrofuran, are used.
Die Zugabe einer anorganischen oder organischen Base, z.B. Natriumcarbonat, Kaliumcarbonat, Pyridin, Picolin, dimethylanilin, als ein Kondensationsmittel führt zu vorteilhaften Ergebnissen.The addition of an inorganic or organic base, e.g. sodium carbonate, Potassium carbonate, pyridine, picoline, dimethylaniline, acts as a condensing agent to beneficial results.
Es muß als überraschend angesellen werden, daß im vorliegenden Fall nicht eTartungsgemäß die Hydroxylgruppe in 14-Stellung, sondern nur die N-Stellung acyliert wird. It must be said as surprising that in the present case not, as expected, the hydroxyl group in the 14-position, but only the N-position is acylated.
Da die Oxogruppe in der 6-Stellung reduzierbar ist, ist es notwendig, dieselbe, vor der Durchführung der Reduktion, als ketalisierte Oxogruppe zu schützen. Ein solcher Schutz wird mit Hilfe eines üblichen Ketalisierungsverfahrens, durch Behandlung mit einem Glykol und einer Säure erreicht. Since the oxo group in the 6-position can be reduced, it is necessary to to protect the same, before carrying out the reduction, as a ketalized oxo group. Such protection is achieved with the help of a conventional ketalization process Treatment achieved with a glycol and an acid.
Die Reduktion kann durch Behandlung des erhaltenen 3 - Methoxy- 6,6 - äthylendioxy- 14-hydroxy-N-acyl-morphinans mit einem metallischen Hydridkomplex, z. B. Lithiumaluminiumhydrid oder Natriumborhydrid, in einem inerten Lösungsmittel, z. Be Äther, Tetrahydrofuran oder Dioxan, erfolgen. The reduction can be carried out by treating the 3-methoxy-6,6 obtained - ethylenedioxy- 14-hydroxy-N-acyl-morphinans with a metallic hydride complex, z. B. lithium aluminum hydride or sodium borohydride, in an inert solvent, z. Be ether, tetrahydrofuran or dioxane.
Die Reaktion kann bei Zimmertemperatur oder unter Erhitzen bis zum Rückfiuß durchgeführt werden.The reaction can be carried out at room temperature or with heating up to Reflux can be carried out.
Nach der Reduktion wird die schützende Ketal gruppe durch eine übliche Entketalisierung, z. B. durch Behandlung mit einer verdünnten Mineralsäure unter Erhitzen abgespalten. After the reduction, the protective ketal group is replaced by a customary Entketalisierung, z. B. by treatment with a dilute mineral acid Cleaved by heating.
Die erfindungsgemäß hergestellten N-substituierten 3-Methoxy-6-oxo-14-hydroxy-morphinane bilden Salze mit organischen und anorganischen Säuren. The N-substituted 3-methoxy-6-oxo-14-hydroxy-morphinans prepared according to the invention form salts with organic and inorganic acids.
Die erfindungsgemäß erhältlichen N-substituierten 3-Methoxy-6-oxo-14-hydroxy-morphinane
und ihre Salze können als Analgetika Verwendung finden. Die analgetische Wirksamkeit
und die Toxizität von zwei erfindungsgemäß erhältlichen N-substituierten 3-methoxy-6-oxo-14-hydroxy-morphinan-Derivaten
zeigt folgende Tabelle:
Ther., Bd. 72 [1941]. S. 74 bis 79) bei Ratten beobachtet und wird als Verhältniszahl zum Morphium angeführt, dessen analgetische Wirksamkeit mit 1 angenommen wurde. Die Toxizität wurde durch intravenöse Verabreichung der Verbindungen an Mäusen bestimmt und gibt den Wert für die LDso an. Der Wert für die LD50 von Morphin ist 350,0 mg/ kg, bestimmt durch intravenöse Injektion bei Mäusen. Ther., Vol. 72 [1941]. Pp. 74 to 79) observed in rats and is given as a ratio to morphine, its analgesic effectiveness with 1 was accepted. The toxicity was assessed by intravenous administration of the compounds determined on mice and gives the value for the LDso at. The value for the LD50 of morphine is 350.0 mg / kg as determined by intravenous injection in mice.
Das erfindungsgemäße Verfahren wird durch die folgenden Beispiele näher erläutert. The process of the invention is illustrated by the following examples explained in more detail.
Beispiel 1 Herstellung von (- )-3-Methoxy-6-oxo- 1 hydroxy-N-äthyl-morphinan-(cis) Eine Lösung bestehend aus 200mg (- )-3-Methoxy-6-oxo-14-hydroxy-morphinan-(cis) in 2 ml Essigsäureanhydrid wird bei Zimmertemperatur, d.h. bei 15 bis 30°C, über Nacht stehengelassen, Das Reaktionsgemisch wird dann mit Wasser vermengt und mit Äther geschüttelt. Die Ätherschicht wird unter vennindertem Druck e;ngeengt und liefert 240 mg des rohen acetvlierten Produktes. Das rohe acetylierte Produkt wird dann auf 4g Tonerde chromatographiert. Die Eluate mit Benzol Chloroform 1 : 1 und Dichlori-nethan werden vereinigt, eingeengt und der Rückstand aus Athanol umkristallisiert, wobei 124 mg an (-)-3-Methoxy-6-oxo-14-hydroxy-N-acetyl-morphinan-(cis), in Form von Kristallen, F. = 196 bis 197-C, erhalten werden. [α]D22 - 187 (Chloroform). Example 1 Preparation of (-) -3-methoxy-6-oxo- 1 hydroxy-N-ethyl-morphinan- (cis) A solution consisting of 200mg (-) -3-methoxy-6-oxo-14-hydroxy-morphinan- (cis) in 2 ml of acetic anhydride is at room temperature, i.e. at 15 to 30 ° C, left to stand overnight. The reaction mixture is then washed with water mingled and shaken with ether. The ether layer is under reduced pressure concentrated and gives 240 mg of the crude acetylated product. The crude acetylated The product is then chromatographed on 4 g of clay. The eluates with benzene chloroform 1: 1 and dichlorinethane are combined and concentrated, and the residue is obtained from ethanol recrystallized, whereby 124 mg of (-) - 3-methoxy-6-oxo-14-hydroxy-N-acetyl-morphinan- (cis), in the form of crystals, m.p. = 196 to 197-C. [α] D22-187 (Chloroform).
Analyse für C19H23NO4 : Berechnet ... C 69,28, H 7,04, N 4,25; gefunden... C69,54, H 7,18, N 4,19.Analysis for C19H23NO4: Calculated ... C 69.28, H 7.04, N 4.25; found... C69.54, H 7.18, N 4.19.
1,85 g nach obiger Vorschrift hergestelltes (-)-3-Methoxy-6-oxo-14-hydroxy-N-acethyl-morphinanphinan-(cis) wird der Behandlung mit 0,1 g p-Toluolsulfonsäure und 8 ml Äthylenglykol in 60 ml Benzol unterworfen und ergibt 2,0 g (- )-3-Methoxy-6,6-äthylendioxy-14-hydroxy-N-acetyl-morphinan-(cis), F. = 257 bis 258°C in: einer Ausbeute von 95%. 1.85 g (-) - 3-methoxy-6-oxo-14-hydroxy-N-acethyl-morphinanphinan- (cis) prepared according to the above is the treatment with 0.1 g of p-toluenesulfonic acid and 8 ml of ethylene glycol in 60 ml Subject to benzene and give 2.0 g of (-) -3-methoxy-6,6-ethylenedioxy-14-hydroxy-N-acetyl-morphinan- (cis), M.p. = 257 to 258 ° C in: a yield of 95%.
600 mg des oben erzeugten (-)-3-Methoxy-6,6-äthylendioxy-14-hydrxy-N-acethyl-morphinan-(eis) werden mit 70 ml Tetrahydrofuran und 500 mg Lithiumaluminiumhydrid vermischt und 6 Stunden bei Zimmertemperatur, d. h. bei 15 bis 30°C, gerührt. Das Reaktionsgemisch wird mit einer kleinen Menge wäßrigem Natriumhydroxyd, zwecks Zersetzung des Uberschusses an Lithiumaluminiumliydlid, vermischt und dann mit Äther geschüttelt. 600 mg of the (-) - 3-methoxy-6,6-ethylenedioxy-14-hydrxy-N-acethyl-morphinan- (ice) produced above are mixed with 70 ml of tetrahydrofuran and 500 mg of lithium aluminum hydride and 6 hours at room temperature, i.e. H. at 15 to 30 ° C, stirred. The reaction mixture is mixed with a small amount of aqueous sodium hydroxide to decompose the excess on lithium aluminum liydlide, mixed and then shaken with ether.
Die Ätherschicht wird unter vermindertem Druck abgedampft und der Rückstand aus Äthanol kristallisiert, wobei 535 mg (- )-3-Methoxy-6,6-äthylendioxy-14-hydroxy-N-äthyl-morphinan-(cis), in Form von Kristallen, F. = 139,5 bis 140,5°C, erhalten werden. [α]D24 - 70,0° (Chloroform).The ether layer is evaporated under reduced pressure and the Residue crystallized from ethanol, with 535 mg of (-) -3-methoxy-6,6-ethylenedioxy-14-hydroxy-N-ethyl-morphinan- (cis), in the form of crystals, m.p. = 139.5 to 140.5 ° C. [α] D24 - 70.0 ° (chloroform).
Analyse für C21H29NO4: Berechnet ... C 70,17, ii 8,13, N 3,90; gefunden ... C 69,42, H 8,16, N3,71.Analysis for C21H29NO4: Calculated ... C 70.17, ii 8.13, N 3.90; found ... C 69.42, H 8.16, N 3.71.
440 mg des erhaltenen (- )-3-Methoxy-6,6-äthylendioxy-14-hydroxy-N-äthyl-morphinan-(cis) werden mit 5 ml n-Chlorwasserstoffsäure vermischt und auf einem Wasserbad 10 Minuten erhitzt. Das Reaktionsgemisch wird mit Ammoniakwasser neutralisiert und mit Dichlorinethan gebohüttelt. Der Dichlormethanextrakt wird abgedampft und der Rückstand aus Äthanol umkristallisiert, wobei 380 mg (-)-3-Methoxy-6-oxo-14-hydroxy-N-äthyl-morphinan-(cis), in Form von Kristallen, F. = 188,5 bis 189,5°C, erhaften werden. [α]D24 -1 -116,0° (Chloroform). 440 mg of the (-) -3-methoxy-6,6-ethylenedioxy-14-hydroxy-N-ethyl-morphinan-(cis) obtained are mixed with 5 ml of n-hydrochloric acid and placed on a water bath for 10 minutes heated. The reaction mixture is neutralized with ammonia water and with dichloromethane bohüttelt. The dichloromethane extract is evaporated and the residue from ethanol recrystallized, whereby 380 mg (-) - 3-methoxy-6-oxo-14-hydroxy-N-ethyl-morphinan- (cis), in the form of crystals, m.p. = 188.5 to 189.5 ° C. [α] D24 -1 -116.0 ° (chloroform).
Das als Ausgangsmaterial verwendete (- )-3-ethoxy-6-oxo-14-hydroxy-morphinan-(cis), F. = 117 bis 1195C wird aus (-)-3-Methoxy-4,14-dihydroxy-6-oxo-N-methyl-morphinan, das nach einem Verfahren von E. Speyer und Mitarbeitern (vgl. The (-) -3-ethoxy-6-oxo-14-hydroxy-morphinan- (cis) used as starting material, F. = 117 to 1195C becomes from (-) - 3-methoxy-4,14-dihydroxy-6-oxo-N-methyl-morphinan, that according to a procedure by E. Speyer and co-workers (cf.
Liebigs Ann., Bd. 430 [1923], S. 1 bis 40, und, bezüglich der Konstitution der erhaltenen Verbindung, Liebigs Ann., Bd. 452 [1927], S. 211 bis 267) hergestellt werden kann, nach üblichen Methoden (vgl.Liebigs Ann., Vol. 430 [1923], pp. 1 to 40, and, regarding the constitution of the compound obtained, Liebigs Ann., Vol. 452 [1927], pp. 211 to 267) can be, according to the usual methods (cf.
Helvetica Chimica Acta, Bd. 34 1951], S. 2211 bis 2217, Tetrahedron, Bd. 15 [1961], S. 144 bis 153) crhalten.Helvetica Chimica Acta, Vol. 34 1951], pp. 2211 to 2217, Tetrahedron, Vol. 15 [1961], pp. 144 to 153).
B e i s p i e l 2 Herstellung von (-)-3-Methoxy-6-oxo-14-hydroxy-N-phenäthyl-morphinan-(cis) Zu einer Lösung von 3,26 g von (-)-3-Methoxy-6-oxo-14-hydroxy-morphinan-(cis) in 30 ml Benzol werden 2,13 g Phenacetylchlorid und 1,08 g Pyridin zugesetzt, und das erhaltene Gemisch wird 3 Stunden bei Rückfluß erhitzt. Nach Kühlen wird das Gemisch mit Wasser gewaschen und das Benzol unter vermindertem Druck entfernt. Hernach wird der Rückstand auf Tonerde, zwecks Entfernung der Verunreinigungen, mit Äther chromatographiert. Die so erhaltene ätherische Lösung wird eingeengt und ergibt 2,74 g (-)-3-Methoxy-6-oxo-14-hydroxy-N-phenacetyl-morphinan-(cis), in Form von Kristallen F. = 191 bis 193°C. [α]D20 - 153,4° (Chloroform, c = 1). IR-Absorption, #maxCHCl@ 3600, 3390, 1720, 1630 cm 1. B e i s p i e l 2 Production of (-) - 3-methoxy-6-oxo-14-hydroxy-N-phenethyl-morphinan- (cis) To a solution of 3.26 g of (-) - 3-methoxy-6-oxo-14-hydroxy-morphinan- (cis) in 30 ml of benzene are added to 2.13 g of phenacetyl chloride and 1.08 g of pyridine, and that The resulting mixture is refluxed for 3 hours. After cooling, the mixture becomes washed with water and the benzene removed under reduced pressure. Afterwards will the residue is chromatographed with ether on alumina to remove the impurities. The ethereal solution thus obtained is concentrated and gives 2.74 g of (-) - 3-methoxy-6-oxo-14-hydroxy-N-phenacetyl-morphinan- (cis), in the form of crystals F. = 191 to 193 ° C. [α] 20 D - 153.4 ° (chloroform, c = 1). IR absorption, # maxCHCl @ 3600, 3390, 1720, 1630 cm-1.
Analyse für C25H27NO4: Berechnet ... C 74,05, H 6,71, N 3,45; gefunden ... C 73,92, H 6,72, N 3,73.Analysis for C25H27NO4: Calculated ... C 74.05, H 6.71, N 3.45; found ... C 73.92, H 6.72, N 3.73.
2,15 g des auf obige Weise erhaltenen (-)-3-Methoxy-6-oxo-14-hydroxy-N-phenacetuyl-morphinans-(cis) werden mit 0,09 g p-Toluolsulfonsäure und 3,29 g Athylenglykol in 50 ml Benzol unter Rückfluß 6 Stunden unter azeotropen Abdestillieren des Reaktionswassers ketalisiert, hernach nacheinander mit Wasser, wäßriger natriumbicarbonatlösung und Wasser gewaschen. Das Benzol wird abgedampft. 2.15 g of the (-) - 3-methoxy-6-oxo-14-hydroxy-N-phenacetuyl-morphinans- (cis) obtained in the above manner are with 0.09 g of p-toluenesulfonic acid and 3.29 g of ethylene glycol in 50 ml of benzene under Reflux ketalized for 6 hours with azeotropic distillation of the water of reaction, then washed successively with water, aqueous sodium bicarbonate solution and water. The benzene is evaporated.
Man erhält 2,02 g rohes (-)-3-Metoxy-6,6-äthylendioxy-14-hydroxy-N-phenactyl-morphinan-(cis) in Form von Kristallen F. = 164 bis 1676°C. [α]D20 -126,0° (Chloroform, c = 1). IR-Absorption #maxCHCl3 3625, 3400,1630, 1085 cm-1.2.02 g of crude (-) - 3-metoxy-6,6-ethylenedioxy-14-hydroxy-N-phenactyl-morphinan- (cis) are obtained in the form of crystals F. = 164 to 1676 ° C. [α] 20 D -126.0 ° (chloroform, c = 1). IR absorption # maxCHCl3 3625, 3400, 1630, 1085 cm-1.
Analyse für C27H,a1NO5: Berechnet... C 72,14, H 6,95, N 3,12; gefunden C 71,92, H 7,02, H 3,24.Analysis for C27H, a1NO5: Calculated ... C 72.14, H 6.95, N 3.12; found C 71.92, H 7.02, H 3.24.
1,54 g (-)-3-Methoxy-6,6-äthylendioxy-14-hydroxy-N-phenacetyl-morphinan-(cis) werden in 40 ml wasserfreiem Tetrahydrofuran gelöst. die erhaltene Lösung wird zu einer Lösung von 0,85 g Lithiumaluminiumhydrid in 40 ml wasserfreiem Äther innerhalb von 15 Minuten zugetropft. Das so erhaltene Gemisch wird 5 Stunden unter Fückfluß behandelt. 1.54 g (-) - 3-methoxy-6,6-ethylenedioxy-14-hydroxy-N-phenacetyl-morphinan- (cis) are dissolved in 40 ml of anhydrous tetrahydrofuran. the solution obtained becomes to a solution of 0.85 g of lithium aluminum hydride in 40 ml of anhydrous ether within added dropwise from 15 minutes. The mixture thus obtained is refluxed for 5 hours treated.
Nach Zersetzen des Uberschusses von Lithiumaluminiumhydrid mit Wasser wird die ätherische Schicht abgetrennt und mit verdünnter Chlorwasserstoffsäure geschüttel. Die Chlorwasserstoffsäureschicht wird mit Natriumhydroxyd alkalisch gemacht und dann mit Äther geschüttelt. Die ätherische Schicht wird auf Tonerde, zwecks Abtrennung der Verunreinigungen, chromatographiert. Die erhaltene ätherische Lösung wird abgedampft, und man erhält 0,92 g (-)-3-Methoxy-6,6-äthylendioxy-14-hydroxy-N-phenäthyl-morphinan-(cis), in Form von Kristallen F. = 123 bis 124°C. [α]D20 -64,3° (Chloroform, c = 1). IR-Absorption #maxCHCl3 3400, 1085 cm-1.After decomposing the excess lithium aluminum hydride with water the ethereal layer is separated and washed with dilute hydrochloric acid shaken. The hydrochloric acid layer becomes alkaline with sodium hydroxide made and then shaken with ether. The ethereal layer is placed on clay, for the purpose of separating off the impurities, chromatographed. The preserved essential The solution is evaporated, and 0.92 g of (-) - 3-methoxy-6,6-ethylenedioxy-14-hydroxy-N-phenethyl-morphinan- (cis) are obtained, in the form of crystals F. = 123 to 124 ° C. [α] 20 D -64.3 ° (chloroform, c = 1). IR absorption # maxCHCl3 3400, 1085 cm-1.
Analyse für C27H33NO4: Berechnet ... C 74,45, H 7,64, N 3,22; gefunden... C 74,51, H 7,75, N 3,32.Analysis for C27H33NO4: Calculated ... C 74.45, H 7.64, N 3.22; found... C 74.51, H 7.75, N 3.32.
0,71 g (-)-3-Methoxy-6,6-äthylendioxy-14-hydroxy-N-phenäthyl-morphinan-(cis) werden mit 30 ml n-Chlorwasserstoffsäure geschüttelt und auf einem Wasserbad 10 Minuten erhitzt. Das Reaktionsgemisch wird mit Ammoniakwasser neutralisie'rt und mit Dichlormethan geschüttelt. Die Dichlormethanlösung wird abgedampft und der Rückstand aus Athanol kristallisiert; man erhält 0,58 g (- )-3-Methoxy-6-oxo- 1 4-hydroxy-N-phenäthyl-morphinan-(cis), in Form von Kristallen F. = 130,5 bis 131°C. 0.71 g (-) - 3-methoxy-6,6-ethylenedioxy-14-hydroxy-N-phenethyl-morphinan- (cis) are shaken with 30 ml of n-hydrochloric acid and on a water bath Heated for 10 minutes. The reaction mixture is neutralized with ammonia water and shaken with dichloromethane. The dichloromethane solution is evaporated and the Residue crystallized from ethanol; 0.58 g of (-) -3-methoxy-6-oxo-1 is obtained 4-hydroxy-N-phenethyl-morphinan- (cis), in the form of crystals, F. = 130.5 to 131 ° C.
[α]D20 - 99,5° (Chloroform, c = 1). IR-Absorption #maxCHCl3 3420, 1710 cm Analyse für C25H29NO3: Berechnet ... C 76,69, H 7,47, N 3,58; gefunden ... C 76,62, H 7,56, N 3,71.[α] 20 D - 99.5 ° (chloroform, c = 1). IR absorption # maxCHCl3 3420, 1710 cm Analysis for C25H29NO3: Calculated ... C 76.69, H 7.47, N 3.58; found ... C 76.62, H 7.56, N 3.71.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1406162 | 1962-04-06 | ||
| JP1406062 | 1962-04-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1286045B true DE1286045B (en) | 1969-01-02 |
Family
ID=26349949
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1963S0084596 Pending DE1286045B (en) | 1962-04-06 | 1963-04-06 | Process for the preparation of N-substituted 3-methoxy-6-oxo-14-hydroxy-morphinan derivatives |
Country Status (3)
| Country | Link |
|---|---|
| CH (1) | CH460036A (en) |
| DE (1) | DE1286045B (en) |
| GB (1) | GB1028407A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE788478A (en) * | 1971-09-08 | 1973-03-06 | Bristol Myers Co | PROCESS FOR PREPARING ANALGESIC COMPOUNDS |
| US3980641A (en) * | 1975-07-31 | 1976-09-14 | Bristol-Myers Company | Process for the preparation of 14-hydroxymorphinans |
| US4017497A (en) | 1975-11-18 | 1977-04-12 | Bristol-Myers Company | Process for the preparation of 14-hydroxymorphinan derivatives |
-
1963
- 1963-04-04 GB GB1348463A patent/GB1028407A/en not_active Expired
- 1963-04-05 CH CH437163A patent/CH460036A/en unknown
- 1963-04-06 DE DE1963S0084596 patent/DE1286045B/en active Pending
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| None * |
Also Published As
| Publication number | Publication date |
|---|---|
| CH460036A (en) | 1968-07-31 |
| GB1028407A (en) | 1966-05-04 |
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