EP0591268A1 - Method for the preparation of 6-methylene steroids - Google Patents

Method for the preparation of 6-methylene steroids

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Publication number
EP0591268A1
EP0591268A1 EP92911939A EP92911939A EP0591268A1 EP 0591268 A1 EP0591268 A1 EP 0591268A1 EP 92911939 A EP92911939 A EP 92911939A EP 92911939 A EP92911939 A EP 92911939A EP 0591268 A1 EP0591268 A1 EP 0591268A1
Authority
EP
European Patent Office
Prior art keywords
steroids
group
hydrogen atom
methylene
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP92911939A
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German (de)
French (fr)
Inventor
Rolf Bohlmann
Henry Laurent
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
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Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP0591268A1 publication Critical patent/EP0591268A1/en
Withdrawn legal-status Critical Current

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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.

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

Abstract

Selon un procédé de préparation de stéroïdes 6-méthyléniques répondant à la formule générale (I), dans laquelle X représente le système cyclique CD des stéroïdes de la série des androstanes oou de la série des pregnanes, à partir de stéroïdes répondant à la formule générale (II), dans laquelle X a la signification susmentionnée, ou à partir des éthers 3-énoliques de ces stéroïdes et de formaldéhyde, la réaction se fait en présence d'amines primaires ou secondaires.According to a process for the preparation of 6-methylene steroids corresponding to the general formula (I), in which X represents the CD ring system of the steroids of the androstane series or of the pregnane series, from steroids corresponding to the general formula (II), in which X has the above meaning, or from the 3-enol ethers of these steroids and formaldehyde, the reaction takes place 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.
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
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
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
woπn 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 *
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 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
woπn 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
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
woπn n die Ziffern 1 oder 2 bedeuten, Y und Z gemeinsam eine Oxogruppe darstellen oder 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.
EP92911939A 1991-06-26 1992-06-15 Method for the preparation of 6-methylene steroids Withdrawn EP0591268A1 (en)

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DE19914121484 DE4121484A1 (en) 1991-06-26 1991-06-26 METHOD FOR PRODUCING 6-METHYLENE STEROIDS
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PCT/EP1992/001366 WO1993000354A1 (en) 1991-06-26 1992-06-15 Method for the preparation of 6-methylene steroids

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EP2246359A1 (en) * 2009-04-23 2010-11-03 Crystal Pharma, S.L.U. Process for obtaining fluorometholone and intermediates therefor
FR3012452A1 (en) 2013-10-28 2015-05-01 Sanofi Sa PROCESS FOR THE PREPARATION OF STEROIDIAN DERIVATIVES
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
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

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