DE3718109A1 - Method for separating products of mespirenone synthesis - Google Patents

Method for separating products of mespirenone synthesis

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Publication number
DE3718109A1
DE3718109A1 DE19873718109 DE3718109A DE3718109A1 DE 3718109 A1 DE3718109 A1 DE 3718109A1 DE 19873718109 DE19873718109 DE 19873718109 DE 3718109 A DE3718109 A DE 3718109A DE 3718109 A1 DE3718109 A1 DE 3718109A1
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DE
Germany
Prior art keywords
methylene
carbolactone
acetylthio
oxo
mespirenone
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DE19873718109
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German (de)
Inventor
Walter Dr Klose
Klaus Dr Nickisch
Dieter Bittler
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Bayer Pharma AG
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Schering AG
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Publication date
Application filed by Schering AG filed Critical Schering AG
Priority to DE19873718109 priority Critical patent/DE3718109A1/en
Publication of DE3718109A1 publication Critical patent/DE3718109A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • C07J53/008—3 membered carbocyclic rings in position 15/16

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Steroid Compounds (AREA)

Abstract

The invention relates to a method for separating the mespirenone/ 7 alpha -acetylthio-15 beta ,16 beta -methylene-3-oxo-17 alpha -pregn-4-ene-21, 17-carbolactone mixture resulting from the microbiological dehydrogenation, which is characterised in that this mixture is reacted with Girard T reagent or is ketalised or subjected to an enol ether formation reaction and subsequently the 7 alpha -acetylthio-15 beta ,16 beta -methylene-3-oxo-17 alpha -pregn-4-ene-21,17- carbolactone derivatives are removed.

Description

Die vorliegende Erfindung betrifft ein Verfahren zur Tren­ nung des bei der mikrobiologischen Dehydrierung anfallen­ den Mespirenon/Promespirenon (7 α-Acetylthio-15 b,16 β- methylen-3-oxo-17 α-pregna-1,4-dien-21,17carbolacton/ 7 α-Acetylthio-15 β,16 β-methylen-3-oxo-17 α-pregn-4-en-21, 17-carbolacton)-Gemisches, dadurch gekennzeichnet, daß man das Gemisch mit Girard T-Reaganz umsetzt oder keta­ lisiert oder einer Enolether-Bildungsreaktion unterwirft und anschließend die Promespirenon (7 α-Acetylthio-15 β, 16 β-methylen-3-oxo-17 α-pregn-4-en-21,17-carbolacton)- Derivate abtrennt.The present invention relates to a process for the separation of the mespirenone / promespirenone (7 α -acetylthio-15 b , 16 β -methylene-3-oxo-17 α- pregna-1,4-diene-21, 17 carbolactone / 7 α -acetylthio-15 β , 16 β -methylene-3-oxo-17 α -pregn-4-en-21, 17-carbolactone) mixture, characterized in that the mixture is reacted with Girard T reagent or keta or subjected to an enol ether formation reaction and then the promespirenone (7 α -acetylthio-15 β , 16 β -methylene-3-oxo-17 α -pregn-4-ene-21,17-carbolactone) - derivatives.

Aus EP 99 853 ist der Aldosteronantagonist Mespirenon (7 a-Acetylthio-15 β,16 β-methylen-3-oxo-17 α-pregna-1,4- dien-21,17-carbolacton) bekannt. In der letzten Stufe der Mespirenon-Synthese wird mikrobiologisch eine 1.2- Doppelbindung eingeführt.EP 99 853 discloses the aldosterone antagonist mespirenone (7 a -acetylthio-15 β , 16 β -methylene-3-oxo-17 α -pregna-1,4-diene-21,17-carbolactone). In the last stage of mespirenone synthesis, a 1.2 double bond is introduced microbiologically.

Es gelingt jedoch nicht, das eingesetzte Promespirenon vollständig zu dehydrieren. Daher ist das gebildete Mespirenon stets noch von 3-6% unumgesetztem Promespirenon begleitet. Versuche, dieses 17 α-Pregn-4-en-21,17-carbolacton durch Kristallisation oder durch Chromatographie abzutrennen, führten nur zu unbefriedigenden Ergebnissen. However, it is not possible to completely dehydrate the promespirenone used. Therefore, the mespirenone formed is still accompanied by 3-6% unreacted promespirenone. Attempts to separate this 17 α -Pregn-4-en-21,17-carbolactone by crystallization or by chromatography only led to unsatisfactory results.

Es wurde nun überraschend gefunden, daß die Umsetzung des rohen Dehydrierungsproduktes mit Hydrazinderivaten vom Typ des Girard T-Reagenzes eine Trennung des Mes­ pirenons von den unerwünschten Beimengungen an Ausgangs­ material ermöglicht. Es ist zwar seit langem aus US 31 33 940, US 36 97 557, Chem. Rev. 62, 205, 1962 und aus Journal of Chemical Edukation 45, 435, 1968 bekannt, Δ 1,4- von Δ 4-3-Ketosteroiden zu trennen.It has now surprisingly been found that the reaction of the crude dehydrogenation product with hydrazine derivatives of the Girard T reagent type enables the measurement of the pirenone from the undesirable additions to starting material. Although it has long been known from US 31 33 940, US 36 97 557, Chem. Rev. 62, 205, 1962 and from Journal of Chemical Education 45, 435, 1968, Δ 1.4 - of Δ 4 -3-keto steroids to separate.

Überraschend und auch für den Fachmann unerwartet ist jedoch, daß diese an sich bekannte Fähigkeit von Girard T- artigen Reagenzien auch bei einer chemisch so labilen Verbindung wie Mespirenon erfolgreich angewandt werden kann. 7 α-Acetylthio-15 β,16 β-methylen-3-oxo-17 α-pregn- 4-en-21,17-carbolacton-Derivate sind sowohl gegenüber Säu­ ren als auch Basen sehr labil. Säuren katalysieren die Umlagerung des 15 b,16 β-Methylen-Lactons zu den in 17- Stellung isomerisierten Derivaten (Tetrahedron Letters 27, 5463, 1986).However, it is surprising and also unexpected for the person skilled in the art that this known ability of Girard T-type reagents can also be successfully used with a chemically unstable compound such as mespirenone. 7 α- acetylthio-15 β , 16 β- methylene-3-oxo-17 α- pregn-4-ene-21,17-carbolactone derivatives are very unstable with both acids and bases. Acids catalyze the rearrangement of the 15 b , 16 β -methylene lactone to the derivatives isomerized in the 17-position (Tetrahedron Letters 27, 5463, 1986).

Nach Einwirkung von Basen spaltet sich normalerweise die 7 α-Thioessigsäure ab und es resultiert das 3-Keto- Δ 4,6-System. Es ist daher erstaunlich, daß das Verfahren wie beschrieben geführt werden kann und daß es nicht zur Eliminierung bzw. Verseifung der Thioessigsäure kommt, dies um so mehr, da die basischen Eigenschaften solcher Hydrazinderivate zur Abspaltung von HBr aus 2.4-Dibrom­ steroiden unter Ausbildung der 1.2,4.5-Doppelbindungen ausgenutzt werden können (GB 7 88 306). Ebenso aus GB 7 88 306 ist es bekannt, Hydrazinderivate des obigen Typs zur Verseifung von Estergruppen zu verwenden. After exposure to bases, the 7 α- thioacetic acid normally cleaves and the 3-keto- Δ 4,6 system results. It is therefore surprising that the process can be carried out as described and that there is no elimination or saponification of the thioacetic acid, all the more because the basic properties of such hydrazine derivatives for the elimination of HBr from 2,4-dibromo steroids to form the 1.2 , 4.5 double bonds can be used (GB 7 88 306). From GB 7 88 306 it is also known to use hydrazine derivatives of the above type for the saponification of ester groups.

Es wurde außerdem gefunden, daß sich Promespirenon von Mespirenon auch mittels anderer Derivatisierungen des Promespirenons abtrennen läßt. Setzt man z. B. das Gemisch der mikrobiologischen Dehydrierung unter den Bedingungen einer Ketalisierungs- oder Enolether-Bildungsreaktion um, so läßt sich selektiv das Promespirenon in das entspre­ chende Derivat überführen. Das Mespirenon reagiert unter den Bedingungen nicht. Bei der Aufarbeitung läßt sich Mespire­ non durch einfache Kristallisation erhalten. Das Ketal oder der Enolether des Promespirenon verbleiben in der Mutterlauge.It was also found that promespirenone is from Mespirenon also by means of other derivatizations of the Promespirenons can be separated. If you put z. B. the mixture microbiological dehydration under the conditions a ketalization or enol ether formation reaction, this allows the promespirenone to be selectively incorporated into the transfer the corresponding derivative. The Mespirenon reacts among the Conditions not. When working up Mespire obtained by simple crystallization. The ketal or the enol ether of promespirenone remain in the Mother liquor.

Die angewandten Ketalisierungs- und Enolether-Bildungs­ reaktionen sind Standard-Reaktionen der Steroidchemie und somit jedem Fachmann bekannt. Die Herstellung des Enol­ ethers des Δ 4-3-Keto-steroids wird in J. Org. Chem. 26, 3925 (1965) beschrieben. Das Ketal wird durch Reaktion des Δ 4-3-Keto-steroids mit 2,2-Dimethyl-propan-1,3-diol in Gegenwart von Pyridinium-p-tosylat in inerten Lösungs­ mitteln, z. B. Dichlormethan, bei Temperaturen zwischen 20-100°C hergestellt, bevorzugt bei 20-30°C.The ketalization and enol ether formation reactions used are standard reactions in steroid chemistry and are therefore known to any person skilled in the art. The preparation of the enol ether of the Δ 4 -3-keto-steroid is described in J. Org. Chem. 26, 3925 (1965). The ketal is by reaction of the Δ 4 -3-keto-steroid with 2,2-dimethyl-propane-1,3-diol in the presence of pyridinium p-tosylate in inert solvents, for. B. dichloromethane, at temperatures between 20-100 ° C, preferably at 20-30 ° C.

Beispiel 1example 1

10,0 g 7 α-Acetylthio-15 β, 16 β-methylen-3-oxo-pregna-1.4- dien-21,17-carbolacton (verunreinigt mit 5,4% 7 α-Acetylthio- 15 β, 16 β-methylen-3-oxo-pregn-4-en-21,17-carbolacton) 15 g 2,2-Dimethyl-propan-1,3-diol, 1.0 g Pyridinium-p-tosylat und 15 ml Orthoameisensäuretriethylester werden in 150 ml Methylen­ chlorid gelöst und 48 h bei Raumtemperatur gerührt. Zur Auf­ arbeitung wird die Reaktionsmischung mit 150 ml gesättigter Natriumhydrogencarbonat-Lösung gewaschen, die Phasen getrennt, die organische Phase getrocknet und im Vakuum eingeengt. Der verbleibende Rückstand wird aus 200 ml Methanol umkristalli­ siert. Es werden 7.0 g 7 α-Acetylthio-15 β, 16 b-methylen-3-oxo- pregna-1.4-dien-21,17-carbolacton erhalten.10.0 g 7 α -acetylthio-15 β , 16 β -methylene-3-oxo-pregna-1.4-diene-21.17-carbolactone (contaminated with 5.4% 7 α -acetylthio-15 β , 16 β - methylene-3-oxo-pregn-4-en-21,17-carbolactone) 15 g of 2,2-dimethyl-propane-1,3-diol, 1.0 g of pyridinium p-tosylate and 15 ml of triethyl orthoformate are dissolved in 150 ml of methylene chloride dissolved and stirred for 48 h at room temperature. For working up, the reaction mixture is washed with 150 ml of saturated sodium bicarbonate solution, the phases are separated, the organic phase is dried and concentrated in vacuo. The remaining residue is recrystallized from 200 ml of methanol. 7.0 g of 7 α -acetylthio-15 β , 16 b -methylene-3-oxopregna-1.4-diene-21.17-carbolactone are obtained.

Fp.: 284-286°C
[α]: -83,9°
Gehalt nch HPLC (mit innerem Standard): 99,2%Mp: 284-286 ° C
[ α ]: -83.9 °
HPLC content (with internal standard): 99.2%

Beispiel 2Example 2

10 g 7 α-Acetylthio-15 β, 16 β-methylen-3-oxo-pregna-1,4-dien- 21,17-carbolacton (verunreinigt mit 5,4% 7 α-Acetylthio- 15 β, 16 β-methylen-3-oxo-pregn-4-en-21,17-carbolacton), 1.0 g Pyridinium-p-tosylat und 100 ml 2,2-Dimethoxypropan werden in 100 ml Dimethylformamid gelöst und 4 Tage bei Raumtemperatur gerührt. Anschließend wird die Reaktionsmischung in 1 l Eis­ wasser eingefüllt, der ausgefallene Niederschlag wird abge­ saugt und aus 200 ml Methanol umkristallisiert. Es werden 6,5 g 7 α-Acetylthio-15 β, 16 β-methylen-3-oxo-pregna-1,4-dien- 21,17-carbolacton erhalten.10 g 7 α -acetylthio-15 β , 16 β -methylene-3-oxo-pregna-1,4-diene-21,17-carbolactone (contaminated with 5.4% 7 α -acetylthio-15 β , 16 β - methylene-3-oxo-pregn-4-en-21,17-carbolactone), 1.0 g of pyridinium p-tosylate and 100 ml of 2,2-dimethoxypropane are dissolved in 100 ml of dimethylformamide and stirred for 4 days at room temperature. The reaction mixture is then poured into 1 liter of ice water, the precipitate which has separated out is suctioned off and recrystallized from 200 ml of methanol. 6.5 g of 7 α- acetylthio-15 β , 16 β- methylene-3-oxo-pregna-1,4-diene-21,17-carbolactone are obtained.

Fp.: 284-286°C
[α]: -83,8°C
Gehalt nach HPLC (mit innerem Standard): 99,2% Mp: 284-286 ° C
[ α ]: -83.8 ° C
HPLC content (with internal standard): 99.2%

Beispiel 3Example 3

Eine Lösung von 20 g 7 α-Acetylthio-15 β,16 β-methylen-3-oxo- pregna-1.4-dien-21,17-carbolacton (verunreinigt mit 5,4% 7 α-Acethylthio-15 b,16 β-methylen-3-oxo-pregn-4-en-21.17-carbo­ lacton) in 330 ml Tetrahydrofuran und 330 ml Methanol wird 13 Std. bei 50°C mit 1,972 g Girard T-Reagenz gerührt. An­ schließend verdünnt man mit 500 ml Wasser, extrahiert mit Dichlormethan, wäscht die vereinigten organischen Phasen mit Wasser und engt im Vakuum zur Trockene ein. Das erhaltene Rohprodukt wird in 2 l Methylenchlorid gelöst und mit 20 g Kieselgel 5 Std. bei Raumtemperatur gerührt, das Kieselgel abfiltriert und das Lösungsmittel im Vakuum auf ca. 40 ml eingeengt und mit Diisopropylether bis zur beginnenden Kristallisation versetzt. Durch Zugabe von weiterem Diiso­ propylether kann noch ein Zweit- und Drittkristallisat erhalten werden.A solution of 20 g of 7 α- acetylthio-15 β , 16 β- methylene-3-oxo-pregna-1.4-diene-21,17-carbolactone (contaminated with 5.4% of 7 α -acetylthio-15 b , 16 β -methylene-3-oxo-pregn-4-en-21.17-carbo lactone) in 330 ml of tetrahydrofuran and 330 ml of methanol is stirred for 13 hours at 50 ° C. with 1.972 g of Girard T reagent. Then it is diluted with 500 ml of water, extracted with dichloromethane, the combined organic phases are washed with water and concentrated to dryness in vacuo. The crude product obtained is dissolved in 2 l of methylene chloride and stirred with 20 g of silica gel for 5 hours at room temperature, the silica gel is filtered off and the solvent is concentrated to about 40 ml in vacuo and diisopropyl ether is added until crystallization begins. A second and third crystallizate can be obtained by adding further diiso propyl ether.

HPLC (mit innerem Standard)HPLC (with internal standard)

K1: 9,3 g 99,9%
K2: 4,0 g 99,8%
K3: 1,4 g 96,7%K 1 : 9.3 g 99.9%
K 2 : 4.0 g 99.8%
K 3 : 1.4 g 96.7%

Claims (1)

Verfahren zur Trennung des bei der mikrobiologischen Dehydrierung anfallenden Mespirenon/Promespirenon (7 α-Acetylthio-15 β,16 β-methylen-3-oxo-17 α-pregna-1,4- dien-21,17-carbolacton/7 α-Acetylthio-15 β,16 β-methylen- 3-oxo-17 α-pregn-4-en-21,17-carbolacton)-Gemisches, dadurch gekennzeichnet, daß man das Gemisch mit Girard T-Reagenz umsetzt oder ketalisiert oder einer Enolether- Bildungsreaktion unterwirft und anschließend die Promes­ pirenon (7 α-Acetylthio-15 β,16 β-methylen-3-oxo-17 α-pregn- 4-en-21,17-carbolacton)-Derivate abtrennt.Process for separating the mespirenone / promespirenone (7 α -acetylthio-15 β , 16 β -methylene-3-oxo-17 α -pregna-1,4-diene-21,17-carbolactone / 7 α - Acetylthio-15 β , 16 β- methylene-3-oxo-17 α -pregn-4-en-21,17-carbolactone) mixture, characterized in that the mixture is reacted with Girard T reagent or ketalized or an enol ether - Subjects formation reaction and then the Promes pirenon (7 α -acetylthio-15 β , 16 β -methylene-3-oxo-17 α -pregn- 4-en-21,17-carbolactone) derivatives separated.
DE19873718109 1987-05-27 1987-05-27 Method for separating products of mespirenone synthesis Withdrawn DE3718109A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3133940A (en) * 1956-04-10 1964-05-19 Glaxo Group Ltd Process for the separation of delta-1, 4-3-keto steroid compounds from mixtures thereof with other 3-keto steroids
DE1238016B (en) * 1965-02-04 1967-04-06 Merck Ag E Process for the preparation of S-alkylated or S-acylated 7alpha-mercapto-delta 1,4-3-keto-steroids
EP0099853B1 (en) * 1982-07-22 1987-06-03 Schering Aktiengesellschaft 7-alpha-acylthio-15,16-methylene-3-oxo-17-alpha-pregna-1,4-diene-21,17-carbolactones, their preparation and use as medicinal agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3133940A (en) * 1956-04-10 1964-05-19 Glaxo Group Ltd Process for the separation of delta-1, 4-3-keto steroid compounds from mixtures thereof with other 3-keto steroids
DE1238016B (en) * 1965-02-04 1967-04-06 Merck Ag E Process for the preparation of S-alkylated or S-acylated 7alpha-mercapto-delta 1,4-3-keto-steroids
EP0099853B1 (en) * 1982-07-22 1987-06-03 Schering Aktiengesellschaft 7-alpha-acylthio-15,16-methylene-3-oxo-17-alpha-pregna-1,4-diene-21,17-carbolactones, their preparation and use as medicinal agents

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Chem. Reviews 62, S.205-221, 1962 *
HOUBEN-WEYL: Methoden der Org. Chemie, Bd. VI, 3, S.222, 1965 *
J. Org. Chem. 26, S.3925-28, 1961 *
Tetrahedron Letters 27, (45), S.5463-66, 1986 *

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