DD143774A5 - PROCESS FOR PREPARING INTERMEDIATE PRODUCTS FOR SYNTHESIS OF 1,9-DIHYDROXY-HEXAHYDRODIBENZOPYRANES - Google Patents
PROCESS FOR PREPARING INTERMEDIATE PRODUCTS FOR SYNTHESIS OF 1,9-DIHYDROXY-HEXAHYDRODIBENZOPYRANES Download PDFInfo
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- DD143774A5 DD143774A5 DD76213370A DD21337076A DD143774A5 DD 143774 A5 DD143774 A5 DD 143774A5 DD 76213370 A DD76213370 A DD 76213370A DD 21337076 A DD21337076 A DD 21337076A DD 143774 A5 DD143774 A5 DD 143774A5
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/12—Antihypertensives
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- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
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- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
- C07C43/2055—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
Description
-* 21 3 3 7 0 - * 21 3 3 7 0
Herstellungsverfahren für Zwischenprodukte zur Synthese von "U9-Bihydroxy-hexahydrodibenzopyrknen. Methods of Preparation of Intermediates for the Synthesis of "U9-Bihydroxy-hexahydrodibenzopyr .
i i
Die Erfindung betrifft ein Verfahren zur Herstellung von Zwischen« produkten für die Synthese von 1,9-Dihydroxyhexahydibenzopyranen, die in 3-Stellung (1) einen Aryl- oder Cycloalkylrest W über einen Alkylenrest gebunden oder (2) einen Methyl-, Aryl- oder Cycloalkylrest aufweisen, dar an die genannte Stellung (a) über 0-, S-, SO- oder SOp«Gruppierung unterbrochenen Alkylenrest oder (b) einen Alkylenrest gebunden ist, der an die genannte 3-Stellung oder den Methyl-, Aryl- bzw. Cycloalkylrest durch eine 0-, S-, SO- oder SO«-Gruppierung gebunden ist»The invention relates to a process for the preparation of intermediates for the synthesis of 1,9-dihydroxyhexahydibenzopyrans, which in the 3-position (1) has an aryl or cycloalkyl radical W bonded via an alkylene radical or (2) a methyl, aryl or Have cycloalkyl radical, is bound to said position (a) via 0-, S-, SO- or SOp "grouping interrupted alkylene or (b) an alkylene radical attached to said 3-position or the methyl, aryl or Cycloalkyl radical is bonded by a 0, S, SO or SO "grouping.
Obgleich heute bereits eine Vielzahl von Analgetika verfügbar ist, geht die Suche nach neuen und verbesserten Mitteln weiter, da ein Mittel fehlt, das zur Bekämpfung verschiedenartiger Schmerzen brauch·Although a variety of analgesics are already available today, the search for new and improved agents continues because of the lack of an agent needed to combat various types of pain.
bar und nur von geringeren Nebeneffekten begleitet ist. Das lange Zeit am häufigsten verwendete Mittel "Aspirin" ist bei schweren Schmerz praktisch wirkungslos, außerdem sind verschiedene unerwünschte Nebenwirkungen bekannt. Andere stärkere Analgetika vie d~ Propexyphen, Codein und Morphin können Suchterscheinungen hervorrufen» Der Bedarf an verbesserten wirksamen Analgetika ist daher offensichtlich«bar and only accompanied by minor side effects. The long-used "aspirin" is practically ineffective in severe pain and various undesirable side effects are known. Other Stronger Analgesics - Propexyphene, Codeine, and Morphine Can Create Seizures "The need for improved effective analgesics is therefore obvious."
Die analgetischen Eigens chaften von 9- Nor-9ß-hydroxyhexahydrocannabinol und anderen cannabinoiden Strukturen, z.B.Δ -Tetrahyarocannabinol (A, -THC) und dessen Hauptmataboliten 11-Hydroxy~ A -THC wurden von Wilson und May, Absts, Papers, Am. Cheia.Soc., 168 Moet», MEDI 11 (1974) und J. Med. Chem., J^, 475-W (1974) beschrieben»The analgesic properties of 9-nor-9β-hydroxyhexahydrocannabinol and other cannabinoid structures, eg Δ-tetrahyarocannabinol (A, -THC) and its major metabolite 11-hydroxy- A- THC were reported by Wilson and May, Absts, Papers, Am. Cheia, Soc., 168 Moet, MEDI 11 (1974) and J. Med. Chem., J ^, 475-W (1974).
Die US-PS 3 507 885 und 3 636 058 beschrieben verschiedene 1-Hydroxy-3-alkyl-6H-dibenzo~/"*b, d 37pyrane, die in 9-Stellung Substituenten wie die Oxogruppe, Hydrocarbyl- und Hydroxygruppe oder Chlor, Hydrocarbylidenreste aufweisen, und Zwischenprodukte zu deren Herstellung·US Pat. Nos. 3,507,885 and 3,636,058 have described various 1-hydroxy-3-alkyl-6H-dibenzo [s], 37-pyrenes which have 9-position substituents such as the oxo group, hydrocarbyl and hydroxy group or chlorine, Hydrocarbylidenreste have, and intermediates for their preparation ·
Die US-PS 3 649 650 offenbart eine Reihe von Tetrahydro-6,6,9-trialkyl-6H-dibenzo /"bjd^pyran-derivaten mit einer&>-Dialkylaminoalkoxygruppe in 1-Stellung, die als Psychotherapeutika wirken»U.S. Patent No. 3,649,650 discloses a series of tetrahydro-6,6,9-trialkyl-6H-dibenzo / "bjd ^ pyran derivatives having a 1-position dialkylaminoalkoxy group which act as psychotherapeutic agents."
Die DT-OS 2 451 934 beschreibt 1,9-Dib.ydroxy-hexahydrodibenzo/~b,d__7 pyrane und 1-Acylderivate davon, die in 3-Stellung einen Alkyl- oder Alkenylrest aufweisen, als hypotensive, psychotrope, sedierende und analgetische Mittel, Die bsi der Herstellung dieser Verbindungen als Vorprodukte verwendeten Hexahydro-9H-dibenzo/"b,d__7 pytan-9-one, die die gleiche Brauchbarkeit \<ie die betreffenden 9-Hydroxyverbindungen haben sollen, werden in der DOS 2 451 932 beschrieben»DT-OS 2 451 934 describes 1,9-dib.hydroxy-hexahydrodibenzo / ~ b, d__7 pyrans and 1-acyl derivatives thereof, which have an alkyl or alkenyl radical in the 3-position, as hypotensive, psychotropic, sedative and analgesic agents The hexahydro-9H-dibenzo / "b, d -7-pytan-9-ones used as precursors for the preparation of these compounds which are said to have the same utility as the corresponding 9-hydroxy compounds are described in DOS 2 451 932"
-3- 213370- 3 - 213370
Die DT-OS 2 Α·15 697 beschreibt 1- Hydroxy-6,6,9-trimethylhexahydrodibenzo /"b,d_7pyran-derivate und bei ihrer Herstellung, auftretende Zwischenprodukte, die in 3-Stellung einen Aralkyl-, substituiertenAralkyl- oder Pyridylalkylrest aufweisen. Sie dienen als Analgetika und milde Tranquilizer.DT-OS 2Α15,697 describes 1-hydroxy-6,6,9-trimethylhexahydrodibenzo / "b, d_7pyran derivatives and intermediates which occur in their preparation and which have an aralkyl, substituted aralkyl or pyridylalkyl radical in the 3-position They serve as analgesics and mild tranquilizers.
Die US-PS 3 856 821 beschreibt eine Reihe 3-alkoxysubstituierter Dibenzo^fbjd^pyi'ane mit antiarthritischer und entzündungshemmender Wirkung sowie Wirkung auf das Zentralnervensystem.US Pat. No. 3,856,821 describes a series of 3-alkoxy-substituted dibenzo ^ fbj ^ pyi'anes having antiarthritic and antiinflammatory activity and action on the central nervous system.
Über eine stsreospezifische Synthese von (~)trans-6a, 7,8,10a-Tetrahydro-3-pöntyl-6,6t9-trimethyl-6H-dibenzo/"b,d>_7rpyran-1-ol, das auch als (~)Λ -Tetrahydrocannabinol bekannt ist, berich~ teten Razdan et al., (J. Am. Chem. Soc, £6, 5860-5» 1974)Via a stereospecific synthesis of (~) trans-6a, 7,8,10a-tetrahydro-3-pöntyl-6,6 t 9-trimethyl-6H-dibenzo / "b, d > _7 r pyran-1-ol, the also known as (~) Λ -tetrahydrocannabinol, reported by Razdan et al., (J. Am. Chem. Soc., 6, 5860-5, 1974).
Das aus einer Stufe bestehende Verfahren besteht in der Umsetzung von ci£/trans~(+)-p-ffentha-2,8-dien-1~ol mit Olive toi in Gegenwart von 1 % Bortrifluorid-ätherat und wasserfreiem Magnesiumsulfat in Methylenchlorid bei O C. Die so entstandene Tetra-hydroverbindung wird nach dem Verfahren von Wildes und anderen, J. Org. Chem. _3_6, 721-3 (1971) in die betreffende 9-Keto-hexahydroverbindung überführt. Das Verfahren be steht in der Umsetzung der 1-Kydroxy-totrahydroverbindung zum Methyläther und dann zum Chlorwasserstoff-Addukt durch Umsetzung mit Zinkchlorid und Chlorwasserstoff bei O0C in Chloroform. Das Addukt wird mit Kaliumtricyclopentylcarbinolat dehydrohalogeniert unter Bildung des entsprechenden 6a,7,8,9,iO,iOa-Haxahydro-3-penthyl~6,6-dimQthyl-9-methylen~ GH-dibenzOj/^bjd^ pyran-1-olmethyläthers. Die Oxidation der 9-Methylengruppo mit Kaliumpermanganat-perjodat ergibt das 9-KetonThe one-step process involves the reaction of ci / trans ~ (+) - p-ffentha-2,8-dien-1-ol with olive toi in the presence of 1 % boron trifluoride etherate and anhydrous magnesium sulfate in methylene chloride C. The resulting tetrahydro compound is converted into the corresponding 9-keto-hexahydro compound by the method of Wildes et al., J. Org. Chem. 3-3, 721-3 (1971). The method be in the reaction of 1-kydroxy-totrahydroverbindung to methyl ether and then to the hydrogen chloride adduct by reaction with zinc chloride and hydrogen chloride at 0 0 C in chloroform. The adduct is dehydrohalogenated with potassium tricyclopentyl carbinolate to give the corresponding 6α, 7,8,9, 10α, 10α-hexahydro-3-penthyl-6,6-dimoethyl-9-methylene-GH-dibenzoj-1-pyrid-1-olmethyl ether , Oxidation of the 9-methylene group with potassium permanganate periodate gives the 9-ketone
Die Demethylierung des Methyläthers mit Pyridiniumchlorid oder einem anderen sauren Reagens führt zum Alkohol. Demethylation of the methyl ether with pyridinium chloride or other acidic reagent leads to alcohol.
213370213370
Bergel und andere, J« Chem. Soc, 286-7 (194-3) untersuchten den Ersatz der Pentylgruppe in 3-Stellung des 7,8,9,10-Tetrahydro-3-pentyl-6,6,9-Trimethyl-6H-dibenzo^b,d_7pyran-1-ol0 durch einen Alkoxyrest (Butoxy, Pentoxy, Nexoxy und Octoxy) und fanden, daß damit biologische Unwirksamkeit eintritt. Vom Hexoxyderivat wird eine schwache Haschisch-Wirkung bei 10 bis 20 mg/kg angegeben. Die restlichen Äther zeigten keine Wirkung in Dosen bis zu 20 mg/kg.Bergel and others, J. Chem. Soc., 286-7 (194-3) investigated the replacement of the pentyl group at the 3-position of the 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl- 6H-dibenzo ^ b, d_7pyran-1-ol0 by an alkoxy radical (butoxy, pentoxy, nexoxy and octoxy) and found to result in biological ineffectiveness. The hexoxy derivative is reported to have a low hash effect at 10 to 20 mg / kg. The remaining ethers showed no effect at doses up to 20 mg / kg.
In einer neueren Studie wird von Loev und anderen, Med„ Chern., 16, 1200-6 (1973) über Vergleiche von 7,8,9,iO-Tetrahydro-3-substituiert-6i6,9-trimethyl-6H-dibenzo/~b,d_7pyran-1-elen berichtet, bei denen der 3-Substituent aus -XH (CH3)C5H.., CH2CH(CH3)C5H1 oder CH(CH3)C5H11 besteht.A recent study by Loev and others, Med. Chern., 16, 1200-6 (1973), compares 7,8,9, 10-tetrahydro-3-substituted-6 , 6,9-trimethyl-6H, dibenzo / ~ b, d_7pyran-1-enes where the 3-substituent is -XH (CH 3 ) C 5 H., CH 2 CH (CH 3 ) C 5 H 1 or CH (CH 3 ) C 5 H 11 exists.
Die Verbindung mit Ätherseitenkette war um 50 % weniger wirksam auf das Zentralnervensystem wie die entsprechende Verbindung, bei der die Alkylseitenkette direkt an den aromatischen Ring gebunden ist und nicht übar ein zwischengeschaltetes Sauerstoffatom und fünfmal so wirksam wie die Verbindung, bei der das Sauerstoffatom durch die Methylengruppe ersetzt ist* Es wurde nun eine Klasse von Verbindungen gefunden, die als Analgetika, hypotensive, antisekrstorische und angstlösende Mittel sowie als Immunosuppressoren und Tranquilizer wirksam sind, nämlich die 1,9-Dihydroxydibenzo /~b,d_7pyrane der Formel I, die nicht narkotisch wirken und keine Sucht verursachen.The linkage with ether side chain was 50 % less effective on the central nervous system than the corresponding compound in which the alkyl side chain is attached directly to the aromatic ring and not an intermediate oxygen atom and five times as effective as the compound where the oxygen atom is through the methylene group There has now been found a class of compounds which are active as analgesics, hypotensive, antisenkrstorische and anxiolytic agents as well as immunosuppressants and tranquilizers, namely the 1,9-Dihydroxydibenzo / ~ b, d_7pyrane of the formula I, which are not narcotic and do not cause addiction.
In einej^priroritätsgleichen Patent (DD 129214) wird ein Verfahren zur Herstellung eines Dibenzo/~b,dJ7pyrans der Formel (I) beschrieben, worin (J die GruppierungIn a same priority patent (DD 129214) a process for the preparation of a dibenzo / ~ b, dJ7pyrans of the formula (I) is described in which (J is the grouping
C oderC or
-5- 213370-5- 213370
bedeutet und R Wasserstoff oder ein Alkanoylrest mit 1 bis 5 Kohlenstoffatomen ist. R bedeutet Wasserstoff, einen Alkaaoylrest mit 1 bis 5 Kohlenstoffatomen oder einen Rest der Formel -CO-(CHp) -NRpR-, worin ρ die Zahl 0 oder eine ganze Zahl von 1 bis h und Rp und R3 einzeln Wasserstoff oder Alkylreste mit 1 bis 4 Kohlenstoffatome oder zusammengenommen mit dem Stickstoffatom, an das sie gebunden sind, einen 5- oder 6-gliedrigen heterozyklischen Piperidino-, Pyrrolo-, Pyrrolidino-, Morpholino- oder R-Alkylpiperazinorest mit 1 bis h Kohlenstoffatomen im Alkylanteil bedeuten. R^ und R1. sind Wasserstoff, Methyl oder Äthyl, Z (a) ein Alkylenrest mit 1 bis 9 Kohlenstoffatomen oder (b) ein Rest der Formel -(alk.) « X-(alkp) ~, worin jeder der Reste (alk.) und (alkp) 1 bis 9 Kohlenstoff atome besitzt, unter der Maßgabe, daß die Summe der Kohlenstoffatome in (alk.) plus (alkp) nicht mehr als 9 beträgt, und worin m und η die Zahl O oder 1 und X, O, S, SO oder SO2 bedeuten. W bezeichnet einen Methyl-, Phenyl-, p-Chlorphenyl~, p-Fluorphenyl-, Pyridyt-, Piperid^l- oder einen Cycloalkylrest mit 3 bis 7 Kohlenstoffatomen oder einen durch Phenyl, p-Chlorphenyl oder p-Fluorphenyl monosubstituierten Cycloalkylrest, unter der Maßgabe, daß wenn W Methyl bedeutet, Z ein Restand R is hydrogen or an alkanoyl radical having 1 to 5 carbon atoms. R is hydrogen, an alkaaoyl radical having 1 to 5 carbon atoms or a radical of the formula -CO- (CHp) -NRpR-, where ρ is the number 0 or an integer from 1 to h and Rp and R 3 are individually hydrogen or alkyl radicals having 1 to 4 carbon atoms or taken together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocyclic piperidino, pyrrolo, pyrrolidino, morpholino or R-alkylpiperazino radical having 1 to h carbon atoms in the alkyl moiety. R ^ and R 1 . R Wasserstoff and R sind are hydrogen, methyl or ethyl, Z (a) is an alkylene radical having 1 to 9 carbon atoms or (b) is a radical of the formula - (alk.) X- (alkp) -, wherein each of the radicals (alk.) and (alkp ) Has 1 to 9 carbon atoms, provided that the sum of carbon atoms in (alk.) Plus (alkp) is not more than 9, and wherein m and η are O or 1 and X, O, S, SO or SO 2 . W denotes a methyl, phenyl, p-chlorophenyl, p-fluorophenyl, pyridyl, piperidyl or a cycloalkyl radical having 3 to 7 carbon atoms or a cycloalkyl radical monosubstituted by phenyl, p-chlorophenyl or p-fluorophenyl with the proviso that when W is methyl, Z is a radical
-(alk^ - X - (alk2)R ~- (alk - X - (alk 2 ) R -
ist» Gemäß der genannten Anmeldung reduziert man eine Verbindung der Formel (II) oder (III) und, falls Q eine GruppierungAccording to the said application, a compound of the formula (II) or (III) is reduced and, if Q is a grouping
H^^ ORH ^^ OR
bedeutet, worin R ein Alkanoylrest ist, setzt man eine Verbindung der Formel (I), worin Qin which R is an alkanoyl radical, one sets a compound of formula (I), wherein Q
H^ ORH ^ OR
213 3 7 0213 3 7 0
bedeutet, wobei R Wasserstoff ist, mit der entsprechenden Säure, dem Säurechlorid oder Säureanhydrid umf where R is hydrogen, with the corresponding acid, the acid chloride or acid anhydride by f
Die Verbindungen der Formel (II) werden durch Umsetzung einer Verbindung der Formel (IV), worin R., R^, Rc» Z und W die gleiche Bedeutung wie bei den Verbindungen der FormelThe compounds of the formula (II) are obtained by reacting a compound of the formula (IV) in which R., R.sup.1, R.sup.2, Z and W have the same meaning as in the compounds of the formula
\/ IfI-JL/ IfI-JL
(I) haben, mit Methyl-3»iKgketon erhalten. Ziel der Erfindung: (I), with methyl-3 »iKgketon. Object of the invention:
Mit der Erfindung soll ein Verfahren zur Herstellung von Verbindungen der Formel (IV), wenn in dieser R. für Wasserstoff steht, also von Verbindungen der allgemeinen Formel (V) angegeben werden. In der allgemeinen Formel (V) bedeuten: Ra und Rc : Wasserstoff, Methyl oder Äthyl, Z (a) : einen Alkylenrest mit 1 bis 9 Kohlenstoffatomen oder (b) : einen Rest der FormelThe invention relates to a process for the preparation of compounds of the formula (IV) when R.sup.1 is hydrogen, ie compounds of the general formula (V). In the general formula (V), Ra and Rc represent hydrogen, methyl or ethyl, Z (a): an alkylene radical having 1 to 9 carbon atoms or (b): a radical of the formula
- (alkn)m - X - CaIkJj)n -, vorin jeder der Reste (alk.) und (alk?) 1 bis 9 Kohlenstoffatome besitzt, unter der Maßgabe, daß die Summe der Kohlenstoffatome in (alk^-plus (alkp)-Rest nicht mehr als 9 beträgt» Außerdem bedeuten:- (alk n) m - X - CaIkJj) n -, each vorin of the radicals (alk) and (alk) has from 1 to 9 carbon atoms, with the proviso that the sum of the carbon atoms (in (alk ^ -plus AlkP.? ) -Rest not more than 9 »
m und η : die Zahl 1 oder Λ X : O, S, SO oder SO2 m and η: the number 1 or Λ X: O, S, SO or SO 2
W j einen Methyl-, Phenyl-, p-Chlorphenyl-,W j is a methyl, phenyl, p-chlorophenyl,
p-Fluorphenyl-, Pyridyl-, Piperid^i- oder Cycloalkylrest mit 3 bis 7 Kohlenstoffatomen oder einen durch Phenyl, p-Chlorphenyl oder p-Fluorphenyl monosabstituierten Cyclo*p-fluorophenyl, pyridyl, piperidinyl or cycloalkyl radical having 3 to 7 carbon atoms or a monosubstituted by phenyl, p-chlorophenyl or p-fluorophenyl cyclo *
- ν - 21 3 3 7 O- ν - 21 3 3 7 O
alkylrest, unter der Maßgabe, daß, venn W Me^thyl bedeutet, Z ein Restwith the proviso that, when W is methyl, Z is a radical
istv is v
Erfindungsgemäß wird so vorgegangen, daß man eine Verbindung der allgemeinen Formel (VI), worin R^, R5, Z und W die obige Bedeutung haben, in Gegenwart von Natriumhydrid mit Äthylformiat umsetzt«According to the invention, a compound of the general formula (VI) in which R 1, R 5 , Z and W have the abovementioned meaning, is reacted with ethyl formate in the presence of sodium hydride.
An einigen Beispielen soll die Erfindung nachfolgend näher erläutert werden«By some examples, the invention will be explained in more detail below «
dl-5-Hydroxy-2,2-dimethyl-7-(1-methyl-4-phenylbutyl)-4-chromanoQdl-5-hydroxy-2,2-dimethyl-7- (1-methyl-4-phenylbutyl) -4-chromanoQ
Ein Gemisch aus 9,6 g 2-(3,5-Dihydroxyphenyl)~5phenyl-pentan und 4»5 g 3-Methylcrotonsäure wird unter Stickstoff auf 125°C erhitzt, dann werden 8,7 ml Bortrifluoridätherat zugesetzt. Nach 1-ßtündigen Erhitzen am Rückfluß wird das Reaktionsgemisch abgekühlt und mit 10 ml Wasser und dann mit 40 ml 6 n-Natriumhydroxidlösung versetzt. Das Gemisch wird 5 Minuten auf einem Dampfbad erhitzt, abgekühlt und mit 6 η-Salzsäure angesäuert. Die wäßrige Phase wird dreimal mit je 100 ml Äther extrahiert und die vereinigten Ätherextrakte werden mit 25 ml 10 %iger Natriumbicarbonatlösung und 25 ml Wasser gewaschen. Die organische Phase wird über Natriumsulfat getrocknet und im Vakuum eingeengt, wobei 12,7 g eines rohen ÖlsA mixture of 9.6 g of 2- (3,5-dihydroxyphenyl) -5-phenyl-pentane and 4 g of 3-methylcrotonic acid is heated to 125 ° C. under nitrogen, then 8.7 ml of boron trifluoride etherate are added. After refluxing for 1 hour, the reaction mixture is cooled and treated with 10 ml of water and then 40 ml of 6N sodium hydroxide solution. The mixture is heated on a steam bath for 5 minutes, cooled and acidified with 6N hydrochloric acid. The aqueous phase is extracted three times with 100 ml of ether and the combined ether extracts are washed with 25 ml of 10% sodium bicarbonate solution and 25 ml of water. The organic phase is dried over sodium sulfate and concentrated in vacuo to give 12.7 g of a crude oil
erhalten werden, das durch Silikagelchromatographie gereinigt wird. Dabei werden 5,0 g dl-5-Hydroxy-2,2-diiaethyl-7-(i-methyl-4~phenylbutyl)-4~chromanon als farbloses Öl erhalten,which is purified by silica gel chromatography. This gives 5.0 g of dl-5-hydroxy-2,2-di-ethyl-7- (i-methyl-4-phenylbutyl) -4-chromanone as a colorless oil,
XR: (CHCl3) C=O '«635 cm"1.XR: (CHCl 3 ) C = O '«635 cm" 1 .
HMR: <f CDCl 1"1*7 (Mf7» 0^ "440^y1* X^ylen), 1,5 (S,6,gem Dimethyl), 2,3-2,9 (M,3,benzylisches Methylen, Methinyl), 2,65 (S,2 (X-Methylen), 6,1-6,35 (M,2,aromatisch), 6,9-7,4· (M,5»aromatisch), 11,53» 11,63 (d,1,Hydroxyl).HMR: <f CDCl 1 " 1 * 7 (Mf 7 » 0 ^ " 440 ^ y 1 * X ^ ylen), 1.5 (S, 6, according to dimethyl), 2.3-2.9 (M, 3, benzylic methylene, methynyl), 2.65 (S, 2 (X-methylene), 6.1-6.35 (M, 2, aromatic), 6.9-7.4 (M, 5) aromatic), 11.53 »11.63 (d, 1, hydroxyl).
Analog viird 2-(3,5-Dihydroxyphenyl)-6-phenylhexan in das dl-5-Hydroxy-2,2~dimethyl-7-(i-methyl-5-phenylpentyl)-4-chromanon (Öl) überführt»Analogously, 2- (3,5-dihydroxyphenyl) -6-phenylhexane is converted to the dl-5-hydroxy-2,2-dimethyl-7- (i-methyl-5-phenylpentyl) -4-chromanone (oil) »
NMR: S ^1 1,2 (d,3CC-Methy 1, J = ? cps), 1,4 (S,6,gem Dimethyl), 1,0-1,9 Z~M, 6,0-CH2-(CH2)3-C(CH )-ArJ^, 2,3-2,8 (M,3,benzylisches Methylen, Methinyl), 2,7 (S,2,oc-Methylen), 6,2-6,4 (M,2,aromatisch), 7,1-7,3 (M,5,aromatisch), 11,6(St1,Hydroxyl), 1-(3»5'-Dihydroxyphenyl)-2-phenyläthan wird in 5«^ydroxy-2,2-dimethyl~7-(2-phenyläthyl)-A-chromanon (Öl) überführt» IR: (CHCl3) C=O 1645 cm"1.NMR: S ^ 1 1.2 (d, 3CC-Methy 1, J = cps), 1.4 (S, 6, according to dimethyl), 1.0-1.9 Z ~ M, 6.0-CH 2 - (CH 2 ) 3 -C (CH) -ArJ ^, 2.3-2.8 (M, 3, benzylic methylene, methynyl), 2,7 (S, 2, oc-methylene), 6,2 -6.4 (M, 2, aromatic), 7.1-7.3 (M, 5, aromatic), 11.6 (S t 1, hydroxyl), 1- (3 »5'-dihydroxyphenyl) -2 -phenylethane is converted into 5-hydroxy-2,2-dimethyl-7- (2-phenylethyl) -A-chromanone (oil). IR: (CHCl 3 ) C = O 1645 cm -1 .
HMR: CTjJc1 1,45 (S,6,gem Dimethyl) 2,65 (S,2, OC-Methylen), 285 (s,4t .3 Äthylen), 6,25 , 6,3 (sd,2, aromatisch), 7,2 (S,5, aromatisch), 11,6 (S,1, Hydroxyl-DgO Überlagerung). MS: (Mol. ion) 296.HMR: CTjJc 1 1.45 (s, 6, gem dimethyl), 2.65 (s, 2, OC-methylene), 285 (s, t 4 .3 ethylene), 6.25, 6.3 (sd, 2 , aromatic), 7.2 (S, 5, aromatic), 11.6 (S, 1, hydroxyl-DgO overlay). MS: (Mol. Ion) 296.
2-(3f5-Dihydroxyphenyl)-4-phenylbutan wird in dl-5«Hydroxy-£,2-. dimsthyl-7-(i-methyl~4phenylpropyl)-4-chromanon (Öl) übergeführt.2- (3f5-Dihydroxyphenyl) -4-phenylbutane is dissolved in dl-5'-hydroxy-, 2-. dimethyl-7- (i-methyl-4-phenylpropyl) -4-chromanone (oil).
-s- 213370 -s-213370
1,3 (d,3,Methyl), 1,45 (S,6,gem Dimethyl),1,3 (d, 3, methyl), 1,45 (S, 6, according to dimethyl),
ς3 1,55-2,1 (M,2,Methylen), 2,25-2,75 (M,3,benzylischas Methylen, Methinyl), 6,15 (d,2,aromatisch), ?,1 (S,5,aromatisch), 11,6 (S,1,Hydroxyl-D20 überlagerung)· MS: (Mol. ion) 324. ς 3 1.55 to 2.1 (M, 2, methylene), 2.25 to 2.75 (M, 3, benzylischas methylene, methinyl), 6.15 (d, 2, aromatic),?, 1 ( S, 5, aromatic), 11.6 (S, 1, hydroxyl-D 2 O overlay) · MS: (mol. Ion) 324.
5,2? g 2~(3,5-Dihydroxyphenyl-5-pbenylpentan werden mit 4,81 ml Bortrifluorid-ätherat und 2,O8 g frisch destillierter Crotonsäure anstelle der 3-Methylcrotonsäure in das dl-5-Hydroxy-2-methyl~ 7~(1-methyl'-4-phenylbutyl)-4-chromanon überführt:5.2? g 2 ~ (3,5-Dihydroxyphenyl-5-pbenylpentane are converted to the dl-5-hydroxy-2-methyl-7-yl with 4.81 ml of boron trifluoride etherate and 2.8 g of freshly distilled crotonic acid in place of the 3-methylcrotonic acid. 1-methyl'-4-phenylbutyl) -4-chromanone:
NMR: <f ™j*. 1,1 (D,3».α-Methyl, J = ? Hz), 1,4NMR: <f j *. 1,1 (D, 3 ».α-methyl, J =? Hz), 1,4
3 (D,3,2-Methyl, J = 7 Hz), 1,3-1,8 (M,4-Äthylen), 2,2-2,9 (M,5c{,«Methylen, benzylisches Methylen, Methinyl), 4,5 (M,1,Methinyläther), 6,1, 6,2, (2D,2,aromatisch, J = 1 Hz), 6,9-7,4 (M,5,aromatisch), 11,7 (S,1, phenolisches3 (D, 3,2-methyl, J = 7Hz), 1,3-1,8 (M, 4-ethylene), 2,2-2,9 (M, 5c {, "methylene, benzylic methylene, Methinyl), 4.5 (M, 1, methynyl ether), 6.1, 6.2, (2D, 2, aromatic, J = 1 Hz), 6.9-7.4 (M, 5, aromatic), 11.7 (S, 1, phenolic
4-(3j5-I>ihydroxyphenyl)-1-phenoxypentan wird in dl-5-Hydroxy-2j2-dimethyl-7-(i-möthyl-4-phenoxybutyl)-4-chrorüanon, hellgelbes Öl, überführt:4- (3j5-i> ihydroxyphenyl) -1-phenoxypentane is converted to dl-5-hydroxy-2j2-dimethyl-7- (i-methyl-4-phenoxybutyl) -4-chorananone, a light yellow oil.
MS: (Mol. ion) 354MS: (Mol. Ion) 354
Rf = O,61 (Silicagel, 18-Benzol:1-Äthylacetat) Analyse: Ber. für C22H26 O^i C: 74,55: H: 7,39 % R f = O, 61 (silica gel, 18-benzene: 1-ethyl acetate) Analysis: Ber. for C22 H26 O ^ i C: 74.55: H: 7.39%
Gefe: C 74,56: H: 7,36 %, Gef e : C 74.56: H: 7.36 %,
4-(3,5-Dihydroxyphenyl)-1-(4-pyridyl)pentan wird in dl-5-Hydroxy-2,2-dimethyl-7-/"i-Giethyl-4-(4-pyridyl)butylJ7~4-chromanon, ein Öl, überführt: Rf" =s 0,39 (Silicagel, 1-Benzol:1~Äthylacetat) NMR: Cp^1 1-1,90 (M,13-H,Methylen, Methyl-Dublett bei 1,20, J = 7 Hz, und gem Dimethyl-Singulett bei 1,5): 2,43-2,86 (M,5-fl,Methylen, Methinyl, einschließlich Singulett '4- (3,5-Dihydroxyphenyl) -1- (4-pyridyl) pentane is converted into dl-5-hydroxy-2,2-dimethyl-7 - / i -giethyl-4- (4-pyridyl) -butyl J7~4 -chromanone, an oil, converted: R f "= s 0.39 (silica gel, 1-benzene: 1 ~ ethyl acetate) NMR: Cp ^ 1 1-1.90 (M, 13-H, methylene, methyl doublet at 1.20, J = 7 Hz, and according to dimethyl singlet at 1.5): 2.43-2.86 (M, 5-fl, methylene, methinyl, including singlet)
21 33721 337
(zwei C-3 H»s bei 2,71): 6,26 (b.d.S, 1-H, aromatisch):(two C-3 Hs at 2.71): 6.26 (b.d.s, 1-H, aromatic):
6,33 (b.d.S,1-H,aromatisch): 7,00-7,20 (b.d.D.2-H-Pyridin aromatisch): 7,25 (b.d.S,1-H,Hydroxyl):6.33 (b.d.S, 1-H, aromatic): 7.00-7.20 (b.d.D.2-H-pyridine aromatic): 7.25 (b.d.S, 1-H, hydroxyl):
8,4i-8,6i (b.d.D,2-H-Pyridin aromatisch).8,4i-8,6i (b.d.D, 2-H-pyridine aromatic).
dl-5-Hydroxy-2,2-dimethyl-?-(1-methyl-3-phenoxypropal)-4-chromanon wird aus 3-(3,5-Dihydroxyphenyl)-1-phenoxybutan hergestellt und fällt als Öl an:dl-5-hydroxy-2,2-dimethyl -? - (1-methyl-3-phenoxypropal) -4-chromanone is prepared from 3- (3,5-dihydroxyphenyl) -1-phenoxybutane and is obtained as an oil:
R a 0,7 (Silicagel, 18-Benzol:1-Äthylacetat) MS: (Mol. ion) 340R a 0.7 (silica gel, 18-benzene: 1-ethyl acetate) MS: (mole ion) 340
Analyse: Bar. für C21H24O^j C: 74,09: Ηί ?*Ή% Analysis: Bar. For C 21 H 24 O ^ j C: 74.09: Ηί ? * Ή%
Gef.: C: 74,04: H: 7,19 %. Found: C: 74.04: H: 7.19 %.
dl-2-(3,5,Dihydroxyphenyl)-1-2-phenyläthoxy)propan wird in dl-2,2»Dimethyl-5-hydroxy-7-/"~1-methyl-2-phenyl-äthoxy)-dl-2- (3,5, dihydroxyphenyl) -1-2-phenylethoxy) propane is converted into dl-2,2'-dimethyl-5-hydroxy-7 - / "1-methyl-2-phenylethoxy" -
(Öl) überführt.(Oil) transferred.
(TJiJJjJ1 1,21 (d, J -a 7 Hz, Methyl), 1,48 (s.gem Dimethyl), 3 2,73 (s, C-3-Methylen), 2,86 (+, J = 7 Hz, CH2Ph), 2,9 (m, Methin), 3,50 (d, J = 7 Hz, -CH2O-)', 3,65 (t, J = 7 Ha, -XH2-), 6,31 (d, J - 1 Hz, ArH), ' 6, 38 (d, J = 1 Hz, ArH), 7,26 (s, Ph) und "3,33 (s,Phenol).(TJiJJjJ 1 1.21 (d, J -a 7 Hz, methyl), 1.48 (s.gem dimethyl), 3 2.73 (s, C-3 methylene), 2.86 (+, J = 7Hz, CH 2 Ph), 2.9 (m, methine), 3.50 (d, J = 7Hz, -CH 2 O-) ', 3.65 (t, J = 7 Ha, -XH 2 -), 6.31 (d, J - 1 Hz, ArH), '6, 38 (d, J = 1 Hz, ArH), 7.26 (s, Ph) and "3.33 (s, phenol) ,
dl- 5-Hydroxy-3~hydroxymethylen-2,2-dimethyl-7-(i-methyl-4-phenylbutyl)-4-chromanondl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (i-methyl-4-phenylbutyl) -4-chromanone
Zu Natriumhydrid, daß erhalten wird beim Waschen von 6,67 g 50 %igem Natriumhydrid in Mineralöldispersion mit Pentan, wird im Verlauf von 30 Minuten eine Lösung von 4,7 g dl-5-Hydroxy-2,2-dimethyl-7-(i'B-Jnethyl-4-phenylbutyl)-4-chromanon und 23,1 g Äthylformiat zugetropft. Das ReaktionsgemischTo sodium hydride obtained by washing 6.67 g of 50% sodium hydride in mineral oil dispersion with pentane, a solution of 4.7 g of dl-5-hydroxy-2,2-dimethyl-7- (30 g) is added over 30 minutes. i'B-methyl-4-phenylbutyl) -4-chromanone and 23.1 g of ethyl formate were added dropwise. The reaction mixture
213370213370
dann auf Raumtemperatur abgekühlt und mit 350 ml Äther versetzt. Das resultierende Gemisch wird 18 Stunden am Rückfluß erhitzt, auf Raumtemperatur abgekühlt und mit 1 n-Salzsäure angesäuert. Die Ätherphase wird abgesondert und die wässrige Phase wird dreimal mit je 100 ml Äther extrahiert» Die vereinigten Ätherextrakte werden über Natriumsulfat getrocknet und im Vakuum eingeengt, wobei 5,7 g dl-5-Hydroxy-3-hydroxymethylen-2,2-dimethyl-7-(i-methyl-4-phenylbutyl)-4-chromanon in Form eines Öls erhalten werden.then cooled to room temperature and treated with 350 ml of ether. The resulting mixture is heated at reflux for 18 hours, cooled to room temperature and acidified with 1N hydrochloric acid. The ether phase is separated and the aqueous phase is extracted three times with 100 ml of ether. The combined ether extracts are dried over sodium sulfate and concentrated in vacuo, whereby 5.7 g of dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl 7- (i-methyl-4-phenylbutyl) -4-chromanone in the form of an oil.
NMR: ^1 1,05-1,8 (M,13,gem Dimethyl, -Methyl, Äthylen), 2,45 (M,3, benzylisches Methylen, Methinyl), 6,2-6,5 (M,2, aromatisch), 7,0-7,6 (M,6, aromatisch, Methinyläther), 11,3 11,36 (2bd.S, 1,phenolisches OH), 13,3 13,5 (2bd.S. 1, Hydroxyl).NMR: ^ 1 1.05-1.8 (M, 13, gem dimethyl, methyl, ethylene), 2.45 (M, 3, benzylic methylene, methinyl), 6.2-6.5 (M, 2 , aromatic), 7.0-7.6 (M, 6, aromatic, methynyl ether), 11.3 11.36 (2bd.S, 1, phenolic OH), 13.3 13.5 (2bd.S. , Hydroxyl).
IRs (CHCl ) C=O 1625 cm"1.IRs (CH 2 Cl 2) C = O 1625 cm -1 .
Auf analoge V/eise werden die Produkte gemäß Beispiel 1 umgewandelt in: dl-5-Hydroxy-3-hydroxymethylen-2,2-dimethyl-7~ (i-iaethyl-5-phenylpentyl)-4—chromanon:In analogous manner, the products of Example 1 are converted to: dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7α (i-ethyl-5-phenylpentyl) -4-chromanone:
NMR: *™x 1,2 (D,3, -Methyl, J = ? cps), 1,6 (S,6,gem Dimethyl), 1,0-2,0 ^fM,6,CH2-(CH2 NMR: * x 1.2 (D, 3, -methyl, J = cps), 1.6 (S, 6, per dimethyl), 1.0-2.0 ^ fM, 6, CH 2 - ( CH 2
2,3-2,8 (M,3,benzylisches Methylen, Methinyl), 6,2-6,4 (M,2,aromatisch),7,1-7,4 (M,6,aromatisch,vinylisch), 11,4 (bd«S,1 phenolisches CH):2.3-2.8 (M, 3, benzylic methylene, methynyl), 6.2-6.4 (M, 2, aromatic), 7.1-7.4 (M, 6, aromatic, vinylic), 11.4 (bd "S, 1 phenolic CH):
5-Hydroxy-3-hydroxymethylen-2,2-dimethyl-7-(2-phenyläthyl)-4-chromanon (Öl): IRi (CHCl ) C = O 1625 cm""1 5-Hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (2-phenylethyl) -4-chromanone (oil): IRi (CHCl 3) C = O 1625 cm -1
NMR: JJ^1 1,5 (S,6,gem Dimethyl), 2,85 (S,4,Äthylen), 6,2, 6,3 (d,2, aromatisch), 7,0-7,5 (M,6, aromatisch, Methinyl), 11,35 (S,1,Hydroxyl-DgO-Überlagerung), 13,4-13,6NMR: JJ ^ 1 1.5 (S, 6, according to dimethyl), 2.85 (S, 4, ethylene), 6.2, 6.3 (d, 2, aromatic), 7.0-7.5 (M, 6, aromatic, methynyl), 11.35 (S, 1, hydroxyl-DgO overlay), 13.4-13.6
(dji.Hydroxyl-DgO-iJberlagerung)(Dji.Hydroxyl-DGO iJberlagerung)
MS: (Mol. ion) 324 MS: (Mol. Ion) 324
dl-5-Hydroxy-3-hydroxymethylen-2,2-^ifflethyl-7-(1-methyl-3-phenylpropyl)-4-chromanon (Öl):dl-5-hydroxy-3-hydroxymethylene-2,2-bis-ethyl-7- (1-methyl-3-phenylpropyl) -4-chromanone (oil):
1,15 (a,3,Methyl), 1,5 (S,6,gem Dimethyl),1.15 (a, 3, methyl), 1.5 (S, 6, according to dimethyl),
1,65-2,1 (M,2,Methylen), 2,25-2,75 (M,3, benzylisches Methylen, Methinyl), 6,15, 6,3 (2d»2, aromatisch), 7,1 (M,6,aromatisch, olefinisches Proton), 11,3 (S,1,Hydroxyl-DgO-Überlagerung), 13,3 13,8 (d,1, Hydroxyl -Dp 0-Ü be rl age rung, MS: (Mol. ion) 3521.65-2.1 (M, 2, methylene), 2.25-2.75 (M, 3, benzylic methylene, methynyl), 6.15, 6.3 (2d »2, aromatic), 7, 1 (M, 6, aromatic, olefinic proton), 11.3 (S, 1, hydroxyl-DgO-overlay), 13.3 13.8 (d, 1, hydroxyl-Dp 0-transition, MS : (Mol. Ion) 352
dl-5-Hydroxy-3-hydroxymethylen-2-methyl-7-(1-methyl-4-phenylbutyl)-4-chroraanon:dl-5-hydroxy-3-hydroxymethylene-2-methyl-7- (1-methyl-4-phenylbutyl) -4-chroraanon:
^1 1,1 (D,3,OC-Methyl, J s ? Hz), 1,5 (D,3,2-Methyl, J I 7 Hz), 1,3-1S8 (M,^-Äthylen), 2,3-2,9 (M,3, benzylisch), 4,9 (M,1, Methinylather), J = 5 Hz), 6,2, 6,3 (2D,2, aromatisch, J = 1 Hz), 6,9-7,4 (M,6,- aromatisch, vinylisch), 11,2 (bd.S,1 phenolisches OH), dl-5-Hydroxy-2,2-dimethyl-7-(i-aethyl-4-phenoxybutyl)-4-chroaanon wird in d,1-5-Hydroxy~3-hydroxymethylen-2,2-di!nothyl~7-(i-methyl-4-phenoxybutyl)-4-chromanon überführt: Rf = 0,44 (Silicagel, 18-Benzol:1-Äthylacetat) MS: (Mol, ion) 382,^ 1 1,1 (D, 3, OC-methyl, J s? Hz), 1,5 (D, 3,2-methyl, J I 7 Hz), 1,3-1 S 8 (M, ^ - Ethylene), 2.3-2.9 (M, 3, benzylic), 4.9 (M, 1, methinyl ether), J = 5 Hz), 6.2, 6.3 (2D, 2, aromatic, J = 1 Hz), 6.9-7.4 (M, 6, - aromatic, vinylic), 11.2 (b.S., 1 phenolic OH), dl-5-hydroxy-2,2-dimethyl-7 (i-Aethyl-4-phenoxybutyl) -4-chroanone is prepared in d, 1-5-hydroxy-3-hydroxymethylene-2,2-di-ethyl-7- (i-methyl-4-phenoxybutyl) -4-chromanone converted: R f = 0.44 (silica gel, 18-benzene: 1-ethyl acetate) MS: (mol, ion) 382,
dl-5-Hydroxyl-2,2-dimethyl-?-/fi-methyl-4-(4-pyridyl)-butylJ7 -4-chromanon wird in d,1-5-Hydroxy-3-hydroxymethylen-2,2~dimethyl-7-/~1-methyl~4-4-pyridyl)butyl-7-/t-chromanon (viskoses Öl) überführt:dl-5-Hydroxyl-2,2-dimethyl -? - /? -methyl-4- (4-pyridyl) -butylJ7 -4-chromanone is converted into d, 1-5-hydroxy-3-hydroxymethylene-2,2? dimethyl-7- / ~ 1-methyl-4-4-pyridyl) -butyl - 7- / t -chromanone (viscous oil):
Rf s 0,15 (Silicagel, 1-Benzol:1-Äthylacetat) dl-2l2-Dim9thyl-5-hydroxy-7-/~1-methyl-2-(2~phenyläthoxy)-äthyl_7 -4-chromanon wird in dl-2,2~Dimethyl-3-hydroxymethylen-5-hydroxy-7-/[~1-iD.ethyl-2-(2-phenyl-äthoxy)äthyl>_7-4-chromanon (Öl) überführt:R f s 0.15 (silica gel, 1-benzene: 1-ethyl acetate) dl-2 l 2-Dimethyl-5-hydroxy-7- / -1-methyl-2- (2-phenylethoxy) ethyl-7 -4-chromanone is in dl-2,2 ~ dimethyl-3-hydroxymethylene-5-hydroxy-7 - / [~ (2-phenyl-ethoxy) ethyl> _7-4-chromanone (oil) converting 1-iD.ethyl-2:
-is- 21 3370-is- 21 3370
Rf a 0,35 (Silicagel, 1:1 Peatan:Äther).R f a 0.35 (silica gel, 1: 1 peatane: ether).
Beispiel 3Example 3
dl-5-Hydroxy-2,2-dimethyl-7-(2-heptyloxy)-4-chromanon.dl-5-hydroxy-2,2-dimethyl-7- (2-heptyloxy) -4-chromanone.
Zu einer Lösung von 18,5 g (87,1 Millimol) 5,7-Dihydroxy-2,2-dimethyl-4-chromanon und 2,44 g (43,5 Millimol) Kaliumhydroxid in 5δ ωΐ N,N-D!methylformamid werden unter Rühren 15,77 g (88,0 Hillimol) 2-Bromheptan zugegeben* Das Gemisch wird 4 Tage auf 100 C erwärmt, auf Raumtemperatur abgekühlt und dann zu einem Gemisch aus 110 ml 1 η-wässriger Natriumhydroxidlösung, 45 ml Wasser und 150 ml Chloroform zugegeben. Das Gemisch wird gerührt und die Chloroformphase wird abgesondert. Die vässrige Phase wird mit weiteren 150 ml Chloroform extrahiert» Die vereinigten Chloroformphason werden zweimal mit je 100 ml 1 n-Natriumhydroxidlösung gewaschen, über Natriumsulfat getrocknet und zu einem Öl eingeengt. Nicht umgesetztes 2-Bromheptan wird abdestilliert und der Rückstand wird durch Silicagel Chromatographie gereinigt. Dabei erhält man 5,90 g (22,1 %) der Titelverbindung in Form eines Öls» HMR: (CDCl3) cT - 12,4 (1-Protonen-Singulett, hydroxylisch), 5,7 und 6,0 (zwei 1-Protonen-Dubletts, J = 3 Hz, aromatische Protonen), 4,1-4,7 (1-Protonen-Multiplett, Äther-Methin), 2,7 (2 Protonen-Singulett, C-3 Methylen), 0,7-2,Q (22 Protonen-Multiplett für die restl» Protonen, gem Dimethyl erscheint als Singulett bei 1,5)·To a solution of 18.5 g (87.1 millimoles) of 5,7-dihydroxy-2,2-dimethyl-4-chromanone and 2.44 g (43.5 millimoles) of potassium hydroxide in 5 δ, N, N, methylformamide 15.77 g (88.0 mmol) of 2-bromoheptane are added with stirring. The mixture is heated to 100 C for 4 days, cooled to room temperature and then added to a mixture of 110 ml of 1 N aqueous sodium hydroxide solution, 45 ml of water and 150 ml Chloroform added. The mixture is stirred and the chloroform phase is separated. The aqueous phase is extracted with a further 150 ml of chloroform. The combined chloroformphasone is washed twice with 100 ml of 1 N sodium hydroxide solution each time, dried over sodium sulphate and concentrated to an oil. Unreacted 2-bromoheptane is distilled off and the residue is purified by silica gel chromatography. This gives 5.90 g (22.1 %) of the title compound as an oil »HMR: (CDCl 3 ) cT - 12.4 (1-proton singlet, hydroxylic), 5.7 and 6.0 (two 1-proton doublets, J = 3 Hz, aromatic protons), 4.1-4.7 (1-proton multiplet, ether-methine), 2.7 (2 proton singlet, C-3 methylene), 0 , 7-2, Q (22 proton multiplet for the restl protons, gem dimethyl appears as a singlet at 1.5) ·
Auf gleiche Weise wird dl-5-^ydroxy-2,2-dimethyl-7-/~2-(5-phenyl)pentyloxy_7-4-chromanon hergestellt, wobei man das 2-Bromheptan durch 2-Brom-5-phenylpentan ersetzt: F. 83 - 840C, IR (KBr) C=O 1629 cm"1 Similarly, dl-5-ydroxy-2,2-dimethyl-7- / 2- (5-phenyl) pentyloxy-7-4-chromanone is prepared to replace the 2-bromoheptane with 2-bromo-5-phenylpentane : F. 83-84 0 C, IR (KBr) C = O 1629 cm "1
-*- 213370- * - 213370
1,3 (D,3α -Methyl, J = 7 Hz), 1,8-2,01.3 (D, 3α-methyl, J = 7 Hz), 1.8-2.0
(M,4,Äthylen), 1,5 (S,6,gem Dimethyl), 2,7 (S,2,Od - Methylen), 2,5-2,9 (M,2,benzylisches Methylen), 4,1-4,7 (M,1, Methin), 5,9-6,1 (M,2,aromatisch), 7,1-7,5 (M,5,aromatisch), 12,2 (S,1, phenolisch). · MS: (Mol. ion) 354(M, 4, ethylene), 1.5 (S, 6, according to dimethyl), 2.7 (S, 2, Od - methylene), 2.5 - 2.9 (M, 2, benzylic methylene), 4 , 1-4,7 (M, 1, methine), 5.9-6.1 (M, 2, aromatic), 7.1-7.5 (M, 5, aromatic), 12.2 (S, 1, phenolic). MS: (Mol. Ion) 354
Analyse: Ber. für C22H26O4: C: 74,55: H: 7,39%Analysis: Ber. for C 22 H 26 O 4: C: 74.55: H: 7.39%
Gef.: C: 74,68: H: 7,46% .Found: C: 74.68: H: 7.46%.
dl- 5-Hydroxy-2,2-dimethyl-7-(1-methyl-3-pheriylpropoxy)~4-chromanon wird unter Verwendung von 2-Brom-4-phenyl-butan als Öl erhalten.dl-5-hydroxy-2,2-dimethyl-7- (1-methyl-3-pheriylpropoxy) -4-chromanone is obtained using 2-bromo-4-phenyl-butane as an oil.
NMRii^clci 1*25' ^»35 (d,3,Methyl), 1,4 (S,6, gem Dimethyl), 1,6-2,4 i(M?2,Methylen), 2,6 (S,2,barxzylisch.es Methylen), 2,85 (S,2,3,α-Methylen), 4,05-4,7 (M,1,Methinyl), 5,9 (6d,2, aromatisch), 7,25 (S,5, aromatisch). NMRii CLCi ^ 1 * 25 ^ »35 (d, 3, methyl), 1.4 (s, 6, gem dimethyl), 1.6-2.4 i (M? 2, methylene), 2.6 ( S, 2, barxzylic.es methylene), 2.85 (S, 2.3, α-methylene), 4.05-4.7 (M, 1, methynyl), 5.9 (6d, 2, aromatic) , 7.25 (S, 5, aromatic).
di-S-Hydroxy-^^-dimethyl^-cyclohexyloxy^-chromamon wird unter Verwendung von Bromcyclohexan erhalten, F6 ?2~75 C. IR (KBr) C s 0 1626 cm"1; OH 3390 cm""1 MS: (Mol, ion) 290di-S-hydroxy - ^^ - dimethyl ^ -cyclohexyloxy ^ -chromomonium is obtained using bromocyclohexane, F 6-2 ~ 75C. IR (KBr) C s 0 1626 cm -1 , OH 3390 cm -1 MS : (Mol, ion) 290
NMR:cf JT^1 1-2,1 (M.IO.C^Q-Cyelohexyl), 1,4 (S,6,gem Dimethyl), 2,65 (S,2,CC -Methylen), 4,0-4,^5 (M,1,Cyclohexyl Methinyl), 5,85-6,05 (M,2,aromatisch), 11,9 (S.Hydroxyl, D3O-Übarlagerung)*NMR: cf JT ^ 1 1-2.1 (M.IO.C ^ Q-cyclohexyl), 1.4 (S, 6, according to dimethyl), 2.65 (S, 2, CC-methylene), 4, 0-4, ^ 5 (M, 1, methinyl cyclohexyl), 5.85 to 6.05 (m, 2, aromatic), 11.9 (S.Hydroxyl, D 3 O-Übarlagerung) *
dl~5~Hydroxy-3-hydroxymethylen-2~2-diraethyl-7-(2-heptyloxy)-4-chromanon·dl ~ 5 ~ hydroxy-3-hydroxymethylene-2 ~ 2-diraethyl-7- (2-heptyloxy) -4-chromanone ·
Zu dem durch Waschen von 9*23 g (192 Millimol) 50 %igem Natriumhydrid in Minoralöldispersion mit Pentan erhaltenen Natriumhydrid wird im Verlauf von 30 Minuten eine Lösung von 5,90 g (19,2 Milli-To the sodium hydride obtained by washing 9 * 23g (192 millimoles) of 50% sodium hydride in mineral oil dispersion with pentane is added a solution of 5.90g (19.2mL) over 30 minutes.
213 3 70213 3 70
mol) dl-5~Hydroxy-2,2-dimethyl-7~(2-heptyloxy)-4-chromanon und 34,9 ml (432 Millimol) Äthylforraiat zugetropft. Nach beendeter Zugabe werden 475 El Äther zugesetzt und das resultierende Gemisch wird am Rückfluß erhitzt. Nach 18 Stunden wird das Reaktionsgemisch auf Raumtemperatur abgekühlt und mit i η-Salzsäure angesäuert« Die organische Phase wird abgesondert und die wässrige Phase wird noch dreimal mit je 125 ml Äther extrahiert. Die vereinigten Ätherextrakte werden über Natriumsulfat getrocknet und im Vakuum eingeengt, wobei man 6,41 g (> 100 fo) dl-5-Hydroxy-3-hydroxymethylen-2,2-dime~ thyl-7-(2-heptyloxy)-4-ehromanon als Öl erhält»mol) dl-5-hydroxy-2,2-dimethyl-7 ~ (2-heptyloxy) -4-chromanone and 34.9 ml (432 millimoles) of ethyl formate were added dropwise. After completion of the addition 475 El ether are added and the resulting mixture is heated to reflux. After 18 hours, the reaction mixture is cooled to room temperature and acidified with 1N hydrochloric acid. The organic phase is separated off and the aqueous phase is extracted three times with 125 ml of ether each time. The combined ether extracts are dried over sodium sulfate and concentrated in vacuo, to give 6.41 g (> 100 fo) of dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (2-heptyloxy) -4 -ehromanon receives as oil »
TMS NMR:cf QKQi 13»^ (ein broites Singulett-Proton, hydroxylisch),TMS NMR: cf QKQi 13 »^ ( a broites singlet proton, hydroxylic),
QQiQqi
11,8 (1 PrDton-Singulett, phenolisch-hydroxylisch), 7,4 (1 breites Proton-Singulett, Vinyl), 6,1 6,0 (2 1-Proton-Dubletts, J = 3 Hz, aromatisch), 4,8-4,2 (1 Proton-Multiplett, Methin), 2,1-0,7 (20 Proton-Multipletts für die restl. Protonen),11.8 (1 PrDton singlet, phenolic-hydroxylic), 7.4 (1 broad proton singlet, vinyl), 6.1 6.0 (2 1 proton doublets, J = 3 Hz, aromatic), 4 , 8-4.2 (1 proton multiplet, methine), 2.1-0.7 (20 proton multiplets for the remaining protons),
Auf gleiche Weise werden entsprechende Verbindungen gemäß Beispiel 6 in folgende Produkte überführt: dl^-Hydroxy-S-hydroxy-·. methylen-2,2-dimethyl-7-/""2-(phenyl)pentoxy<-7-4-chromanon (Öl)» NMR:dT ^j1 1,3 (D,3OC -Methyl, J = 7Hz), 1,3-2,0 (M,4,In the same way, corresponding compounds are converted according to Example 6 in the following products: dl ^ -hydroxy-S-hydroxy- ·. Methylene-2,2-dimethyl-7 - / "" 2- (phenyl) pentoxy <- 7-4-chromanone (oil) »NMR: dT ^ j 1 1.3 (D, 3OC-methyl, J = 7Hz) , 1.3-2.0 (M, 4,
Äthylen), 31,4 (S,6,gem Dimethyl), 2,3-2,8 (bd., T,2-benzylisches Methylen), 4,1-4,7 (M,1,Methin), 5,8-6,0 (M,2, aromatisch), 7,0-7,4 (M,6, aromatisch und vinylisch), 10,0 (S,1, phenolisch), 13»3 (bd,S,1, hydroxylisch;Ethylene), 3 1,4 (S, 6, according to dimethyl), 2,3-2,8 (bd, T, 2-benzylic methylene), 4,1-4,7 (M, 1, methine), 5.8-6.0 (M, 2, aromatic), 7.0-7.4 (M, 6, aromatic and vinylic), 10.0 (S, 1, phenolic), 13 »3 (bd, p , 1, hydroxylic;
dl-5-flydroxy-3-hydroxymethylen-2,2-dimethyl-7-/~2-(4-phenyl)-butyloxy__7~4-chromanon (Öl).dl-5-flydroxy-3-hydroxymethylene-2,2-dimethyl-7- / 2- (4-phenyl) -butyloxy-7-4-chromanone (oil).
dl ^-Hydroxy^-hydroxyme thyl en-2 ,2-dime thyl -7-cy el ohexyl oxy-4-chromanon;dl ^ -hydroxy ^ -hydroxy-methyl-2-dimethyl-7-cyanohexyl oxy-4-chromanone;
IR: (KBr) C = O 1620 cm**1· OH 3420 cm"1 MS: (Mol. ion) 318IR: (KBr) C = O 1620 cm ** 1 x OH 3420 cm " 1 MS: (Mol. Ion) 318
213370213370
Nlffis ^CDCl, Ί»1"2^ (MjIO1C5H10-CyClOh6XyI), 1,55 (S,6,gem Dimethyl), 4,1-4,5 (Mji-Cyclohexyl-Methinyl), 5,9-6,1 (M,2, aromatisch), 7,1-7,5 (d,l,Methinyl), 11,6 (S,1, Hydroxyl, D^O-Überlagerung). Nlffis ^ CDCl, Ί » 1 " 2 ^ (MjIO 1 C 5 H 10 -CyClOh 6 XyI), 1,55 (S, 6, according to dimethyl), 4,1-4,5 (Mji-cyclohexyl-methynyl), 5.9-6.1 (M, 2, aromatic), 7.1-7.5 (d, l, methynyl), 11.6 (S, 1, hydroxyl, D ^ O overlay).
dX~5-Hydroxy-3-hydroxymethylen-2,2-dimethyl-?-(1-methyl-3-phenoxypropyl)-4-chromanon, Öl (aus der Verbindung gemäß Beispiel 1):dX ~ 5-hydroxy-3-hydroxymethylene-2,2-dimethyl -? - (1-methyl-3-phenoxypropyl) -4-chromanone, oil (from the compound of Example 1):
R. = 0,42 (Silicagel, 18-Benzol:1-Äthylacetat) MS: (Mol. ion) 368.R. = 0.42 (silica gel, 18-benzene: 1-ethyl acetate) MS: (mole ion) 368.
dl-5"Hydrpxy-2,2-dime thyl-7-(1-methyl-4-phenylbutoxy)-4-chro-dl-5 "-hydroxy-2,2-dimethyl-7- (1-methyl-4-phenylbutoxy) -4-chro
manon. .manon. ,
Ein Gemisch aus 16,4 g (100 Millimol) 5-Phenyl-2~pentanol, 28 ml (200 Millimol) Triethylamin und 80 ml trockenem Tetrahydrofuran wird in Stickst of atmosphäre in einem Eis/Wasserbad abgekühlt. Dann werden 8,5 ml (110 Millimol) Methansulfonylchlorid in 20 ml trockenem Tetrahydrofuran mit solcher Geschwindigkeit zugetropft, daß die Temperatur im wesentlichen konstant bleibt. Das Gemisch wird auf Raumtemperatur erwärmen gelassen und dann wird das Triäthylamin-Hydrochlorid abfiltriert. Der Filterkuchen wird mit trockenem Tetrahydrofuran gewaschen und Waschlösung und FiItrat werden bei vermindertem Druck eingeengt, wobei man das Produkt als Öl erhält. Das Öl wird in 100 ml Chloroform gelöst und die Lösung wird zweimal mit je 100 ml Wasser und einmal mit 20 ml gesättigter Natriumchloridlösung gewaschen. Beim Abdunsten des Lösungsmittels werden 21,7 g (89,7 %) 5-Phenyl-2-pentanol-mesylat erhalten, das in der nächsten Verfahrensstufe ohne weitere Reinigung eingesetzt werden.A mixture of 16.4 g (100 millimoles) of 5-phenyl-2-pentanol, 28 ml (200 millimoles) of triethylamine and 80 ml of dry tetrahydrofuran is cooled in an atmosphere of nitrogen / water bath. Then, 8.5 ml (110 millimoles) of methanesulfonyl chloride in 20 ml of dry tetrahydrofuran are added dropwise at such a rate that the temperature remains substantially constant. The mixture is allowed to warm to room temperature and then the triethylamine hydrochloride is filtered off. The filter cake is washed with dry tetrahydrofuran and washing solution and filtrate are concentrated under reduced pressure to give the product as an oil. The oil is dissolved in 100 ml of chloroform and the solution is washed twice with 100 ml of water and once with 20 ml of saturated sodium chloride solution. Upon evaporation of the solvent, 21.7 g (89.7 %) of 5-phenyl-2-pentanol mesylate are obtained, which are used in the next process stage without further purification.
2133 702133 70
Ein Gemisch aus 2,08 g (10 Millimol) 2,2-Dimethyl-5,7-dihydroxy-4-chromanon, 2,76 g (20 Millimol) Kaliumcarbonat,10 ml Ν,Ν-Dimethylformamid und 2,64 g (11 Millimol) 5-Phenyl-2~ pentanol-mesylat wird in Stickstoffatmosphäre in einem Ölbad Λ 3/4 Stunden auf 80 bis 820C erwärmt. Dann wird das Gemisch auf Saumtemperatur abgekühlt und in 100 ml Eis/Wasser gegossen· Pie wässrige Lösung wird zweimal mit je 25 ml Äthylacetat extrahiert und die vereinigten Extrakte werden nacheinander dreimal mit 25 ml Wasser und einmal mit 25 ml gesättigter Natriumchloridlösung gewaschen· Der Extrakt wird über Magnesiumsulfat getrocknet, mit Kohle entfärbt und eingeengt, wobei man das Produkt als Öl erhält, das beim Animpfen mit reinem Produkt kristallisiert; F, 83 - 840C, quantitative Ausbeute·A mixture of 2.08 g (10 millimoles) of 2,2-dimethyl-5,7-dihydroxy-4-chromanone, 2.76 g (20 millimoles) of potassium carbonate, 10 ml of Ν, Ν-dimethylformamide and 2.64 g ( 11 millimoles) of 5-phenyl-2 ~ pentanol mesylate is heated in a nitrogen atmosphere in an oil bath Λ 3/4 hours at 80 to 82 0 C. Then, the mixture is cooled to hematural temperature and poured into 100 ml of ice / water. Pie aqueous solution is extracted twice with 25 ml of ethyl acetate each time and the combined extracts are washed successively three times with 25 ml of water and once with 25 ml of saturated sodium chloride solution dried over magnesium sulfate, decolorized with charcoal and concentrated to give the product as an oil which crystallizes on inoculation with pure product; F, 83-84 0 C, quantitative yield
Auf gleiche Weise werden die folgenden Verbindungen aus den entsprechenden 2,2~R.Rt--5»7-Dihydroxy-4~chromanonen und Alkanolen hergestellt· Die nicht literaturbekannten Alkanole werden aus den betreffenden Aldehyden oder Ketonen durch Wittig-Reaktion gemäß allgemeiner Formel VI mit Z=(alko) dargestellt:In the same way, the following compounds are prepared from the corresponding 2,2-R- t -5 -7-dihydroxy-4-chromanones and alkanols. The alkanols which are not known from the literature are prepared from the aldehydes or ketones concerned by Wittig reaction according to general formula VI represented by Z = (alko):
213370213370
•. β. 213 3 70•. β. 213 3 70
alkg Walkg W
>3 4-?C6H4 > 3 4 -? C 6 H 4
>3 · 4-ClCgH4 > 3 × 4 ClCgH 4
>A C6H5> A C 6 H 5
\ 4-FCgH4 \ 4-FCgH4
CH(CH3)(CH2)2 4"FC6H4 CH (CH 3 ) (CH 2 ) 2 4 "FC 6 H 4
CH2 C6H5 CH 2 C 6 H 5
CH2 C6H5 CH 2 C 6 H 5
CHg 4-FCgH4 CHg 4-FCgH 4
/" tr f*Vt /* it/ "trf * Vt / * it
CH3 CH3 — C6H5 CH 3 CH 3 - C 6 H 5
CH3 CH3 . ^-FC6H4 CH 3 CH 3 . ^ -FC 6 H 4
C2H5 H — 4-ClC6H4 C 2 H 5 H - 4-ClC 6 H 4
C2H5 C2H5 C 2 H 5 C 2 H 5
HH . — 4-FC6H4 HH. - 4-FC 6 H 4
CH PH r* trCH PH r * tr
3 3 ""3*53 3 "" 3 * 5
H H- CjH5 H H-CjH 5
213370213370
5H9 5 H 9
2-(C6H5)C5H8 2- (C 6 H 5 ) C 5 H 8
4-pypiryl 4-piperidyl4-pyryl 4-piperidyl
-CH2- CHj-CH 2 - CHj
CHjCHj
CHjCHj
CH3 CH 3
CHjCHj
213 3 7 0213 3 7 0
CtT rt τι fPXX \ CVt CtTrtτιfPXX \ CVt
2 5 2 5 ά 3 J 2 5 2 5 ά 3 y
CH3 CH3 CH 3 CH 3
rtTJ TJrtTJ TJ
WU ·, UWU ·, U
-CH(CH3)CH(CH )--CH (CH 3 ) CH (CH) -
dl-5-Hydroxy-2,2-dimethyl-7-(2-heptylmercapto)-4-chromanon.dl-5-hydroxy-2,2-dimethyl-7- (2-heptylmercapto) -4-chromanone.
Zu einerj Lösung von 19,7 g (87,1 Millimol) 5-Hydroxy-7-mercapto-2,2-dimethyl-4-chromanon und 2,44 g (43,5 Millimol) KaIiumhydroxid in 58 ml Ν,Ν-Dimethylformamid werden unter Rühren 15,77 g (88,0 MilliEol) 2-Bromheptan zugegeben. Das Gemisch wird 4 Tage auf 1000C erhitzt, dann auf Raumtemperatur abgekühlt und zu einem Gemisch aus 110 ml 1 n-vJässriger Natriumhydroxidlösung, 45 ml Wasser und 150 ml Chloroform zugegeben. Das resultierende Gemisch wird bewegt, die Phasen werden getrennt und die wässrige Phase wird mit weiteren 150 ml Chloroform extrahiert« Die vereinigten Chloroformphasen werden zweimal mit je 100 ml 1 n-Natriumhydroxidlösung gewaschen, über Natriumsulfat getrocknet und zu einem Öl eingeengt. Nicht umgesetztes 2-Bromheptan wird abdestilliert und dor Rückstand wird durch Silicagelchromatographie gereinigt, wobei man die Titelverbindung erhält.To a solution of 19.7 g (87.1 millimoles) of 5-hydroxy-7-mercapto-2,2-dimethyl-4-chromanone and 2.44 g (43.5 millimoles) of potassium hydroxide in 58 ml of Ν, Ν- Dimethylformamide with stirring 15.77 g (88.0 milliole) of 2-bromoheptane was added. The mixture is heated for 4 days at 100 0 C, then cooled to room temperature and added to a mixture of 110 ml of 1N-sodium hydroxide vJässriger, 45 ml of water and 150 ml of chloroform. The resulting mixture is agitated, the phases are separated and the aqueous phase is extracted with another 150 ml of chloroform. The combined chloroform phases are washed twice with 100 ml of 1 N sodium hydroxide solution, dried over sodium sulfate and concentrated to an oil. Unreacted 2-bromoheptane is distilled off and the residue is purified by silica gel chromatography to give the title compound.
Die folgenden Verbindungen werden analog aus den betreffenden Reaktionsteilnehraern der Formel Br-(alkp)2~W und dem entsprechenden 5-Hydroxy-7-mercapto~2,2-R.Rt--substituiert-4-chromanon hergestellt (allgemeine Formel VI mit Z = (alkp) '· The following compounds are prepared analogously from the respective Reaktionssteilnehraern the formula Br- (alkp) 2 ~ W and the corresponding 5-hydroxy-7-mercapto ~ 2,2-RR t - substituted-4-chromanone (general formula VI with Z = (alkp) '·
(alkg)(Alkg)
.23- 21.23-21
(al(al
& 21 3 3 70 & 21 3 3 70
Z-WZ-W
Z-WZ-W
OHOH
CH1 K. CH 1 K.
o ohoh, oh
Z-V/Z-V /
Z-WZ-W
Claims (1)
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DD76203283A DD137837A5 (en) | 1975-11-03 | 1976-11-01 | PROCESS FOR THE PREPARATION OF INTERMEDIATE PRODUCTS FOR THE SYNTHESIS OF 1,9-DIHYDROXY-HEXAHYDRO-DIBENZOPYRANES |
DD76213370A DD143774A5 (en) | 1975-11-03 | 1976-11-01 | PROCESS FOR PREPARING INTERMEDIATE PRODUCTS FOR SYNTHESIS OF 1,9-DIHYDROXY-HEXAHYDRODIBENZOPYRANES |
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DD76203283A DD137837A5 (en) | 1975-11-03 | 1976-11-01 | PROCESS FOR THE PREPARATION OF INTERMEDIATE PRODUCTS FOR THE SYNTHESIS OF 1,9-DIHYDROXY-HEXAHYDRO-DIBENZOPYRANES |
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- 1976-10-21 ZA ZA766281A patent/ZA766281B/en unknown
- 1976-10-22 PH PH19046A patent/PH14811A/en unknown
- 1976-10-27 ES ES452772A patent/ES452772A1/en not_active Expired
- 1976-11-01 RO RO7688274A patent/RO71411A/en unknown
- 1976-11-01 RO RO7695639A patent/RO75876A/en unknown
- 1976-11-01 DD DD7600195548A patent/DD129214A5/en unknown
- 1976-11-01 DD DD76203283A patent/DD137837A5/en unknown
- 1976-11-01 DD DD76213370A patent/DD143774A5/en unknown
- 1976-11-01 RO RO7695638A patent/RO76124A/en unknown
- 1976-11-01 RO RO7695637A patent/RO76006A/en unknown
- 1976-11-01 YU YU02681/76A patent/YU268176A/en unknown
- 1976-11-02 HU HU76PI550A patent/HU178321B/en unknown
- 1976-11-02 NO NO763725A patent/NO148745C/en unknown
- 1976-11-02 PT PT65781A patent/PT65781B/en unknown
- 1976-11-02 JP JP51132264A patent/JPS5277065A/en active Granted
- 1976-11-02 FI FI763131A patent/FI763131A/fi not_active Application Discontinuation
- 1976-11-02 CS CS767070A patent/CS207571B2/en unknown
- 1976-11-02 DK DK495876A patent/DK495876A/en not_active Application Discontinuation
- 1976-11-03 BG BG7634599A patent/BG27552A3/en unknown
- 1976-11-03 EG EG680/76A patent/EG12648A/en active
- 1976-11-03 BG BG7636486A patent/BG28057A4/en unknown
- 1976-11-03 PL PL1976193435A patent/PL125297B1/en not_active IP Right Cessation
- 1976-11-03 BG BG7736485A patent/BG28058A4/en unknown
- 1976-11-03 SU SU762416855A patent/SU843748A3/en active
-
1977
- 1977-07-14 AR AR268433A patent/AR220521A1/en active
- 1977-07-19 PH PH20008A patent/PH14383A/en unknown
- 1977-07-26 SU SU772506503A patent/SU677661A3/en active
- 1977-07-29 SU SU772505754A patent/SU677660A3/en active
- 1977-09-29 ES ES462784A patent/ES462784A1/en not_active Expired
- 1977-09-29 ES ES462783A patent/ES462783A1/en not_active Expired
-
1978
- 1978-02-16 SU SU782579903A patent/SU784772A4/en active
-
1979
- 1979-09-21 CH CH852079A patent/CH622790A5/en not_active IP Right Cessation
- 1979-11-15 JP JP54148293A patent/JPS5943958B2/en not_active Expired
-
1980
- 1980-05-29 PH PH24092A patent/PH16788A/en unknown
- 1980-12-16 JP JP55177955A patent/JPS5943955B2/en not_active Expired
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