DE1176133B - Process for the preparation of 16-methylene-17ª-acetoxy-progesterone derivatives - Google Patents

Process for the preparation of 16-methylene-17ª-acetoxy-progesterone derivatives

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Publication number
DE1176133B
DE1176133B DEM51304A DEM0051304A DE1176133B DE 1176133 B DE1176133 B DE 1176133B DE M51304 A DEM51304 A DE M51304A DE M0051304 A DEM0051304 A DE M0051304A DE 1176133 B DE1176133 B DE 1176133B
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Prior art keywords
methylene
progesterone
acetoxy
dehydro
derivatives
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German (de)
Inventor
Dipl-Chem Dr Fritz Von Werder
Dr Ulrich Jahn
Dr Harald Metz
Dipl-Chem Dr Karl-Heinz Bork
Dipl-Chem Dr Klaus Brueckner
Dipl-Chem Dr Heinz-J Mannhardt
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Merck KGaA
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E Merck AG
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Priority to DEM51304A priority Critical patent/DE1176133B/en
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

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

Description

BUNDESREPUBLIK DEUTSCHLAND Internat. Kl.: C 07 cFEDERAL REPUBLIC OF GERMANY Internat. Class: C 07 c

DEUTSCHESGERMAN

PATENTAMTPATENT OFFICE

AUSLEGESCHRIFTEDITORIAL

Deutsche Kl.: 12ο-25/β5German class: 12ο-25 / β5

Nummer: 1 176 133Number: 1 176 133

Aktenzeichen: M 51304IV b / 12 οFile number: M 51304IV b / 12 ο

Anmeldetag: 30. Januar 1960 Filing date: January 30, 1960

Auslegetag: 20. August 1964Opening day: August 20, 1964

Die Erfindung betrifft ein Verfahren zur Herstellung von le-Methylen-na-acetoxy-progesteronderivaten der allgemeinen Formel IIThe invention relates to a process for the preparation of le-methylene-na-acetoxy-progesterone derivatives of the general formula II

CH3 CH 3

CO
/OCOCH3 CO
/ OCOCH 3

CH2 CH 2

IIII

sowie von deren in 1(2)- und/oder 6(7)-Stellung ungesättigten Derivaten. Bei den in 1(2)- und/oder 6(7)-StelIung ungesättigten Derivaten bedeutet X Wasserstoff, Fluor, Chlor oder eine Methyigruppe. Falls die 1(2)- und 6(7)-Bindungen gesättigt sind, bedeutet X Fluor oder Chlor.as well as their in 1 (2) - and / or 6 (7) position unsaturated derivatives. In the case of the derivatives unsaturated in the 1 (2) and / or 6 (7) position, X denotes Hydrogen, fluorine, chlorine or a methyl group. If the 1 (2) and 6 (7) bonds are saturated, X means fluorine or chlorine.

Die Substituenten in 6-Stellung können α- oder ^-Konfiguration besitzen, je nachdem, welches Steroid als Ausgangsmaterial verwendet wurde und je nach den angewendeten Reaktionsbedingungen.The substituents in the 6-position can be α- or ^ Configuration, depending on which steroid was used as the starting material and depending on the reaction conditions used.

Es wurde gefunden, daß diese neuen Verbindungen " gegenüber den analogen Verbindungen, die in 16-Stellung keine Methylengruppe enthalten, eine verstärkte progestative Wirkung, insbesondere bei oraler Verabreichung, besitzen.It was found that these new compounds "compared to the analogous compounds that are in the 16-position do not contain a methylene group, an increased progestative effect, especially when administered orally, own.

Gegenstand der Erfindung ist ein Verfahren zur Herstellung von neuen lo-Methylen-na-acetoxyprogesteron-derivaten der obengenannten Formel II sowie von deren in 1(2)- und/oder 6(7)-Stellung ungesättigten Derivaten, das darin besteht, daß man ein 16-Methylen-17a-hydroxy-progesteron-derivat derThe invention relates to a process for the preparation of new lo-methylene-na-acetoxyprogesterone derivatives of the above formula II and their derivatives unsaturated in the 1 (2) and / or 6 (7) position, which consists in that one a 16-methylene-17a-hydroxy-progesterone derivative der

allgemeinen Formel I, _,TT general formula I, _, TT

CH3 CH 3

F=CH2 F = CH 2

Verfahren zur Herstellung von 16-Methylen-17a-acetoxy-progesteron-derivaten Process for the preparation of 16-methylene-17a-acetoxy-progesterone derivatives

AnmeldenRegister

E. Merck Aktiengesellschaft,E. Merck Aktiengesellschaft,

Dannstadt, Frankfurter Str. 250Dannstadt, Frankfurter Str. 250

Als Erfinder benannt:Named as inventor:

DipL-Chem. Dr. Karl-Heinz Bork,DipL-Chem. Dr. Karl-Heinz Bork,

Griesheim bei Darmstadt,Griesheim near Darmstadt,

DipL-Chem. Dr. Klaus Brückner,DipL-Chem. Dr. Klaus Brückner,

Dr. Ulrich Jahn,Dr. Ulrich Jahn,

DipL-Chem. Dr. Heinz-Jürgen Mannhardt,DipL-Chem. Dr. Heinz-Jürgen Mannhardt,

Dr. Harald Metz,Dr. Harald Metz,

DipL-Chem. Dr. Fritz von Werder, Därmstadt - -DipL-Chem. Dr. Fritz von Werder, Därmstadt - -

(das in 1(2)- und/oder 6(7)-Stellung ungesättigt sein kann und worin X die angegebene Bedeutung hat) mit einem AcetyHerungsmittel in an sich bekannter Weise behandelt.(which can be unsaturated in the 1 (2) and / or 6 (7) position and where X has the meaning given) treated with an AcetyHermittel in a known manner.

Die Acetylierung gelingt nach den bekannten und üblichen Acetylierungsmethoden fur tertiäre Hydroxylgruppen. Als Acetylierungsmittel kann man z. B. Essigsäureanhydrid in Gegenwart einer Säure verwenden. Besonders geeignet ist ein Gemisch von Essigsäureanhydrid und Eisessig, gegebenenfalls mit einem Zusatz von p-Toluolsulfonsäure. Selbstverständlich kann man als Acetylierungsmittel auch Acetylchlorid oder Keten verwenden.The acetylation takes place according to the known and customary acetylation methods for tertiary hydroxyl groups. The acetylating agent can be, for. B. acetic anhydride in the presence of an acid use. A mixture of acetic anhydride and glacial acetic acid, optionally with an addition of p-toluenesulfonic acid. Of course acetyl chloride or ketene can also be used as the acetylating agent.

Im einzelnen können nach dem Verfahren der Erfindung z. B. die folgenden Verbindungen hergestellt werden: o-Dehydro-lo-methylen-na-acetoxyprogesteron 6 - Dehydro - 6 - methyl -16 - methylen- YIa- acetoxy - progesteron, 6α- Fluor -16 - methylen-17 a-acetoxy- progesteron, 6 β - Chlor- 16-methylen-17a-acetoxy-progesteron, 6-Fhior-6-dehydro-16-methylen-17a-acetoxy-progesteron, o-Chlor-o-dehydrolo-methylen-net-acetoxy-progesteron sowie die entsprechenden in 1(2)-Stelhing ungesättigten Derivate der genannten lö-Methylen-na-acetoxy-progesteronderivate. Ferner können noch hergestellt werden l-Dehydro-16-methylen-17a-acetoxy-progesteronund 1 -Dehydro-6-methyl-16-methylen-17a-acetoxy-progesteron (Fp. 234 bis 235°C, [a]B = —126° (Dioxan), max = 242 πΐμ, El- = 427).In detail, according to the method of the invention, for. B. the following compounds are produced: o-dehydro-lo-methylen-na-acetoxyprogesteron 6 - dehydro - 6 - methyl -16 - methylen- YIa acetoxy - progesterone, 6α- fluoro -16 - methylene-17 a-acetoxy- progesterone, 6 β - chloro-16-methylen-17a-acetoxy-progesterone, 6-Fhior-6-dehydro-16-methylene-17a-acetoxy-progesterone, o-chloro-o-dehydrolo-methylene-net-acetoxy-progesterone as well as the corresponding in 1 (2) -Stelhing unsaturated derivatives of the above-mentioned Lö-methylen-na-acetoxy-progesterone derivatives. In addition, l-dehydro-16-methylene-17a-acetoxy-progesterone and 1-dehydro-6-methyl-16-methylene-17a-acetoxy-progesterone (melting point 234 to 235 ° C, [a] B = - 126 ° (dioxane), m ax = 242 πΐμ, Electric = 427).

Die als Ausgangsmaterial benötigten 16-Methylen-I7a-hydroxy-progesteron-derivate können aus denThe 16-methylene-17a-hydroxy-progesterone derivatives required as starting material can from the

«9 657/485«9 657/485

entsprechenden 16^-Methyl-loa, 17a-oxido-steroiden durch Behandlung mit mindestens katalytischen Mengen einer starken Säure hergestellt werden, wofür im Rahmen der vorliegenden Erfindung Schutz nicht begehrt wird. .corresponding 16 ^ -Methyl-loa, 17a-oxido-steroids are produced by treatment with at least catalytic amounts of a strong acid, for which protection is not sought in the context of the present invention. .

Die neuen, verfahrensgemäß herstellbaren Verbindungen können in der Humanmedizin als progesteronwirksame Therapeutika eingesetzt werden. Sie eignen sich z. B. als Mittel zur Bekämpfung eines drohenden Abortus oder zur Restitution der Uterus- to Schleimhäute und sind insbesondere oral gut wirksam. Ferner können diese neuen lo-Methylen-na-acetoxyprogesteron-derivate zu allen pharmazeutisch üblichen Anwendungsformen verarbeitet werden. Sie können z. B. unter Verwendung der üblichen Hilfs- und Füllstoffe zu Pillen, Tabletten, Dragees, Suppositorien usw. und unter Zuhilfenahme üblicher Lösungsmittel oder Lösungsvermittler zu Emulsionen, Suspensionen oder Injektionslösungen verarbeitet werden.The new compounds which can be prepared according to the method can be used in human medicine as progesterone Therapeutics are used. They are suitable e.g. B. as a means of combating a threatened abortion or restitution of the uterus Mucous membranes and are particularly effective orally. Furthermore, these new lo-methylene-na-acetoxyprogesterone derivatives can be processed into all pharmaceutically customary forms of application. You can e.g. B. using the usual auxiliary and fillers into pills, tablets, coated tablets, suppositories, etc. and with the help of common ones Solvents or solubilizers processed into emulsions, suspensions or injection solutions will.

Pharmakologische Vergleichsversuche über die gestagene Wirksamkeit vonPharmacological comparative tests on the gestagenic effectiveness of

1. o-Dehydro-o-methyl-16-methylen-17a-acetoxyprogesteron (Beispiel 4),1. o-Dehydro-o-methyl-16-methylene-17a-acetoxyprogesterone (Example 4),

2. o-Dehydro-o-chlor-lö-methylen-nct-acetoxyprogesteron (Beispiel 8),2. o-Dehydro-o-chloro-Lö-methylene-nct-acetoxyprogesterone (Example 8),

3. !,o-Bis-dehydro-o-methyl-lo-methylen-na-acetoxy-progesteron (Beispiel 10),3.!, O-bis-dehydro-o-methyl-lo-methylen-na-acetoxy-progesterone (Example 10),

4. 1 -Dehydro-oa-methyl-16-methylen-17a-acetoxyprogesteron (Beispiel 11),4. 1-Dehydro-oa-methyl-16-methylene-17a-acetoxyprogesterone (Example 11),

5. ö-Chlor-o-dehydro-Ha-acetoxy-progesteron als Vergleichssubstanz.5. ö-chloro-o-dehydro-Ha-acetoxy-progesterone as Comparison substance.

I.I.

Die Versuche wurden durchgeführt nach der Methode von C 1 a u b e r g (Klinische Wochenschrift, 1930, S. 2004), modifiziert nach M c P h a i 1 (Journal of Physiology, Bd. 83 £1935], S. 145). Juvenile weibliche Kaninchen, also solche, die noch keine eigene Gelbkörperhormonproduktion haben, 4P werden in diesem Test durch Verabreichung von Follikelhormon zur Ausbildung der Proliferationsphase im Uterus gebracht. Anschließend werden sie 5 Tage lang mit der zu testenden Substanz auf oralem Wege behandelt. Zur Auswertung der Gelbkörperhormonwirkung werden am folgenden Tage die Uteri herauspräpariert und histologisch auf Stärke und Zahl der Uterindrüsen untersucht. Die Bewertung erfolgt nach dem Schema von McPhail. Aus den von mehreren Schnitten der Drüsen und an mehreren Tieren erhaltenen Werten werden jeweils die Mittelwerte gebildet.The experiments were carried out according to the method of C 1 auberg (Klinische Wochenschrift, 1930, p. 2004), modified from M c P hai 1 (Journal of Physiology, Vol. 83 £ 1935], p. 145). In this test, juvenile female rabbits, i.e. those who do not yet have their own luteum hormone production, 4P are induced to develop the proliferation phase in the uterus by administering follicular hormone. They are then treated orally with the substance to be tested for 5 days. To evaluate the effect of the corpus luteum hormone, the uteri are dissected out on the following day and examined histologically for the size and number of the uterine glands. The evaluation is carried out according to the McPhail scheme. The mean values are formed from the values obtained from several sections of the glands and from several animals.

Verbindungen eine erheblich bessere gestagene Wirksamkeit aufweisen als die Vergleichssubstanz.Compounds have a significantly better gestagenic activity than the comparison substance.

Beispiel 1example 1

10 g 6-Dehydro-l 6-methylen-17a-hydroxy-progesteron werden in 200 ml Essigester gelöst, 500 mg p-Toluolsulfonsäure zugefügt und in die Lösung 6,5 g Keten (= 5facher molarer Überschuß) eingeleitet. Die Lösung bleibt 6 Stunden bei Zimmertemperatur stehen, wird dann mit Äther verdünnt und durch Schütteln mit Natriumhydrogencarbonatlösung vom überschüssigen Keten befreit. Die Lösung wird stark eingeengt und das auskristallisierende 6 - Dehydro - 16 - methylen -17 α - acetoxyprogesteron abgesaugt. Zur völligen Reinigung kann nochmals aus Äther umkristallisiert werden. Fp. 226 bis 227°C. Nach weiterem mehrmaligem Umkristallisieren schmilzt die Verbindung bei 233 bis 234 C; [a\D = -130,2 (Chloroform); kmax = 281,5 πΐμ; E}^. = 740.10 g of 6-dehydro-l 6-methylene-17a-hydroxy-progesterone are dissolved in 200 ml of ethyl acetate, 500 mg of p-toluenesulfonic acid are added and 6.5 g of ketene (= 5-fold molar excess) are introduced into the solution. The solution remains at room temperature for 6 hours, is then diluted with ether and freed from excess ketene by shaking with sodium hydrogen carbonate solution. The solution is strongly concentrated and the 6-dehydro-16-methylene-17 α-acetoxyprogesterone which crystallizes out is suctioned off. For complete purification, it can be recrystallized from ether again. Mp 226-227 ° C. After repeated recrystallization, the compound melts at 233 to 234 C; [a \ D = -130.2 (chloroform); k max = 281.5 πΐµ; E} ^. = 740.

Beispiel 2Example 2

20 g l-Dehydro-lo-methylen-na-hydroxy-progesteron werden in 200 ml Essigsäure gelöst und 40 ml Essigsäureanhydrid so'vie 2 g p-ToIuolsulfonsäure zugegeben. Die Mischung bleibt 24 Stunden bei Zimmertemperatur stehen, wird dann unter Rühren in etwa 3 1 Wasser eingegossen und der ausgefallene Niederschlag abgesaugt. Das rohe 1-Dehydro- 16-methylen-I7a-acetoxy-progesteron wird aus Äther umkristallisiert. Fp. 216 bis 217°C; [a]a = -114,6° (Dioxan); ;W=242 πΐμ; E!*„=449.20 g of l-dehydro-lo-methylen-na-hydroxy-progesterone are dissolved in 200 ml of acetic acid and 40 ml of acetic anhydride and 2 g of p-toluenesulfonic acid are added. The mixture remains at room temperature for 24 hours, is then poured into about 3 liters of water with stirring and the precipitate which has separated out is filtered off with suction. The crude 1-dehydro-16-methylene-17a-acetoxy-progesterone is recrystallized from ether. Mp 216-217 ° C; [a] a = -114.6 ° (dioxane); ; W = 242 πΐμ; E! * "= 449.

H. VersuchsergebnisseH. Experimental Results

Beispiel 4 Example 4 Beispiel 8 Example 8 Beispiel 10 Example 10

Beispiel 11 Example 11

ö-Chlor-o-dehydro-l 7a-acetoxyprogesteron ö-chloro-o-dehydro-l 7a-acetoxyprogesterone

GestageneProgestins

Wirksamkeiteffectiveness

(bezogen auf(based on

Progesteron= 1)Progesterone = 1)

6 539
12 3006 539
12 300

5850
131005850
13100

4 5004,500

Beispiel 3Example 3

Analog Beispiel 1 wird 1,6-Bis-dehydro- 16-methylen-17a-hydroxy-progesteron zu 1,6-Bis-dehydro-16 - methylen -17 α - acetoxy - progesteron acetyliert; ^^ = 223, 256, 296 ηΐμ; El* = 313, 255, 346; Fp. 212 bis 214°C; Ia]0 = -195,9° (Dioxan).Analogously to Example 1, 1,6-bis-dehydro-16-methylene-17a-hydroxy-progesterone is acetylated to 1,6-bis-dehydro-16-methylene-17α-acetoxy-progesterone; ^^ = 223, 256, 296 ηΐμ; E1 * = 313, 255, 346; Mp 212-214 ° C; Ia] 0 = -195.9 ° (dioxane).

Beispiel 4Example 4

Analog Beispiel 2 wird 6-Dehydro-6-methyl- 16-methylen-17a-hydroxy-progesteron zu 6-Dehydro-6-methyl-lö-methylen-na-acetoxy-progesteron acetyliert. Fp. 218 bis 220°C; [a]a =-128° (Chloroform); Zmax = 287 Πΐμ, Ej*„ = 637.Analogously to Example 2, 6-dehydro-6-methyl-16-methylene-17a-hydroxy-progesterone is acetylated to 6-dehydro-6-methyl-6-methylene-na-acetoxy-progesterone. Mp 218-220 ° C; [a] a = -128 ° (chloroform); Zmax = 287 Πΐμ, Ej * „= 637.

Beispiel 5Example 5

Analog Beispiel 2 wird 6a-Fluor-I6-methyleo-17a-hydroxy-progesteron zu 6a-Fluor-I6-methylen-17a-acetoxy-progesteron acetyliert. λΜαχ = 237 πΐμ.Analogously to Example 2, 6a-fluoro-16-methyleo-17a-hydroxy-progesterone is acetylated to 6a-fluoro-16-methylene-17a-acetoxy-progesterone. λ Μ αχ = 237 πΐμ.

B ei spie! 6Eg spit! 6th

Analog Beispiel 1 wird 6-Dehydro-6-fluor-16-methylen -17 α - hydroxy- progesteron zu 6 - Dehydro-6 - fluor - 16 - methylen - 17 α - acetoxy - progesteron acetyliert. Xmax = 282 πΐμ, Ε} L = 643.Analogously to Example 1, 6-dehydro-6-fluoro-16-methylene-17 α-hydroxy-progesterone is acetylated to 6-dehydro-6-fluoro-16-methylene-17 α-acetoxy-progesterone. X max = 282 πΐμ, Ε} L = 643.

Beispiel 7Example 7

Analog Beispiel 2 wird o/J-Chlor-lo-methylen-17a-hydroxy-progesteron zu o/J-Chlor-lo-methylen-17et-acetoxy-progesteron acetyliert; Xmax = 238,5 πΐμ.Analogously to Example 2, o / I-chloro-lo-methylene-17a-hydroxy-progesterone is acetylated to o / I-chloro-lo-methylene-17et-acetoxy-progesterone; X ma x = 238.5 πΐμ.

Aus den Versuchsergebnissen geht hervor, daß die nach dem Verfahren der Erfindung hergestelltenFrom the test results it can be seen that those produced by the method of the invention

5555

6o6o

Beispiel 8Example 8

Analog Beispiel 2 wird o-Dehydro-o-chlor-lo-methyJen-17a-hydroxy-progesteron zu 6-Dehydro-6 - chlor - 16 - methylen - 17 α - acetoxy - progesteron acetyliert. Aus Methanol umkristallisiert, schmilztAnalogously to Example 2, o-dehydro-o-chloro-lo-methyJen-17a-hydroxy-progesterone is used to 6-dehydro-6 - chloro - 16 - methylene - 17 α - acetoxy - progesterone acetylated. Recrystallized from methanol, melts

das Produkt bei 211 bis 212°C;
Eil = 680.the product at 211-212 ° C;
Express = 680.

Beispiel 9Example 9

Analog Beispiel 2 wird 6/3-Fluor-16-methylen-17a-hydroxy-progesteron zu 6ß-Fluor-16-methylen-17a-acetoxy-progesteron acetyliert. Fp. 189 bis 1910C; [a]D = -125,3° (Chloroform); Xmax = 233 πΐμ; ε = 13 700.Analogously to Example 2, 6/3-fluoro-16-methylene-17a-hydroxy-progesterone is acetylated to 6ß-fluoro-16-methylene-17a-acetoxy-progesterone. M.p. 189 to 191 ° C; [a] D = -125.3 ° (chloroform); X max = 233 πΐµ; ε = 13,700.

Beispiel 10Example 10

Analog Beispiel 2 wird l,6-Bis-dehy.dro-6-methyl-16-methylen-17a-hydroxy-progesteron zu 1,6-Bis-dehydro - 6 - methyl -16 - methylen -17 α - acetoxy - progesteron acetyliert. Xmax = 227, 253, 302 πΐμ; Fp. 223 bis 2260C; [a]„ = -193,3° (Dioxan); Eil = 356, 241, 310.Analogously to Example 2, 1,6-bis-dehydro-6-methyl-16-methylene-17a-hydroxy-progesterone is converted to 1,6-bis-dehydro-6-methyl-16-methylene-17 α-acetoxy-progesterone acetylated. Xmax = 227, 253, 302 πΐµ; M.p. 223 to 226 ° C; [a] n = -193.3 ° (dioxane); Express = 356, 241, 310.

Beispiel 11Example 11

Analog Beispiel 2 wird l-Dehydro-oa-methyl-16-methylen-17a-hydroxy-progesteron zu 1-Dehydro-6 α - methyl -16 - methylen -17 α - acetoxy - progesteron acetyliert. Xmax = 244 ΐημ, E{1 = 385; Fp. 235 bis 2370C; [a]o = -124° (CHCl3).Analogously to Example 2, 1-dehydro-oa-methyl-16-methylene-17a-hydroxy-progesterone is acetylated to 1-dehydro-6α-methyl-16-methylene-17α-acetoxy-progesterone. X max = 244 ΐηµ, E {1 = 385; Mp 235-237 0 C. [a] o = -124 ° (CHCl 3 ).

Beispiel 12Example 12

Analog Beispiel 2 wird l-Dehydro-6a-fluor-16-methylen -17 α - hydroxy - progesteron zu 1 - Dehydro-6 α - fluor -16 - methylen -17 α - acetoxy - progesteron acetyliert. Fp. 241 bis 242°C; [a]D = -124° (Chloroform); Xmax = 242 πΐμ; Eil = 445.Analogously to Example 2, l-dehydro-6a-fluoro-16-methylene -17α-hydroxy-progesterone is acetylated to 1-dehydro-6α-fluoro-16-methylene -17α-acetoxy-progesterone. Mp 241-242 ° C; [a] D = -124 ° (chloroform); X max = 242 πΐµ; Express = 445.

Beispiel 13Example 13

Analog Beispiel 2 wird l,6-Bis-dehydro-6-fluor-16-methylen-17a-hydroxy-progesteron zu 1,6-Bisdehydro -6-fluor-16- methylen -17 α - acetoxy - progesteron acetyliert. Xmax = 224, 256, 295 πΐμ.Analogously to Example 2, 1,6-bis-dehydro-6-fluoro-16-methylene-17a-hydroxy-progesterone is acetylated to 1,6-bisdehydro-6-fluoro-16-methylene -17α-acetoxy-progesterone. X max = 224, 256, 295 πΐμ.

Claims (1)

Patentanspruch:Claim: Verfahren zur Herstellung von 16-Methylen-17a-acetoxy-progesteron-derivaten der allgemeinen FormelProcess for the preparation of 16-methylene-17a-acetoxy-progesterone derivatives the general formula CH3 CH 3 /OCOCH3 / OCOCH 3 F=CH2 F = CH 2 sowie von deren in 1(2)- und/oder 6(7)-Stellung ungesättigten Derivaten, worin X Fluor oder Chlor bedeutet, falls die 1(2)- und 6(7)-Bindüngen gesättigt sind, und X Wasserstoff, Fluor, Chlor oder CH3 bedeutet, falls sich in 1(2)- und/oder 6(7)-Stellung eine Doppelbindung befindet, dadurch gekennzeichnet, daß man das zugrunde liegende Steroid mit freier Hydroxylgruppe in 17a-Stellung mit einem Acetylierungsmittel in an sich bekannter Weise behandelt. and of their derivatives unsaturated in the 1 (2) and / or 6 (7) -position, in which X is fluorine or chlorine if the 1 (2) and 6 (7) bonds are saturated, and X is hydrogen or fluorine , Chlorine or CH 3 , if there is a double bond in the 1 (2) and / or 6 (7) position, characterized in that the underlying steroid with a free hydroxyl group in the 17a position with an acetylating agent in itself treated in a known way. In Betracht gezogene Druckschriften:
Journ. Am. Chem. Soc, Bd. 75 (1953), S. 3489 bis 3492;Considered publications:
Journ. At the. Chem. Soc, 75: 3489 to 3492 (1953); Journ. Org. Chem., Bd. 21 (1956), S. 240 und 241.Journ. Org. Chem., 21, 240 and 241 (1956).
DEM51304A 1960-01-30 1960-01-30 Process for the preparation of 16-methylene-17ª-acetoxy-progesterone derivatives Pending DE1176133B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DEM51304A DE1176133B (en) 1960-01-30 1960-01-30 Process for the preparation of 16-methylene-17ª-acetoxy-progesterone derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEM51304A DE1176133B (en) 1960-01-30 1960-01-30 Process for the preparation of 16-methylene-17ª-acetoxy-progesterone derivatives
DEM44160A DE1174314B (en) 1960-01-30 1960-01-30 Process for the preparation of 16-methylene-9ª-fluoro-11ª-hydroxy-17ª-acetoxy-progesterone derivatives

Publications (1)

Publication Number Publication Date
DE1176133B true DE1176133B (en) 1964-08-20

Family

ID=7304892

Family Applications (4)

Application Number Title Priority Date Filing Date
DEM51304A Pending DE1176133B (en) 1960-01-30 1960-01-30 Process for the preparation of 16-methylene-17ª-acetoxy-progesterone derivatives
DEM51305A Pending DE1176134B (en) 1960-01-30 1960-01-30 Process for the preparation of 1-dehydro-16-methylene-17ª-acetoxy-progesterone derivatives
DEM44160A Pending DE1174314B (en) 1960-01-30 1960-01-30 Process for the preparation of 16-methylene-9ª-fluoro-11ª-hydroxy-17ª-acetoxy-progesterone derivatives
DEM51303A Pending DE1176132B (en) 1960-01-30 1960-01-30 Process for the preparation of unsaturated 16-methylene-17ª-acetoxy-progesterone derivatives

Family Applications After (3)

Application Number Title Priority Date Filing Date
DEM51305A Pending DE1176134B (en) 1960-01-30 1960-01-30 Process for the preparation of 1-dehydro-16-methylene-17ª-acetoxy-progesterone derivatives
DEM44160A Pending DE1174314B (en) 1960-01-30 1960-01-30 Process for the preparation of 16-methylene-9ª-fluoro-11ª-hydroxy-17ª-acetoxy-progesterone derivatives
DEM51303A Pending DE1176132B (en) 1960-01-30 1960-01-30 Process for the preparation of unsaturated 16-methylene-17ª-acetoxy-progesterone derivatives

Country Status (7)

Country Link
BR (1) BR6125904D0 (en)
CH (4) CH393317A (en)
DE (4) DE1176133B (en)
DK (1) DK115180B (en)
FR (1) FR881M (en)
GB (1) GB963427A (en)
SE (3) SE301800B (en)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2865808A (en) * 1958-06-09 1958-12-23 Pfizer & Co C 16-methylene pregnene derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Also Published As

Publication number Publication date
SE301800B (en) 1968-06-24
FR881M (en) 1961-10-23
SE310675B (en) 1969-05-12
CH395081A (en) 1965-07-15
DE1174314B (en) 1964-07-23
CH395082A (en) 1965-07-15
BR6125904D0 (en) 1973-05-29
SE302123B (en) 1968-07-08
DK115180B (en) 1969-09-15
CH393316A (en) 1965-06-15
DE1176134B (en) 1964-08-20
GB963427A (en) 1964-07-08
DE1176132B (en) 1964-08-20
CH393317A (en) 1965-06-15

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