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WO1998004579A1 - Method of producing 3-sulfanato-oxy-estra-1,3,5(10)-trien derivates (ii) - Google Patents

Method of producing 3-sulfanato-oxy-estra-1,3,5(10)-trien derivates (ii) Download PDF

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Publication number
WO1998004579A1
WO1998004579A1 PCT/EP1997/003707 EP9703707W WO9804579A1 WO 1998004579 A1 WO1998004579 A1 WO 1998004579A1 EP 9703707 W EP9703707 W EP 9703707W WO 9804579 A1 WO9804579 A1 WO 9804579A1
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estra
carbon atoms
bonds
trien
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German (de)
French (fr)
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Helmut HÄUSER
Michael Meyer
Daniel Ramirez
Maria Elena Rodriguez
Lucia Ibanez
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003

Definitions

  • the invention relates to a process for the preparation of 3-sulfanato-oxy-estra-l, 3,5 (10) -triene derivatives of the general formula I.
  • X denotes a carbonyl group, a hydroxymethylene group, an alkoxymethylene group with 2 to 6 carbon atoms in the alkoxy radical, a benzyloxymethylene group, an acyloxymethylene group with a maximum of 8 carbon atoms in the acyl radical or an alkylenedioxymethylene group with 2 to 6 carbon atoms in the alkylene radical and Z + represents an alkali metal cation, a 3-hydroxy-estra-1,3,5 (10) -triene derivative of the general formula II
  • the alkali metal salts of the general formula I are pharmacologically active substances which are referred to as conjugated estrogens (Pharmacopeia / Forum May, June 1991, p 1951-1962 and J. of Chromatography 224, 1981, p 355-370 and 224, 1982, p 234-239).
  • conjugated estrogens are prepared from the 3-hydroxy-estra-1,3,5 (10) -triene derivatives of the general formula ⁇ in such a way - by combining them with a sulfur trioxide in the presence of sodium hydride -Pyridine complex is implemented (US Pat. Nos. 3,391, 169, 5,210,081 and 5,288,717).
  • the process according to the invention has the advantage that the by-product runs poorer, so that, as a rule, purer process products can be obtained in large-scale processes without expensive cleaning operations in higher yields.
  • reaction of the 3-hydroxy-estra-1,3,5 (10) -triene derivatives of the general formula II with an alkali metal alcoholate and sulfur trioxide-pyridine complex can be carried out in such a way that the
  • the reaction partner is dissolved or suspended in a solvent which is inert to this reagent, optionally with stirring at - 25 ° C to 50 ° C (for the sake of simplicity at room temperature) until completion or reaction.
  • Sodium or potassium alcohols of lower alcohols such as methanol, ethanol, propanol, isopropanol or tert are preferably used as alkali metal alcoholates.
  • Butanol used.
  • Sodium methylate in a concentration of 1.2 to 10.0 mol sodium methylate per mol steroid has proven to be particularly suitable.
  • Suitable inert solvents for this reaction are, for example, polar ethers, such as dioxane, 1,2-dimethoxyethanol or, in particular, tetrahydrofuran.
  • the optimum reaction time is determined in a manner known per se using customary analysis, for example by means of thin-layer or gas chromatography. It is usually 30 minutes to 2 hours.
  • EXAMPLE 2 In an analogous manner, 100.0 g of the sodium salt of 3-sulfanato-oxy-estra-l can be obtained from 100.0 g of Estra-l, 3.5 (10), 7-tetraen-3.17 ⁇ -diol, 3.5 (10), 7-tetraen-17 ⁇ -ol, which contains 7% sodium acetate as stabilizer.

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

Abstract

The invention concerns a method of producing 3-sulfanato-oxy-estra-1,3,5(10)-trien derivates of the general formula (I) where the bonds marked with --- symbolize three single bonds, two single bonds and a double bond or two conjugated double bonds, X means a carbonyl group, an hydroxy-methylene group, an alkoxy-methylene group with two to six carbon atoms in the alkoxy residue, a benzyl oxymethylene group, an acyl oxymethylene group with up to eight carbon atoms in the acyl residue or an alkylene dioxymethylene group with two to six carbon atoms in the alkylene residue, and Z+ represents an alkali-metal cation, by reacting a 3-hydroxy-estra-1,3,5(10)-trien derivate in the presence of an alkali-metal alcoholate with a sulphur trioxide-pyridine complex.

Description

Verfahren zur Herstellung von 3-Sulfanato-oxy-estra-l,3,5(10)-trien- Process for the preparation of 3-sulfanato-oxy-estra-l, 3,5 (10) -triene-

Derivaten IIDerivatives II

Die Erfindung betrifft ein Verfahren zur Herstellung von 3-Sulfanato-oxy-estra- l,3,5(10)-trien-Derivaten der allgemeinen Formel IThe invention relates to a process for the preparation of 3-sulfanato-oxy-estra-l, 3,5 (10) -triene derivatives of the general formula I.

Figure imgf000003_0001
Figure imgf000003_0001

worinwherein

die mit gekennzeichneten Bindungen drei Einfachbindungen, zweithe bonds marked with three single bonds, two

Einfachbindungen und eine Doppelbindung oder zwei konjugierte Doppelbindungen symbolisieren, X eine Carbonylgruppe, eine Hydroxymethylengruppe, eine Alkoxymethylengruppe mit 2 bis 6 Kohlenstoffatomen im Alkoxyrest, eine Benzyloxymethylengruppe, eine Acyloxymethylengruppe mit maximal 8 Kohlenstoffatomen im Acylrest oder eine Alkylendioxymethylengruppe mit 2 bis 6 Kohlenstoffatomen im Alkylenrest bedeutet und Z+ ein Alkalimetallkation darstellt, wobei ein 3-Hydroxy-estra-l,3,5(10)-trien-Derivat der allgemeinen Formel IISingle bonds and a double bond or two conjugated double bonds symbolize, X denotes a carbonyl group, a hydroxymethylene group, an alkoxymethylene group with 2 to 6 carbon atoms in the alkoxy radical, a benzyloxymethylene group, an acyloxymethylene group with a maximum of 8 carbon atoms in the acyl radical or an alkylenedioxymethylene group with 2 to 6 carbon atoms in the alkylene radical and Z + represents an alkali metal cation, a 3-hydroxy-estra-1,3,5 (10) -triene derivative of the general formula II

Figure imgf000003_0002
Figure imgf000003_0002

worin und X die gleiche Bedeutung wie in Formel I besitzen, in Gegenwart eines Alkalimetallalkoholats mit einem Schwefeltrioxid-Pyridin-Komplex umsetzt.in which and X have the same meaning as in formula I, in the presence of an alkali metal alcoholate with a sulfur trioxide-pyridine complex.

Bekanntlich sind die Alkalimetallsalze der allgemeinen Formel I pharmakologisch wirksame Substanzen, die man als konjugierte Estrogene bezeichnet (Pharmacopeia/Forum May, June 1991, p 1951 - 1962 und J. of Chromatography 224, 1981, p 355 - 370 und 224, 1982, p 234 - 239).As is known, the alkali metal salts of the general formula I are pharmacologically active substances which are referred to as conjugated estrogens (Pharmacopeia / Forum May, June 1991, p 1951-1962 and J. of Chromatography 224, 1981, p 355-370 and 224, 1982, p 234-239).

Nach dem bekannten Stand der Technik werden diese konjugierten Estrogene aus den 3-Hydroxy-estra-l,3,5(10)-trien-Derivaten der allgemeinen Formel π in der Weise hergestellt-, indem man diese in Gegenwart von Natriumhydrid mit einem Schwefeltrioxid-Pyridin-Komplex umsetzt (US-PS 3.391, 169, US-PS 5.210,081 und US-PS 5.288,717).According to the known prior art, these conjugated estrogens are prepared from the 3-hydroxy-estra-1,3,5 (10) -triene derivatives of the general formula π in such a way - by combining them with a sulfur trioxide in the presence of sodium hydride -Pyridine complex is implemented (US Pat. Nos. 3,391, 169, 5,210,081 and 5,288,717).

Dieses vorbekannte Verfahren hat aber den Nachteil, daß bei ihm häufig beträchtliche Anteile an Nebenprodukten gebildet werden. Besonders ausgeprägt ist die Nebenproduktbildung , wenn man als Ausgangverbindungen 3-Hydroxyestra- l,3,5(10)-trien-Derivate der allgemeinen Formel II verwendet, die isolierte Doppelbindungen im B-Ring des Steroids besitzen, wie zum Beispiel das Equilin. Hierbei bilden sich viele Nebenprodukte, es kommt leicht zu Verschiebungen der Doppelbindung und somit zu zu Disproportionierung der Verfahrensprodukte.However, this known method has the disadvantage that it often forms considerable proportions of by-products. The formation of by-products is particularly pronounced if 3-hydroxyestra, 3,5 (10) -triene derivatives of the general formula II are used as starting compounds which have isolated double bonds in the B ring of the steroid, such as, for example, equilin. Many by-products are formed here, the double bond is easily shifted and the process products are disproportionated.

Demgegenüber hat das erfmdungsgemäße Verfahren den Vorteil, daß es Nebenprodukt ärmer abläuft, so daß man in der Regel ohne aufwendige Reinigungsoperationen in höheren Ausbeuten reinere Verfahrensprodukte im großtechnischen Verfahren erhält.In contrast, the process according to the invention has the advantage that the by-product runs poorer, so that, as a rule, purer process products can be obtained in large-scale processes without expensive cleaning operations in higher yields.

Die Durchführung des erfindungsgemäßen Verfahrens erfolgt unter Bedingungen, die dem Fachmann an sich bekannt sind.The process according to the invention is carried out under conditions which are known per se to the person skilled in the art.

So kann man beispielsweise die Umsetzung der 3-Hydroxy-estra-l,3,5(10)-trien- Derivate der allgemeinen Formel II mit einem Alkalimetallalkoholat und Schwefeltrioxid-Pyridin-Komplex in der Weise durchführen, indem man den dieFor example, the reaction of the 3-hydroxy-estra-1,3,5 (10) -triene derivatives of the general formula II with an alkali metal alcoholate and sulfur trioxide-pyridine complex can be carried out in such a way that the

Reaktionspartner in einem gegenüber diesem Reagenz inerten Lösungsmittel löst oder suspendiert, gegebenenfalls unter Rühren bei - 25 °C bis 50 °C (einfachheitshalber bei Raumtemperatur) bis zur Beendigung oder Umsetzung aufbewahrt. Als Alkalimetallalkoholate werden vorzugsweise Natrium- oder Kaliumal oholate niederer Alkohole wie Methanol, Ethanol, Propanol, Isopropanol oder tert. Butanol verwendet. Als besonders geeignet hat sich Natriummethylat in einer Konzentration von 1,2 bis 10,0 mol Natriummethylat pro Mol Steroid erwiesen.The reaction partner is dissolved or suspended in a solvent which is inert to this reagent, optionally with stirring at - 25 ° C to 50 ° C (for the sake of simplicity at room temperature) until completion or reaction. Sodium or potassium alcohols of lower alcohols such as methanol, ethanol, propanol, isopropanol or tert are preferably used as alkali metal alcoholates. Butanol used. Sodium methylate in a concentration of 1.2 to 10.0 mol sodium methylate per mol steroid has proven to be particularly suitable.

Für diese Reaktion eignen sich als inerte Lösungsmittel beispielsweise polare Ether, wie Dioxan, 1,2-Dimethoxyethanol oder insbesondere Tetrahydrofuran. Die optimale Reaktionszeit wird mittels der üblichen Analytik, so beispielsweise mittels Dünnschicht- oder Gaschromatographie in an sich bekannter Weise ermittelt. Sie beträgt normalerweise 30 Minuten bis 2 Stunden.Suitable inert solvents for this reaction are, for example, polar ethers, such as dioxane, 1,2-dimethoxyethanol or, in particular, tetrahydrofuran. The optimum reaction time is determined in a manner known per se using customary analysis, for example by means of thin-layer or gas chromatography. It is usually 30 minutes to 2 hours.

Die nachfolgenden Ausführungsbeispiele dienen zur näheren Erläuterung des erfindungsgemäßen Verfahrens.The following exemplary embodiments serve to explain the method according to the invention in more detail.

Beispiel 1:Example 1:

Unter Argon-Atmosphäre löst man 5,0 g 3-Hydroxy-estra-l,3,5(10)-trien-17-on in 60 ml Tetrahydrofuran und kühlt auf -10 °C ab. Nach Zugabe von 1,4 g Natriummethylat rührt man die erhaltene Suspension eine Stunde lang bei dieser Temperatur und fügt ebenfalls bei - 10 °C 3,5 g Pyridin-Schwefeltrioxid-Komplex (Aldrich Chem. Comp. Inc., Milwaukee USA; L. F. Fieser und M. Fieser, Reagents for Organic Synthesis, John Wiley and Sons, Inc. New York et al. i, 1127 und 1128, 2, 393 - 394, 3_, 275 - 276) zu. Die so erhaltene Lösung wird 0,5 Stunden bei 0 ° C und 2,0 Stunden bei Raumtemperatur gerührt. Danach wird mit Wasser und einer Lösung von 0,35 g Natriumacetat in 50 ml Methanol versetzt und im Vakuum zur Trockne eingeengt.5.0 g of 3-hydroxy-estra-l, 3,5 (10) -trien-17-one are dissolved in 60 ml of tetrahydrofuran under an argon atmosphere and the mixture is cooled to -10 ° C. After adding 1.4 g of sodium methylate, the suspension obtained is stirred for one hour at this temperature and 3.5 g of pyridine-sulfur trioxide complex (Aldrich Chem. Comp. Inc., Milwaukee USA; LF Fieser) are also added at -10 ° C. and M. Fieser, Reagents for Organic Synthesis, John Wiley and Sons, Inc. New York et al. i, 1127 and 1128, 2, 393 - 394, 3_, 275 - 276). The solution thus obtained is stirred for 0.5 hours at 0 ° C and 2.0 hours at room temperature. Then water and a solution of 0.35 g of sodium acetate in 50 ml of methanol are added and the mixture is evaporated to the dry state in a vacuum.

Es wird mit Methyl-tert.-butylether versetzt, der verbleibende Niederschlag abgesugt, dieser mit Ethanol gewaschen und im Vakuum getrocknet.Methyl tert-butyl ether is added, the remaining precipitate is filtered off with suction, washed with ethanol and dried in vacuo.

Es werden 6,2 g des Natriumsalzes von 3-Sulfanato-oxy-estra-l, 3,5(10), 8-tetraen-17- en erhalten. [α]20 = 182 ° (c = 0,5 in Wasser.6.2 g of the sodium salt of 3-sulfanato-oxy-estra-1,3,5 (10), 8-tetraen-17-ene are obtained. [α] 20 = 182 ° (c = 0.5 in water.

Beispiel 2: In analoger Weise lassen sich aus 100,0 g Estra-l,3,5(10),7-tetraen-3,17α-diol 100,0 g des Natriumsalzes des 3-Sulfanato-oxy-estra-l,3,5(10),7-tetraen-17α-ol, welches 7 % Natriumacetat als Stabilisator enthält erhalten. EXAMPLE 2 In an analogous manner, 100.0 g of the sodium salt of 3-sulfanato-oxy-estra-l can be obtained from 100.0 g of Estra-l, 3.5 (10), 7-tetraen-3.17α-diol, 3.5 (10), 7-tetraen-17α-ol, which contains 7% sodium acetate as stabilizer.

Claims

Patentanspruch Claim 1. Verfahren zur Herstellung von 3-Sulfaoxy-estra-l,3,5(10)-trien-Derivaten der allgemeinen Formel I1. Process for the preparation of 3-sulfaoxy-estra-1,3,5 (10) -triene derivatives of the general formula I. wonnwonn die mit gekennzeichneten Bindungen drei Einfachbindungen, zweithe bonds marked with three single bonds, two Einfachbindungen und eine Dopelbindung oder zwei konjugierte Doppelbindungen symbolisieren,Symbolize single bonds and a double bond or two conjugated double bonds, X eine Carbonylgruppe, eine Hydroxymethylengruppe, eine Alkoxymethylengruppe mit 2 bis 6 Kohlenstoffatomen im Alkoxyrest, eine Benzyloxymethylengruppe, eineX is a carbonyl group, a hydroxymethylene group, an alkoxymethylene group having 2 to 6 carbon atoms in the alkoxy radical, a benzyloxymethylene group, one Acyloxymethylengruppe mit maximal 8 Kohlenstoffatomen im Acylrest oder eineAcyloxymethylene group with a maximum of 8 carbon atoms in the acyl radical or one Alkylendioxymethylengruppe mit 2 bis 6 Kohlenstoffatomen im Alkylenrest bedeutet undAlkylenedioxymethylengruppe with 2 to 6 carbon atoms in the alkylene radical means and Z+ ein Alkalimetallkation darstellt, Z + represents an alkali metal cation, dadurch gekennzeichnet, daß man ein 3-Hydroxy-estra-l,3,5(10)-trien-Derivat der allgemeinen Formel IIcharacterized in that a 3-hydroxy-estra-1,3,5 (10) -triene derivative of the general formula II
Figure imgf000007_0001
Figure imgf000007_0001
 worin und x die gleiche Bedeutung wie in Formel I besitzen, in Gegenwart eines Alkalimetallalkoholats mit einem Schwefeltrioxid-Pyridin-Komplex umsetzt. wherein and x have the same meaning as in formula I, in the presence of an alkali metal alcoholate with a sulfur trioxide-pyridine complex.
PCT/EP1997/003707 1996-07-25 1997-07-11 Method of producing 3-sulfanato-oxy-estra-1,3,5(10)-trien derivates (ii) Ceased WO1998004579A1 (en)

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WO2008100769A3 (en) * 2007-02-09 2009-01-29 Wyeth Corp Process for selective sulfation of aromatic hydroxyl groups

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DE19631543C1 (en) * 1996-07-25 1997-11-20 Schering Ag 3-Sulphatoxy-oestra-1,3,5(10)-tri:ene derivatives preparation

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US4021458A (en) * 1974-04-18 1977-05-03 Schering Aktiengesellschaft Process for the preparation of 3-hemisulfate-17α-hydroxy steroids
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J. DUSZA ET AL: "The Preparation of Estradiol-17.beta.-Sulfates with Triethylamine-Sulfur Trioxide", STEROIDS., vol. 45, no. 3-4, March 1985 (1985-03-01) - April 1985 (1985-04-01), SAN FRANCISCO US, pages 303 - 315, XP002044784 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008100769A3 (en) * 2007-02-09 2009-01-29 Wyeth Corp Process for selective sulfation of aromatic hydroxyl groups

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