DE1156407B - Process for the preparation of 6-chloro-6-dehydro-16-methylene-17ª ‡ -acetoxy-progesterone - Google Patents

Process for the preparation of 6-chloro-6-dehydro-16-methylene-17ª ‡ -acetoxy-progesterone

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Publication number
DE1156407B
DE1156407B DEM44345A DEM0044345A DE1156407B DE 1156407 B DE1156407 B DE 1156407B DE M44345 A DEM44345 A DE M44345A DE M0044345 A DEM0044345 A DE M0044345A DE 1156407 B DE1156407 B DE 1156407B
Authority
DE
Germany
Prior art keywords
progesterone
methylene
acetoxy
chloro
dehydro
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.)
Pending
Application number
DEM44345A
Other languages
German (de)
Inventor
Dipl-Chem Dr Karl-Heinz Bork
Dipl-Chem Dr Klaus Brueckner
Dr Ulrich Jahn
Dipl-Chem Dr Heinz J Mannhardt
Dipl-Chem Dr Fritz V Werder
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.)
Merck KGaA
Original Assignee
E Merck AG
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 E Merck AG filed Critical E Merck AG
Priority to DEM44345A priority Critical patent/DE1156407B/en
Publication of DE1156407B publication Critical patent/DE1156407B/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Verfahren zur Herstellung von 6-Chlor-6-dehydro-16-methylen-17a-acetoxy-progesteron Oral wirksame Progesteronderivate haben in der letzten Zeit in der Gynäkologie erhöhte Bedeutung erlangt.Process for the preparation of 6-chloro-6-dehydro-16-methylene-17a-acetoxy-progesterone Orally effective progesterone derivatives have recently increased in gynecology Gained importance.

Gegenstand der Erfindung ist ein Verfahren zur Herstellung von 6-Chlor-6-dehydro-16-methylen-17a-acetoxy-progesteron (II), das darin besteht. daß man in an sich bekannter Weise 6a,7a-Oxido-16-methylen-17a-acetoxy-progesteron (1) durch Behandlung mit mindestens molaren Mengen Chlorwas.serstoff, zweckmäßig in Gegenwart eines inerten organischen Lösungsmittels, entweder direkt oder durch anschließende Dehydratisierung des primär gebildeten 6ß-Chlor-7a-hydroxy-steroids in das 6-Chlor-6-dehydro- 16-methylen- 1 7a-acetoxy-progesteron überführt.The invention relates to a process for the preparation of 6-chloro-6-dehydro-16-methylene-17a-acetoxy-progesterone (II) which consists therein. that in a known manner 6a, 7a-oxido-16-methylene-17a-acetoxy-progesterone (1) by treatment with at least molar amounts of Chlorwas.serstoff, expediently in the presence of an inert organic solvent, either directly or by subsequent dehydration of the primarily formed 6ß-chloro-7a-hydroxy-steroids in the 6-chloro-6-dehydro-16-methylene- 1 7a-acetoxy-progesterone transferred.

Das als Ausgangsmaterial für das Verfahren nach der Erfindung erforderliche 6a,7a-Oxido- 16-methylen-17a-acetoxy-progesteron kann auf folgendem Wege gewonnen werden: Man verwendet das z. B. aus 16-Dehydro-16-methyl-progesteron durch Epoxydation leicht zugängliche 16a, 1 7a-Oxido- 1 6-methyl-progesteron, das durch Behandlung in beliebiger Reihenfolge mit Chloranil und mindestens katalytischen Mengen einer starken Säure in 6-Dehydro-16-methylen-]7a-hydroxy-progesteron umgewandelt werden kann. Letztere Verbindung läßt sich durch Umsetzung mit einem üblichen Acetylierungsmittel leicht in das zugehörige 6-Dehydro-16-methylen-]7a-acetoxy-progesteronumwandeln. Dieses so hergestellte Progesteronderivat kann durch Behandlung mit einem Epoxydierungsmittel in das als Ausgangsmaterial flür das Verfahren der Erfindung verwendete 6a,7a-Oxido-16-methylen-17a-acetoxy-progesteron umgewandelt werden. Das Chlorierungsverfahren nach der Erfindung wird zweckmäßigerweise in Gegenwart eines inerten organischen Lösungsmittels durchgeführt. Als Lösungsmittel für diese Reaktion kommen z. B. die folgenden in Frage: Dioxan, Eisessig, Benzol, Essig-Für die Herstellung der verfahrensgemäß eingesetzten Ausgangsverbindung wird im Rahmen der vorliegenden Erfindung Schutz nicht begehrt.The 6a, 7a-oxido-16-methylene-17a-acetoxy-progesterone required as starting material for the process according to the invention can be obtained in the following way: The z. B. from 16-dehydro-16-methyl-progesterone by epoxidation easily accessible 16a, 1 7a-Oxido- 1 6-methyl-progesterone, which by treatment in any order with chloranil and at least catalytic amounts of a strong acid in 6-dehydro- 16-methylene] 7a-hydroxy-progesterone can be converted. The latter compound can easily be converted into the associated 6-dehydro-16-methylene] 7a-acetoxy-progesterone by reaction with a customary acetylating agent. This progesterone derivative thus prepared can be converted into the 6a, 7a-oxido-16-methylene-17a-acetoxy-progesterone used as a starting material for the process of the invention by treatment with an epoxidizing agent. The chlorination process according to the invention is expediently carried out in the presence of an inert organic solvent. As a solvent for this reaction, for. B. the following in question: Dioxane, glacial acetic acid, benzene, vinegar-Protection is not sought for the preparation of the starting compound used according to the process in the context of the present invention.

Nach dem Verfahren der Erfindung gelingt es, das oral progestativ hochwirksame 6-Chlor-6-dehydro-16-methylen-17a-acetoxy-progesteron (11) herzustellen. Das Verfahren nach der Erfindung ist im folgenden Reaktionsschema skizziert: ester, Chloroform oder auch Gemische derselben. Besonders geeignet ist ein Gemisch aus Dioxan und Eisessig. Man arbeitet zweckmäßig bei Reaktionstemperaturen von etwa O'C bis zur Siedetemperatur des jeweiligen Lösungsmittels. Der für die Chlorierung verwendete Chlorwasserstoff muß mindestens in molaren Mengen angewendet werden, da ein Chloratom in das Molekül eingeführt wird. Verwendet man mit Wasser mischbare Lösungsmittel, so kann man den flür die Aufspaltung notwendigen Chlorwasserstoff in Form wäßriger Salzsäure anwenden. Die Umsetzung benötigt bei Raumtemperatur mehrere Tage. Man kann die Umsetzung auch in zwei Stufen vornehmen, indem man das nach der HCI-Behandlung primär gebildete 611-Chlor-7a-hydroxy-steroid isoliert und anschließend mit einem Dehydratisierungsmittel behandelt. Die Isolierung dieses als Zwischenprodukt anfallenden 61,1-Chlor-7(,t-hydroxy-steroids ist jedoch nicht erforderlich.According to the method of the invention, it is possible to produce 6-chloro-6-dehydro-16-methylene-17a-acetoxy-progesterone (11) , which is highly effective orally progestational. The process according to the invention is outlined in the following reaction scheme: ester, chloroform or mixtures thereof. A mixture of dioxane and glacial acetic acid is particularly suitable. It is expedient to work at reaction temperatures of about O'C to the boiling point of the respective solvent. The hydrogen chloride used for the chlorination must be used in at least molar amounts, since a chlorine atom is introduced into the molecule. If water-miscible solvents are used, the hydrogen chloride necessary for the splitting can be used in the form of aqueous hydrochloric acid. The reaction takes several days at room temperature. The reaction can also be carried out in two stages by isolating the 611-chloro-7a-hydroxy-steroid primarily formed after the HCl treatment and then treating it with a dehydrating agent. It is not necessary, however, to isolate this intermediate 61,1-chloro-7 (, t-hydroxy steroid.

Das nach dem erfindungsgemäßen Verfahren hergestellte 6-Chlor-6-dehydro- 16-methylen- 1 7a-acetoxyprogesteron (11) besitzt eine sehr hohe Progesteronwirkung bei oraler Applikation. Man kann die Verbindung zu den üblichen festen pharmazeutischen Zubereitungsformen verarbeiten. Zum Beispiel kann man Pillen, Tabletten, Drag&s oder Suppositorien herstellen. Als Formullerungshilfsmittel eignen sich die üblichen Substanzen zur Herstellung der genannten pharmazeutischen Zubereitungsarten, z. B. Stärke oder Zucker.The 6-chloro-6-dehydro-16-methylene- 1 7a-acetoxyprogesterone (11) produced by the process according to the invention has a very high progesterone effect when administered orally. The compound can be processed into the usual solid pharmaceutical preparation forms. For example, you can make pills, tablets, drag & s or suppositories. The usual substances for the production of the pharmaceutical preparation types mentioned are suitable as formulation auxiliaries, e.g. B. starch or sugar.

Die neue Verbindung kann in der Gynäkologie eingesetzt werden und zeichnet sich gegenüber den anderen bekannten progestativ wirkenden Steroiden durch besonders hohe Wirksamkeit bei oraler Applikation aus. So entfaltet das verfahrensgemäß erhaltene 6-Chlor-6-dehydro-1 6-methylen-17a-acetoxy-progesteron (11) im Clauberg-Test (Journal of Physiology, Bd. 83 [1935], S. 145) die 2,7fache gestagene Wirkung gegenüber dem bisher als wirksamstes Gestagen bekannten 6-Chlor-6-dehydro-17a-acetoxy-progesteron.The new compound can be used in gynecology and is distinguished from the other known steroids with a progestational effect by its particularly high effectiveness when administered orally. Thus, the 6-chloro-6-dehydro-1 6-methylene-17a-acetoxy-progesterone (11) obtained according to the method unfolds 2.7-fold in the Clauberg test (Journal of Physiology, Vol. 83 [1935], p. 145) Gestagenic effect compared to 6-chloro-6-dehydro-17a-acetoxy-progesterone, which is known to be the most effective progesterone to date.

Beispiel 1 20 g 6a,7a-Oxido-16-methylen-17a-acetoxy-progesteron werden in 200 ml Dioxan und 400 ml Eisessig gelöst, mit 10 ml konzentrierter Salzsäure versetzt und 10 Tage bei Raumtemperatur stehengelassen. Danach wird das Reaktionsgemisch in Wasser eingegossen, der Niederschlag abgesaugt, mit Wasser gewaschen und getrocknet. Das erhaltene 6-Chlor-6-dehydro- 16-methylen- 17a-acetoxy-progesteron kann durch Umkristallisation aus Methanol gereinigt werden. Das UV-Spektrum der Verbindung besitzt ein Maximum bei 282 m#L; EI'cimo = 680, Fp. 211 bis 212'C. Beispiel 2 a) 3,4 g 6("7(x-Oxido-16-rnethylen-17a-acetoxyprogesteron werden in 68 ml Eisessig und 34 ml Dioxan zusammen mit 2,5 ml konzentrierter Salzsäure 30 Minuten bei Raumtemperatur stehengelassen. Das Reaktionsgemisch wird danach in Wasser eingegossen, der Niederschlag des 6#-Chlor-7a-hydroxy-16-methylen-17a-acetoxy-progesterons abgesaugt, gewaschen und getrocknet; = 240 mu; EI'%' = 382. Example 1 20 g of 6a, 7a-oxido-16-methylene-17a-acetoxy-progesterone are dissolved in 200 ml of dioxane and 400 ml of glacial acetic acid, 10 ml of concentrated hydrochloric acid are added and the mixture is left to stand for 10 days at room temperature. The reaction mixture is then poured into water, and the precipitate is filtered off with suction, washed with water and dried. The 6-chloro-6-dehydro-16-methylene-17a-acetoxy-progesterone obtained can be purified by recrystallization from methanol. The UV spectrum of the compound has a maximum at 282 m # L; EI'cimo = 680, m.p. 211 to 212'C. Example 2 a) 3.4 g of 6 ("7 (x-oxido-16-methylene-17a-acetoxyprogesterone) in 68 ml of glacial acetic acid and 34 ml of dioxane together with 2.5 ml of concentrated hydrochloric acid are left to stand at room temperature for 30 minutes then poured into water, the precipitate of 6 # -chloro-7a-hydroxy-16-methylene-17a-acetoxy-progesterone filtered off with suction, washed and dried; = 240 μ; EI '%' = 382.

b) 3,5g 6fl-Chlor-7a-hydroxy-1 6-methylen-17a-acetoxy-progesteron werden unter den Bedingungen des Beispiels 1 zum 6-Chlor-6-dehydro-16-methylen-17a-acetoxy-progesteron umgesetzt; i."" = 282 mli; EI'%' = 680; F. 211 bis 212'C. b) 3.5 g of 6fl-chloro-7a-hydroxy- 16-methylene-17a-acetoxy-progesterone are converted under the conditions of Example 1 to 6-chloro-6-dehydro-16-methylene-17a-acetoxy-progesterone; i. "" = 282 ml; EI '%' = 680; F. 211 to 212'C.

Claims (1)

PATENTANSPRUCH: Verfahren zur Herstellung von 6-Chlor-6-dehydro-16-methylen-17a-acetoxy-progesteron, dadurch gekennzeichnet, daß man in an sich bekannter Weise 6a,7a-Oxido- 1 6-methylen- 1 7a-acetoxy-progesteron durch Behandlung mit mindestens molaren Mengen Chlorwasserstoff, zweckmäßig in Gegenwart eines inerten organischen Lösungsmittels, entweder direkt oder durch anschließende Dehydratisier-ung des primär gebildeten 6ß-Chlor-7a-hydroxy-steroids in das 6-Chlor-6-dehydro-16-methylen-17a-acetoxy-progesteron überführt. In Betracht gezogene Druckschriften: Deutsche Auslegeschrift Nr. 1075 114. PATENT CLAIM: Process for the preparation of 6-chloro-6-dehydro-16-methylene-17a-acetoxy-progesterone, characterized in that 6a, 7a-oxido- 1 6-methylene- 1 7a-acetoxy- progesterone by treatment with at least molar amounts of hydrogen chloride, expediently in the presence of an inert organic solvent, either directly or by subsequent dehydration of the 6β-chloro-7a-hydroxy-steroid formed primarily into 6-chloro-6-dehydro-16-methylene -17a-acetoxy-progesterone transferred. Documents considered: German Auslegeschrift No. 1075 114.
DEM44345A 1960-02-16 1960-02-16 Process for the preparation of 6-chloro-6-dehydro-16-methylene-17ª ‡ -acetoxy-progesterone Pending DE1156407B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DEM44345A DE1156407B (en) 1960-02-16 1960-02-16 Process for the preparation of 6-chloro-6-dehydro-16-methylene-17ª ‡ -acetoxy-progesterone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DEM44345A DE1156407B (en) 1960-02-16 1960-02-16 Process for the preparation of 6-chloro-6-dehydro-16-methylene-17ª ‡ -acetoxy-progesterone

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1075114B (en) * 1960-02-11 E Merck Aktiengesellschaft, Darmstadt Process for the preparation of unsaturated 6 halo-3 keto-steroids

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1075114B (en) * 1960-02-11 E Merck Aktiengesellschaft, Darmstadt Process for the preparation of unsaturated 6 halo-3 keto-steroids

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