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WO1987005940A1 - PROCESS FOR THE PRODUCTION OF 17aalpha-HYDROXY-D-HOMO-1,4-PREGNADIENE-3,20-DION - Google Patents

PROCESS FOR THE PRODUCTION OF 17aalpha-HYDROXY-D-HOMO-1,4-PREGNADIENE-3,20-DION Download PDF

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Publication number
WO1987005940A1
WO1987005940A1 PCT/DE1987/000143 DE8700143W WO8705940A1 WO 1987005940 A1 WO1987005940 A1 WO 1987005940A1 DE 8700143 W DE8700143 W DE 8700143W WO 8705940 A1 WO8705940 A1 WO 8705940A1
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Prior art keywords
homo
hydroxy
pregnadiene
dion
production
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Ceased
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PCT/DE1987/000143
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German (de)
French (fr)
Inventor
Alfred Weber
Mario Kennecke
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Bayer Pharma AG
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Schering AG
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Priority to FI875322A priority Critical patent/FI875322A7/en
Publication of WO1987005940A1 publication Critical patent/WO1987005940A1/en
Priority to DK636887A priority patent/DK636887A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P33/00—Preparation of steroids
    • C12P33/02—Dehydrogenating; Dehydroxylating
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids

Definitions

  • the invention relates to the method characterized in the claim.
  • the 17a ⁇ -hydroxy-D-homo-1,4-pregnadiene-3,20-dione is known to be an important intermediate for the synthesis of pharmacologically active D-homo-steroids (DE-A-23 14 592, DE-A-24 45 818 and DE-A-24 45 817). With the help of the method according to the invention, it is possible to make this connection much easier
  • Procedure runs in the desired manner; because it is known that the microorganism Bacillus lentus ATCC 13805 is generally not suitable for the oxidation of 3 ⁇ -hydroxy- ⁇ 5 steroids to 3-oxo- ⁇ 4 steroids.
  • the process according to the invention is carried out under the same fermentation conditions which are also used in the known microbiological ⁇ 1 dehydrogenation of steroids with the microorganism Bacillus lentus ATCC 13805.
  • Suitable substrate solvents are, for example, methanol, ethanol, glycol monomethyl ether, dimethylformamide or dimethyl sulfoxide).
  • the emulsification of the substrate can be effected, for example, by dissolving it in micronized form or in a water-miscible solvent (such as methanol, ethanol, acetone, glycol monomethyl ether, dimethylformamide or dimethyl sulfoxide) with strong turbulence in (preferably decalcified) water, which is the usual Contains emulsification aids.
  • a water-miscible solvent such as methanol, ethanol, acetone, glycol monomethyl ether, dimethylformamide or dimethyl sulfoxide
  • Fatty acid esters of polyglycols Fatty acid esters of polyglycols.
  • suitable emulsifiers are the commercially available wetting agents Tegin (R) , Tween (R) and Span (R) .
  • the optimal substrate concentration, substrate addition time and fermentation time depend on the structure of the substrate used and the type of microorganism used. As is generally required in the case of microbiological steroid conversions, these quantities must be determined in individual cases by preliminary tests as are known to the person skilled in the art.
  • the culture broth is extracted 3 times with 20 l of methyl isobutyl ketone, the extract in a rotary evaporator at max. Concentrated 50 ° C under vacuum. This is followed by purification by chromatography on aluminum oxide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Microbiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Steroid Compounds (AREA)

Abstract

Process for the production of 17a alpha -hydroxy-D-homo-1,4-pregnadiene-3,20-dion of formula (I) characterized by the fact that 3 beta ,17a alpha -dihydroxy-D-homo-5-pregnene-20-one of formula (II) is fermented with Bacillus lentus ATCC 13805.

Description

Verfahren zur Herstellung von 17aα-Hydroxy-D-homo- 1,4-pregnadien-3,20-dion Process for the preparation of 17aα-hydroxy-D-homo-1,4-pregnadiene-3,20-dione

Die Erfindung betrifft das in dem Patentanspruch gekennzeichnete Verfahren.The invention relates to the method characterized in the claim.

Das 17aα-Hydroxy-D-homo-1,4-pregnadien-3,20-dion ist bekanntlich ein wichtiges Zwischenprodukt zur Synthese pharmakologisch wirksamer D-Homo-Steroide (DE-A-23 14 592, DE-A-24 45 818 und DE-A-24 45 817). Mit Hilfe des erfindungsgemäßen Verfahrens ist es möglich, diese Verbindung auf wesentlich einfacheremThe 17aα-hydroxy-D-homo-1,4-pregnadiene-3,20-dione is known to be an important intermediate for the synthesis of pharmacologically active D-homo-steroids (DE-A-23 14 592, DE-A-24 45 818 and DE-A-24 45 817). With the help of the method according to the invention, it is possible to make this connection much easier

Wege herzustellen, als dies nach den bekannten Verfahren der Fall ist. Für den Fachmann ist es überraschend, daß diesesWays to produce than is the case according to the known methods. It is surprising to the person skilled in the art that this

Verfahren in gewünschter Weise abläuft; denn es ist bekannt, daß sich der Mikroorganismus Bacillus lentus ATCC 13805 im allgemeinen nicht zur Oxidation von 3ß-Hydroxy-Δ5-steroiden zu 3-Oxo-Δ4-Steroiden eignet.Procedure runs in the desired manner; because it is known that the microorganism Bacillus lentus ATCC 13805 is generally not suitable for the oxidation of 3β-hydroxy-Δ 5 steroids to 3-oxo-Δ 4 steroids.

Abgesehen von der Verwendung einer anderen Ausgangsverbindung, wird das erfindungsgemäße Verfahren unter den gleichen Fermentat iαnsbedingungen durchgeführt, welche man auch bei den bekannten mikrobiologischen Δ1-Dehydrierungen von Steroiden mit dem Mikroorganismus Bacillus lentus ATCC 13805 anwendet.Apart from the use of another starting compound, the process according to the invention is carried out under the same fermentation conditions which are also used in the known microbiological Δ 1 dehydrogenation of steroids with the microorganism Bacillus lentus ATCC 13805.

Unter den für diesen Mikroorganismus üblicherweise verwendeten Kulturbedingungen werden in einem geeigneten Nährmedium unter Belüften, Submerskulturen angezüchtet. Dann setzt man den Kulturen das Substrat (in einem geeigneten Lösungsmittel gelöst oder vorzugsweise in emulgierter Form) zu und fermentiert, bis eine maximale Substratumwandlung erreicht ist. Geeignete Substratlösungsmittel sind beispielsweise Methanol, Äthanol, Glykolmonomethyläther, Dimethylformamid oder Dimethylsulfoxyd). Die Emulgierung des Substrats kann beispielsweise bewirkt werden, indem man dieses in mikronisierter Form oder in einem mit Wasser mischbaren Lösungsmittel (wie Methanol, Äthanol, Aceton, Glykolmonomethyläther, Dimethylformamid oder Dimethylsulfoxyd) gelöst unter starker Turbulenz in (vorzugsweise entkalktem) Wasser, welches die üblichen Emulgationshilfen enthält eindüst. Geeignete Emulgationshilfen sind nichtionogene Emulgatoren, wie zum Beispiel Äthylenoxyaddukte oderUnder the culture conditions usually used for this microorganism, submerged cultures are grown in a suitable nutrient medium with aeration. Then the cultures (in a suitable solvent or preferably in emulsified form) are added to the cultures and fermented until a maximum conversion of the substrate is achieved. Suitable substrate solvents are, for example, methanol, ethanol, glycol monomethyl ether, dimethylformamide or dimethyl sulfoxide). The emulsification of the substrate can be effected, for example, by dissolving it in micronized form or in a water-miscible solvent (such as methanol, ethanol, acetone, glycol monomethyl ether, dimethylformamide or dimethyl sulfoxide) with strong turbulence in (preferably decalcified) water, which is the usual Contains emulsification aids. Suitable emulsification aids are nonionic emulsifiers, such as, for example, ethyleneoxy adducts or

Fettsäureester von Pαlyglykolen. Als geeignete Emulgatoren seien die handelsüblichen Netzmittel Tegin(R), Tween(R) und Span(R) beispielsmäßig genannt.Fatty acid esters of polyglycols. Examples of suitable emulsifiers are the commercially available wetting agents Tegin (R) , Tween (R) and Span (R) .

Die optimale Substratkonzentration, Substratzugabezeit und Fermentationsdauer ist von der Struktur des verwendeten Substrates und der Art des verwendeten Mikroorganismus abhängig. Diese Größen müssen, wie dies bei mikrobiologischen Steroidumwandlungen allgemein erforderlich ist, im Einzelfall durch Vorversuche, wie sie dem Fachmann geläufig sind, ermittelt werden.The optimal substrate concentration, substrate addition time and fermentation time depend on the structure of the substrate used and the type of microorganism used. As is generally required in the case of microbiological steroid conversions, these quantities must be determined in individual cases by preliminary tests as are known to the person skilled in the art.

Das nachfolgende Beispiel dient zur Erläuterung des erfindungsgemäßen Verfahrens. Beispiel:The following example serves to explain the method according to the invention. Example:

Ein 2 1-Erlenmeyerkolben mit 1 1 sterilem Nährmedium, enthaltend 1,5 % PeptonA 2 1 Erlenmeyer flask with 1 1 sterile culture medium containing 1.5% peptone

1,2 % Cornsteep liquor1.2% cornsteep liquor

-eingestellt auf pH 6,5-wird mit einer Suspension einer Bacillus lentus ATCC 13805-Trockenkultur beimpft und 48 Stunden lang bei 30°C mit 180 Umdrehungen pro Minute geschüttelt.- adjusted to pH 6.5 - is inoculated with a suspension of a Bacillus lentus ATCC 13805 dry culture and shaken for 48 hours at 30 ° C at 180 revolutions per minute.

Ein 50 1-Fermenter mit 30 1 steriler Nährlösung, enthaltendA 50 1 fermenter containing 30 1 sterile nutrient solution

0,05 % Glucosemonohydrat0.05% glucose monohydrate

1,0 % Hefeextrakt1.0% yeast extract

0,5 % Cornsteep liquor0.5% cornsteep liquor

4,0 ml Silikon SH4.0 ml silicone SH

- eingestellt auf pH 7,0-wird mit 1 1 der Bacillus lentus-Anzuchtskultur beimpft und 24 Stunden lang bei 30°C unter Belüftung von 2 m₃ pro Stunde und Rühren mit 50 Umdrejiungen pro Minute inkubiert.- Adjusted to pH 7.0 is inoculated with 1 1 of the Bacillus lentus cultivation culture and incubated for 24 hours at 30 ° C. with aeration of 2 m 3 per hour and stirring with 50 revolutions per minute.

Ein 50 1-Fermenter mit 30 1 steriler Nährlösung, enthaltendA 50 1 fermenter containing 30 1 sterile nutrient solution

0,05 % Glucosemonohydrat0.05% glucose monohydrate

1,0 % Hefeextrakt1.0% yeast extract

0,5 % Cornsteep liquor0.5% cornsteep liquor

4,0 ml Silikon SH4.0 ml silicone SH

-eingestellt auf pH 7,0-wird mit 3 1 Bacillus lentus Vorkultur beimpft und unter Belüftung von 2 m₃ pro Stunde und Rühren mit 300 Umdrehungen pro Minute bei 30°C 6 Stunden inkubiert. Dann setzt man der Kultur 15 g in 375 ml Dimethylformamid gelöstes und sterilfiltriertes 3ß,17aα-Dihydroxy-D-homo-4-pregnen-20-on zu und fermentiert weitere 25 Stunden lang.- adjusted to pH 7.0 - is inoculated with 3 1 Bacillus lentus preculture and incubated with aeration of 2 m ₃ per hour and stirring at 300 revolutions per minute at 30 ° C for 6 hours. 15 g of sterile-filtered 3β, 17aα-dihydroxy-D-homo-4-pregnen-20-one are then added to the culture and the mixture is fermented for a further 25 hours.

Nach erfolgter Fermentation wird die Kulturbrühe 3x mit je 20 1 Methylisobutylketon extrahiert, der Extrakt im Rotationsverdampfer bei max. 50° C unter Vakuum eingeengt. Anschließend erfolgt eine Reinigung durch Chromatographie an Aluminiumoxyd.After fermentation, the culture broth is extracted 3 times with 20 l of methyl isobutyl ketone, the extract in a rotary evaporator at max. Concentrated 50 ° C under vacuum. This is followed by purification by chromatography on aluminum oxide.

Man erhält 10,5 g 17aα-Hydroxy-D-homo-1,4-pregnadien-3,20-dion. 10.5 g of 17aα-hydroxy-D-homo-1,4-pregnadiene-3,20-dione are obtained.

Claims

PatentanspruchClaim Verfahren zur Herstellung von 17aα-Hydroxy-D-homo-1,4-pregnadien-3,20-dion der FormelProcess for the preparation of 17aα-hydroxy-D-homo-1,4-pregnadiene-3,20-dione of the formula
Figure imgf000007_0001
Figure imgf000007_0001
 dadurch gekennzeichnet, daß man 3ß,17aα-Dihydroxy-D-homo-4pregnen-20-on der Formelcharacterized in that 3ß, 17aα-dihydroxy-D-homo-4pregnen-20-one of the formula
Figure imgf000007_0002
Figure imgf000007_0002
 mit Bacillus lentus ATCC 13805 fermentiert. fermented with Bacillus lentus ATCC 13805.
PCT/DE1987/000143 1986-04-03 1987-04-01 PROCESS FOR THE PRODUCTION OF 17aalpha-HYDROXY-D-HOMO-1,4-PREGNADIENE-3,20-DION Ceased WO1987005940A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
FI875322A FI875322A7 (en) 1986-04-03 1987-04-01 Process for the preparation of 17α-hydroxy-D-homo-1,4-pregnadiene-3,20-dione.
DK636887A DK636887A (en) 1986-04-03 1987-12-03 PROCEDURE FOR PREPARING 17A ALFA-HYDROXY-D-HOMO-1,4-PREGNADIEN-3,20-DION

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP3611371.9 1986-04-03
DE3611371 1986-04-03

Publications (1)

Publication Number Publication Date
WO1987005940A1 true WO1987005940A1 (en) 1987-10-08

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EP (1) EP0261187A1 (en)
JP (1) JPS63502878A (en)
FI (1) FI875322A7 (en)
WO (1) WO1987005940A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992003571A1 (en) * 1990-08-18 1992-03-05 Schering Aktiengesellschaft Berlin Und Bergkamen Process for producing 4-pregnene-3,20-dione and its derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108541825B (en) * 2018-05-21 2021-07-06 浙江理工大学 A kind of preparation method of novel antibacterial fish feed

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3102080A (en) * 1960-05-20 1963-08-27 Schering Ag Method of producing 1,4-diene-3-ketosteroids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3102080A (en) * 1960-05-20 1963-08-27 Schering Ag Method of producing 1,4-diene-3-ketosteroids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chemische Berichte, Band 113, Nr. 1, Januar 1980, Verlag Chemie, GmbH, (Weinheim, DE), K. KIESLICH et al.: "Darstellung von Unterschiedlichen Mono- und Diketostrukturen von D-Homo-4-Pregnen-3, 20-Dion und D-Homo-1, 4-Pregnadien-3, 20-Dion", siehe seiten 205, 217 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992003571A1 (en) * 1990-08-18 1992-03-05 Schering Aktiengesellschaft Berlin Und Bergkamen Process for producing 4-pregnene-3,20-dione and its derivatives
US5391484A (en) * 1990-08-18 1995-02-21 Schering Aktiengesellschaft Process for the production of 4-pregnene-3,20-dione and its derivatives using mycobacterium NRRL B-3805

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Publication number Publication date
EP0261187A1 (en) 1988-03-30
FI875322A0 (en) 1987-12-02
JPS63502878A (en) 1988-10-27
FI875322L (en) 1987-12-02
FI875322A7 (en) 1987-12-02

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