EP0555247A1 - Epoxycarbacyclin precursors, their preparation and their use - Google Patents

Epoxycarbacyclin precursors, their preparation and their use

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Publication number
EP0555247A1
EP0555247A1 EP19910918068 EP91918068A EP0555247A1 EP 0555247 A1 EP0555247 A1 EP 0555247A1 EP 19910918068 EP19910918068 EP 19910918068 EP 91918068 A EP91918068 A EP 91918068A EP 0555247 A1 EP0555247 A1 EP 0555247A1
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EP
European Patent Office
Prior art keywords
group
formula
tert
butyl
reaction
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EP19910918068
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German (de)
French (fr)
Inventor
Michael Harre
Jürgen Westermann
Klaus Nickisch
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the invention relates to epoxycarbacyclin intermediates, processes for their stereospecific production from Z isomers of the corresponding carbacycin precursors and their use for the production of pharmaceutically active carbacyclins.
  • EP 335827 describes a process which protects the Z-allyl alcohols of the formula IV on the hydroxyl group by formation of the acetate and returns them to the starting material (ketone) from which the allyl alcohols can be prepared again by hydroxylation and periodate cleavage of the double bond.
  • the invention consists of the epoxycarbacyclin precursors of the formula I
  • A is a -C ⁇ C group
  • W is a hydroxymethylene group in which the OH group is protected by a trialkylsilyl diphenylalkylsilyl or triphenylsilyl group,
  • D is a -CH-CH 2 group
  • E is a -C ⁇ C group
  • R 1 is a hydroxyl group which, like the hydroxyl group, can be substituted in W.
  • R 2 represents a straight-chain or branched alkyl, alkenyl or alkynyl group with 1-7 C atoms and
  • R 3 represents a tetrahydropyranyl or tetrahydrofuranyl group.
  • the alkyl radical of the diphenylalkylsilyl group in W and R 1 can be, for example, methyl,
  • Ethyl, propyl, tert-butyl and hexyl mean, ie have 1-6 C atoms.
  • the straight-chain or branched alkyl group with 1-7 C atoms in R 2 can be, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n- Heptyl.
  • Alkenyl with 1-7 C atoms for R 2 means propenyl, butenyl, 2-butenyl,
  • alkenyls with 1-4 C atoms are preferred.
  • the alkynyl groups with 1-7 C atoms for R 2 also contain alkynyls
  • the invention also relates to a process for the preparation of compounds of the formula I, characterized in that a bicyclo [3.3.0] oct-3-ylidene ethanol of the formula II
  • reaction with dihydrofuran or dihydropyran takes place under acid catalysis in an inert solvent, such as tetrahydrofuran, diethyl ether, dioxane, ethylene glycol dimethyl ether, methylene chloride, hexane, heptane, toluene to give an acetal.
  • an inert solvent such as tetrahydrofuran, diethyl ether, dioxane, ethylene glycol dimethyl ether, methylene chloride, hexane, heptane, toluene to give an acetal.
  • Acid catalysis can be carried out by mineral acids such as hydrochloric or sulfuric acid or acidic ion exchangers or organic acids, e.g. Trifluoroacetic acid take place.
  • the reaction temperature is not critical; it is expedient to do this at room temperature.
  • the epoxidation of the slotted derivatives can be carried out using the reagents known to the person skilled in the art, the magnesium salt of perphthalic acid or m-chloroperbenzoic acid being particularly preferred.
  • the reaction can be carried out with the addition of sodium hydrogen carbonate or potassium hydrogen carbonate in order to prevent acid-catalyzed decomposition reactions.
  • the epoxidation is generally carried out between 0.degree. C. and 60.degree. C. in an inert solvent such as hexane, heptane, dichloromethane, 1,2-dichloroethane, diethyl ether or tetrahydrofuran.
  • an inert solvent such as hexane, heptane, dichloromethane, 1,2-dichloroethane, diethyl ether or tetrahydrofuran.
  • the invention also consists in the use of the epoxycarbacyclin precursors of the formula I for the preparation of allyl alcohols of the formula III,
  • the protected epoxides of the formula I can be opened with a phosphorus compound of the formula VI.
  • reaction takes place between 0 ° C and 30 ° C in an inert solvent such as tetrahydrofuran, diethyl ether, dichloromethane, 1,2-dichloroethane, hexane, toluene etc.
  • inert solvent such as tetrahydrofuran, diethyl ether, dichloromethane, 1,2-dichloroethane, hexane, toluene etc.
  • reaction of the ring-opened epoxy compounds with R 5 Q takes place between 0 ° C and 50 ° C in an inert solvent such as tetrahydrofuran, diethyl ether, dichloromethane, He ⁇ an, toluene etc., preferably in the solvent in which the epoxy opening is also carried out (one-pot reaction ).
  • an inert solvent such as tetrahydrofuran, diethyl ether, dichloromethane, He ⁇ an, toluene etc.
  • the phosphonium salt IX spontaneously undergoes elimination to give derivatives of the formula X in which A, W, D, E, R 1 , R 2 and R 3 have the meaning given in formula I.
  • the compounds of the general formula X are converted into the E-allyl alcohols of the formula III by splitting off the allylic hydroxyl protective group R 3 .
  • the protective group is split off selectively under acidic catalysis.
  • Mineral acids such as hydrochloric or sulfuric acid or organic acids such as trifluoroacetic acid, citric acid etc. in water. Methanol or ethanol decompose the very sensitive allyl alcohol (III) or split off the silyl protective groups.
  • the desired product can be obtained from the reaction mixture using conventional methods.
  • a suitable recovery method involves pouring the reaction mixture into water, extracting it with a water-immiscible organic solvent, drying the organic extract, and finally distilling the solvent from the extract to obtain the desired product.
  • the product can optionally be further prepared using conventional techniques such as recrystallization n Thin layer chromatography or column chromatography can be cleaned.
  • tetrahydrofuranyl group or tetrahydropyranyl group as the OH protective group R 3 is critical because it does not react with the phosphorus compound and can be split off in the presence of the silyl ether or the sensitive allyl alcohol III.
  • octane-3,2'-oxirane] 66.26 g of monoperoxyphthalic acid Mg salt * 6 H 2 O and 127.4 g of NaHCO 3 are suspended in 500 ml of THF and 46.5 g (1S, 2S, 3R, 5S) -3-tert-butyl-dimethylsilyloxy- 2 - [(3S, 4S) -3-tert-butyldimethylsilyloxy-4-methyl-1,6-nonadiinyl] -7- [(Z) -2-perhydro-2-furyloxy) ethylidene] bicyclo [3 . 3.0] added dropwise octane.
  • the suspension is stirred for 3 hours at room temperature and then heated to 50 ° C. for 4 hours.
  • the mixture is cooled to room temperature, 300 ml of MTB are added and 175 ml of saturated sodium sulfite solution are added dropwise, the temperature of the solution being kept at 20 °.
  • the reaction mixture is diluted with 200 ml of water and 100 ml of MTB and the phases are separated.
  • the aqueous phase is extracted twice with 200 ml of MTB, the combined organic phases are washed twice with 200 ml of water, dried over sodium and concentrated on a rotary evaporator.
  • the mixture is stirred at 10-20 C for one hour. 19.64 ml of methyl iodide are added dropwise at 10-20 ° C. The solution becomes colorless and a white precipitate (methyl diphenyl phosphine oxide) precipitates.
  • the mixture is stirred for 15 minutes. 200 ml of water and 200 ml of MTB are added to the reaction mixture, the phases are separated and the aqueous phase is extracted with 100 ml of MTB. The combined organic phases are washed with 200 ml of water and 100 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is filtered through 600 g of silica gel.
  • the solution is cooled to 20-23 ° C., the ion exchanger is filtered off, washed with 100 ml of isopropanol and the filtrate is mixed with 100 ml of saturated sodium bicarbonate solution (pH 8-9).
  • the mixture is concentrated to about 150 ml and taken up in 200 ml of ethyl acetate and 200 ml of water, the organic phase is separated off and the aqueous phase is extracted three times with 200 ml of ethyl acetate each time.
  • the combined organic phases are washed with 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator.

Abstract

La présente invention se rapporte à des produits intermédiaires de carbacycline époxy, au procédé pour leur fabrication sur la base de Z-isomères des progéniteurs de carbacycline correspondants, ainsi qu'à leur utilisation pour la fabrication de carbacyclines pharmacologiquement efficaces.The present invention relates to epoxy carbacycline intermediates, to the process for their manufacture on the basis of Z-isomers of the corresponding carbacycline progenitors, as well as to their use for the manufacture of pharmacologically effective carbacyclines.

Description

EPOXYCARBACYCLINVORSTUFEN, DEREN HERSTELLUNG UND VERWENDUNG  EPOXYCARBACYCLINE PREPARATIONS, THEIR PRODUCTION AND USE
Die Erfindung betrifft Epoxycarbacyclinzwischenprodukte, Verfahren zu ihrer stereospezifischen Herstellung aus Z-Isomeren der entsprechenden Carbacy- clinvorstufen und ihre Verwendung zur Herstellung von pharmazeutisch wirksamen Carbacyclinen. The invention relates to epoxycarbacyclin intermediates, processes for their stereospecific production from Z isomers of the corresponding carbacycin precursors and their use for the production of pharmaceutically active carbacyclins.
In EP 335827 wird ein Verfahren beschrieben, das die Z-Allylalkohole der Formel IV an der Hydroxygruppe durch Bildung des Acetats schützt und durch Hydroxylierung und Perjodatspaltung der Doppelbindung zum Ausgangsmaterial (Keton), aus dem die Allylalkohole wieder hergestellt werden können, zurückführt. EP 335827 describes a process which protects the Z-allyl alcohols of the formula IV on the hydroxyl group by formation of the acetate and returns them to the starting material (ketone) from which the allyl alcohols can be prepared again by hydroxylation and periodate cleavage of the double bond.
Bei der Synthese der Allylalkohole wird dann allerdings ein ca. 50 zu 50In the synthesis of the allyl alcohols, however, an approx. 50 to 50
Gemisch der Stereoisomeren III und IV gebildet, welches chromatographisch getrennt werden muß. Mixture of stereoisomers III and IV formed, which must be separated by chromatography.
Aus DE 33 38 832 sind Epoxycarbacyclincärbonsäure-Derivate der allgemeinen DE 33 38 832 are epoxycarbacyclincarboxylic acid derivatives of the general
Formel formula
und deren Nutzung zur Umwandlung von Z- in E-Isomere bekannt, denen das Sauerstoffatom in der oberen Kette fehlt. and their use for converting Z isomers into E isomers that lack the upper chain oxygen atom.
E. Vedejs und P.L. Fuchs beschreiben die Inversion von einfachen Epoxiden mit dieser Methode ( J . Am. Chem.Soc. (1973), 822 und J. Am. Chem. Soc. (1971), 4072). Bei der Synthese von (5E)-3-0xa-6a-carba-prostaglandin-I2-Derivaten der Formel E. Vedejs and PL Fuchs describe the inversion of simple epoxides using this method (J. Am. Chem. Soc. (1973), 822 and J. Am. Chem. Soc. (1971), 4072). In the synthesis of (5E) -3-0xa-6a-carba-prostaglandin-I 2 derivatives of the formula
worin A, W, D, E und R2 die in der Formel I angegebene Bedeutung haben, wird eine Stufe durchlaufen, die zu etwa 50% aus dem gewünschten Allylal- kohol mit einer E-konfigurierten Doppelbindung III, in which A, W, D, E and R 2 have the meaning given in formula I, a step is carried out which consists of approximately 50% of the desired allyl alcohol with an E-configured double bond III,
(III) (III)
worin A, W, D, E, R1 und R2 die in der allgemeinen Formel I angegebene Bedeutung haben, und zu etwa 50% aus dem für die weitere Synthese unbrauchbaren Allylalkohol IV mit einer Z-konfigurierten Doppelbindung, in which A, W, D, E, R 1 and R 2 have the meaning given in the general formula I, and about 50% from the allyl alcohol IV with a Z-configured double bond, which is unusable for further synthesis,
(IV) (IV)
worin A, W, D, E, R1 und R2 die in der Formel I angegebene Bedeutung haben, besteht. where A, W, D, E, R 1 and R 2 have the meaning given in formula I.
Die Mischung der E- und Z-Alkohole der Formeln III und IV muß chromatographisch getrennt werden.  The mixture of the E and Z alcohols of the formulas III and IV must be separated by chromatography.
In DE 30 48 906, 33 06 123 und 33 06 125 werden derartige E-konfigurierte Alkohole der Formel III zu pharmakologisch wirksamen (5E)-3-oxa-6a-carbaprostaglandin-I2 -Derivaten II umgesetzt (siehe auch W. Skuballa et al., J. Med. Chem. (1986), 29, 313). In DE 30 48 906, 33 06 123 and 33 06 125 such E-configured alcohols of the formula III are converted into pharmacologically active (5E) -3-oxa-6a-carbaprostaglandin-I 2 derivatives II (see also W. Skuballa et al., J. Med. Chem. (1986), 29, 313).
Über die Epoxycarba cyclinzwis chenprodukte der Formel I gelingt es in vorteilhafter Weise, die für die weitere Synthese wertlosen, Z-konfigurierten Allylalkohole der Formel IV dem Carbacyclinsyntheseverfahren als E-Isomere zuzuführen. About the Epoxycarba cyclinzwis chen products of formula I it is possible in an advantageous manner to supply the Z-configured allyl alcohols of formula IV which are worthless for the further synthesis to the carbacyclin synthesis process as E-isomers.
Die Erfindung besteht aus den Epoxycarbacyclinvorstufen der Formel I,  The invention consists of the epoxycarbacyclin precursors of the formula I
(I) (I)
worin wherein
A eine -C≡C-Gruppe,  A is a -C≡C group,
W eine Hydroxymethylengruppe, in der die OH-Gruppe durch eine Trialkylsilyl Diphenylalkylsilyl- oder Triphenylsilylgruppe geschützt ist,  W is a hydroxymethylene group in which the OH group is protected by a trialkylsilyl diphenylalkylsilyl or triphenylsilyl group,
CH3 CH 3
D eine -CH-CH2 -Gruppe, D is a -CH-CH 2 group,
E eine -C≡C-Gruppe, E is a -C≡C group,
R1 eine Hydroxygruppe, die wie die Hydroxygruppe in W substituiert sein R 1 is a hydroxyl group which, like the hydroxyl group, can be substituted in W.
kann,  can,
R2 eine geradkettige oder verzweigte Alkyl-, Alkenyl- oder Alkinylgruppe mit 1-7 C-Atomen bedeutet und R 2 represents a straight-chain or branched alkyl, alkenyl or alkynyl group with 1-7 C atoms and
R3 eine Tetrahydropyranyl- oder Tetrahydrofuranylgruppe darstellt. Die Alkylreste der Trialkylsilylgruppe in W und R1 können gleich oder verschieden sein und 1-8 C-Atome enthalten, wie z.B. Dimethyl-tert.-butylsilyl, Triethylsilyl, Triisopropylsilyl, Thexyldimethylsilyl (Thexyl = 2,3,3- Trimethylpropyl). R 3 represents a tetrahydropyranyl or tetrahydrofuranyl group. The alkyl radicals of the trialkylsilyl group in W and R 1 can be the same or different and contain 1-8 C atoms, such as dimethyl tert-butylsilyl, triethylsilyl, triisopropylsilyl, thexyldimethylsilyl (thexyl = 2,3,3-trimethylpropyl).
Der Alkylrest der Diphenylalkylsilylgruppe in W und R1 kann z.B. Methyl,The alkyl radical of the diphenylalkylsilyl group in W and R 1 can be, for example, methyl,
Ethyl, Propyl, tert.-Butyl und Hexyl bedeuten, d.h. 1-6 C-Atome aufweisen. Die geradkettige oder verzweigte Alkylgruppe mit 1-7 C-Atomen in R2 kann z.B. sein: Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, tert.-Butyl, n-Pentyl, n-Hexyl, n-Heptyl. Bevorzugt sind Alkylgruppen mit 1-4 C-Ethyl, propyl, tert-butyl and hexyl mean, ie have 1-6 C atoms. The straight-chain or branched alkyl group with 1-7 C atoms in R 2 can be, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n- Heptyl. Alkyl groups with 1-4 C-
Atomen. Atoms.
Alkenyl mit 1-7 C-Atomen für R2 bedeutet Propenyl, Butenyl, 2-Butenyl,Alkenyl with 1-7 C atoms for R 2 means propenyl, butenyl, 2-butenyl,
3-Butenyl, Isobutenyl, u.s.w. Bevorzugt sind Alkenyle mit 1-4 C-Atomen. Bei den Alkinylgruppen mit 1-7 C-Atomen für R2 sind ebenfalls Alkinyle mit3-butenyl, isobutenyl, etc. Alkenyls with 1-4 C atoms are preferred. The alkynyl groups with 1-7 C atoms for R 2 also contain alkynyls
1-4 C-Atomen bevorzugt, wie z.B. -CH -C≡CH, -C=C-CH , -CH -C=C-CH . 1-4 carbon atoms preferred, e.g. -CH -C≡CH, -C = C-CH, -CH -C = C-CH.
-CH2-CH2-C≡CH u.s.w. -CH 2 -CH 2 -C≡CH etc
Die Erfindung betrifft außerdem ein Verfahren zur Herstellung von Verbindungen der Formel I, dadurch gekennzeichnet, daß man ein Bicyclo[3.3.0]oct- 3-yliden-ethanol der Formel II  The invention also relates to a process for the preparation of compounds of the formula I, characterized in that a bicyclo [3.3.0] oct-3-ylidene ethanol of the formula II
worin A, W, D, E, R1 und R2 die oben angegebene Bedeutungen haben, nach vorheriger, unter Säurekatalyse durchgeführter Umsetzung mit Dihydrofuran oder -pyran epoxidiert. wherein A, W, D, E, R 1 and R 2 have the meanings given above, after previous reaction carried out under acid catalysis with dihydrofuran or -pyran.
Die Umsetzung mit Dihydrofuran oder Dihydropyran geschieht unter Säurekatalyse in einem inerten Lösungsmittel, wie Tetrahydrofuran, Diethylether, Di- oxan, Ethylenglycol-dimethylether, Methylenchlorid, Hexan, Heptan, Toluol zu einem Acetal. The reaction with dihydrofuran or dihydropyran takes place under acid catalysis in an inert solvent, such as tetrahydrofuran, diethyl ether, dioxane, ethylene glycol dimethyl ether, methylene chloride, hexane, heptane, toluene to give an acetal.
Die Säurekatalyse kann durch Mineralsäuren wie Salz- oder Schwefelsä ure oder sauren Ionenaustauscher oder organische Säuren, wie z.B. Trifluoressigsäure erfolgen. Die Reaktionstemperatur ist nicht kritisch, zweckmäßig erfolgt sie bei Raumtemperatur. Acid catalysis can be carried out by mineral acids such as hydrochloric or sulfuric acid or acidic ion exchangers or organic acids, e.g. Trifluoroacetic acid take place. The reaction temperature is not critical; it is expedient to do this at room temperature.
Die Epoxidierung der geschlitzten Derivate kann mit den dem Fachmann bekannten Reagenzien durchgeführt werden, besonders bevorzugt sind das Magnesiumsalz der Perphthalsäure oder m-Chlorperbenzoesäure. The epoxidation of the slotted derivatives can be carried out using the reagents known to the person skilled in the art, the magnesium salt of perphthalic acid or m-chloroperbenzoic acid being particularly preferred.
Die Umsetzung kann unter Zusatz von Natriumhydrogencarbonat oder Kaliumhy- drogencarbonat erfolgen, um säurekatalysierte Zersetzungsreaktionen zu verhindern.  The reaction can be carried out with the addition of sodium hydrogen carbonate or potassium hydrogen carbonate in order to prevent acid-catalyzed decomposition reactions.
Die Epoxidierung wird im allgemeinen zwischen 0°C und 60°C in einem inerten Lösungsmittel, wie Hexan, Heptan, Dichlormethan, 1,2-Dichlorethan, Diethylether oder Tetrahydrofuran durchgeführt. The epoxidation is generally carried out between 0.degree. C. and 60.degree. C. in an inert solvent such as hexane, heptane, dichloromethane, 1,2-dichloroethane, diethyl ether or tetrahydrofuran.
Die Erfindung besteht außerdem in der Verwendung der Epoxycarbacyclinvorstufen der Formel I zur Herstellung von Allylalkoholen der Formel III, The invention also consists in the use of the epoxycarbacyclin precursors of the formula I for the preparation of allyl alcohols of the formula III,
(III) (III)
worin A , W, D , E , R 1 und R2 die oben angegebene Bedeutung haben , durch Umsetzung mit einer Phosphorverbindung der Formel VI , wherein A, W, D, E, R 1 and R 2 have the meaning given above, by reaction with a phosphorus compound of the formula VI,
Li-P ( R4 ) 2 ( VI ) , worin R4 eine C6-C10-Arylgruppe oder eine C7-C13-Aralkylgruppe bedeutet, anschließender Umsetzung mit einer Verbindung der Formel VII. Li-P (R 4 ) 2 (VI), in which R 4 represents a C 6 -C 10 aryl group or a C 7 -C 13 aralkyl group, subsequent reaction with a compound of formula VII.
R5-Q (VII), worin R5 eine C1 -C4 -Alkylgruppe und Q ein Halogenatom, eine C1-C4 -Alkylsul- fonyloxygruppe oder eine C6-C7-Arylsulfonyloxygruppe bedeutet, und Abspaltung der allylischen Hydroxylschutzgruppe. R 5 -Q (VII), wherein R 5 is a C 1 -C 4 alkyl group and Q is a halogen atom, a C 1 -C 4 alkylsulfonyloxy group or a C 6 -C 7 arylsulfonyloxy group, and cleavage of the allylic hydroxyl protective group .
Die geschützten Epoxide der Formel I lassen sich mit einer Phosphorverbindung der Formel VI öffnen. The protected epoxides of the formula I can be opened with a phosphorus compound of the formula VI.
Die Umsetzung erfolgt zwischen 0°C und 30°C in einem inerten Lösungsmittel, wie Tetrahydrofuran, Diethylether, Dichlormethan, 1,2-Dichlorethan, Hexan, Toluol etc. The reaction takes place between 0 ° C and 30 ° C in an inert solvent such as tetrahydrofuran, diethyl ether, dichloromethane, 1,2-dichloroethane, hexane, toluene etc.
Die Reaktion der ringgeöffneten Epoxyverbindungen mit R5Q erfolgt zwischen 0°C und 50°C in einem inerten Lösungsmittel, wie Tetrahydrofuran, Diethylether, Dichlormethan, Heκan, Toluol etc., bevorzugt in dem Lösungsmittel, in dem auch die Epoxidöffnung durchgeführt wird (Eintopfreaktion). The reaction of the ring-opened epoxy compounds with R 5 Q takes place between 0 ° C and 50 ° C in an inert solvent such as tetrahydrofuran, diethyl ether, dichloromethane, Heκan, toluene etc., preferably in the solvent in which the epoxy opening is also carried out (one-pot reaction ).
Das Phosphoniumsalz IX erleidet spontan eine Eliminierung zu Derivaten der Formel X, in denen A, W, D, E, R1, R2 und R3 die in der Formel I angegebene Bedeutung haben. The phosphonium salt IX spontaneously undergoes elimination to give derivatives of the formula X in which A, W, D, E, R 1 , R 2 and R 3 have the meaning given in formula I.
Die Verbindungen der allgemeinen Formel X werden durch Abspaltung der allylischen Hydroxylschutzgruppe R3 in die E-Allylalkohole der Formel III umgewandelt. The compounds of the general formula X are converted into the E-allyl alcohols of the formula III by splitting off the allylic hydroxyl protective group R 3 .
Die selektive Abspaltung der Schutzgruppe erfolgt unter saurer Katalyse. The protective group is split off selectively under acidic catalysis.
Mineralsäuren wie Salz- oder Schwefelsäure oder organische Säuren, wie Trifluoressigsäure, Zitronensäure etc. in Wasser. Methanol oder Ethanol führen zur Zersetzung des sehr empfindlichen Allylalkohols (III) oder spalten die Silylschutzgruppen ab. Mineral acids such as hydrochloric or sulfuric acid or organic acids such as trifluoroacetic acid, citric acid etc. in water. Methanol or ethanol decompose the very sensitive allyl alcohol (III) or split off the silyl protective groups.
Überraschenderweise wurde gefunden, daß die Schutzgruppenspaltung in Isopropanol mit saurem Ionenaustauscher (Amberlyst 15) bei erhöhter Temperatur sehr sauber und vollständig gelingt. Surprisingly, it was found that the splitting of the protective groups in isopropanol with an acidic ion exchanger (Amberlyst 15) succeeds very cleanly and completely at elevated temperature.
Mit dem oben beschriebenen fünfstufigen Verfahren wird somit die vollständige und stereospezifische Umwandlung der Verbindungen mit der Formel IV zu Verbindungen der Formel III erreicht. With the five-step process described above, the complete and stereospecific conversion of the compounds with the formula IV to compounds of the formula III is thus achieved.
Nach Beendigung der Reaktion kann das gewünschte Produkt aus der Reaktionsmischung mit Hilfe herkömmlicher Methoden gewonnen werden. Beispielsweise umfaßt eine geeignete Gewinnungsmethode das Gießen der Reaktionsmischung in Wasser, Extraktion mit einem mit Wasser nicht mischbaren organischen Lösungsmittel, das Trocknen des organischen Eκtraktes und schließlich die Destillation des Lösungsmittels aus dem Extrakt, um das gewünschte Produkt zu gewinnen. Das Produkt kann gegebenenfalls weiter mit Hilfe üblicher Techniken, wie der Umkristallisation, der präparativ n Dünnschichtchromatographie oder der Säulenchromatographie gereinigt werden. After the reaction has ended, the desired product can be obtained from the reaction mixture using conventional methods. For example, a suitable recovery method involves pouring the reaction mixture into water, extracting it with a water-immiscible organic solvent, drying the organic extract, and finally distilling the solvent from the extract to obtain the desired product. The product can optionally be further prepared using conventional techniques such as recrystallization n Thin layer chromatography or column chromatography can be cleaned.
Die entsprechenden Umsetzungen mit Verbindungen der Formel IV mit ungeschützter Hydroxylgruppe (R3 =H) gelingen nicht. The corresponding reactions with compounds of the formula IV with an unprotected hydroxyl group (R 3 = H) are unsuccessful.
Die Wahl der Tetrahydrofuranylgruppe oder Tetrahydropyranylgruppe als OH- Schutzgruppe R3 ist kritisch, weil diese nicht mit der Phosphorverbindung reagiert und sich in Gegenwart der Silylether bzw. des empfindlichen Allyl- alkohols III abspalten läßt. The choice of the tetrahydrofuranyl group or tetrahydropyranyl group as the OH protective group R 3 is critical because it does not react with the phosphorus compound and can be split off in the presence of the silyl ether or the sensitive allyl alcohol III.
Die in dem Verfahren beschriebenen Ausgangsverbindungen III und IV sind in den DE-OS 30 48 906, 33 06 123 und 33 06 125 beschrieben. The starting compounds III and IV described in the process are described in DE-OS 30 48 906, 33 06 123 and 33 06 125.
Die Erfindung wird durch die folgenden Beispiele erläutert : The invention is illustrated by the following examples:
Beispiel 1 example 1
(1S,2S,3R,5S)-3-tert.Butyl-dimethylsilyloxy-2-[(3S,4S)-3-tert.butyl-dimethylsilyloxy-4-methyl-1,6-nonadlinyl]-7-[(Z)-2-perhydro-2-furyloxy)-ethylyden]-bicyclo[3. 3.0]octan  (1S, 2S, 3R, 5S) -3-tert-butyl-dimethylsilyloxy-2 - [(3S, 4S) -3-tert-butyl-dimethylsilyloxy-4-methyl-1,6-nonadlinyl] -7 - [( Z) -2-perhydro-2-furyloxy) ethylylene] bicyclo [3. 3.0] octane
50 g 2- (Z)-(1S,5S,6S,7R)-7-tert.Butyl-dimethyldilyloxy-6-[(3S,4S)-3-tert.- butyl-dimethylsilyloxy-4-methyl-1.6-nonadiinyl]-bicyclo[3.3.09]oct-3-yliden -ethanol werden unter Stickstoff in 1000 ml Heκan gelöst. Bei Raumtemperatur werden 2 g Amberlyst 15 und 64 g Dihydroduran zugegeben. Die gelbliche Lösung wird 12 Stunden bei Raumtemperatur nachgerührt. DC-Kontrolle (Hexan/ MTB 8:2) zeigt komplette Umsetzung (Rf AM = 0.13, RF Prod. = 0.55). 150 ml Natriumhydrogencarbonatlösung werden schnell zugetropft und es wird 30 Minuten nachgerührt. Die Hexanphase wird abgetrennt, über Natriumsulfat getrocknet und am Rotationsverdampfer eingeengt. 2000 g Silicagel, Laufmittel: Heκan/Ethylacetat 95:5. 50 g of 2- (Z) - (1S, 5S, 6S, 7R) -7-tert-butyl-dimethyldilyloxy-6 - [(3S, 4S) -3-tert-butyl-dimethylsilyloxy-4-methyl-1.6- nonadiinyl] -bicyclo [3.3.09] oct-3-ylidene-ethanol are dissolved under nitrogen in 1000 ml HeKan. 2 g of Amberlyst 15 and 64 g of dihydrodurane are added at room temperature. The yellowish solution is stirred for 12 hours at room temperature. DC control (hexane / MTB 8: 2) shows complete implementation (Rf AM = 0.13, RF Prod. = 0.55). 150 ml of sodium hydrogen carbonate solution are quickly added dropwise and stirring is continued for 30 minutes. The hexane phase is separated off, dried over sodium sulfate and concentrated on a rotary evaporator. 2000 g silica gel, mobile phase: Heκan / ethyl acetate 95: 5.
Ausbeute: 47.8 g = 84,7 % d.Th. Yield: 47.8 g = 84.7% of theory
(1S,2S,3R,5S)-3-tert.Butyl-dimethylsιlyloxy-2-[(3S,4S)-3-tert.butyl-dimethylsilyloxy-4-methyl-1.6-nonadiinyl]-7-[(Z)-2-perhydro-2-furyloxy)-ethylyden]-bicyclo[3. 3.0]octan  (1S, 2S, 3R, 5S) -3-tert-butyl-dimethylsilyloxy-2 - [(3S, 4S) -3-tert-butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl] -7 - [(Z) -2-perhydro-2-furyloxy) ethylylene] bicyclo [3. 3.0] octane
Analyse: C H O Si Analysis: C H O Si
ber. 70,29 10.16 10.3 9.13  calc. 70.29 10.16 10.3 9.13
gef. 69.92 10.07 - -  found 69.92 10.07 - -
Stufe 2 Level 2
(1S,5S,6S,7R)-7-tert.Butyl-dimethylsilyloxy-6-[(3S,4S)-3-tert.butyl-dime- thylsilyloxy-4-methyl-1.6-nonadiinyl]-3-(perhydro-2-furyloxymethyl)spiro- [bicyclo[3. 3.0]octan-3,2'-oxiran] 66,26 g Monoperoxyphthalsäure-Mg-Salz*6 H2O und 127,4 g NaHCO3 werden in 500 ml THF suspendiert und 46,5 g ( 1S,2S,3R,5S)-3-tert.Butyl-dimethylsilyloxy-2-[(3S,4S)-3-tert.butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl]-7- [(Z)-2-perhydro-2-furyloxy)-ethyliden]-bicyclo[3. 3.0]octan zugetropft. Die Suspension wird 3 Stunden bei Raumtemperatur gerührt und anschließend für 4 Stunden auf 50°C erwärmt. Die Mischung wird auf Raumtemperatur abgekühlt, es werden 300 ml MTB zugegeben und 175 ml gesättigte Natriumsulfit-Lösung zugetropft, dabei wird die Temperatur der Lösung auf 20° gehalten. Die (1S, 5S, 6S, 7R) -7-tert-butyl-dimethylsilyloxy-6 - [(3S, 4S) -3-tert-butyl-dimethyl-silyloxy-4-methyl-1,6-nonadiinyl] -3- (perhydro -2-furyloxymethyl) spiro- [bicyclo [3. 3.0] octane-3,2'-oxirane] 66.26 g of monoperoxyphthalic acid Mg salt * 6 H 2 O and 127.4 g of NaHCO 3 are suspended in 500 ml of THF and 46.5 g (1S, 2S, 3R, 5S) -3-tert-butyl-dimethylsilyloxy- 2 - [(3S, 4S) -3-tert-butyldimethylsilyloxy-4-methyl-1,6-nonadiinyl] -7- [(Z) -2-perhydro-2-furyloxy) ethylidene] bicyclo [3 . 3.0] added dropwise octane. The suspension is stirred for 3 hours at room temperature and then heated to 50 ° C. for 4 hours. The mixture is cooled to room temperature, 300 ml of MTB are added and 175 ml of saturated sodium sulfite solution are added dropwise, the temperature of the solution being kept at 20 °. The
Reaktionsmischung wird mit 200 ml Wasser und 100 ml MTB verdünnt und die Phasen getrennt. Die wässrige Phase wird zweimal mit je 200 ml MTB eκtra- hiert die die vereinigten organischen Phasen zweimal mit je 200 ml Wasser gewaschen, über Natrium getrocknet und am Rotationsverdampfter eingeengt. The reaction mixture is diluted with 200 ml of water and 100 ml of MTB and the phases are separated. The aqueous phase is extracted twice with 200 ml of MTB, the combined organic phases are washed twice with 200 ml of water, dried over sodium and concentrated on a rotary evaporator.
Ausbeute: 46,06 g = 96,5 % d. Th. Yield: 46.06 g = 96.5% of theory. Th.
MS,5S,6S,7R)-7-tert.Butyl-dimethylsilyloxy-6-[(3S,4S)-3-tert.butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl]-3-(perhydro-2-furyloxymethyl)spiro- -[bicyclo[3. 3.0]octan-3,2'-oxiran]  MS, 5S, 6S, 7R) -7-tert-butyl-dimethylsilyloxy-6 - [(3S, 4S) -3-tert.-butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl] -3- (perhydro- 2-furyloxymethyl) spiro- - [bicyclo [3. 3.0] octane-3,2'-oxirane]
Analyse: C H O Si Analysis: C H O Si
ber. 68.51 9,90 12,67 8.90  calc. 68.51 9.90 12.67 8.90
gef. 68,37 9,71 - - Stufe 3  found 68.37 9.71 - - Level 3
Lithium-diphenylphosphid Lithium diphenyl phosphide
Zu 3,67 g Lithium-Draht in einem trockenem 100 ml Dreihalskolben in 50 ml THF werden bei 20-22°C Innentemperatur 39 g Chlor-diphenyl-phosphin zugetropft. Es wird über Nacht bei Raumtemperatur (20-23°C) nachgerührt, dabei wird die Reaktions vervollständigt. Der Überschuß Li-Draht verbleibt an der Oberfläche der Lösung. Mit einer Spritze wird ein Aliquot der tiefroten Lösung entnommen, mit Wasser in einem Meßkolben hydrolysiert und ein Aliquot davon gegen 0,01 n HCl titriert. To 3.67 g of lithium wire in a dry 100 ml three-necked flask in 50 ml of THF, 39 g of chloro-diphenylphosphine are added dropwise at an internal temperature of 20-22 ° C. The mixture is stirred overnight at room temperature (20-23 ° C), the reaction is completed. The excess Li wire remains on the surface of the solution. An aliquot of the deep red solution is removed with a syringe, hydrolyzed with water in a volumetric flask and an aliquot thereof is titrated against 0.01N HCl.
Ausbeute: quantitativ  Yield: quantitative
Analytik: Titration gegen 0,01 n HCl Analysis: titration against 0.01 N HCl
Gehalt Gesamtalkali 1,55 m Stufe 4 Total alkali content 1.55 m Level 4
(1S,2S,3R,5S)-3-tert.Butyl-dimethylsilyloxy-2-[(3S.4S)-3-tert.butyl- 1,6-nonadiinyl]-7-[2-perhydro-2-furyloxy)-1-diphenylphosphanyl-ethyl]- bιcyclo[3. 3.0]octan-7-ol und (1S, 2S, 3R, 5S) -3-tert-butyl-dimethylsilyloxy-2 - [(3S.4S) -3-tert-butyl-1,6-nonadiinyl] -7- [2-perhydro-2-furyloxy ) -1-diphenylphosphanyl-ethyl] - bιcyclo [3rd 3.0] octan-7-ol and
(1S,2S,3R,5S)-3-tert.Butyl-dimethylsilyloxy-2-[(3S,4S)-3-tert.butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl]-7-[2-perhydro-2-furyloxy)-1-diphenyl- methyl-phosphonium-ethyl]-bicyclo[3.3.0]-octan-7-ol-Jocid und  (1S, 2S, 3R, 5S) -3-tert-butyl-dimethylsilyloxy-2 - [(3S, 4S) -3-tert-butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl] -7- [2 -perhydro-2-furyloxy) -1-diphenyl-methyl-phosphonium-ethyl] -bicyclo [3.3.0] -octan-7-ol-jocid and
(1S,2S,3R,5S)3-tert.Butyl-dimethylsilyloxy-2-[(3S,4S)-3-tert.butyl-dimethylsilyloxy-4methyl-1,6-nonadiinyl]-7-[(E)-2-perhydro-2-furyloxy)-ethylyden]-bicyclo[3.3.0]octan  (1S, 2S, 3R, 5S) 3-tert-butyl-dimethylsilyloxy-2 - [(3S, 4S) -3-tert-butyl-dimethylsilyloxy-4methyl-1,6-nonadiinyl] -7 - [(E) - 2-perhydro-2-furyloxy) ethylylene] bicyclo [3.3.0] octane
45.5 g (1S,5S,6S,7R)-7-tert.Butyl-dimethylsilyloxy-6-[(3S.4S)-3-tert.butyl- dimethylsilyloxy-4-methyl-1,6-nonadiinyl]-3-(perhydro-2-furyloxymethyl)- spiro-[bicyclo[3. 3.0]octan-3,2'-oxiran] werden in 280 ml abs. THF gelöst. Bei ca. 10°C Innentemperatur wird eine Losung von 110 ml Lithiumdiphenyl- phosphid (1,55 m) zugetropft. Die Losung färbt sich gegen Ende der Zugabe dunkelrot. Es wird eine Stunde bei 10-20 C nachgerührt. Bei 10-20°C werden 19,64 ml Methyliodid zugetropft. Die Lösung wird farblos und ein weißer Niederschlag (Methyl-diphenyl-phosphinoxid) fällt aus. Es wird 15 Minuten nachgerührt. Zur Reaktionsmischung werden 200 ml Wasser und 200 ml MTB zuzugeben, die Phasen getrennt und die wässrige Phase mit 100 ml MTB eκtrahiert. Die vereinigten organischen Phasen werden mit 200 ml Wasser und 100 ml gesättigter Kochsalzlösung gewaschen, über Natriumsulfat getrocknet und eingeengt. Das Rohprodukt wird über 600 g Kieselgel filtriert. 45.5 g (1S, 5S, 6S, 7R) -7-tert-butyl-dimethylsilyloxy-6 - [(3S.4S) -3-tert-butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl] -3- (perhydro-2-furyloxymethyl) - spiro- [bicyclo [3rd 3.0] octane-3,2'-oxirane] are abs in 280 ml. THF solved. A solution of 110 ml of lithium diphenyl phosphide (1.55 m) is added dropwise at an internal temperature of approx. 10 ° C. The solution turns dark red towards the end of the addition. The mixture is stirred at 10-20 C for one hour. 19.64 ml of methyl iodide are added dropwise at 10-20 ° C. The solution becomes colorless and a white precipitate (methyl diphenyl phosphine oxide) precipitates. The mixture is stirred for 15 minutes. 200 ml of water and 200 ml of MTB are added to the reaction mixture, the phases are separated and the aqueous phase is extracted with 100 ml of MTB. The combined organic phases are washed with 200 ml of water and 100 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is filtered through 600 g of silica gel.
(Laufmittel Hexan/Ethylacetat 95:5). (Solvent: hexane / ethyl acetate 95: 5).
Ausbeute: 35,5 g = 80,0 7. d. Th. Yield: 35.5 g = 80.0 7. d. Th.
(1S,2S,3R,5S)-3-tert.Butyl-dimethylsilyloxy-2-[(3S,4S)-3-tert.butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl]-7-[(E)-2-perhydro-2-furyloxy)-ethy- liden]-bicyclo[3. 3.0]octan  (1S, 2S, 3R, 5S) -3-tert-butyl-dimethylsilyloxy-2 - [(3S, 4S) -3-tert-butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl] -7 - [( E) -2-perhydro-2-furyloxy) ethylidene] bicyclo [3. 3.0] octane
Analyse : C H O Si Analysis: C H O Si
ber . 70 . 29 1 0 . 16 10 . 4 9 . 13  about. 70. 29 1 0. 16 10. 4 9. 13
gef . 70 . 21 9 , 85 - - Stufe 5 : found 70. 21 9, 85 - - Level 5:
2-<(E)-(1S ,5S, 6S, 7R)-7-tert.Butyl-dimethylsilyloxy-6-[(3S.4S)-3-tert.- butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl]-bicyclo[3.3.0]oct-3-yliden>-ethanol 2 - <(E) - (1S, 5S, 6S, 7R) -7-tert-butyl-dimethylsilyloxy-6 - [(3S.4S) -3-tert-butyl-dimethylsilyloxy-4-methyl-1,6 -nonadiinyl] -bicyclo [3.3.0] oct-3-ylidene> ethanol
30 g MS, 2S, 3R, 5S)-3-tert.Butyl-dimethylsilyloxy-2-[(3S,4S)-3-tert.- butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl]-7-[(E)-2-(perhydro-2-furyl- oxy)-ethyliden]-bicyclo[3.3.0]octan werden in 375 ml Isopropanol gelöst. Bei 20-23°C werden 6 g Amberlyst 15 zugegeben und die Mischung für 4,5 Stunden auf 50°C Innentemperarur erwärmt. Die Lösung wird auf 20-23°C abgekühlt, der Ionentauscher abfiltriert, mit 100 ml Isopropanol nachgewaschen und das Filtrat mit 100 ml gesättigter Natriumbicarbonatlösung versetzt (pH 8-9). Die Mischung wird auf ca. 150 ml eingeengt und in 200 ml Ethylacetat und 200 ml Wasser aufgenommen, die organische Phase abgetrennt und die wässrige Phase dreimal mit je 200 ml Ethylacetat extrahiert. Die vereinigten organischen Phasen werden mit 200 ml gesättigter Kochsalzlösung gewaschen, über Natriumsulfat getrocknet, filtriert und am Rotationsverdampfer eingeengt. Das Rohprodukt wird chromatographisch auf Kieselgel gereinigt. Ausbeute: 19,48 g = 73,3 % d. Th. 30 g MS, 2S, 3R, 5S) -3-tert-butyl-dimethylsilyloxy-2 - [(3S, 4S) -3-tert-butyl-dimethylsilyloxy-4-methyl-1,6-nonadiinyl] -7- [(E) -2- (perhydro-2-furyloxy) ethylidene] bicyclo [3.3.0] octane are dissolved in 375 ml isopropanol. 6 g of Amberlyst 15 are added at 20-23 ° C. and the mixture is heated to an internal temperature of 50 ° C. for 4.5 hours. The solution is cooled to 20-23 ° C., the ion exchanger is filtered off, washed with 100 ml of isopropanol and the filtrate is mixed with 100 ml of saturated sodium bicarbonate solution (pH 8-9). The mixture is concentrated to about 150 ml and taken up in 200 ml of ethyl acetate and 200 ml of water, the organic phase is separated off and the aqueous phase is extracted three times with 200 ml of ethyl acetate each time. The combined organic phases are washed with 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product is purified chromatographically on silica gel. Yield: 19.48 g = 73.3% of theory. Th.
Analyse: C H O Si Analysis: C H O Si
ber. 70.52 10,36 8.81 10.31  calc. 70.52 10.36 8.81 10.31
gef. 70.23 9.91 - -  found 70.23 9.91 - -

Claims

PATENTANSPRÜCHE PATENT CLAIMS
1. Epoxycarbacyclinvorstufen der Formel I, 1. epoxycarbacyclin precursors of the formula I,
(I) (I)
worin  wherein
A eine -C≡C-Gruppe,  A is a -C≡C group,
W eine Hydroxymethylengruppe, in der die OH-Gruppe durch eine Trialkylsilyl-, Diphenylalkylsilyl- oder Triphenylsilylgruppe geschützt ist, CH3 W is a hydroxymethylene group in which the OH group is protected by a trialkylsilyl, diphenylalkylsilyl or triphenylsilyl group, CH 3
D eine -CH-CH2 -Gruppe, D is a -CH-CH 2 group,
E eine -C≡C-Gruppe,  E is a -C≡C group,
R1 eine Hydroxygruppe, die wie die Hydroxygruppe in W substituiert sein kann, R 1 is a hydroxyl group which, like the hydroxyl group, can be substituted in W,
R2 eine geradkettige oder verzweigte Alkyl-, Alkenyl- oder Alkinylgruppe mit 1-7 C-Atomen bedeutet und R 2 represents a straight-chain or branched alkyl, alkenyl or alkynyl group with 1-7 C atoms and
R3 eine Tetrahydropyranyl- oder Tetrahydrofuranylgruppe darstellt. R 3 represents a tetrahydropyranyl or tetrahydrofuranyl group.
2. Verfahren zur Herstellung von Verbindungen der Formel I, dadurch gekennzeichnet, daß man ein Bicyclo[3.3.0]oct-3-yliden-ethanol der Formel II 2. A process for the preparation of compounds of the formula I, characterized in that a bicyclo [3.3.0] oct-3-ylidene-ethanol of the formula II
(II) (II)
worin A, W, D, E, R1 und R2 die oben angegebene Bedeutungen haben, nach vorheriger, unter Säurekatalyse durchgeführter Umsetzung mit Dihydrofuran oder -pyran epoxidiert. wherein A, W, D, E, R 1 and R 2 have the meanings given above, after previous reaction carried out under acid catalysis with dihydrofuran or -pyran.
3. Verwendung der Epoxycarbacyclinvorstufen der Formel I zur Herstellung von Allylalkoholen der Formel III 3. Use of the epoxycarbacyclin precursors of the formula I for the preparation of allyl alcohols of the formula III
(III) (III)
worin A, W, D, E, R1 und R2 die oben angegebene Bedeutung haben, durchwherein A, W, D, E, R 1 and R 2 have the meaning given above, by
Umsetzung mit einer Phosphorverbindung der Formel VI, Reaction with a phosphorus compound of the formula VI,
Li-P(R4 )2 (VI) worin R4 eine C6 -C10 -Arylgruppe oder eine C7-C13-Aralkylgruppe bedeutet, anschließender Umsetzung mit einer Verbindung der Formel VII, Li-P (R 4 ) 2 (VI) in which R 4 represents a C 6 -C 10 aryl group or a C 7 -C 13 aralkyl group, followed by reaction with a compound of the formula VII,
R5-Q (VII) worin R5 eine C1-C4 -Alkylgruppe und Q ein Halogenatom, eine C1-C4 -Alkyl- sulfonyloxygruppe oder eine C6 -C7-Arylsulfonyloxygruppe bedeutet, und Abspaltung der allylischen Hydroxylschutzgruppen. R 5 -Q (VII) wherein R 5 is a C 1 -C 4 alkyl group and Q is a halogen atom, a C 1 -C 4 alkylsulfonyloxy group or a C 6 -C 7 arylsulfonyloxy group, and cleavage of the allylic hydroxyl protective groups.
EP19910918068 1990-10-26 1991-10-25 Epoxycarbacyclin precursors, their preparation and their use Withdrawn EP0555247A1 (en)

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