[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO1993000354A1 - Method for the preparation of 6-methylene steroids - Google Patents

Method for the preparation of 6-methylene steroids Download PDF

Info

Publication number
WO1993000354A1
WO1993000354A1 PCT/EP1992/001366 EP9201366W WO9300354A1 WO 1993000354 A1 WO1993000354 A1 WO 1993000354A1 EP 9201366 W EP9201366 W EP 9201366W WO 9300354 A1 WO9300354 A1 WO 9300354A1
Authority
WO
WIPO (PCT)
Prior art keywords
steroids
group
hydrogen atom
methylene
preparation
Prior art date
Application number
PCT/EP1992/001366
Other languages
German (de)
French (fr)
Inventor
Rolf Bohlmann
Henry Laurent
Original Assignee
Schering Aktiengesellschaft Berlin Und Bergkamen
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft Berlin Und Bergkamen filed Critical Schering Aktiengesellschaft Berlin Und Bergkamen
Priority to JP5501211A priority Critical patent/JPH07500086A/en
Priority to EP92911939A priority patent/EP0591268A1/en
Publication of WO1993000354A1 publication Critical patent/WO1993000354A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16

Definitions

  • the invention relates to a process for the preparation of 6-methylene steroids of the general sub-formula I.
  • wo ⁇ n X symbolizes the CD ring system of steroids of the androstane series or Pregnan series from steroids of the general sub-formula II
  • wo ⁇ n X has the meaning given above, or the 3-enol ethers of these steroids and formaldehyde, which is characterized in that the reaction is carried out in the presence of primary or secondary amines.
  • EP-B 0034115 already describes a process for the preparation of 6-methylene steroids of the general sub-formula I from steroids of the general sub-formula II and formaldehyde.
  • This known method is preferably carried out using phosphoric acid derivatives such as phosphorus pentoxide, phosphorus oxychloride or phosphorus oxybromide as the condensing agent.
  • phosphoric acid derivatives such as phosphorus pentoxide, phosphorus oxychloride or phosphorus oxybromide
  • phosphate-containing wastewater is produced in the preparation of the reaction mixture, the disposal of which is economical portable conditions is known to be quite problematic.
  • Another serious disadvantage of the previously known process is that it gives only very unsatisfactory yields of the desired process product in the reaction of steroids with a free IIß-hydroxy group (SYNTHESIS, 1982, p 34-40, especially Table 1, No. 6n).
  • the method according to the invention has the advantage that such environmentally harmful wastewater does not occur. Furthermore, it has the advantage that it is also in the
  • the starting compounds for the process according to the invention can contain the same substituents in the CD ring system X as the previously known process.
  • the process according to the invention is of particular importance in the context of the synthesis of highly effective 6 ⁇ -methyl corticoids.
  • the process according to the invention can also be carried out with steroids as the starting substance which have a free hydroxyl group in the 11 ⁇ position, since substances of this type, such as hydrocortisone, are often commercially available preparations.
  • steroids In the previously known processes, one must either start from steroids with a protected II ⁇ -hydroxyl group, the elimination of which is usually not unproblematic or introduce the II ⁇ -hydroxyl group subsequently by microbiological means, which is very complex and requires considerable know-how.
  • steroids of the general sub-formula II are particularly preferred, those as CD ring system X those of the general sub-formula III
  • wo ⁇ n n are the numbers 1 or 2
  • Alkylidendioxy distru with up to 6 carbon atoms mean or wherein R2 symbolizes a hydrogen atom, a hydroxy group or an acyloxy group with up to 8 carbon atoms and R3 represents a hydrogen atom or a methyl group.
  • the starting compounds can contain, for example, the same protective groups as those in the previously known process. However, it has already been mentioned that protective groups of this type are not necessary for carrying out the process according to the invention.
  • acyloxy groups R- and R2 of these substances are the benzoyloxy group or straight-chain or branched alkanoyloxy groups such as the acetoxy group, the propionyloxy group, the butyryloxy group, the 1-methylpropionyloxy group, the 1,1-dimethylpropionyloxy group or the hexanoyloxy group.
  • the isopropylidenedioxy group may be mentioned as the alkylidenedioxy group.
  • R4 represents an alkyl group with 1 to 4 carbon atoms, to be converted and then converted into the 6-methylene steroids of the general sub-formula I.
  • the method according to the invention can also be used using aqueous formaldehyde solution or using condensation products of formaldehyde, such as 1,3,5-trioxane or paraformaldehyde, from which formaldehyde is formed in the course of the reaction.
  • the process is carried out in the presence of primary or secondary amines. It corresponds to the type of reaction known under the name aminomethylation or Mannich reaction.
  • Suitable amines are, for example, those of the general sub-formula V *
  • R5 and Rg together represent the grouping - (CH2) 2-Q- (CH2) 2 ⁇ with Q in the meaning of a carbon-carbon bond, a methylene group or an oxygen atom or in which
  • R5 is an alkyl group with up to 8 carbon atoms, a benzyl group or an alkyl group optionally containing up to 4 carbon atoms or
  • Alkoxy groups and / or fluorine atoms or chlorine atoms substituted phenyl radical and Rg has the same meaning as R5 or symbolizes a hydrogen atom.
  • N-methylaniline has been used as the amine component, but it can be considered certain that other amines, such as, for example, pyrrolidine, piperidine, morpholine, diethylamine, diisopropylamine or N-methylbenzylamine, are also used Implementation of the method according to the invention are suitable.
  • the components are in an inert solvent (for example an ether, such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) or a chlorinated hydrocarbon (such as dichloromethane, trichloromethane, tetrachloromethane, 1 , 1,2,2-tetrachloroethane etc.) dissolved or suspended.
  • an inert solvent for example an ether, such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.
  • a chlorinated hydrocarbon such as dichloromethane, trichloromethane, tetrachloromethane, 1 , 1,2,2-tetrachloroethane etc.
  • the reaction is preferably carried out in the presence of acids as catalysts (for example mineral acids such as hydrogen chloride, sulfuric acid or phosphoric acid or preferably strong organic acids such as trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid).
  • acids for example mineral acids such as hydrogen chloride, sulfuric acid or phosphoric acid or preferably strong organic acids such as trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid.
  • the reaction temperature is usually 0 ° C to 120 ° C.
  • reaction parameters are the same that are usually used in Mannich reactions.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

Described is a method for the preparation of 6-methylene steroids of general formula (I), in which X represents the CD ring system of the androstane-series or pregnane-series steroids, from steroids of general formula (II), in which X is as defined above, or from the 3-enol ethers of these steroids, and formaldehyde. The method is characterized in that the reaction is carried out in the presence of primary or secondary amines.

Description

Verfahren zur Herstellung von 6-MethyIensteroiden Process for the production of 6-methyl steroids
Die Erfindung betrifft ein Verfahren zur Herstellung von 6-Methylensteroiden der allgemeinen Teilformel IThe invention relates to a process for the preparation of 6-methylene steroids of the general sub-formula I.
Figure imgf000003_0001
Figure imgf000003_0001
woπn X das CD-Ringsystem von Steroiden der Androstanreihe oder Pregnanreihe symbolisiert aus Steroiden der allgemeinen Teilformel IIwoπn X symbolizes the CD ring system of steroids of the androstane series or Pregnan series from steroids of the general sub-formula II
Figure imgf000003_0002
Figure imgf000003_0002
woπn X die oben genannte Bedeutung besitzt, oder den 3-Enolethern dieser Steroide und Formaldehyd, welches dadurch gekennzeichnet ist, daß man die Umsetzung in Gegenwart primärer oder sekundärer Amine durchführt.woπn X has the meaning given above, or the 3-enol ethers of these steroids and formaldehyde, which is characterized in that the reaction is carried out in the presence of primary or secondary amines.
In der EP-B 0034115 ist bereits ein Verfahren zur Herstellung von 6-Methylensteroiden der allgemeinen Teilformel I aus Steroiden der allgemeinen Teilformel II und Formaldehyd beschrieben.EP-B 0034115 already describes a process for the preparation of 6-methylene steroids of the general sub-formula I from steroids of the general sub-formula II and formaldehyde.
Dieses vorbekannte Verfahren wird vorzugsweise unter Verwendung von Phosphorsäure- Derivaten, wie Phosphorpentoxid, Phosphoroxychlorid oder Phosphoroxybromid als Kondensationsmittel durchgeführt. Dies hat zur Folge, daß bei der Aufbereitung der Reaktionsmischung phosphathaltige Abwässer anfallen, deren Entsorgung unter ökonomisch tragbaren Bedingungen bekanntlich recht problematisch ist. Ein weiterer schwerwiegender Nachteil des vorbekannten Verfahrens ist es, daß es bei der Umsetzung von Steroiden mit einer freien llß-Hydroxygruppe nur sehr unbefriedigende Ausbeuten an gewünschtem Verfahrensprodukt liefert (SYNTHESIS, 1982, p 34-40, speziell Tabelle 1, Nr. 6n).This known method is preferably carried out using phosphoric acid derivatives such as phosphorus pentoxide, phosphorus oxychloride or phosphorus oxybromide as the condensing agent. As a result, phosphate-containing wastewater is produced in the preparation of the reaction mixture, the disposal of which is economical portable conditions is known to be quite problematic. Another serious disadvantage of the previously known process is that it gives only very unsatisfactory yields of the desired process product in the reaction of steroids with a free IIß-hydroxy group (SYNTHESIS, 1982, p 34-40, especially Table 1, No. 6n).
Demgegenüber hat das erfindungsgemäße Verfahren den Vorzug, daß bei ihm derartig umweltbelastende Abwässer nicht anfallen. Ferner hat es den Vorzug, daß es auch bei derIn contrast, the method according to the invention has the advantage that such environmentally harmful wastewater does not occur. Furthermore, it has the advantage that it is also in the
Umsetzung von Steroiden mit einer llß-Hydroxygruppe befriedigende Ausbeuten an Verfahrensprodukt liefert.Reaction of steroids with a llß-hydroxy group provides satisfactory yields of process product.
Die Ausgangsverbindungen für das erfindungsgemäße Verfahren können im CD-Ring¬ system X die gleichen Substituenten enthalten, wie das vorbekannte Verfahren. Von besonderer Bedeutung ist das erfindungsgemäße Verfahren aber im Rahmen der Synthese von hochwirksamen 6α-Methylkortikoiden. (EP-B 0054786, EP-B 0072547, EP-A 0095894, EP- B 0100874, EP-B 0110041, EP-B 0112467, EP-B 0149222 und EP-B 0149464). Gerade zur Synthese dieser Verbindungen ist es besonders vorteilhaft, daß das erfindungsgemäße Verfahren auch mit solchen Steroiden als Ausgangssubstanz durchgeführt werden kann, die in der llß-Position eine freie Hydroxygruppe besitzen, denn derartige Substanzen, wie zum Beispiel das Hydrocortison sind oft handelsübliche Präparate. Bei den vorbekannten Verfahren muß man entweder von Steroiden mit einer geschützten llß-Hydroxygruppe ausgehen, deren Abspaltung meist nicht unproblematisch ist oder die llß-Hydroxygruppe nachträglich auf mikrobiologischem Wege einführen, was sehr aufwendig ist und erhebliches know how erfordert.The starting compounds for the process according to the invention can contain the same substituents in the CD ring system X as the previously known process. However, the process according to the invention is of particular importance in the context of the synthesis of highly effective 6α-methyl corticoids. (EP-B 0054786, EP-B 0072547, EP-A 0095894, EP-B 0100874, EP-B 0110041, EP-B 0112467, EP-B 0149222 and EP-B 0149464). For the synthesis of these compounds in particular, it is particularly advantageous that the process according to the invention can also be carried out with steroids as the starting substance which have a free hydroxyl group in the 11β position, since substances of this type, such as hydrocortisone, are often commercially available preparations. In the previously known processes, one must either start from steroids with a protected IIβ-hydroxyl group, the elimination of which is usually not unproblematic or introduce the IIβ-hydroxyl group subsequently by microbiological means, which is very complex and requires considerable know-how.
Im Sinne dieser gewerblichen Verwertbarkeit sind solche Steroide der allgemeinen Teilformel II besonders bevorzugt, die als CD-Ringsystem X solche der allgemeinen Teilformel IIIIn terms of this commercial utility, steroids of the general sub-formula II are particularly preferred, those as CD ring system X those of the general sub-formula III
Figure imgf000004_0001
Figure imgf000004_0001
woπn n die Ziffern 1 oder 2 bedeuten, Y und Z gemeinsam eine Oxogruppe darstellen oder Y ein Wasserstoffatom symbolisiert und Z ein Wasserstoffatom oder eine freie oder geschützte Hydroxygruppe bedeutet, worin R* ein Wasserstoffatom, ein Halogenatom, eine Hydroxygruppe oder eine Acyloxygruppe mit bis zu 8 Kohlenstoffatomen darstellt und worin R2 und R3 gemeinsam eine Kohlenstoff-Kohlenstoffbindung oder einewoπn n are the numbers 1 or 2, Y and Z together represent an oxo group or Y symbolizes a hydrogen atom and Z represents a hydrogen atom or a free or protected hydroxyl group, in which R * represents a hydrogen atom, a halogen atom, a hydroxyl group or an acyloxy group having up to 8 carbon atoms and in which R2 and R3 together represent a carbon-carbon bond or a
Alkylidendioxygruppe mit bis zu 6 Kohlenstoffatomen bedeuten oder worin R2 ein Wasserstoffatom, eine Hydroxygruppe oder eine Acyloxygruppe mit bis zu 8 Kohlenstoffatomen symbolisiert und R3 ein Wasserstoffatom oder eine Methylgruppe bedeutet, enthalten.Alkylidendioxygruppe with up to 6 carbon atoms mean or wherein R2 symbolizes a hydrogen atom, a hydroxy group or an acyloxy group with up to 8 carbon atoms and R3 represents a hydrogen atom or a methyl group.
Als geschützte llß-Hydroxygruppen können die Ausgangsverbindungen beispielsweise die gleichen Schutzgruppen enthalten, wie bei denjenigen des vorbekannten Verfahrens. Es wurde aber bereits erwähnt, daß derartige Schutzgruppen zur Druchführung des erfindungsgemäßen Verfahrens nicht erforderlich sind.As protected IIβ-hydroxy groups, the starting compounds can contain, for example, the same protective groups as those in the previously known process. However, it has already been mentioned that protective groups of this type are not necessary for carrying out the process according to the invention.
Als Acyloxygruppen R- und R2 dieser Substanzen seien beispielsweise die Benzoyloxygruppe oder geradkettige oder verzweigte Alkanoyloxygruppen, wie die Acetoxygruppe, die Propionyloxygruppe, die Butyryloxygruppe, die 1-Methylpropionyl- oxygruppe, die 1,1-Dimethylpropionyloxygruppe oder die Hexanoyloxygruppe erwähnt.Examples of acyloxy groups R- and R2 of these substances are the benzoyloxy group or straight-chain or branched alkanoyloxy groups such as the acetoxy group, the propionyloxy group, the butyryloxy group, the 1-methylpropionyloxy group, the 1,1-dimethylpropionyloxy group or the hexanoyloxy group.
Als Alkylidendioxygruppe sei die Isopropylidendioxygruppe erwähnt.The isopropylidenedioxy group may be mentioned as the alkylidenedioxy group.
Diese Verbindungen können direkt als Ausgangssubstanzen für das erfindungsgemäße Verfahren verwendet werden. Andererseits ist es aber auch möglich, diese Substanzen durch Umsetzung mit den entsprechenden Orthoameisensäureestern und niederen .Alkoholen intermediär in die entsprechenden 3-Enolether der allgemeinen Teilformel IVThese compounds can be used directly as starting substances for the process according to the invention. On the other hand, however, it is also possible to intermediately convert these substances into the corresponding 3-enol ethers of the general sub-formula IV by reaction with the corresponding orthoformic acid esters and lower alcohols
Figure imgf000005_0001
woπn
Figure imgf000005_0001
woπn
R4 eine Alkylgruppe mit 1 bis 4 Kohlenstoffatoemen darstellt, zu überführen und diese dann in die 6-Methylensteroide der allgemeinen Teilformel I umzuwandeln. Ebenso wie das vorbekannte Verfahren kann auch das erfmdungsgemäße Verfahren unter Verwendung wässriger Formaldehydlösung oder unter Verwendung von Kondensationsprodukten des Formaldehyds, wie das 1,3,5-Trioxan oder der Paraformaldehyd, aus denen im Reaktionsverlauf intermediär Formaldehyd gebildet wird, verwendet werden.R4 represents an alkyl group with 1 to 4 carbon atoms, to be converted and then converted into the 6-methylene steroids of the general sub-formula I. Like the previously known method, the method according to the invention can also be used using aqueous formaldehyde solution or using condensation products of formaldehyde, such as 1,3,5-trioxane or paraformaldehyde, from which formaldehyde is formed in the course of the reaction.
Erfindungsgemäß wird das Verfahren in Gegenwart von primären oder sekundären Aminen durchgeführt. Es entspricht dem ReaJ tionstyp, der unter der Bezeichnung Aminomethylierung oder Mannich-Reaktion bekannt ist.According to the invention, the process is carried out in the presence of primary or secondary amines. It corresponds to the type of reaction known under the name aminomethylation or Mannich reaction.
Zur Durchführung derartiger Mannich-Reaktion kann man bekanntlich die unterschiedlichsten primären oder sekundären Amine anwenden (SYNTHESIS 1973, 703- 775).It is known that a wide variety of primary or secondary amines can be used to carry out such a Mannich reaction (SYNTHESIS 1973, 703-775).
Geeignete Amine sind beispielsweise solche der allgemeinen Teilformel V * Suitable amines are, for example, those of the general sub-formula V *
Figure imgf000006_0001
worin R5 und Rg gemeinsam die Gruppierung -(CH2)2-Q-(CH2)2~ mit Q in der Bedeutung einer Kohlenstoff-Kohlenstoff-Bindung, einer Methylengruppe oder eines Sauerstoffatoms darstellen oder worin
Figure imgf000006_0001
wherein R5 and Rg together represent the grouping - (CH2) 2-Q- (CH2) 2 ~ with Q in the meaning of a carbon-carbon bond, a methylene group or an oxygen atom or in which
R5 eine Alkylgruppe mit bis zu 8 Kohlenstoffatomen, eine Benzylgruppe oder einen gegebenenfalls durch bis zu 4 Kohlenstoffatome enthaltende Alkylgruppe oderR5 is an alkyl group with up to 8 carbon atoms, a benzyl group or an alkyl group optionally containing up to 4 carbon atoms or
Alkoxygruppen und/oder Fluoratome oder Chloratome substituierten Phenylrest bedeutet und Rg die gleiche Bedeutung wie R5 besitzt oder ein Wasserstoffatom symbolisiert.Alkoxy groups and / or fluorine atoms or chlorine atoms substituted phenyl radical and Rg has the same meaning as R5 or symbolizes a hydrogen atom.
Bei den bislang durchgeführten Versuchen wurde das N-Methylanilin als Aminkomponente verwendet, es kann aber als sicher angesehen weden, daß auch weitere Amine, wie zum Beispiel das Pyrrolidin, das Piperidin, das Morpholin, das Diethylamin, das Diisopropylamin oder das N-Methylbenzylamin zur Durchführung des erfindungsgemäßen Verfahrens geeignet sind.In the experiments carried out to date, the N-methylaniline has been used as the amine component, but it can be considered certain that other amines, such as, for example, pyrrolidine, piperidine, morpholine, diethylamine, diisopropylamine or N-methylbenzylamine, are also used Implementation of the method according to the invention are suitable.
Zur Durchführung des erfindungsgemäßen Verfahrens werden die Komponenten in einem inerten Lösungsmittel (beispielsweise einem Ether, wie Diethylether, Diisopropylether, Dibutylether, Tetrahydrofuran, Dioxan, 1,2-Dimethoxyethan, etc.) oder einem Chlorkohlenwasserstoff, (wie Dichlormethan, Trichlormethan, Tetrachlormethan, 1,1,2,2- Tetrachlorethan etc.) gelöst oder suspendiert. Die Reaktion wird vorzugsweise in Gegenwart von Säuren als Katalysatoren (z.B. Mineralsäuren, wie Chlorwasserstoff, Schwefelsäure oder Phosphorsäure oder vorzugsweise starken organischen Säuren, wie Trifluoressigsäure, Methansulfonsäure oder Trifluormethansulfonsäure) durchgeführt. Die Reaktionstemperatur beträgt in der Regel 0 °C bis 120 °C.To carry out the process according to the invention, the components are in an inert solvent (for example an ether, such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) or a chlorinated hydrocarbon (such as dichloromethane, trichloromethane, tetrachloromethane, 1 , 1,2,2-tetrachloroethane etc.) dissolved or suspended. The reaction is preferably carried out in the presence of acids as catalysts (for example mineral acids such as hydrogen chloride, sulfuric acid or phosphoric acid or preferably strong organic acids such as trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid). The reaction temperature is usually 0 ° C to 120 ° C.
Im übrigen sind die Reaktionsparameter die gleichen, die man bei Mannich-Reaktionen üblicherweise anwendet.Otherwise, the reaction parameters are the same that are usually used in Mannich reactions.
Die nachfolgenden Ausführungsbeispiele dienen zur Erläuterung des erfindungsgemäßen Verfahrens und zur Verwendung des Verfahrensproduktes. The following exemplary embodiments serve to explain the process according to the invention and to use the process product.
I. Beispiele für das erfindungsgemäße Verfahren:I. Examples of the process according to the invention:
Beispiel 1example 1
2.4 g 21-Acetoxy-llß,17α-dihydroxy-pregn-4-en-3,20-dion (Hydrocortisonacetat) werden in 25 ml Tetrahydrofuran suspendiert und mit 980 mg Paraformaldehyd sowie 6.34 g N- Methylaniliniumtrifluoracetat 2_5 Stunden bei 80 °C Badtemperatur gerührt. Dann wird mit Dichlormethan verdünnt, 3 mal mit IN-Salzsäure extrahiert, mit Natriumhydrogencarbonat und Kochsalzlösung gewaschen, über Natriumsulfat getrocknet und im Vakuum zur Trockne eingeengt. Man erhält 3.6 g rohes 21-Acetoxy-llß,17α-dihydroxy-6-methyIen-pregn-4-en- 3,20-dion, das an 400 g Kieselgel mit Hexan/Essigester chromatographiert wird. Man erhält 1.2 g reines 21-Acetoxy-llß,17α-dihydroxy-6-methylen-pregn-4-en-3,20-dion vom Schmelzpunkt 205 °C.2.4 g of 21-acetoxy-11ß, 17α-dihydroxy-pregn-4-en-3,20-dione (hydrocortisone acetate) are suspended in 25 ml of tetrahydrofuran and with 980 mg of paraformaldehyde and 6.34 g of N-methylanilinium trifluoroacetate for 2_5 hours at 80 ° C bath temperature touched. Then it is diluted with dichloromethane, extracted 3 times with IN hydrochloric acid, washed with sodium hydrogen carbonate and brine, dried over sodium sulfate and evaporated to dryness in vacuo. 3.6 g of crude 21-acetoxy-11β, 17α-dihydroxy-6-methylene-pregn-4-ene-3.20-dione are obtained, which is chromatographed on 400 g of silica gel with hexane / ethyl acetate. 1.2 g of pure 21-acetoxy-11β, 17α-dihydroxy-6-methylene-pregn-4-en-3.20-dione with a melting point of 205 ° C. are obtained.
Beispiel 2Example 2
5 g 21-Acetoxy-llß,17α-dihydroxy-pregn-4-en-3,20-dion (Hydrocortisonacetat) werden in 50 ml Tetrahydrofuran, 15 ml Triethylorthoformiat sowie 15 ml Ethanol suspendiert und mit 500 mg Pyridiniumtosylat 1 Stunde bei 40 °C Badtemperatur gerührt. Anschließend wird mit 5.5 ml N-Methylanilin und 6.5 ml 40 iger Formaldehydlösung eine weitere Stunde bei 40 °C Badtemperatur gerührt. Dann wird mit weinsaurem Eiswasser/Kochsalz gefallt, in Dichlormethan aufgenommen, mit Natriumhydrogencarbonat und Kochsalzlösung gewaschen, über Natriumsulfat getrocknet und im Vakuum zur Trockne eingeengt. Man erhält 5.8 g rohes 21-Acetoxy-llß,17α-dihydroxy-6-methylen-pregn-4-en-3,20-dion, das an 600 g Kieselgel mit Hexan/Essigester chromatographiert wird. Man erhält 2.1 g reines 21- Acetoxy-llß,17α-dihydroxy-6-methylen-pregn-4-en-3,20-dion vom Schmelzpunkt 205 °C.5 g of 21-acetoxy-llß, 17α-dihydroxy-pregn-4-en-3,20-dione (hydrocortisone acetate) are suspended in 50 ml of tetrahydrofuran, 15 ml of triethyl orthoformate and 15 ml of ethanol and with 500 mg of pyridinium tosylate for 1 hour at 40 ° C bath temperature stirred. The mixture is then stirred for a further hour at a bath temperature of 40 ° C. with 5.5 ml of N-methylaniline and 6.5 ml of 40% formaldehyde solution. It is then precipitated with tartaric ice water / sodium chloride, taken up in dichloromethane, washed with sodium hydrogen carbonate and sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. 5.8 g of crude 21-acetoxy-11β, 17α-dihydroxy-6-methylene-pregn-4-en-3,20-dione are obtained, which is chromatographed on 600 g of silica gel with hexane / ethyl acetate. 2.1 g of pure 21-acetoxy-11β, 17α-dihydroxy-6-methylene-pregn-4-en-3.20-dione are obtained with a melting point of 205 ° C.
II. Beispiel für die Verwendung des VerfahrensproduktesII. Example of the use of the process product
a) 2.1 g 21-Acetoxy-llß,17α-dihydroxy-6-methylen-pregn-4-en-3,20-dion werden in 9 ml Cyclohexen und 14 ml Ethanol vorgelegt und mit 170 mg 10% Palladium auf Kohle 8 Stunden unter Rückfluß gerührt. Nach dem Abkühlen wird der Katalysator abgesaugt und mit Ethanol nachgewaschen, das Filtrat wird mit 2 Tropfen konz. Salzsäure versetzt, im Vakuum auf 1/3 eingeengt, mit Eis/Kochsalz gefallt, abgesaugt, mit Wasser neutral gewaschen und im Vakuum bei 70 °C getrocknet. Nach dem Umkristallisieren des Rohprodukts aus Aceton-Hexan erhält man 1.78 g reines 21-Acetoxy-llß,17α-dihydroxy- 6α-methyl-pregn-4-en-3,20-dion vom Schmelzpunkt 208-9 °C; [a]τ) =+137° in Pyridin.a) 2.1 g of 21-acetoxy-11ß, 17α-dihydroxy-6-methylene-pregn-4-en-3,20-dione are placed in 9 ml of cyclohexene and 14 ml of ethanol and with 170 mg of 10% palladium on carbon for 8 hours stirred under reflux. After cooling, the catalyst is filtered off and washed with ethanol, the filtrate is concentrated with 2 drops. Hydrochloric acid added, concentrated to 1/3 in vacuo, precipitated with ice / common salt, suction filtered, washed neutral with water and dried in vacuo at 70 ° C. After recrystallization of the crude product from acetone-hexane, 1.78 g of pure 21-acetoxy-11β, 17α-dihydroxy-6α-methyl-pregn-4-en-3,20-dione are obtained, melting point 208-9 ° C .; [a] τ ) = + 137 ° in pyridine.
b) 1.78 g reines 21-Acetoxy-llß,17α-dihydroxy-6α-methyl-pregn-4-en-3,20-dion werden in 18 ml Dioxan gelöst und mit 1.8 g Dichlordicyanobenzochinon 14 Stunden bei 120 °C Badtemperatur gerührt. Nach dem Abkühlen wird das überschüssige Dichlordicyano- benzochinon abfiltriert, das Filtrat im Vakuum zur Trockne eingeengt, und der Rückstand an Kieselgel mit einem Dichlormethan/Aceton-Gradienten (0-20% Aceton) gereinigt. Man isoliert 1.23 g 21-Acetoxy-llß,17α-dihydroxy-6α-methyl-pregna-l,4-dien-3,20-dion. Schmelzpunkt 227-8 °C; [ά ) +100° in Pyridin.b) 1.78 g of pure 21-acetoxy-11β, 17α-dihydroxy-6α-methyl-pregn-4-en-3,20-dione are dissolved in 18 ml of dioxane and with 1.8 g of dichlorodicyanobenzoquinone for 14 hours at 120 ° C. Bath temperature stirred. After cooling, the excess dichlorodicyano-benzoquinone is filtered off, the filtrate is evaporated to the dry state in a vacuum, and the residue is purified on silica gel using a dichloromethane / acetone gradient (0-20% acetone). 1.23 g of 21-acetoxy-11β, 17α-dihydroxy-6α-methyl-pregna-l, 4-diene-3,20-dione are isolated. Melting point 227-8 ° C; [ά) + 100 ° in pyridine.
1.4 g 21-Acetoxy-llß,17α-dihydroxy-6α-methyl-pregna-l,4-dien-3,20-dion werden in 7 ml 0.2 N methanolischer Kaliumhydroxidlösung suspendiert und 1 Stunde bei 25 °C gerührt. Dann wird mit Eis/Kochsalz gefallt, abgesaugt, mit Wasser neutralgewaschen und im Vakuum bei 70 °C getrocknet. Man erhält 1.1 g llß,17α,21-Trihydroxy-6α-methyl- pregna-l,4-dien-3,20-dion. 1.4 g of 21-acetoxy-11β, 17α-dihydroxy-6α-methyl-pregna-l, 4-diene-3,20-dione are suspended in 7 ml of 0.2 N methanolic potassium hydroxide solution and stirred at 25 ° C. for 1 hour. Then it is precipitated with ice / common salt, suction filtered, washed neutral with water and dried in vacuo at 70 ° C. 1.1 g of 11β, 17α, 21-trihydroxy-6α-methyl-pregna-l, 4-diene-3,20-dione are obtained.

Claims

Patentansprüche: Claims:
1. Verfahren zur Herstellung von 6-Methylensteroiden der allgemeinen Teilformel I1. Process for the preparation of 6-methylene steroids of general formula I
Figure imgf000010_0001
woπn
Figure imgf000010_0001
woπn
X das CD-Ringsystem von Steroiden der Androstanreihe oder Pregnanreihe symbolisiert aus Steroiden der allgemeinen Teilformel IIX symbolizes the CD ring system of steroids of the androstane series or Pregnan series from steroids of the general sub-formula II
Figure imgf000010_0002
Figure imgf000010_0002
woπn X die oben genannte Bedeutung besitzt, oder den 3-Enolethern dieser Steroide und Formaldehyd, dadurch gekennzeichnet, daß man die Umsetzung in Gegenwart primärer oder sekundärerwoπn X has the meaning given above, or the 3-enol ethers of these steroids and formaldehyde, characterized in that the reaction in the presence of primary or secondary
Amine durchführt.Performs amines.
2. Verfahren zur Herstellung von 6-Methylsteroiden gemäß Patentanspruch 1, dadurch gekennzeichnet, daß X das CD-Ringsystem der allgemeinen Teilformel III2. A process for the preparation of 6-methyl steroids according to claim 1, characterized in that X is the CD ring system of the general sub-formula III
Figure imgf000010_0003
woπn n die Ziffern 1 oder 2 bedeuten, Y und Z gemeinsam eine Oxogruppe darstellen oder
Figure imgf000010_0003
where n denotes the digits 1 or 2, Y and Z together represent an oxo group or
Y ein Wasserstoffatom symbolisiert und Z ein Wasserstoffatom oder eine freie oder geschützte Hydroxygruppe bedeutet, R*L ein W.asserstoffatom, ein Halogenatom, eine Hydroxygruppe oder eine Acyloxygruppe mit bis zu 8 Kohlenstoffatomen darstellt und worin R2 und R3 gemeinsam eine Kohlenstoff-Kohlenstoffbindung oder eineY symbolizes a hydrogen atom and Z represents a hydrogen atom or a free or protected hydroxyl group, R * L represents a W. hydrogen atom, a halogen atom, a hydroxyl group or an acyloxy group with up to 8 carbon atoms and in which R2 and R3 together represent a carbon-carbon bond or a
Alkylidendioxygruppe mit bis zu 6 Kohlenstoffatomen bedeuten oder worin R2 ein Wasserstoffatom, eine Hydroxygruppe oder eine Acyloxygruppe mit bis zu 8Alkylidendioxygruppe with up to 6 carbon atoms mean or wherein R2 represents a hydrogen atom, a hydroxy group or an acyloxy group with up to 8
Kohlenstoffatomen symbolisiert und R3 ein Wasserstoffatom oder eine Methylgruppe bedeutet.Symbolizes carbon atoms and R3 represents a hydrogen atom or a methyl group.
3. 21-Acetoxy-llß,17α-dihydroxy-6-methylen-pregn-4-en-3,20-dion. 3. 21-acetoxy-11ß, 17α-dihydroxy-6-methylene-pregn-4-en-3,20-dione.
PCT/EP1992/001366 1991-06-26 1992-06-15 Method for the preparation of 6-methylene steroids WO1993000354A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5501211A JPH07500086A (en) 1991-06-26 1992-06-15 Method for producing 6-methylene steroids
EP92911939A EP0591268A1 (en) 1991-06-26 1992-06-15 Method for the preparation of 6-methylene steroids

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4121484.6 1991-06-26
DE19914121484 DE4121484A1 (en) 1991-06-26 1991-06-26 METHOD FOR PRODUCING 6-METHYLENE STEROIDS

Publications (1)

Publication Number Publication Date
WO1993000354A1 true WO1993000354A1 (en) 1993-01-07

Family

ID=6435018

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/001366 WO1993000354A1 (en) 1991-06-26 1992-06-15 Method for the preparation of 6-methylene steroids

Country Status (4)

Country Link
EP (1) EP0591268A1 (en)
JP (1) JPH07500086A (en)
DE (1) DE4121484A1 (en)
WO (1) WO1993000354A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010122096A1 (en) * 2009-04-23 2010-10-28 Crystal Pharma, S.L.U. Process for obtaining fluorometholone and intermediates therefor
WO2015063408A2 (en) 2013-10-28 2015-05-07 Sanofi Method for preparing steroidal derivatives
CN110655549A (en) * 2018-06-29 2020-01-07 天津药业研究院有限公司 Preparation method of 6 beta-methylprednisolone

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3006453A1 (en) 2014-10-08 2016-04-13 Cosmo Technologies Ltd. 17alpha-monoesters and 17alpha,21-diesters of cortexolone for use in the treatment of tumors
RU2663484C1 (en) * 2017-05-18 2018-08-06 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) METHOD OF PREPARATION 6α-METHYLHYDROCORTISONE OR ESTERS THEREOF FROM HYDROCORTISONE 21-ACETATE
RU2664101C1 (en) * 2017-06-30 2018-08-15 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) Method for producing 6-methylenehydrocortisone or esters thereof from hydrocortisone 21-acetate
RU2663483C1 (en) * 2017-12-29 2018-08-06 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) Method of preparing 6-(n-methyl-n-phenyl)aminomethyl-hydrocortisone esters thereof from hydrocortisone 21-acetate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0326340A2 (en) * 1988-01-26 1989-08-02 FARMITALIA CARLO ERBA S.r.l. Improvement in the synthesis of 6-methylene derivatives of androsta-1,4-diene-3,17-dione

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0326340A2 (en) * 1988-01-26 1989-08-02 FARMITALIA CARLO ERBA S.r.l. Improvement in the synthesis of 6-methylene derivatives of androsta-1,4-diene-3,17-dione

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HELVETICA CHIMICA ACTA. Bd. 56, Nr. 7, 7. November 1973, BASEL CH Seiten 2396 - 2404; F. SCHNEIDER ET AL: 'Über den Verlauf der Umsetztung von Steroid-3,5-dienaminen mit Formaldehyde' *
HELVETICA CHIMICA ACTA. Bd. 63, Nr. 7, 29. Oktober 1980, BASEL CH Seiten 1867 - 1890; M. MÜLLER ET AL: '197. D-Homosteroide I. Synthese von Gestagen-Wirksamen D-Homopregnan-Derivaten' *
JOURNAL OF MEDICINAL CHEMISTRY. Bd. 34, Nr. 8, August 1991, WASHINGTON US Seiten 2464 - 2468; K. NICKISCH ET AL: 'Aldosterone Antagonists 4. Synthesis and Activities of Steroidal 6,6-Ethylene-15,16-Methylene 17-Spirolactones' *
SYNTHESIS. Nr. 1, Januar 1982, STUTTGART DE Seiten 34 - 40; K. ANNEN ET AL: 'A simple Method for 6-Methylenation of 3-Oxo-delta-4-steroids' *
TETRAHEDRON, (INCL. TETRAHEDRON REPORTS) Bd. 25, Nr. 5, März 1969, OXFORD GB Seiten 1155 - 1158; D. BURN ET AL: 'Modified Steroid Hormones - LI. Application of the Vilsmeier Reaction to 11-Beta-Hydroxy Steroids' *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010122096A1 (en) * 2009-04-23 2010-10-28 Crystal Pharma, S.L.U. Process for obtaining fluorometholone and intermediates therefor
EP2246359A1 (en) * 2009-04-23 2010-11-03 Crystal Pharma, S.L.U. Process for obtaining fluorometholone and intermediates therefor
WO2015063408A2 (en) 2013-10-28 2015-05-07 Sanofi Method for preparing steroidal derivatives
US9783569B2 (en) 2013-10-28 2017-10-10 Sanofi Method for preparing 6-alkylated steroidal derivatives and corresponding alkylated 5,6,7,8-tetrahydronaphthalene-2(4 alpha.H)-ones
CN110655549A (en) * 2018-06-29 2020-01-07 天津药业研究院有限公司 Preparation method of 6 beta-methylprednisolone
CN110655549B (en) * 2018-06-29 2022-06-14 天津药业研究院股份有限公司 Preparation method of 6 beta-methylprednisolone

Also Published As

Publication number Publication date
EP0591268A1 (en) 1994-04-13
JPH07500086A (en) 1995-01-05
DE4121484A1 (en) 1993-01-07

Similar Documents

Publication Publication Date Title
EP0749438B1 (en) Novel silyl compounds and their use
WO1993000354A1 (en) Method for the preparation of 6-methylene steroids
DE2916889A1 (en) IMPROVED PROCESS FOR THE PRODUCTION OF 6-HALOGEN PREGNANS
DD155994A5 (en) PROCESS FOR THE PREPARATION OF 6-METHYLENE STEROIDS
DE69215125T2 (en) Cardioactive steroids
DE3226164A1 (en) INTRODUCTION OF A FLUORATOM
WO1986000907A1 (en) Process for the manufacture of 6alpha-methyl steroids
DD150223A5 (en) PROCESS FOR THE PRODUCTION OF STEROIDS
CH494216A (en) Process for the preparation of 6-aminomethyl-3,5-steroids bearing an etherified hydroxyl group in the 3-position
EP0201452A2 (en) Process for the preparation of 17-alpha-ethynyl-17-beta-hydroxy-18-methyl-estra-4,15-dien-3-one and the starting products for this process
DE2905674A1 (en) STEROID COMPOUNDS AND THE METHOD OF MANUFACTURING THEM
DE2207421C3 (en) 15?, 16? -Methylene-4-oestrene-17? -ols or acylates, processes for their production and medicaments containing them
DE3012888C2 (en)
EP0127864A2 (en) D-homo-4,9,16-estratrienes, their preparation and pharmaceutical compositions containing them
DE958841C (en) Process for the preparation of 4, 17 (20) -pregnadiene-11ª ‡ (or 11ª ‰), -21-diol-3-one
DE953975C (en) Process for the production of 3-ketopregnans unsaturated in the 4 (5) position
DE2137557C3 (en) Process for the production of Acyloxy Delta 4 androstenen or ostrenen
DE1593687C (en) Process for the production of new benzo square bracket on d, square bracket mer to steroids of the androstane and preg nan series
DE1568688C3 (en) Process for the production of 3-oxo-4,6-dehydro-19-nor-steroids, as well as 17 beta-hydroxy-8 alpha, 10 alpha-estra-4,6-dien-3-one
DE1250435B (en)
DE2056512C3 (en)
DE1593377C (en) Process for the hydrolysis of 17alpha, 20, 20,21 bismethylene dioxysteroids of the Pregnan series
DE2803661A1 (en) Pregnane derivs. microbiological 11-beta-hydroxylation - using starting materials 17 alpha-substd. by an acetal group
DE1300942B (en) Process for the preparation of 19-hydroxy-ª € 5-androstene or 19-hydroxy-ª € 5-pregnancy derivatives
DE2749104A1 (en) 17-Ethynyl-17-hydroxy-18-methyl-4,15-oestradiene-3-one derivs. prodn. - from intermediates with ethylene di:thio:ketal protecting group

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): HU JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 1992911939

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1992911939

Country of ref document: EP

ENP Entry into the national phase

Ref country code: US

Ref document number: 1994 170162

Date of ref document: 19940504

Kind code of ref document: A

Format of ref document f/p: F

ENP Entry into the national phase

Ref country code: US

Ref document number: 1995 537027

Date of ref document: 19950929

Kind code of ref document: A

Format of ref document f/p: F

WWW Wipo information: withdrawn in national office

Ref document number: 1992911939

Country of ref document: EP