DE1181704B - Process for the preparation of an isomer mixture of 16ª ‡ -methylated 3ª ‡, 23-diacyloxy-17 (20) -epoxy-21-normethyl-11-oxo-22-cholen-24 (20) -lactones - Google Patents

Process for the preparation of an isomer mixture of 16ª ‡ -methylated 3ª ‡, 23-diacyloxy-17 (20) -epoxy-21-normethyl-11-oxo-22-cholen-24 (20) -lactones

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Publication number
DE1181704B
DE1181704B DEM51071A DEM0051071A DE1181704B DE 1181704 B DE1181704 B DE 1181704B DE M51071 A DEM51071 A DE M51071A DE M0051071 A DEM0051071 A DE M0051071A DE 1181704 B DE1181704 B DE 1181704B
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Germany
Prior art keywords
normethyl
oxo
diacyloxy
methyl
isomer mixture
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Pending
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DEM51071A
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German (de)
Inventor
Meyer Sletzinger
Sandor Karady
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Merck and Co Inc
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Merck and Co Inc
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Publication of DE1181704B publication Critical patent/DE1181704B/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • 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
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Description

Verfahren zur Herstellung eines Isomerengemisches von 16a-methylierten 3a,23-Diacyloxy-17(20)-epoxy-21-normethyl-11-oxo@ 22-cholen-24(20)-lactonen Die Erfindung betrifft ein Verfahren zur Herstellung eines Isomerengemisches von in 16a-Stellung durch eine Methylgruppe substituierten 3a,23-Diacyloxy-17(20)-epoxy-21-normethyl-11-oxo-22-cholen-24(20)-lactonen.Process for the preparation of an isomer mixture of 16a-methylated 3a, 23-Diacyloxy-17 (20) -epoxy-21-normethyl-11-oxo @ 22-cholen-24 (20) -lactones Die The invention relates to a process for the preparation of an isomer mixture of in 3a, 23-diacyloxy-17 (20) -epoxy-21-normethyl-11-oxo-22-cholen-24 (20) -lactones substituted 16a-position by a methyl group.

Diese neuen Verbindungen lassen sich nach dem Verfahren der Patentanmeldung M 41128 IVb/12 o (vgl. die deutsche Auslegeschrift 1 163 322) durch Hydrolyse in 16a-Methyl-3a,17a-dihydroxy-pregnan-11,20-dion überführen, das seinerseits leicht in 16 a - Methyl - 17 a, 21 - dihydroxy - 1, 4 - pregnadien-3,11,20-trion umgewandelt werden kann. Die letztgenannte Verbindung zeichnet sich durch eine äußerst starke entzündungshemmende Aktivität aus.These new compounds can be prepared according to the procedure of the patent application M 41128 IVb / 12 o (see German Auslegeschrift 1 163 322) by hydrolysis in 16a-methyl-3a, 17a-dihydroxy-pregnan-11,20-dione transfer, which in turn easily converted to 16 a - methyl - 17 a, 21 - dihydroxy - 1, 4 - pregnadiene-3,11,20-trione can be. The latter connection is extremely strong anti-inflammatory activity.

Für das erfindungsgemäße Verfahren verwendet man als Ausgangsstoff 16 a-Methyl-3 a-hydroxy-11,20-dioxo-21-oxalyl-pregnan,das durch die folgende Formel dargestellt werden kann Durch Umsetzung des 16a-Methyl-3a-hydroxy-11,20-dioxo-21-oxalyl-pregnans mit einem Carbonsäureanhydrid unter der katalytischen Wirkung einer starken Säure, wie Perchlorsäure, Bromwasserstoffsäure oder Dinitrobenzolsulfonsäure, in an sich bekannter Weise gelangt man zu einem Isomerengemisch von 3a,23-Diacyloxy-16a-methyl-21-normethyl-I 1-oxo-17(20),22-choladien-24(20)-lacton, welches durch die folgende Formel dargestellt werden kann: worin R' eine Acyloxygruppe bedeutet. Die Umsetzung des erhaltenen Isomerengemisches von 3 a, 23-Diacyloxy-16 a-methyl-21-normethyl-11-oxo-17(20),22-choladien-24(20)-lacton mit einer Persäure, wie Monoperphthalsäure, Peressigsäure oder Perbenzoesäure, in an sich bekannter Weise führt zu dem Isomerengemisch des entsprechenden 3 a, 23 -Diacyloxy-16 a-methyl-17(20)-epoxy-21-normethyl-11-oxo-22-cholen-24(20)-lactons, welches durch die folgende Formel dargestellt werden kann worin R' die obige Bedeutung hat.The starting material used for the process according to the invention is 16 a-methyl-3 a-hydroxy-11,20-dioxo-21-oxalyl-pregnane, which can be represented by the following formula By reacting 16a-methyl-3a-hydroxy-11,20-dioxo-21-oxalyl-pregnane with a carboxylic acid anhydride under the catalytic action of a strong acid, such as perchloric acid, hydrobromic acid or dinitrobenzenesulfonic acid, a mixture of isomers is obtained in a manner known per se of 3a, 23-diacyloxy-16a-methyl-21-normethyl-I 1-oxo-17 (20), 22-choladiene-24 (20) -lactone, which can be represented by the following formula: wherein R 'represents an acyloxy group. The reaction of the obtained isomer mixture of 3 a, 23-diacyloxy-16 a-methyl-21-normethyl-11-oxo-17 (20), 22-choladiene-24 (20) -lactone with a peracid such as monoperphthalic acid, peracetic acid or Perbenzoic acid, in a manner known per se, leads to the isomer mixture of the corresponding 3 a, 23 -diacyloxy-16 a-methyl-17 (20) -epoxy-21-normethyl-11-oxo-22-cholen-24 (20) -lactone , which can be represented by the following formula where R 'has the above meaning.

Es ist bekannt, 3a-Hydroxy-11,20-dioxo-21-oxalylpregnan mit einem Carbonsäureanhydrid in 3a,23-Diacyloxy-21-normethyl-11-oxo-17 (20), 22-choladieno-24(20)-lacton und dieses durch Einwirkung einer Persäure in 3a,23-Diacyloxy-17(20)-epoxy-21-normethyl-I1-oxo-22-choleno-24(20)-lacton überzuführen. Hierbei handelt es sich jedoch um Verbindungen, die in 16-Stellung nicht methyiiert sind. Auf Grund des Verhaltens dieser in 16-Stellung nicht methylierten Steroide war nicht vorauszusehen, daß sich die durch die Anwesenheit einer 16a-ständigen Methylgruppe sterisch gehinderte 20-Carbonylgruppe von 16a -Methyl-20-keto-steroiden bei der verfahrensgemäßen Umsetzung als reaktionsfähig erweisen würde; denn es bestanden keine Erfahrungen, welche erwarten ließen, daß 20-Ketosteroide mit einer Methylgruppe in 16-Stellung Umsetzungen der 20-Carbonylgruppe zugänglich sind.It is known 3a-hydroxy-11,20-dioxo-21-oxalylpregnane with a Carboxylic anhydride in 3a, 23-diacyloxy-21-normethyl-11-oxo-17 (20), 22-choladieno-24 (20) -lactone and this through the action of a Peracid in 3a, 23-diacyloxy-17 (20) -epoxy-21-normethyl-11-oxo-22-choleno-24 (20) -lactone convict. However, these are connections that are in the 16-position are not methylated. Due to the behavior of these not methylated in the 16-position Steroids could not have been foreseen by the presence of a 16a permanent Methyl group sterically hindered 20-carbonyl group of 16a -methyl-20-keto-steroids would prove to be responsive to the procedural implementation; because it passed no experience suggesting that 20-keto steroids with a methyl group in the 16-position reactions of the 20-carbonyl group are accessible.

Das folgende Beispiel erläutert das erfindungsgemäße Verfahren. Beispiel Eine Aufschlämmung von 1,0g 3a-Hydroxy-16ri-methyl-11,20-dioxo-21-oxalyl-pregnan in 10 ccm Essigsäureanhydrid wurde mit 30 mg 2,4-Dinitrobenzolsulfonsäure versetzt. Nach etwa 15 Minuten war der feste Stoff vollständig in Lösung gegangen. Die Lösung wurde 2,5 Stunden bei 25'C gerührt und dann im Vakuum auf dem Wasserbad bei 50°C zu einem dicken Sirup eingeengt. Der Sirup wurde in 25 ccm Benzol gelöst und zweimal mit je 10 ccm 2,5 n-Natronlauge und 10 ccm Wasser gewaschen. Nach dem Trocknen der Benzollösung über Magnesiumsulfat wurde das Reaktionsgemisch im Vakuum zu 1,2 g eines amorphen festen Stoffes eingedampft, der ein Isomerengemisch von 3a,23-Diacetoxy-16 a-methyl-21-normetliyl-11-oxo-17 (20), 22-choladien-24(20)-lacton war; f Max,oH = 2970, E"/0 432. Das rohe Isomerengemisch von 3a,23-Diacetoxy-16.z-methyl-21-normethyl-1 I -oxo-17 (20), 22-choladien-24(20)-lacton wurde aus 4 ccm Äthanol umkristallisiert: Ausbeute --- 950 mg (820,!0). f mdX'C" = 2980, E% 474.The following example explains the method according to the invention. example A slurry of 1.0 g of 3a-hydroxy-16ri-methyl-11,20-dioxo-21-oxalyl-pregnane 30 mg of 2,4-dinitrobenzenesulfonic acid were added to 10 cc of acetic anhydride. After about 15 minutes the solid was completely dissolved. The solution was stirred for 2.5 hours at 25'C and then in vacuo on a water bath at 50 ° C concentrated to a thick syrup. The syrup was dissolved in 25 cc of benzene and twice Washed with 10 ccm of 2.5 N sodium hydroxide solution and 10 ccm of water. After drying the Benzene solution over magnesium sulfate, the reaction mixture was 1.2 g in vacuo an amorphous solid, which is an isomer mixture of 3a, 23-diacetoxy-16 was α-methyl-21-normethyl-11-oxo-17 (20), 22-choladiene-24 (20) -lactone; f Max, oH = 2970, E "/ 0 432. The crude mixture of isomers of 3a, 23-diacetoxy-16.z-methyl-21-normethyl-1 I -oxo-17 (20), 22-choladien-24 (20) -lactone was recrystallized from 4 cc of ethanol: Yield --- 950 mg (820,! 0). f mdX'C "= 2980, E% 474.

8,5 g des in Essigsäureäthylester gelösten Isomerengemisches von 3a,23-Diacetoxy-l6a-methyl-21-normethyl-ll-oxo-17(20),22-choladien-24(20)-lacton wurden zu 110 ccm einer Lösung von Perbenzoesäure in Benzol zugesetzt und 140 Stunden bei 25`C stehengelassen. Das Reaktionsgemisch wurde dann auf 15°C gekühlt und mit 50 ccm Wasser gewaschen. Schließlich wurde die überschüssige Säure durch dreimaliges Extrahieren mit je 50 ccm 10%iger Natriumbicarbonatlösung und anschließendes zweimaliges Waschen mit je 50 ccm Wasser entfernt. Die wäßrige Schicht wurde zweimal mit je 25 ccm Benzol ausgewaschen, und die vereinigten organischen Extrakte wurden über Natriumsulfat getrocknet, filtriert und im Vakuum zu einem öligen Rückstand eingeengt. Dieser Rückstand kristallisierte leicht. Die Ausbeute war quantitativ. Zur Trennung von dem Benzoesäureäthylester wurde der kristalline Rückstand mit 160 ccm Petroläther zum Rückfuß erhitzt und filtriert. Der kristalline Niederschlag, ein Isomerengemisch von 3a,23-Diacetoxy-17 (20) - epoxy -16 (x - methyl - 21- normethyl-11-oxo-22-cholen-24(20)-lacton, wog 8,9 g (Ausbeute = 1000/0). jmax,nifril - 2260, E% 228.8.5 g of the isomer mixture dissolved in ethyl acetate of 3a, 23-diacetoxy-16a-methyl-21-normethyl-ll-oxo-17 (20), 22-choladiene-24 (20) -lactone were added to 110 ccm of a solution of Perbenzoic acid in benzene added and left to stand at 25 ° C for 140 hours. The reaction mixture was then cooled to 15 ° C. and washed with 50 cc of water. Finally, the excess acid was removed by extracting it three times with 50 cc of 10% sodium bicarbonate solution each time and then washing it twice with 50 cc of water each time. The aqueous layer was washed out twice with 25 cc of benzene each time, and the combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to an oily residue. This residue crystallized easily. The yield was quantitative. To separate the ethyl benzoate, the crystalline residue was heated to the reef with 160 cc of petroleum ether and filtered. The crystalline precipitate, an isomer mixture of 3a, 23-diacetoxy-17 (20) -epoxy-16 (x-methyl-21-normethyl-11-oxo-22-cholen-24 (20) -lactone, weighed 8.9 g (Yield = 1000/0). Jmax, nifril - 2260, E% 228.

Das als Ausgangsstoff dienende 3a-Hydroxy-16a-methyl-11,20-dioxo-21-oxalyl-pregnan kann nach dem Verfahren der Patentanmeldung M 41128 IVb/12 o durch Umsetzung eines 3a-Acyloxy-(oder -Hydroxy)-16r£-methyl-pregnan-11,20-dions mit einem Oxalsäurealkylester und Hydrolyse des hierbei erhaltenen Alkylesters des entsprechenden 3«-Acyloxy- (bzw. -Hydroxy)-16a-methyl-11,20-dioxo-21-oxalyl-pregnans dargestellt werden.The starting material 3a-hydroxy-16a-methyl-11,20-dioxo-21-oxalyl-pregnane can according to the method of patent application M 41128 IVb / 12 o by implementing a 3a-Acyloxy- (or -hydroxy) -16r £ -methyl-pregnane-11,20-dione with an oxalic acid alkyl ester and hydrolysis of the resulting alkyl ester of the corresponding 3 «-acyloxy (or -hydroxy) -16a-methyl-11,20-dioxo-21-oxalyl-pregnans can be represented.

Claims (1)

Patentanspruch Verfahren zur Herstellung eines Isomerengemisches von 16u-methylierten 3a,23-Diacyloxy-17(20)-epoxy-21-normethyl-11-oxo-22-cholen-24(20)-lactonen der allgemeinen Formel in der R' eine Acyloxygruppe bedeutet, d a -durch gekennzeichnet, daß man in an sich bekannter Weise 16«-Methyl-3a-hydroxy-11,20-dioxo-21-oxalyl-pregnan mit einem Carbonsäureanhydrid in Gegenwart einer starken Säure als Katalysator umsetzt und das erhaltene Isomerengemisch des 16rz-Methyl-3a,23-diacyloxy-21 - normethyl - I I - oxo - 17 (20), 22 - choladien-24(20)-lactons der allgemeinen Formel in der R' die vorstehend genannte Bedeutung hat, mit einer Persäure reagieren läßt. In Betracht gezogene Druckschriften USA.-Patentschriften Nr. 2 740 782, 2 740 783. A process for the preparation of an isomer mixture of 16u-methylated 3a, 23-diacyloxy-17 (20) -epoxy-21-normethyl-11-oxo-22-cholen-24 (20) -lactones of the general formula in which R 'is an acyloxy group means that, in a manner known per se, 16'-methyl-3a-hydroxy-11,20-dioxo-21-oxalyl-pregnane is reacted with a carboxylic anhydride in the presence of a strong acid as a catalyst and the isomer mixture obtained is the 16rz-methyl-3a, 23-diacyloxy-21 - normethyl - II - oxo - 17 (20), 22 - choladiene-24 (20) -lactones of the general formula in which R 'has the meaning given above, can react with a peracid. Referred to U.S. Patents Nos. 2,740,782, 2,740,783.
DEM51071A 1958-04-25 1959-04-10 Process for the preparation of an isomer mixture of 16ª ‡ -methylated 3ª ‡, 23-diacyloxy-17 (20) -epoxy-21-normethyl-11-oxo-22-cholen-24 (20) -lactones Pending DE1181704B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2740782A (en) * 1952-10-24 1956-04-03 Upjohn Co Steroids
US2740783A (en) * 1952-10-24 1956-04-03 Upjohn Co Steroids

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2740782A (en) * 1952-10-24 1956-04-03 Upjohn Co Steroids
US2740783A (en) * 1952-10-24 1956-04-03 Upjohn Co Steroids

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