CH624967A5 - Process for the preparation of polyhalogenated steroids - Google Patents
Process for the preparation of polyhalogenated steroids Download PDFInfo
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- CH624967A5 CH624967A5 CH1549976A CH1549976A CH624967A5 CH 624967 A5 CH624967 A5 CH 624967A5 CH 1549976 A CH1549976 A CH 1549976A CH 1549976 A CH1549976 A CH 1549976A CH 624967 A5 CH624967 A5 CH 624967A5
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- 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
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
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- 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
- C07J5/0046—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 substituted in position 17 alfa
- C07J5/0061—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 substituted in position 17 alfa substituted in position 16
- C07J5/0069—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 substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—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 substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von neuen polyhalogenierten Steroiden, und zwar von 9a,21-Diha-10 logen-llß,17a-di-hydroxy-6a-fluor-16a-methyl-pregna-l,4-di-en-3,20-dion-17-estern der allgemeinen Formel The invention relates to a process for the preparation of new polyhalogenated steroids, namely from 9a, 21-diha-10 logen-llß, 17a-di-hydroxy-6a-fluoro-16a-methyl-pregna-l, 4-di-en- 3,20-dione-17-esters of the general formula
15 15
:H2X2 : H2X2
/sf » / sf »
OAc OAc
I I I I
s\ /\ s \ / \
• • v • • • • • v • • •
i 1 Xli 3 i 1 Xli 3
✓ V V ✓ V V
(I) (I)
25 25th
worin Ac und Xi die oben angegebenen Bedeutungen haben und Ra der Acylrest einer organischen Sulfonsäure ist, mit einem Alkalimetallhalogenid MX2, worin M ein Alkalimetall und X2 Chlor oder Brom bedeutet, in Anwesenheit eines aprotischen organischen Lösungsmittels, dessen dielektrische Konstante mindestens 29 beträgt, behandelt. wherein Ac and Xi have the meanings given above and Ra is the acyl radical of an organic sulfonic acid, treated with an alkali metal halide MX2, where M is an alkali metal and X2 is chlorine or bromine, in the presence of an aprotic organic solvent, the dielectric constant of which is at least 29.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass man mit einem Lithiumhalogenid LÌX2 behandelt. 2. The method according to claim 1, characterized in that one is treated with a lithium halide LÌX2.
3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass man Dimethylformamid als Lösungsmittel verwendet. 3. The method according to claim 1, characterized in that dimethylformamide is used as the solvent.
4. Verfahren nach einem der Ansprüche 1-3, dadurch gekennzeichnet, dass man eine Verbindung der Formel I herstellt, worin Xi für Chlor oder Fluor, X2 für Chlor und Ac für den Acylrest einer niederaliphatischen Monocarbonsäure mit 2 bis 7 Kohlenstoffatomen steht. 4. The method according to any one of claims 1-3, characterized in that a compound of formula I is prepared, wherein Xi is chlorine or fluorine, X2 is chlorine and Ac is the acyl radical of a lower aliphatic monocarboxylic acid having 2 to 7 carbon atoms.
5. Verfahren gemäss einem der Ansprüche 1-3, dadurch gekennzeichnet, dass man eine Verbindung der Formel I herstellt, worin Ac für Propionyl steht. 5. The method according to any one of claims 1-3, characterized in that a compound of formula I is prepared in which Ac is propionyl.
6. Verfahren nach einem der Ansprüche 1-3, dadurch gekennzeichnet, dass man 21-Chlor-6a,9a-difluor-llß,17a-dihydroxy-16a-methyl-pregna-l,4-dien-3,20-dion-17-propio-nat herstellt. 6. The method according to any one of claims 1-3, characterized in that 21-chloro-6a, 9a-difluoro-llß, 17a-dihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione- 17-propio-nat.
7. Verfahren nach einem der Ansprüche 1-3, dadurch gekennzeichnet, dass man 21-Chlor-6a,9a-difluor-llß,17a-dihydroxy-16a-methyl-pregna-l,4-dien-3,20-dion-17-acetat herstellt. 7. The method according to any one of claims 1-3, characterized in that 21-chloro-6a, 9a-difluoro-llß, 17a-dihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione- 17-acetate produces.
8. Verfahren nach einem der Ansprüche 1-3, dadurch gekennzeichnet, dass man 21-Chlor-6a,9a-difluor-llß,17a-dihydroxy-16a-methyl-pregna-1,4-dien-3,20-dion-17-valeria-nat herstellt. 8. The method according to any one of claims 1-3, characterized in that 21-chloro-6a, 9a-difluoro-llß, 17a-dihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione- 17-valeria-nat.
In unserer Schweizerischen Patentschrift Nr. 621 801 wurde ein Verfahren zur Herstellung von 2-Chlor-9a,21-dihalogen- In our Swiss Patent No. 621 801 a process for the production of 2-chloro-9a, 21-dihalogen-
worin Xi Chlor oder Fluor, X2 Brom oder Chlor und Ac den Acylrest einer Carbonsäure darstellt. wherein Xi represents chlorine or fluorine, X2 bromine or chlorine and Ac represents the acyl radical of a carboxylic acid.
Nachstehend mit «nieder» bezeichnete kohlenstoffhaltige 30 Verbindungen und Reste enthalten vorzugsweise bis und mit 7 Kohlenstoffatome. Carbon-containing compounds and radicals hereinafter referred to as “lower” preferably contain up to and with 7 carbon atoms.
Eine Acylgruppe Ac leitet sich vorzugsweise von den in der Steroidchemie gebräuchlichen Carbonsäuren mit 1 bis 18 Kohlenstoffatomen, insbesondere von entsprechenden alipha-35 tischen, cycloaliphatischen, cycloaliphatisch-aliphatischen, aromatischen oder aliphatischen Carbonsäuren ab. Der Rest Ac ist insbesondere ein geradkettiges oder verzweigtes Nieder-alkanoyl, z.B. Acetyl, Propionyl, Butyryl, Isobutyryl, Valeryl, Isovaleryl, Pivaloyl, 2-Äthyl-butyryl, 2,2- oder 3,3-Dimethyl-40 butyryl, Hexanoyl oder Heptanoyl, aber auch ein Hydroxy-niederalkanoyl, z.B. 3-Hydroxypropionyl, Phenoxyniederalka-noyl, z.B. Phenoxyacetyl, Halogenniederalkanoyl, z.B. Chlor-acetyl, oder Carboxyniederalkanoyl, z.B. 3-Carboxy-propionyl oder 4-Carboxy-butyryl, Alkenoyl, z.B. Undecylenoyl, 45 Cycloalkylniederalkanoyl, z.B. Cyclopentyl-propionyl oder Cyclohexylacetyl, gegebenenfalls substituiertes Benzoyl, z. B. Benzoyl, oder gegebenenfalls substituiertes Phenylniederalka-noyl oder -niederalkanoyl, z. B. Phenylacetyl. An acyl group Ac is preferably derived from the carboxylic acids with 1 to 18 carbon atoms customary in steroid chemistry, in particular from corresponding aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or aliphatic carboxylic acids. The radical Ac is in particular a straight-chain or branched lower alkanoyl, e.g. Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 2-ethyl-butyryl, 2,2- or 3,3-dimethyl-40-butyryl, hexanoyl or heptanoyl, but also a hydroxy-lower alkanoyl, e.g. 3-hydroxypropionyl, phenoxy lower alkanoyl, e.g. Phenoxyacetyl, halogeno lower alkanoyl e.g. Chloroacetyl, or carboxy lower alkanoyl, e.g. 3-carboxy-propionyl or 4-carboxy-butyryl, alkenoyl, e.g. Undecylenoyl, 45 cycloalkyl-lower alkanoyl, e.g. Cyclopentyl-propionyl or cyclohexylacetyl, optionally substituted benzoyl, e.g. B. benzoyl, or optionally substituted phenyl-lower alka-noyl or lower alkanoyl, e.g. B. Phenylacetyl.
Die erfindungsgemäss hergestellten Verbindungen besitzen so wertvolle pharmakologische Eigenschaften. So zeichnen sie sich durch eine hervorragende antiinflammatorische Wirksamkeit, z.B. bei lokaler Anwendung, aus, die sich z.B. im Roh-wattegranulomtest an der Ratte in einem Dosisbereich von etwa 0,001 bis etwa 0,3 mg/Pellet nachweisen lässt. Bei glei-55 eher Versuchsanordnung sind die ersten Anzeichen einer systemischen Wirkung, z.B. die Abnahme des Körper- und insbesondere des Nebennieren- und Thymus-Gewichts, erst oberhalb der Dosis von 0,3 mg/Pellet bemerkbar. Wegen der günstigen Verteilung der biologischen Eigenschaften sind die 60 neuen Verbindungen in allen Indikationen, für die sich Gluco-corticoide mit entzündungshemmenden Eigenschaften eignen, insbesondere jedoch als lokal anzuwendende antiinflammatorische Glucocorticoide, z.B. zur Behandlung von entzündlichen Dermatosen, wie Ekzemen, Dermatiden, oder partiell corticoid-65 resistenden Dermatosen, z. B. Psoriasis, verwendbar. Sie können zudem als wertvolle Zwischenprodukte zur Herstellung anderer nützlicher Stoffe, insbesondere anderer pharmakologisch wirksamer Steroide, Anwendung finden. The compounds produced according to the invention thus have valuable pharmacological properties. They are characterized by excellent anti-inflammatory effectiveness, e.g. with local application, which e.g. can be demonstrated in the raw wattegranuloma test on the rat in a dose range of about 0.001 to about 0.3 mg / pellet. The first signs of a systemic effect, e.g. the decrease in body and especially adrenal and thymus weight, only noticeable above the dose of 0.3 mg / pellet. Because of the favorable distribution of the biological properties, the 60 new compounds are in all indications for which glucocorticoids with anti-inflammatory properties are suitable, but in particular as locally applicable anti-inflammatory glucocorticoids, e.g. for the treatment of inflammatory dermatoses, such as eczema, dermatids, or partially corticoid-65-resistant dermatoses, e.g. B. psoriasis, can be used. They can also be used as valuable intermediates for the production of other useful substances, in particular other pharmacologically active steroids.
3 3rd
624 967 624 967
Es betrifft in erster Linie Verbindungen der Formel I, worin Xi Fluor oder Chlor, Xz Chlor, und Ac Niederalkanoyl, z.B. Propionyl, darstellt. It primarily relates to compounds of formula I in which Xi is fluorine or chlorine, Xz chlorine, and Ac lower alkanoyl, e.g. Propionyl.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel The process according to the invention is characterized in that a compound of the general formula
CH0OR CH0OR
„owVf3f° V "OwVf3f ° V
! i" H« ! i "H"
S \l^;\ / \ / „„ S \ l ^; \ / \ / „„
• • • • • »CH • • • • • »CH
I I X,I 3 I I X, I 3
• • I. • • • I. •
e/ v y e / v y
F F
worin Xi und Ac die oben angegebenen Bedeutungen haben und Ra für den Acylrest einer organischen Sulfonsäure steht, mit einem Alkalimetallhalogenid der Formel M-X2 (V), worin M für ein Alkalimetall steht, in Anwesenheit eines aprotischen organischen Lösungsmittels, dessen dielektrische Konstante mindestens 29 beträgt, behandelt. wherein Xi and Ac have the meanings given above and Ra stands for the acyl radical of an organic sulfonic acid, with an alkali metal halide of the formula M-X2 (V), where M stands for an alkali metal, in the presence of an aprotic organic solvent, the dielectric constant of which is at least 29 is treated.
Der Acylrest Ra einer organischen Sulfonsäure ist insbesondere derjenige einer aliphatischen oder carbocyclischen, gegebenenfalls ungesättigten bzw. aromatischen Sulfonsäure. Solche Säuren sind u.a. gegebenenfalls substituierte, z.B. haloge-nierte, Niederalkansulfonsäuren, Cycloalkansulfonsäuren, worin der Cycloalkylrest mono- oder polycyclisch sein kann, oder gegebenenfalls durch Niederalkyl, z. B. Methyl, Nieder-alkoxy, z. B. Methoxy, Halogen, z. B. Chlor oder Brom, und/ oder Nitro, substituierte Benzolsulfonsäuren. Als typische Beispiele solcher Säuren seien die Trifluormethansulfonsäure, (+)-Campher-10-sulfonsäure, 4-Brom-benzolsulfonsäure und 3-Nitrobenzolsulfonsäure, insbesondere p-Toluolsulfonsäure und vor allem Methansulfonsäure erwähnt. The acyl radical Ra of an organic sulfonic acid is in particular that of an aliphatic or carbocyclic, optionally unsaturated or aromatic sulfonic acid. Such acids include optionally substituted, e.g. halogenated, lower alkanesulfonic acids, cycloalkanesulfonic acids, in which the cycloalkyl radical can be mono- or polycyclic, or optionally by lower alkyl, e.g. B. methyl, lower alkoxy, e.g. B. methoxy, halogen, e.g. B. chlorine or bromine, and / or nitro, substituted benzenesulfonic acids. Typical examples of such acids are trifluoromethanesulfonic acid, (+) - camphor-10-sulfonic acid, 4-bromobenzenesulfonic acid and 3-nitrobenzenesulfonic acid, in particular p-toluenesulfonic acid and especially methanesulfonic acid.
Die Austauschreaktion wird in der üblichen, an sich bekannten Weise durchgeführt. Als Alkalimetall M kommt vorzugsweise Lithium in Betracht. Als aprotische organische Lösungsmittel können insbesondere Diniederalkylsulfoxide, z.B. Dimethylsulfoxid, N,N-Diniederalkylamide von niederali-. phatischen Carbonsäuren, z.B. N,N-Dimethylformamid oder N,N-Dimethylacetamid, Niederalkannitrile, z.B. Acetonitril, Hexaniederalkylphosphoramide, z. B. Hexamethylphosphor-amid, oder auch Ketone, insbesondere aliphatische oder cyclo-aliphatische Ketone mit höchstens 10 Kohlenstoffatomen, wie entsprechende Alkanone, z.B. Aceton, 2-Butanon, 2- oder 3-Pentanon, 2-Hexanon oder 4-Decanon, oder Cycloalkanone mit höchstens 8 Ringkohlenstoffatomen, z.B. Cyclopentanon oder Cyclohexanon, oder Gemische von solchen Lösungsmitteln verwendet werden. The exchange reaction is carried out in the usual manner known per se. Lithium is preferably used as the alkali metal M. As aprotic organic solvents, in particular, lower alkyl sulfoxides, e.g. Dimethyl sulfoxide, N, N-di-lower alkylamides from lower ali-. phatic carboxylic acids, e.g. N, N-dimethylformamide or N, N-dimethylacetamide, lower alkanitriles, e.g. Acetonitrile, hexane-lower alkylphosphoramides, e.g. B. hexamethylphosphoramide, or ketones, especially aliphatic or cyclo-aliphatic ketones with at most 10 carbon atoms, such as corresponding alkanones, e.g. Acetone, 2-butanone, 2- or 3-pentanone, 2-hexanone or 4-decanone, or cycloalkanones with at most 8 ring carbon atoms, e.g. Cyclopentanone or cyclohexanone, or mixtures of such solvents can be used.
Die Reaktion führt man zweckmässig zwischen Raumtemperatur und der Siedetemperatur des Reaktionsgemisches durch, wobei man mit mindestens einem Äquivalent des Alka-limetallhalogenids der Formel V umsetzt. The reaction is expediently carried out between room temperature and the boiling temperature of the reaction mixture, reaction being carried out with at least one equivalent of the alkali metal halide of the formula V.
Die Ausgangsstoffe der Formel II sind bekannt oder können in an sich bekannter Weise hergestellt werden, z.B. indem man in einem 6a-Fluor-llß-17a,21-trihydroxy-16a-methyl-9a-Xi-pregna-l,4-dien-3,20-dion-17-ester die 21-Hydroxygruppe durch Behandeln mit einem reaktionsfähigen Derivat einer organischen Sulfonsäure der Formel Ra-OH (VI), insbesondere mit einem entsprechenden Sulfonsäurechlorid der Formel Ra-Cl (Via), in Gegenwart einer Base, z.B. Pyridin, in die gewünschte organische Sulfonyloxygruppe -ORa umwandelt. The starting materials of formula II are known or can be prepared in a manner known per se, e.g. by treating the 21-hydroxy group in a 6a-fluoro-11β-17a, 21-trihydroxy-16a-methyl-9a-Xi-pregna-l, 4-diene-3,20-dione-17-ester by treatment with a reactive Derivative of an organic sulfonic acid of the formula Ra-OH (VI), in particular with a corresponding sulfonic acid chloride of the formula Ra-Cl (Via), in the presence of a base, for example Pyridine, converted into the desired organic sulfonyloxy group -ORa.
Die gemäss der vorliegenden Erfindung hergestellten neuen Verbindungen der Formel I finden Verwendung als medizinische Wirkstoffe, vorzugsweise zur Behandlung von Entzündungen, in erster Linie als lokal anzuwendende antiinflammatorische Glucocorticoide, üblicherweise in Form von pharmazeutischen Präparaten, insbesondere solchen zur topischen Anwendung. The new compounds of the formula I prepared according to the present invention are used as medicinal active substances, preferably for the treatment of inflammation, primarily as locally applicable anti-inflammatory glucocorticoids, usually in the form of pharmaceutical preparations, in particular those for topical use.
Die nachfolgenden Beispiele illustrieren die oben beschriebene Erfindung; sie sollen jedoch diese in ihrem Umfang in keiner Weise einschränken. Temperaturen werden in Celsiusgraden angegeben. The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees Celsius.
Beispiel example
Eine Lösung von 6,0 g 6a,9a-Difluor-llß,17a,21-tri-hydroxy-16a-methylpregna-l,4-dien-3,20-dion-17-propionat-21-methansulfonat in 150 ml Dimethylformamid wird mit 18 g trockenem Lithiumchlorid versetzt und während 16 Stunden bei 100° unter einer Stickstoffatmosphäre gerührt. Das abgekühlte Gemisch wird auf Eiswasser ausgegossen; der entstandene Niederschlag wird abfiltriert, mit Wasser gut gewaschen und in Chloroform gelöst. Die organische Lösung wird nach dem Trocknen unter Wasserstrahlvakuum eingedampft und der Rückstand mittels präparativer Dünnschichtchromatographie auf Silikagel mit einem 50:50-Gemisch von Toluol und Äthyl-acetat als flüssige Phase aufgetrennt. Durch Auswaschen der Hauptzone mit Äthylacetat erhält man das 21-Chlor-6a,9a-difluor-llß,17a-dihydroxy-16a-methyl-pregna-l,4-dien-3,20-dion-17-propionat, das nach Umkristallisieren aus einem Gemisch von Chloroform, Methanol und Diäthyläther bei 268° (Zers.) schmilzt. A solution of 6.0 g of 6a, 9a-difluoro-11ß, 17a, 21-tri-hydroxy-16a-methylpregna-l, 4-diene-3,20-dione-17-propionate-21-methanesulfonate in 150 ml of dimethylformamide 18 g of dry lithium chloride are added and the mixture is stirred at 100 ° for 16 hours under a nitrogen atmosphere. The cooled mixture is poured onto ice water; the precipitate formed is filtered off, washed well with water and dissolved in chloroform. After drying, the organic solution is evaporated under a water jet vacuum and the residue is separated by means of preparative thin layer chromatography on silica gel with a 50:50 mixture of toluene and ethyl acetate as the liquid phase. Washing the main zone with ethyl acetate gives 21-chloro-6a, 9a-difluoro-11ß, 17a-dihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione-17-propionate, which after recrystallization melts from a mixture of chloroform, methanol and diethyl ether at 268 ° (dec.).
In analoger Weise, aber ausgehend vom entsprechenden 17-Acetat-21-methansulfonat bzw. 17-Valerianat-21-methansul-fonat wird das 21-Chlor-6a,9a-difluor-llß,17a-dihydroxy-16a-methyl-pregna-l,4-dien-3,20-dion-17-acetat, Smp. 269-271°, und 21-Chlor-6a,9a-difluor-llß,17a-dihydroxy-16a-methylpregna-l,4-dien-3,20-dion-17-valerianat, Smp. 244— 245°, erhalten. Analogously, but starting from the corresponding 17-acetate-21-methanesulfonate or 17-valerianate-21-methanesulfonate, the 21-chloro-6a, 9a-difluoro-11ß, 17a-dihydroxy-16a-methyl-pregna- 1,4-diene-3,20-dione-17-acetate, mp. 269-271 °, and 21-chloro-6a, 9a-difluoro-11ß, 17a-dihydroxy-16a-methylpregna-l, 4-diene- 3.20-dione-17-valerianate, mp 244-245 °.
Das als Ausgangsstoff verwendete 21-Methansulfonat des 6a,9a-Difluor-llß,17a,21-trihydroxy-16a-methyl-pregna-l,4-dien-3,20-dion-17-acetats,-17-propionats bzw. -17-valeria-nats wird durch Verestern der 21-Hydroxygruppe im entsprechenden 6 a, 9 a-Difluor-11 ß, 17 a,21 -trihydroxy-16 a-methyl-l,4-pregna-dien-3,20-dion-17-ester durch Behandeln mit Methansulfonsäurechlorid in Gegenwart von Pyridin bei Zimmertemperatur erhalten, z.B. in der folgenden Weise: The 21-methanesulfonate of 6a, 9a-difluoro-11ß, 17a, 21-trihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione-17-acetate, -17-propionate or -17-valeria-nats is obtained by esterifying the 21-hydroxy group in the corresponding 6 a, 9 a-difluoro-11β, 17 a, 21 -trihydroxy-16 a-methyl-l, 4-pregna-diene-3.20- Dion-17-ester obtained by treatment with methanesulfonic acid chloride in the presence of pyridine at room temperature, for example in the following way:
Eine Lösung von 2,75 g 6a,9a-Difluor-llß,17a,21-trihy-droxy-16a-methyl-pregna-l,4-dien-3,20-dion-17-propionat in 60 ml Pyridin wird bei ca. —10° unter Rühren mit 2,23 ml Methansulfonsäurechlorid tropfenweise versetzt und dann bei Zimmertemperatur noch 21 Stunden stehen gelassen. Das Reaktionsgemisch wird anschliessend auf 1,5 1 Eiswasser gegossen und 20 Minuten gerührt. Der ausgefallene Niederschlag wird abgenutscht, mit Wasser gewaschen, in Methylenchlorid aufgenommen, die Lösung getrocknet und im Wasserstrahlvakuum eingedampft. Das so erhaltene 21-Mesylat ist dünnschichtchromatographisch praktisch rein. Es wird ohne eine weitere Reinigung direkt weiterverarbeitet. A solution of 2.75 g of 6a, 9a-difluoro-11ß, 17a, 21-trihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione-17-propionate in 60 ml of pyridine is added 2.23 ml of methanesulfonic acid chloride are added dropwise with stirring at about −10 ° and then left to stand at room temperature for a further 21 hours. The reaction mixture is then poured onto 1.5 l of ice water and stirred for 20 minutes. The precipitate is filtered off, washed with water, taken up in methylene chloride, the solution dried and evaporated in a water jet vacuum. The 21-mesylate thus obtained is practically pure by thin layer chromatography. It is processed directly without further cleaning.
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Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU75903A LU75903A1 (en) | 1976-09-29 | 1976-09-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH624967A5 true CH624967A5 (en) | 1981-08-31 |
Family
ID=19728370
Family Applications (9)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1549976A CH624967A5 (en) | 1976-09-29 | 1976-12-09 | Process for the preparation of polyhalogenated steroids |
| CH1172177A CH632279A5 (en) | 1976-09-29 | 1977-09-26 | Process for the preparation of polyhalogenated steroids |
| CH853780A CH625808A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH853980A CH625810A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH853880A CH625809A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH683281A CH632000A5 (en) | 1976-09-29 | 1981-10-26 | Process for the preparation of polyhalogenated steroids |
| CH683181A CH631999A5 (en) | 1976-09-29 | 1981-10-26 | Process for the preparation of polyhalogenated steroids |
| CH683081A CH631998A5 (en) | 1976-09-29 | 1981-10-26 | Process for the preparation of polyhalogenated steroids |
| CH4682A CH632521A5 (en) | 1976-09-29 | 1982-01-06 | Process for the preparation of polyhalogenated steroids |
Family Applications After (8)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1172177A CH632279A5 (en) | 1976-09-29 | 1977-09-26 | Process for the preparation of polyhalogenated steroids |
| CH853780A CH625808A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH853980A CH625810A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH853880A CH625809A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
| CH683281A CH632000A5 (en) | 1976-09-29 | 1981-10-26 | Process for the preparation of polyhalogenated steroids |
| CH683181A CH631999A5 (en) | 1976-09-29 | 1981-10-26 | Process for the preparation of polyhalogenated steroids |
| CH683081A CH631998A5 (en) | 1976-09-29 | 1981-10-26 | Process for the preparation of polyhalogenated steroids |
| CH4682A CH632521A5 (en) | 1976-09-29 | 1982-01-06 | Process for the preparation of polyhalogenated steroids |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS5356652A (en) |
| AT (3) | AT363197B (en) |
| AU (1) | AU514200B2 (en) |
| BE (1) | BE859120A (en) |
| CA (1) | CA1101410A (en) |
| CH (9) | CH624967A5 (en) |
| CY (1) | CY1178A (en) |
| DD (1) | DD133150A5 (en) |
| DE (1) | DE2743069A1 (en) |
| DK (1) | DK146017C (en) |
| ES (1) | ES462763A1 (en) |
| FR (1) | FR2366311A1 (en) |
| GB (1) | GB1563638A (en) |
| HK (1) | HK16683A (en) |
| HU (1) | HU175218B (en) |
| IE (1) | IE46047B1 (en) |
| IL (1) | IL53012A (en) |
| KE (1) | KE3258A (en) |
| LU (1) | LU75903A1 (en) |
| MY (1) | MY8400092A (en) |
| NL (1) | NL7710089A (en) |
| SE (1) | SE436751B (en) |
| SG (1) | SG3383G (en) |
| ZA (1) | ZA775800B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL187577C (en) * | 1978-04-05 | 1991-11-18 | Sibla Srl | 3-ACETOXY-9BETA, 11BETA-EPOXY-PREGNA-1,3,5-TRIEN, PROCESS FOR THE PREPARATION THEREOF, AND PROCESS FOR THE PREPARATION OF 6-alpha-halogen-1,4-diene-3-ones. |
| DE3227312A1 (en) * | 1982-07-19 | 1984-01-19 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW 6.16 DIMETHYL CORTICOIDS, THEIR PRODUCTION AND USE |
| EP0523132A1 (en) * | 1990-03-27 | 1993-01-20 | Schering Corporation | PROCESS FOR 9$g(a)-HYDROXY STEROID DEHYDRATION |
| US5972922A (en) * | 1990-06-11 | 1999-10-26 | Alcon Laboratories, Inc. | Steroids which inhibit angiogenesis |
| MXPA04005188A (en) | 2001-11-29 | 2004-08-11 | Taro Pharma Ind | Method for the production of 6-alpha-fluoro corticosteroids. |
| US8809307B2 (en) | 2010-11-22 | 2014-08-19 | Dow Pharmaceutical Sciences, Inc. | Pharmaceutical formulations containing corticosteroids for topical administration |
| US11957753B2 (en) | 2010-11-22 | 2024-04-16 | Bausch Health Ireland Limited | Pharmaceutical formulations containing corticosteroids for topical administration |
| ES2812451T3 (en) | 2015-06-18 | 2021-03-17 | Bausch Health Ireland Ltd | Topical compositions comprising a corticosteroid and a retinoid to treat psoriasis |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB898292A (en) * | 1959-03-18 | 1962-06-06 | Upjohn Co | Improvements in or relating to steroids and the manufacture thereof |
| US3644340A (en) * | 1970-03-19 | 1972-02-22 | Syntex Corp | Preparation of 21-chloro steroids |
| US3992422A (en) * | 1975-08-14 | 1976-11-16 | Schering Corporation | Process for the preparation of 21-halogeno-21-desoxy-17α-acyloxy-20-keto-pregnenes |
-
1976
- 1976-09-29 LU LU75903A patent/LU75903A1/xx unknown
- 1976-12-09 CH CH1549976A patent/CH624967A5/en not_active IP Right Cessation
-
1977
- 1977-06-08 SE SE7706673A patent/SE436751B/en not_active IP Right Cessation
- 1977-06-09 DK DK256977A patent/DK146017C/en not_active IP Right Cessation
- 1977-09-14 NL NL7710089A patent/NL7710089A/en not_active Application Discontinuation
- 1977-09-24 DE DE19772743069 patent/DE2743069A1/en active Granted
- 1977-09-26 CH CH1172177A patent/CH632279A5/en not_active IP Right Cessation
- 1977-09-27 FR FR7729043A patent/FR2366311A1/en active Granted
- 1977-09-27 CA CA287,560A patent/CA1101410A/en not_active Expired
- 1977-09-27 GB GB40131/77A patent/GB1563638A/en not_active Expired
- 1977-09-27 AU AU29148/77A patent/AU514200B2/en not_active Expired
- 1977-09-27 CY CY1178A patent/CY1178A/en unknown
- 1977-09-27 DD DD7700201226A patent/DD133150A5/en unknown
- 1977-09-28 IL IL53012A patent/IL53012A/en unknown
- 1977-09-28 ZA ZA00775800A patent/ZA775800B/en unknown
- 1977-09-28 IE IE1979/77A patent/IE46047B1/en not_active IP Right Cessation
- 1977-09-28 HU HU77CI1774A patent/HU175218B/en unknown
- 1977-09-28 BE BE181243A patent/BE859120A/en not_active IP Right Cessation
- 1977-09-28 AT AT0691077A patent/AT363197B/en not_active IP Right Cessation
- 1977-09-29 JP JP11619377A patent/JPS5356652A/en active Granted
- 1977-09-29 ES ES462763A patent/ES462763A1/en not_active Expired
-
1979
- 1979-02-28 AT AT0151279A patent/AT363202B/en not_active IP Right Cessation
- 1979-02-28 AT AT0151379A patent/AT363203B/en not_active IP Right Cessation
-
1980
- 1980-11-18 CH CH853780A patent/CH625808A5/en not_active IP Right Cessation
- 1980-11-18 CH CH853980A patent/CH625810A5/en not_active IP Right Cessation
- 1980-11-18 CH CH853880A patent/CH625809A5/en not_active IP Right Cessation
-
1981
- 1981-10-26 CH CH683281A patent/CH632000A5/en not_active IP Right Cessation
- 1981-10-26 CH CH683181A patent/CH631999A5/en not_active IP Right Cessation
- 1981-10-26 CH CH683081A patent/CH631998A5/en not_active IP Right Cessation
-
1982
- 1982-01-06 CH CH4682A patent/CH632521A5/en not_active IP Right Cessation
-
1983
- 1983-01-20 SG SG33/83A patent/SG3383G/en unknown
- 1983-01-21 KE KE3258A patent/KE3258A/en unknown
- 1983-05-19 HK HK166/83A patent/HK16683A/en not_active IP Right Cessation
-
1984
- 1984-12-30 MY MY92/84A patent/MY8400092A/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |