CH625809A5 - Process for the preparation of polyhalogenated steroids - Google Patents
Process for the preparation of polyhalogenated steroids Download PDFInfo
- Publication number
- CH625809A5 CH625809A5 CH853880A CH853880A CH625809A5 CH 625809 A5 CH625809 A5 CH 625809A5 CH 853880 A CH853880 A CH 853880A CH 853880 A CH853880 A CH 853880A CH 625809 A5 CH625809 A5 CH 625809A5
- Authority
- CH
- Switzerland
- Prior art keywords
- dione
- alpha
- diene
- chlorine
- beta
- Prior art date
Links
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
- 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
-
- 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]
-
- 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
-
- 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)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von io neuen polyhalogenierten Steroiden, und zwar von 9a,21-Diha-logen-llß,17a-di-hydroxy-6a-fluor-16a-methyl-pregna-l,4-dien-3,20-dion-17-estern der allgemeinen Formel The invention relates to a process for the preparation of new polyhalogenated steroids, namely 9a, 21-diha-logen-11ß, 17a-di-hydroxy-6a-fluoro-16a-methyl-pregna-l, 4-dien-3, 20-dione-17-esters of the general formula
(I) (I)
worin X] Chlor oder Fluor, X2 Brom oder Chlor, und Ac eine von einer Carbonsäure abgeleitete Acylgruppe darstellt, dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel wherein X] chlorine or fluorine, X2 bromine or chlorine, and Ac represents an acyl group derived from a carboxylic acid, characterized in that a compound of the general formula
«••••OAc «•••• OAc
. CP3U° ! ! . CP3U °! !
^ \l/ \ / \ / *. ^ \ l / \ / \ / *.
i i ! ch3 i i! ch3
ai) ai)
worin Ac und X2 die oben angegebenen Bedeutungen haben, mit einem Halogenwasserstoff HX1; worin Xj Chlor oder Fluor bedeutet, oder mit einem den Halogenwasserstoff HXj abgebenden Mittel behandelt. wherein Ac and X2 have the meanings given above, with a hydrogen halide HX1; wherein Xj is chlorine or fluorine, or treated with a hydrogen halide donating agent.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass man mit wasserfreiem Chlorwasserstoff in einem indifferenten organischen Lösungsmittel behandelt. 2. The method according to claim 1, characterized in that one is treated with anhydrous hydrogen chloride in an inert organic solvent.
3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass man mit Fluorwasserstoffsäure in Form eines Adduktes mit mit Harnstoff behandelt. 3. The method according to claim 1, characterized in that treated with hydrofluoric acid in the form of an adduct with urea.
4. Verfahren nach einem der Ansprüche 1-3, dadurch gekennzeichnet, dass man eine Verbindung der Formel I herstellt, worin X] für Chlor oder Fluor, X2 für Chor 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 in which X] 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 one produces a compound of formula I, wherein 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-1,4-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-1,4-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-l lß,17a-dihydroxy-16a-methyl-pregna-1,4-dien-3,20-dion-17-vale-rianat herstellt. 8. The method according to any one of claims 1-3, characterized in that 21-chloro-6a, 9a-difluoro-lß, 17a-dihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione -17-vale-rianat.
20 20th
\ / \l i • \ / \ l i •
^ Xl/îV / \ / *. ^ Xl / îV / \ / *.
• « T • * • • «T • * •
i ; xii <*3 i; xii <* 3
</ v v </ v v
S S
F F
OAc OAc
(I) (I)
worin Xj Chlor oder Fluor, X2 Brom oder Chlor und Ac den Acylrest einer Carbonsäure darstellt. where Xj 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 ensprechenden aliphatischen, 35 cycloaliphatischen, 1 cycloaliphatisch-aliphatischen, aromatischen oder araliphatischen Carbonsäuren ab. Der Rest Ac ist insbesondere ein geradkettiges oder verzweigtes Niederalkano-yl, z.B. Acetyl, Propionyl, Butyryl, Isobutyryl, Valeryl, Isovale-ryl, Pivaloyl, 2-Äthyl-butyryl, 2,2- oder 3,3-Dimethyl-butyryl, 40 Hexanoyl oder Heptanoyl, aber auch ein Hydroxyniederalkano-yl, z.B. 3-Hydroxypropionyl, Phenoxyniederalkanoyl, z.B. Phenoxyacetyl, Halogenniederalkanoyl, z.B. Chloracetyl, oder Carboxyniederalkanoyl, z.B. 3-Carboxy-propionyl oder 4-Carboxy-butyryl, Alkenoyl, z.B. Undecylenoyl, Cycloalkyl-45 niederalkanoyl, z.B. Cyclopentyl-propionyl oder Cyclohexyl-acetyl, gegebenenfalls substituiertes Benzoyl, z.B. Benzoyl, oder gegebenenfalls substituiertes Phenylniederalkanoyl oder -niederalkenoyl, 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, 35 cycloaliphatic, 1 cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acids. The radical Ac is in particular a straight-chain or branched lower alkano-yl, e.g. Acetyl, propionyl, butyryl, isobutyryl, valeryl, isovalale, pivaloyl, 2-ethylbutyryl, 2,2- or 3,3-dimethylbutyryl, 40 hexanoyl or heptanoyl, but also a hydroxy-lower alkano-yl, 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, cycloalkyl-45 lower alkanoyl, e.g. Cyclopentyl-propionyl or cyclohexyl-acetyl, optionally substituted benzoyl, e.g. Benzoyl, or optionally substituted phenyl-lower alkanoyl or lower alkenoyl, e.g. Phenylacetyl.
Die erfingungsgemäss 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 Rohwattegra-nulomtest an der Ratte in einem Dosisbereich von etwa 0,001 bis etwa 0,3 mg/Pellet nachweisen lässt. Bei gleicher Versuchs-55 anordnung 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 neuen Verbindungen in al-60 len Indikationen, für die sich Glucocorticoide mit entzündungshemmenden Eigenschaften eignen, insbesondere jedoch als lokal anzuwendende antiinflammatorische Glucocorticoide, z.B. zur Behandlung von entzündlichen Dermatosen, wie Ekzemen, Dermatiden, oder partiell corticoidresistenden Dermatosen, 65 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. in the raw cotton wool test on the rat in a dose range of about 0.001 to about 0.3 mg / pellet. With the same experimental arrangement, 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 new compounds are in all-60 indications for which glucocorticoids with anti-inflammatory properties are suitable, but especially as locally applicable anti-inflammatory glucocorticoids, e.g. for the treatment of inflammatory dermatoses, such as eczema, dermatids, or partially corticoid-resistant dermatoses, 65 e.g. Psoriasis, usable. They can also be used as valuable intermediates for the production of other useful substances, in particular other pharmacologically active steroids.
3 3rd
625 809 625 809
Es betrifft in erster Linie Verbindungen der Formel I, worin X! Fluor oder Chlor, X2 Chlor, und Ac Niederalkanoyl, z.B. Propionyl, darstellt. It primarily relates to compounds of the formula I in which X! Fluorine or chlorine, X2 chlorine, and Ac lower alkanoyl, e.g. Propionyl.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel 5 The process according to the invention is characterized in that a compound of the general formula 5
/ \ / \
• • • • • OAc • • • • • OAc
. 1 ! . 1 !
^ \l/ \ / \ / ~. • • • • • ^ \ l / \ / \ / ~. • • • • •
III CH. III CH.
• • • J • • • J
(/ v V % (/ v V%
« «
F F
10 10th
15 15
(Ii) (Ii)
worin X2 und Ac die oben angegebenen Bedeutungen haben, 20 mit einem Halogenwasserstoff der Formel HX], worin Xj Chlor oder Fluor bedeutet, behandelt. wherein X2 and Ac have the meanings given above, 20 treated with a hydrogen halide of the formula HX], in which Xj is chlorine or fluorine.
Die Aufspaltung der 9ß, llß-Oxidogruppe in einem Ausgangsmaterial der Formel II durch Behandeln mit einem Halogenwasserstoff der Formel HXj, d.h. mit Chlorwasserstoff oder 25 Fluorwasserstoff, wird in an sich bekannterWeise vorgenommen, wobei man zweckmässig einen wasserfreien Halogenwasserstoff, gegebenenfalls in Gegenwart eines indifferenten Lösungsmittels, wie Chloroform, Tetrahydrofuran oder insbesondere Dimethylformamid, Fluorwasserstoff auch in wässriger Lö- 30 sung, verwendet. The cleavage of the 9β, 11ß-oxido group in a starting material of formula II by treatment with a hydrogen halide of formula HXj, i.e. with hydrogen chloride or hydrogen fluoride, is carried out in a manner known per se, suitably using an anhydrous hydrogen halide, optionally in the presence of an inert solvent such as chloroform, tetrahydrofuran or in particular dimethylformamide, hydrogen fluoride also in an aqueous solution.
Anstelle des Halogenwasserstoffs HXi kann man auch ein Fluorwasserstoff- oder Chlorwasserstoff-abgebendes Mittel, wie das Salz einer solchen Säure mit einer tertiären organischen Base (z.B. Pyridin) oder, insbesondere im Fall von Fluorwasser- 35 stoff, eine ähnliche geeignete Additionsverbindung verwenden. Ein besonders günstiges Verfahren wird im US-Patent Nr. 3 211 758 beschrieben, wonach man Fluorwasserstoff in Form eines Adduktes mit einem Carbaminsäure- oder Thiocarbamin-säure-Derivat, insbesondere mit Harnstoff, zur Anwendung 40 bringt. Instead of the hydrogen halide HXi, it is also possible to use a hydrogen fluoride or hydrogen chloride donor, such as the salt of such an acid with a tertiary organic base (e.g. pyridine) or, particularly in the case of hydrogen fluoride, a similar suitable addition compound. A particularly favorable process is described in US Pat. No. 3,211,758, according to which hydrogen fluoride is used in the form of an adduct with a carbamic acid or thiocarbamic acid derivative, in particular with urea.
Die Ausgangsstoffe der Formel II können in an sich bekannter Weise erhalten werden, z.B. durch Abspalten von Wasser aus einem 6a-Fluor-llß,17a-dihydroxy-16a-methyl-21-X2-pregna-l,4-dien-3,20-dion-17-ester, z.B. durch Behandeln mit einem geeigneten Säurechlorid, wie Phosphoroxychlorid oder Methasulfonsäurechlorid, in Gegenwart einer Base, z.B. Pyridin, Anlagern von unterbromiger Säure (die z.B. in Form von N-Bromacetamid oder -succinimid verwendet wird) an die 9,11-Doppelbindung des so erhaltenen 6a-Fluor-17a-hydr-oxy-16a-methyl-21 -X2-pregna-1,4,9(11 )-trien-3,20-dion-17-esters und Abspalten von Bromwasserstoff aus der entsprechenden 9a-Brom-llß-hydroxy-Verbindung durch Behandeln mit einer Base, z.B. einem Alkalimetallcarbonat oder -hydroxid, z.B. Kaliumcarbonat oder Kaliumhydroxid, unter Bildung des The starting materials of formula II can be obtained in a manner known per se, e.g. by splitting off water from a 6a-fluoro-11ß, 17a-dihydroxy-16a-methyl-21-X2-pregna-l, 4-diene-3,20-dione-17-ester, e.g. by treatment with a suitable acid chloride such as phosphorus oxychloride or methasulfonic acid chloride in the presence of a base, e.g. Pyridine, deposits of sub-bromine acid (which is used, for example, in the form of N-bromoacetamide or succinimide) on the 9.11 double bond of the 6a-fluoro-17a-hydroxy-16a-methyl-21 -X2-pregna thus obtained -1,4,9 (11) -triene-3,20-dione-17-esters and cleavage of hydrogen bromide from the corresponding 9a-bromo-11ß-hydroxy compound by treatment with a base, for example an alkali metal carbonate or hydroxide, e.g. Potassium carbonate or potassium hydroxide, forming the
45 45
50 50
gewünschten Ausgangsmaterials der Formel II. In den obigen Zwischenprodukten hat X2 die vorstehend gegebenen Bedeutungen. desired starting material of formula II. In the above intermediates, X2 has the meanings given above.
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 should not restrict their scope in any way. Temperatures are given in degrees Celsius.
Beispiel 1 example 1
In einem Kunststoffgefäss wird 1,5 g 21-Chlor-6a-fluor-9ß,llß-epoxy-17a-hydroxy-16a-methyl-pregna-l,4-dien-3,20-dion-17-propionat mit 30 ml eines Reagens, zubereitet durch Vermischen von 20 g Harnstoff mit 26,5 g wasserfreiem flüssigem Fluorwasserstoff, Übergossen und während 3 Stunden unter Eiskühlung gerührt. Das Reaktionsgemisch wird auf 115 ml eiskalte gesättigte Ammoniak-Lösung gegossen, mit Essigsäure schwach angesäuert und zweimal mit Chloroform extrahiert. Die orgamschen Phasen werden vereinigt, mit eiskalter verdünnter Natronaluge gewaschen, getrocknet und im Wasserstrahlvakuum eingedampft. Das Rohprodukt wird über eine 100-fache Gewichtsmenge Kieselgel (Stufensäule) chromato-graphiert. Die mit einem Gemisch von Methylenchlorid-Me-thanol (99:1) eluierten Fraktionen ergeben 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 Diäthyl-äther bei 268 ° (Zers.) schmilzt. In a plastic vessel, 1.5 g of 21-chloro-6a-fluoro-9ß, 11ß-epoxy-17a-hydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione-17-propionate with 30 ml of a reagent prepared by mixing 20 g of urea with 26.5 g of anhydrous liquid hydrogen fluoride, pouring over and stirring for 3 hours under ice cooling. The reaction mixture is poured onto 115 ml of ice-cold saturated ammonia solution, weakly acidified with acetic acid and extracted twice with chloroform. The organic phases are combined, washed with ice-cold dilute sodium hydroxide solution, dried and evaporated in a water jet vacuum. The crude product is chromatographed over a 100-fold amount by weight of silica gel (step column). The fractions eluted with a mixture of methylene chloride-methanol (99: 1) give 21-chloro-6a, 9a-difluoro-11ß, 17a-dihydroxy-16a-methyl-pregna-1, 4-diene-3.20 -dione-17-propionate, which melts after recrystallization from a mixture of chloroform, methanol and diethyl ether at 268 ° (dec.).
In analoger Weise, aber ausgehend vom entsprechenden 17-Acetat bzw. 17-Valerianat wird das 21-Chlor-6a, 9a-difluor-1 lß, 17a-dihydroxy-16a-methyl-pregna-l,4-dien-3,20-dion-17-acetat, Smp. 269-271 °, und 21-Chlor-6a,9a-difluor-1 lß, 17a-dihydroxy-16a-methyl-pregna-l,4-dien-3,20-dion-17-valerianat, Smp. 244-245 °, erhalten. In an analogous manner, but starting from the corresponding 17-acetate or 17-valerianate, the 21-chloro-6a, 9a-difluoro-1ß, 17a-dihydroxy-16a-methyl-pregna-l, 4-diene-3.20 -dione-17-acetate, mp. 269-271 °, and 21-chloro-6a, 9a-difluoro-1 let, 17a-dihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione- 17-valerianat, mp 244-245 °, obtained.
Beispiel 2 Example 2
In eine Lösung von 1,3 g 21-Chlor-6a-fluor-9ß,llß-ep-oxy-17 a-hydroxy-16a-methyl-pregna-1,4-dien-3,20-dion-propionat in 65 ml Chloroform wird während 30 Minuten bei 00 Chlorwasserstoffgas eingeleitet. Das Gemisch wird weitere 30 Minuten bei 00 stehen gelassen, mit Chloroform verdünnt, mit einer eiskalten gesättigten Natriumhydrogencarbonat-Lösung gewaschen, getrocknet und im Vakuum eingedampft. Das erhaltene Rohprodukt wird an 100-facher Gewichtsmenge Silicagel (Stufensäule) chromatographiert. Das gewünschte Produkt wird mit einem 99:1-Gemisch von Methylenchlorid-Methanol elu-iert. Nach Kristallisation aus Methylenchlorid-Äther erhält man 9a, 21 -Dichlor-6a-fluor-11 ß, 17 a-dihydroxy-16a-methyl-pregna-l,4-dien-3,20-dion-17-propionat, Smp. 267-268 °. In a solution of 1.3 g of 21-chloro-6a-fluoro-9ß, 11ß-ep-oxy-17 a-hydroxy-16a-methyl-pregna-1,4-diene-3,20-dione-propionate in 65 ml of chloroform is introduced for 30 minutes at 00 hydrogen chloride gas. The mixture is left to stand at 00 for a further 30 minutes, diluted with chloroform, washed with an ice-cold saturated sodium hydrogen carbonate solution, dried and evaporated in vacuo. The crude product obtained is chromatographed on 100 times the amount by weight of silica gel (step column). The desired product is eluted with a 99: 1 mixture of methylene chloride-methanol. After crystallization from methylene chloride ether, 9a, 21 -dichlor-6a-fluoro-11β, 17a-dihydroxy-16a-methyl-pregna-l, 4-diene-3,20-dione-17-propionate, mp. 267-268 °.
C C.
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 |
|---|---|
| CH625809A5 true CH625809A5 (en) | 1981-10-15 |
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 |
| 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 |
| CH853780A CH625808A5 (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 |
| CH683081A CH631998A5 (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 |
| CH4682A CH632521A5 (en) | 1976-09-29 | 1982-01-06 | Process for the preparation of polyhalogenated steroids |
Family Applications Before (3)
| 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 |
| CH853980A CH625810A5 (en) | 1976-09-29 | 1980-11-18 | Process for the preparation of polyhalogenated steroids |
Family Applications After (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH853780A CH625808A5 (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 |
| CH683081A CH631998A5 (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 |
| 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) | DE2743069C2 (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 |
| AU7556291A (en) * | 1990-03-27 | 1991-10-21 | Schering Corporation | Process for 9alpha-hydroxy steroid dehydration |
| US5972922A (en) * | 1990-06-11 | 1999-10-26 | Alcon Laboratories, Inc. | Steroids which inhibit angiogenesis |
| BR0214520A (en) | 2001-11-29 | 2006-05-30 | Taro Pharmaceuticals Usa Inc | Method for the preparation of 6alphafluoro 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 |
| LT3310389T (en) | 2015-06-18 | 2020-11-10 | Bausch Health Ireland Limited | Topical compositions comprising a corticosteroid and a retinoid for treating 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 DE2743069A patent/DE2743069C2/en not_active Expired
- 1977-09-26 CH CH1172177A patent/CH632279A5/en not_active IP Right Cessation
- 1977-09-27 DD DD7700201226A patent/DD133150A5/en unknown
- 1977-09-27 CA CA287,560A patent/CA1101410A/en not_active Expired
- 1977-09-27 FR FR7729043A patent/FR2366311A1/en active Granted
- 1977-09-27 CY CY1178A patent/CY1178A/en unknown
- 1977-09-27 GB GB40131/77A patent/GB1563638A/en not_active Expired
- 1977-09-27 AU AU29148/77A patent/AU514200B2/en not_active Expired
- 1977-09-28 BE BE181243A patent/BE859120A/en not_active IP Right Cessation
- 1977-09-28 IL IL53012A patent/IL53012A/en unknown
- 1977-09-28 HU HU77CI1774A patent/HU175218B/en unknown
- 1977-09-28 ZA ZA00775800A patent/ZA775800B/en unknown
- 1977-09-28 AT AT0691077A patent/AT363197B/en not_active IP Right Cessation
- 1977-09-28 IE IE1979/77A patent/IE46047B1/en not_active IP Right Cessation
- 1977-09-29 ES ES462763A patent/ES462763A1/en not_active Expired
- 1977-09-29 JP JP11619377A patent/JPS5356652A/en active Granted
-
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 CH853980A patent/CH625810A5/en not_active IP Right Cessation
- 1980-11-18 CH CH853880A patent/CH625809A5/en not_active IP Right Cessation
- 1980-11-18 CH CH853780A patent/CH625808A5/en not_active IP Right Cessation
-
1981
- 1981-10-26 CH CH683281A patent/CH632000A5/en not_active IP Right Cessation
- 1981-10-26 CH CH683081A patent/CH631998A5/en not_active IP Right Cessation
- 1981-10-26 CH CH683181A patent/CH631999A5/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
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AT363201B (en) | METHOD FOR PRODUCING NEW 9ALPHA, 21-DIHALOGEN-11BETA, 17ALPHA-DIHYDROXY-6ALPHA- | |
| CH625809A5 (en) | Process for the preparation of polyhalogenated steroids | |
| DE2061754A1 (en) | New 21 Mercapto steroids from Pregnan and a process for their manufacture | |
| EP0077541B1 (en) | Delta-1,3,5-3-chloro-11 beta, 16 alpha, 17 alpha, 21-tetrahydroxy-pregnan-20-one-16,17-acetonide derivatives, process for their preparation and pharmaceutical preparations containing them | |
| US3627757A (en) | 6-alkanoylthio-4-en-3-oxo steroids and process for production thereof | |
| CH622270A5 (en) | Process for the preparation of polyhalosteroids | |
| AT363200B (en) | METHOD FOR PRODUCING NEW 9ALPHA, 21-DIHALOGEN-11BETA, 17ALPHA-DIHYDROXY-6ALPHA- | |
| DE2225324C3 (en) | Process for the preparation of 6 a, 21-difluoro-20oxopregnane steroids | |
| DE1793270A1 (en) | 16alpha, 17alpha-methylene steroid compounds and processes for their preparation | |
| DE1468632C (en) | öalpha Acetylthio 4 en 3 on steroids and process for their production | |
| AT363204B (en) | METHOD FOR PRODUCING MULTIPLE HALOGENED STEROIDS | |
| AT364098B (en) | METHOD FOR PRODUCING NEW ESTERS OF ANDROSTADIEN-17-CARBONIC ACIDS | |
| DE1668205A1 (en) | Process for making 9ss, 10alpha steroids | |
| DE1145170B (en) | Process for the preparation of 9,11-oxidosteroids of the androstane and pregnane series | |
| CH505809A (en) | 5,10-Seco steroids of the androstane and pregnane series (I) Where S is an androstane or pregnane residue and the molecule may be further subst. and more | |
| CH549001A (en) | Halo-pregnanes anti-inflammatories | |
| DE1468632B1 (en) | 6alpha-acetylthio-4-en-3-one steroids and process for their preparation | |
| CH631185A5 (en) | Multiply halogenated steroids | |
| CH356767A (en) | Method of making steroids | |
| DE1793774A1 (en) | METHOD OF DEHYDRATION OF ANOR-B-HOMO-STEROIDS | |
| DE1048915B (en) | Process for the preparation of 6-methyl-9ª ‡, 21-difluoro-11ª ‰, 17ª ‡ -dioxy-1,4-pregnadiene-3,20-dione and its 11-keto analogues | |
| CH544082A (en) | Progestational 3-keto-delta-4 or 4 6 or 1 4 -3-alkoxy | |
| DE1029375B (en) | Process for the dehydration of 11-oxysteroids of the androstane and pregnane series | |
| DE1189547B (en) | Process for the preparation of therapeutically active steroid compounds | |
| DE1126866B (en) | Process for the preparation of 21-fluorosteroids of the pregnane series |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |