DE1240078B - Process for the preparation of 16, 17-methylene-delta 1,3,5 (10) -oestratriene derivatives - Google Patents

Process for the preparation of 16, 17-methylene-delta 1,3,5 (10) -oestratriene derivatives

Info

Publication number
DE1240078B
DE1240078B DESCH36188A DESC036188A DE1240078B DE 1240078 B DE1240078 B DE 1240078B DE SCH36188 A DESCH36188 A DE SCH36188A DE SC036188 A DESC036188 A DE SC036188A DE 1240078 B DE1240078 B DE 1240078B
Authority
DE
Germany
Prior art keywords
methylene
preparation
delta
derivatives
general formula
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
DESCH36188A
Other languages
German (de)
Inventor
Dr Hans-Guenter Lehmann
Dr Friedmund Neumann
Dr Rudolf Wiechert
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
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 Schering AG filed Critical Schering AG
Priority to DESCH36188A priority Critical patent/DE1240078B/en
Publication of DE1240078B publication Critical patent/DE1240078B/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group

Description

BUNDESREPUBLIK DEUTSCHLANDFEDERAL REPUBLIC OF GERMANY

Int. Cl.:Int. Cl .:

C07cC07c

DEUTSCHESGERMAN

PATENTAMTPATENT OFFICE

PATENTSCHRIFTPATENT LETTERING

Deutsche Kl.: 12 ο -25/07 German class: 12 ο -25/07

Nummer:Number:

Aktenzeichen:File number:

Anmeldetag:Registration date:

Sch36188IVb/12oSch36188IVb / 12o

2. Dezember 19642nd December 1964

11. Mai 1967May 11, 1967

30. November 1967November 30, 1967

Auslegetag:Display day:

Ausgabetag:Issue date:

Patentschrift stimmt mit der Auslegeschrift übereinThe patent specification corresponds to the patent specification

Gegenstand der Erfindung ist ein Verfahren zur Herstellung von bisher nicht beschriebenen Derivaten des lo.n-Methylen-zl^'WO'-östratriens der allgemeinen FormelThe invention relates to a process for the preparation of derivatives not previously described des lo.n-methylene-zl ^ 'WO'-oestratrienes of the general formula

CH2 CH 2

R2 R 2

in der Ri und R2 niedere Alkylreste oder Acylreste physiologisch vertretbarer Säuren bedeuten, ohne daß Ri mit R2 identisch sein muß.in which Ri and R 2 mean lower alkyl radicals or acyl radicals of physiologically acceptable acids, without Ri having to be identical to R 2.

Das Verfahren ist dadurch gekennzeichnet, daß man in ein /:1l-3-5(l0>'l6-östratetraen-derivat der allgemeinen FormelThe process is characterized in that in a /: 1 l - 3 - 5 ( l0 > 16 -estratetraene derivative of the general formula

in der Ri und R2 die gleiche Bedeutung wie oben besitzen, nach an sich bekannten Methoden die Methylengruppe in 16,17-Stellung einführt. Zur Einführung der Methylengruppe eignet sich besonders der Umsatz des z]1'3'5(10'-16-östratetraen-derivates mit Methylenjodid in Gegenwart von verkupfertem Zink.in which Ri and R 2 have the same meaning as above, introduces the methylene group in the 16,17-position according to methods known per se. The conversion of the z] 1 ' 3 ' 5 ( 10 '- 16 -estratetraene derivative with methylene iodide in the presence of copper-plated zinc is particularly suitable for introducing the methylene group.

Die nach dem erfindungsgemäßen Verfahren erhaltenen' Substanzen zeichnen sich durch eine ausgezeichnete physiologische Wirksamkeit aus. So zeigt z. B. das 16i)17-Methylen-/l1'3'5<10>-östratrien-3,17-diol-diacetat im Allen-Doisy-Test, subkutan der Ratte verabfolgt, eine dreifach stärkere östrogene Aktivität als das handelsübliche östradiol-17-acetat.The substances obtained by the process according to the invention are distinguished by excellent physiological effectiveness. So shows z. B. the 16 i) 17-methylene / l 1 ' 3 ' 5 < 10 > -estratriene-3,17-diol diacetate in the Allen-Doisy test, administered subcutaneously to the rat, a three times stronger estrogenic activity than the commercial one estradiol-17-acetate.

Beispiel 1example 1

, Eine Mischung aus 65 ml absolutem Diäthyläther, 6,5 ml Ätliylenglykoldimethyläther, 5,2 ml Methylen-Verfahren zur Herstellung von, A mixture of 65 ml of absolute diethyl ether, 6.5 ml of Ätliylenglykoldimethyläther, 5.2 ml of methylene method for production of

16,17-Methylen-zi *■ ·3·5 <10>-östratrien-derivaten16,17-methylene-zi * ■ · 3 · 5 < 10 > -estratriene derivatives

Patentiert für:Patented for:

Schering Aktiengesellschaft,
Berlin 65, Müllerstr. 170/172Schering Aktiengesellschaft,
Berlin 65, Mullerstrasse. 170/172

Als Erfinder benannt:"
Dr. Hans-Günter Lehmann,
Dr. Friedmund Neumann,
Dr. Rudolf Wiechert, BerlinNamed as inventor: "
Dr. Hans-Günter Lehmann,
Dr. Friedmund Neumann,
Dr. Rudolf Wiechert, Berlin

jodid, 1 Kriställchen Jod und. 6,55 g verkupfertem Zinkstaub wird bei Zimmertemperatur gut gerührt. Man wartet den Start der Methylenentstehung ab, führt ihn, wenn nötig, durch kurzes Erwärmen auf etwa 6O0C herbei oder dämpft eine stürmische Reaktion durch Kühlung. Unter Rühren gibt man nun 3,55 g /l1-3-5<10>-16-östratetraen-3,17-diol-diacetat in drei Portionen hinzu und läßt die Reaktion bei etwa 25°C mild unter ständigem Rühren ablaufen. Nach 24, 48 und 72 Stunden werden je 2,3 g verkupferter Zinkstaub und je 2,8 ml Methylenjodid hinzugegeben, und nach der letzten Zugabe wird die Mischung'noch 24 Stunden gerührt. Man saugt vom Zink und von den Zinksalzen ab, wäscht mit Äther gründlich nach, wäscht das Filtrat erschöpfend mit Wasser, trocknet die Ätherphase und zieht im Vakuum die flüchtigen Lösungsmittel ab. Man chromatographiert an Silicagel. Aus den Benzolfraktionen gewinnt man nach Umkristallisieren aus Essigester 250 mg 16,17-Methylen-/l1-3.5<1°)-östratrien-3,17-dioldiacetat vom Schmelzpunkt 121 bis 122° C.iodide, 1 crystal of iodine and. 6.55 g of copper-plated zinc dust is stirred well at room temperature. One waits the start of the formation from methyl, executes it, if necessary, by briefly heating to about 6O 0 C induced or attenuates a stormy reaction by cooling. With stirring, is then added 3.55 g / l 1 - 3 - 5 <10> - 16 -östratetraen-3,17-diol diacetate in three portions and added leaving the reaction at about 25 ° C mild proceed under constant stirring. After 24, 48 and 72 hours, 2.3 g of copper-plated zinc dust and 2.8 ml of methylene iodide each are added, and after the last addition, the mixture is stirred for a further 24 hours. The zinc and zinc salts are filtered off with suction, washed thoroughly with ether, the filtrate is washed exhaustively with water, the ether phase is dried and the volatile solvents are removed in vacuo. It is chromatographed on silica gel. From the benzene fractions is obtained by recrystallization from 250 mg of 16,17-methylene Essigester / l 1-3. 5 < 1 °) -estratriene-3,17-diol diacetate with a melting point of 121 to 122 ° C.

B e i s ρ i e 1 2B e i s ρ i e 1 2

Man verfährt wie im Beispiel 1, jedoch mit 3,26 g ^1,3.5(io). ie. östratetraen - 3,17 - diol - 3 - methyläther-1'7-acetat als Ausgangsmaterial. Aus den Benzolfraktionen der Chromatographie isoliert man 240 mg 16,17 - Methylen - zl1·3·5«10' - östratrien - 3,17 - dioi-3-methyläther-17-acetat als öl.The procedure is as in Example 1, but with 3.26 g ^ 1.3.5 (io). ie. Oestratetraen - 3,17 - diol - 3 - methyl ether-1'7-acetate as starting material. 240 mg of 16.17 - methylene - zl 1 · 3 · 5 « 10 '- estatriene - 3.17 - di-3-methyl ether-17-acetate are isolated as an oil from the benzene fractions of the chromatography.

709 734/330709 734/330

Claims (1)

Patentanspruch:Claim: Verfahren zur Herstellung von 16,17-Methylen- |i.3.5(io). östratricn - derivaten der allgemeinen FormelProcess for the preparation of 16,17-methylene | i.3.5 (io). östratricn - derivatives of the general formula O —RiO —Ri CH2 CH 2 IOIO R2-OR 2 -O worin Ri und Ro niedere Alkylreste oder Acylreste physiologisch vertretbarer Säuren bedeuten, wobei Ri und R2 verschieden sein können, dadurch gekennzeichnet, daß man ein ,11.3.5(io).ie. östratetraeii der allgemeinen Formelwherein Ri and Ro are lower alkyl radicals or acyl radicals of physiologically acceptable acids, where Ri and R 2 can be different, characterized in that one, 11.3.5 (io) .ie. östratetraeii of the general formula O —RiO —Ri R2-OR 2 -O in der Ri und R2 die gleiche Bedeutung wie oben besitzen, in an sich bekannter Weise mit einem Methylenierungsmittel, insbesondere Methylenjodid in Gegenwart von verkupfertem Zink, umsetzt.in which Ri and R 2 have the same meaning as above, is reacted in a manner known per se with a methylenating agent, in particular methylene iodide in the presence of copper-plated zinc.
DESCH36188A 1964-12-02 1964-12-02 Process for the preparation of 16, 17-methylene-delta 1,3,5 (10) -oestratriene derivatives Pending DE1240078B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DESCH36188A DE1240078B (en) 1964-12-02 1964-12-02 Process for the preparation of 16, 17-methylene-delta 1,3,5 (10) -oestratriene derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DESCH36188A DE1240078B (en) 1964-12-02 1964-12-02 Process for the preparation of 16, 17-methylene-delta 1,3,5 (10) -oestratriene derivatives

Publications (1)

Publication Number Publication Date
DE1240078B true DE1240078B (en) 1967-05-11

Family

ID=7433765

Family Applications (1)

Application Number Title Priority Date Filing Date
DESCH36188A Pending DE1240078B (en) 1964-12-02 1964-12-02 Process for the preparation of 16, 17-methylene-delta 1,3,5 (10) -oestratriene derivatives

Country Status (1)

Country Link
DE (1) DE1240078B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2130285A1 (en) * 1971-03-15 1972-11-03 Hoffmann La Roche

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2130285A1 (en) * 1971-03-15 1972-11-03 Hoffmann La Roche

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