DE10055820C1 - Preparation of 16,17-cyclohexylmethylene-dioxy-pregnadiene derivative, useful as glucocorticoid, by reacting 16,17-ketal with cyclohexylaldehyde to give high epimeric purity - Google Patents

Preparation of 16,17-cyclohexylmethylene-dioxy-pregnadiene derivative, useful as glucocorticoid, by reacting 16,17-ketal with cyclohexylaldehyde to give high epimeric purity

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Publication number
DE10055820C1
DE10055820C1 DE2000155820 DE10055820A DE10055820C1 DE 10055820 C1 DE10055820 C1 DE 10055820C1 DE 2000155820 DE2000155820 DE 2000155820 DE 10055820 A DE10055820 A DE 10055820A DE 10055820 C1 DE10055820 C1 DE 10055820C1
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Prior art keywords
preparation
ketal
cyclohexylmethylene
cyclohexylaldehyde
formula
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DE2000155820
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German (de)
Inventor
Beate Gutterer
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Covis Pharma GmbH
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Byk Gulden Lomberg Chemische Fabrik GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring

Abstract

Preparation of 11 beta , 16 alpha (R)-16,17-((cyclohexylmethylene) bis-oxy)-11,21-dihydroxy-pregna-1,4-diene-3,20-dione or its 21-isobutyryl ester (I) in at least 90% (R)-epimeric purity comprises reacting the corresponding 16,17-ketal (II) with cyclohexylaldehyde. Preparation of 11 beta , 16 alpha (R)-16,17-((cyclohexylmethylene) bis-oxy)-11,21-dihydroxy-pregna-1,4-diene-3,20-dione or its 21-isobutyryl ester of formula (I) in at least 90% (R)-epimeric purity comprises reacting the corresponding 16,17-ketal of formula (II) with cyclohexylaldehyde. R = H or isobutyryl; and R1, R2 = 1-4C alkyl.

Description

Die Erfindung betrifft ein neues Verfahren zur Herstellung eines bekannten Glucocorticoids, das in der pharmazeutischen Industrie zur Herstellung von Arzneimitteln verwendet wird.The invention relates to a new method for producing a known glucocorticoids, which in the pharmaceutical industry used for the manufacture of pharmaceuticals.

In der Internationalen Patentanmeldung WO 9422899 werden neue Prednisolonderivate und ein Verfahren zu ihrer Herstellung beschrieben. Bei dem Verfahren wird 16-Hydroxyprednisolon mit Cyclohexanaldehyd umgesetzt. - In der Deutschen. Patentanmeldung DE 41 29 535 werden neue Glucocorticoide und ein Verfahren zu ihrer Herstellung offenbart. Das Verfahren ist dadurch gekennzeichnet, dass Pregna-1,4-dien-3,20-dion-16,17-dihydroxyverbindungen in Form ihrer 16,17- Diesterderivate mit Aldehyden (z. B. mit Cyclohexanaldehyd) zu den gewünschten Endprodukten umgesetzt werden.In international patent application WO 9422899 new prednisolone derivatives and a Process for their preparation described. In the process, 16-hydroxyprednisolone is used Cyclohexanaldehyde implemented. - In the German. Patent application DE 41 29 535 are new Glucocorticoids and a process for their preparation are disclosed. The procedure is thereby characterized in that Pregna-1,4-diene-3,20-dione-16,17-dihydroxy compounds in the form of their 16,17- Diester derivatives with aldehydes (e.g. with cyclohexanaldehyde) to the desired end products be implemented.

Die Erfindung betrifft ein Verfahren zur Herstellung der Verbindungen der Formel 1,
The invention relates to a process for the preparation of the compounds of formula 1,

worin
R Wasserstoff (H) oder Isobutyryl [CO-CH(CH3)2] bedeutet, in mindestens 90% R-epimerenreiner Form.wherein
R is hydrogen (H) or isobutyryl [CO-CH (CH 3 ) 2 ], in at least 90% pure R-epimer form.

Es wurde nun gefunden, dass man zu den Verbindungen der Formel 1 auf einfache Weise in guter Ausbeute und überraschend hoher Epimerenreinheit gelangt, wenn man nicht von der 16,17- Dihydroxyverbindung oder vom 16,17-Diesterderivat, sondern- vom entsprechenden 16,17-Ketal, insbesondere vom 16,17-Acetonid ausgeht. It has now been found that the compounds of formula 1 can be obtained in a simple manner in good Yield and surprisingly high epimer purity, if you do not from the 16.17- Dihydroxy compound or from the 16,17-diester derivative, but from the corresponding 16,17-ketal, in particular starts from 16,17-acetonide.  

Gegenstand der Erfindung ist somit ein Verfahren zur Herstellung der Verbindungen der Formel in überwiegend epimerenreiner Form, das dadurch gekennzeichnet ist, dass man Verbindungen der Formel 2,
The invention thus relates to a process for the preparation of the compounds of the formula in predominantly epimeric form, which is characterized in that compounds of the formula 2

worin
R Wasserstoff (H) oder Isobutyryl [CO-CH(CH3)2] bedeutet,
R1 1-4C-Alkyl bedeutet und
R2 1-4C-Alkyl bedeutet,
mit Cyclohexanaldehyd umsetzt.wherein
R denotes hydrogen (H) or isobutyryl [CO-CH (CH 3 ) 2 ],
R1 denotes 1-4C-alkyl and
R2 is 1-4C-alkyl,
reacted with cyclohexanaldehyde.

Bevorzugt wird das Verfahren mit solchen Verbindungen der Formel 2 durchgeführt, in denen R1 und R2 jeweils Methyl (CH3) bedeuten.The process is preferably carried out with compounds of the formula 2 in which R1 and R2 each denote methyl (CH 3 ).

Die Umsetzung erfolgt in geeigneten Lösungsmitteln wie Ethern, z. B. Dioxan, Diisopropylether, Estern, z. B. Essigsäureethylester, halogenierten Kohlenwasserstoffen, z. B. Methylenchlorid, Chloroform, nitrierten Kohlenwasserstoffen, z. B. Nitromethan, 2-Nitropropan oder bevorzugt 1- Nitropropan, oder ohne Losungsmittel, unter Zusatz von katalytischen oder auch größeren Mengen Säure, wie Mineralsäuren, z. B. Tetrafluorborsäure oder insbesondere Perchlorsäure, oder Sulfonsäuren, insbesondere Methansulfonsäure, bei Temperaturen von vorteilhafterweise 0°C bis 60°C.The reaction takes place in suitable solvents such as ethers, e.g. B. dioxane, diisopropyl ether, Esters, e.g. B. ethyl acetate, halogenated hydrocarbons, e.g. B. methylene chloride, Chloroform, nitrated hydrocarbons, e.g. B. nitromethane, 2-nitropropane or preferably 1- Nitropropane, or without solvent, with the addition of catalytic or even larger amounts Acid, such as mineral acids, e.g. B. tetrafluoroboric acid or in particular perchloric acid, or Sulphonic acids, especially methanesulphonic acid, at temperatures of advantageously 0 ° C to 60 ° C.

Die Umsetzung des 16-Hydroxyprednisolon-ketals der Formel 2 mit Cyclohexanaldehyd liefert normalerweise ein Epimerengemisch. Überraschenderweise wird erfindungsgemäß durch geeignete Reaktionsbedingungen die Umsetzung aber so gesteuert, dass das gewünschte und in Formel 1 angegebene R-Epimer (bezogen auf die absolute Konfiguration am C-22) bei der Verbindung 1 mit R = Wasserstoff (H) zu mindestens 90%, bevorzugt mindestens 95%, insbesondere mindestens 97% - bezogen auf die Gesamtausbeute - entsteht.The reaction of the 16-hydroxyprednisolone ketal of formula 2 with cyclohexanaldehyde provides usually a mixture of epimers. Surprisingly, according to the invention by suitable Reaction conditions controlled the implementation so that the desired and in Formula 1 specified R-epimer (based on the absolute configuration on the C-22) at the Compound 1 with R = hydrogen (H) at least 90%, preferably at least 95%, in particular at least 97% - based on the total yield - arises.

Zur überwiegenden Herstellung des R-Epimers werden beispielsweise folgende Bedingungen bevorzugt: Als Lösungsmittel halogenierte Kohlenwasserstoffe (wie Methylenchlorid oder Chloroform) oder nitrierte Kohlenwasserstoffe (wie Nitromethan, 2-Nitropropan oder bevorzugt 1-Nitropropan) und als Katalysator Methansulfonsäure (bei Temperaturen von 10°C bis 40°C) oder 35-70%ige, insbesondere 60-70%ige Perchlorsäure (bei Temperaturen von 0°C bis 40°C, vorzugsweise 15°C bis 30°C, insbesondere 20°C bis 25°C).The following conditions are used, for example, for the predominant production of the R epimer preferred: halogenated hydrocarbons as solvents (such as methylene chloride or chloroform)  or nitrated hydrocarbons (such as nitromethane, 2-nitropropane or preferably 1-nitropropane) and as a catalyst methanesulfonic acid (at temperatures from 10 ° C to 40 ° C) or 35-70%, in particular 60-70% perchloric acid (at temperatures from 0 ° C to 40 ° C, preferably 15 ° C to 30 ° C, especially 20 ° C to 25 ° C).

Sofern das R-Epimer in reinerer Form gewünscht wird, als dies aufgrund der Reaktionsbedingungen erzielbar ist, können der Umsetzung geeignete Trenn- und Reinigungsschritte - wie beispielsweise präparative HPLC, oder fraktionierte Kristallisation wie in der Internationalen Patentanmeldung WO 9809982 beschrieben - nachgeschaltet werden.If the R-epimer is desired in a purer form than because of the reaction conditions can be achieved, the implementation of suitable separation and cleaning steps - such as preparative HPLC, or fractional crystallization as in the international patent application WO 9809982 described - be connected.

Das folgende Beispiel dient der näheren Erläuterung der Erfindung: The following example serves to explain the invention in more detail:  

Beispielexample 1. 16,17-[(Cyclohexylmethylen)bis(oxy)]-11,21-dihydroxy-pregna-1,4-dien-3,20-dion[11β,16α(R)]1. 16.17 - [(cyclohexylmethylene) bis (oxy)] - 11,21-dihydroxy-pregna-1,4-diene-3,20-dione [11β, 16α (R)]

20 g Desonide werden in 70 ml 1-Nitropropan suspendiert und unter Eiskühlung langsam mit 12,6 ml 70%iger Perchlorsäure und 6,6 g Cyclohexanaldehyd versetzt. Die Reaktionsmischung wird über Nacht bei Raumtemperatur gerührt und dann filtriert. Der Filterkuchen wird in 90 ml DMF gelöst und unter. Rühren in Natriumhydrogencarbonatlösung getropft. Der Niederschlag wird abgesaugt, mit Wasser gewaschen und getrocknet. Man erhält 19 g der Titelverbindung mit einem Epimerenverhältnis R/S von 97,8/2,2.20 g desonides are suspended in 70 ml 1-nitropropane and slowly with ice cooling with 12.6 ml 70% perchloric acid and 6.6 g of cyclohexanaldehyde were added. The reaction mixture is over Stirred at room temperature overnight and then filtered. The filter cake is dissolved in 90 ml DMF and under. Stir in sodium bicarbonate solution. The precipitate is suctioned off with Washed water and dried. 19 g of the title compound with an epimer ratio are obtained R / S of 97.8 / 2.2.

Claims (9)

1. Verfahren zur Herstellung der Verbindungen der Formel 1,
worin
R Wasserstoff (H) oder Isobutyryl [CO-CH(CH3)2] bedeutet,
in mindestens 90% R-epimerenreiner Form,
dadurch gekennzeichnet, dass man Verbindungen der Formel 2,
worin
R Wasserstoff (H) oder Isobutyryl [CO-CH(CH3)2] bedeutet,
R1 1-4C-Alkyl bedeutet und
R2 1-4C-Alkyl bedeutet,
mit Cyclohexanaldehyd umsetzt.1. Process for the preparation of the compounds of formula 1,
wherein
R denotes hydrogen (H) or isobutyryl [CO-CH (CH 3 ) 2 ],
in at least 90% pure R-epimer form,
characterized in that compounds of the formula 2,
wherein
R denotes hydrogen (H) or isobutyryl [CO-CH (CH 3 ) 2 ],
R1 denotes 1-4C-alkyl and
R2 is 1-4C-alkyl,
reacted with cyclohexanaldehyde. 2. Verfahren nach Anspruch 1, wobei R Wasserstoff (H) bedeutet.2. The method of claim 1, wherein R is hydrogen (H). 3. Verfahren nach Anspruch 1, wobei R Isobutyryl [CO-CH(CH3)2] bedeutet.3. The method of claim 1, wherein R is isobutyryl [CO-CH (CH 3 ) 2 ]. 4. Verfahren nach Anspruch 1, wobei R1 und R2 jeweils Methyl (CH3) bedeuten. 4. The method of claim 1, wherein R1 and R2 each represent methyl (CH 3 ). 5. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass als Losungsmittel ein halogenierter oder nitrierter Kohlenwasserstoff verwendet wird.5. The method according to claim 1, characterized in that a halogenated solvent or nitrated hydrocarbon is used. 6. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass als Katalysator Methansulfonsäure verwendet wird.6. The method according to claim 1, characterized in that the catalyst is methanesulfonic acid is used. 7. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass als Katalysator Perchlorsäure verwendet wird.7. The method according to claim 1, characterized in that perchloric acid as a catalyst is used. 8. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass bei Temperaturen zwischen 0°C und 40°C gearbeitet wird.8. The method according to claim 1, characterized in that at temperatures between 0 ° C and 40 ° C is worked. 9. Verfahren nach Anspruch 1 zur Herstellung der Verbindung der Formel 1, worin R Wasserstoff (H) bedeutet, in über 95% epimerenreiner Form, dadurch gekennzeichnet, dass man Verbindungen der Formel 2, worin R Wasserstoff (H), R1 Methyl (CH3) und R2 Methyl (CH3) bedeutet, mit Cyclohexanaldehyd unter Verwendung von Perchlorsäure als Katalysator bei Temperaturen zwischen 0°C und 40°C umsetzt.9. The method according to claim 1 for the preparation of the compound of formula 1, wherein R is hydrogen (H), in more than 95% epimeric form, characterized in that compounds of formula 2, wherein R is hydrogen (H), R1 is methyl (CH 3 ) and R2 means methyl (CH 3 ), reacted with cyclohexanaldehyde using perchloric acid as a catalyst at temperatures between 0 ° C. and 40 ° C.
DE2000155820 2000-11-10 2000-11-10 Preparation of 16,17-cyclohexylmethylene-dioxy-pregnadiene derivative, useful as glucocorticoid, by reacting 16,17-ketal with cyclohexylaldehyde to give high epimeric purity Expired - Lifetime DE10055820C1 (en)

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DE2000155820 DE10055820C1 (en) 2000-11-10 2000-11-10 Preparation of 16,17-cyclohexylmethylene-dioxy-pregnadiene derivative, useful as glucocorticoid, by reacting 16,17-ketal with cyclohexylaldehyde to give high epimeric purity

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007054974A2 (en) * 2005-09-28 2007-05-18 Arch Pharmalab Limited A green chemistry process for the preparation of pregnadiene esters
WO2008015696A2 (en) * 2006-05-23 2008-02-07 Cadila Healthcare Limited Process for preparing ciclesonide
CN106290695A (en) * 2015-06-25 2017-01-04 重庆华邦制药有限公司 Desonide and the separation of related impurities and assay method
US10668167B2 (en) 2016-06-02 2020-06-02 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
US10772970B2 (en) 2017-12-01 2020-09-15 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4129535A1 (en) * 1990-09-07 1992-03-12 Elmu Sa Novel PREGNA-1,4-DIEN-3,20-DION-16-17-ACETAL-21-ESTERS, METHOD FOR THE PREPARATION, COMPOSITION, AND METHODS OF TREATMENT
WO1994022899A1 (en) * 1993-04-02 1994-10-13 Byk Gulden Lomberg Chemische Fabrik Gmbh New prednisolone derivates
WO1998009982A1 (en) * 1996-09-03 1998-03-12 Byk Gulden Lomberg Chemische Fabrik Gmbh Process for r-epimer enrichment of 16,17-acetal derivatives of 21-acyloxy pregan-1,4-dien-11.beta.,16.alpha.,17.alpha.-triol-3,20-dione derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4129535A1 (en) * 1990-09-07 1992-03-12 Elmu Sa Novel PREGNA-1,4-DIEN-3,20-DION-16-17-ACETAL-21-ESTERS, METHOD FOR THE PREPARATION, COMPOSITION, AND METHODS OF TREATMENT
WO1994022899A1 (en) * 1993-04-02 1994-10-13 Byk Gulden Lomberg Chemische Fabrik Gmbh New prednisolone derivates
WO1998009982A1 (en) * 1996-09-03 1998-03-12 Byk Gulden Lomberg Chemische Fabrik Gmbh Process for r-epimer enrichment of 16,17-acetal derivatives of 21-acyloxy pregan-1,4-dien-11.beta.,16.alpha.,17.alpha.-triol-3,20-dione derivatives

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007054974A2 (en) * 2005-09-28 2007-05-18 Arch Pharmalab Limited A green chemistry process for the preparation of pregnadiene esters
WO2007054974A3 (en) * 2005-09-28 2007-08-30 Arch Pharmalab Ltd A green chemistry process for the preparation of pregnadiene esters
WO2008015696A2 (en) * 2006-05-23 2008-02-07 Cadila Healthcare Limited Process for preparing ciclesonide
WO2008015696A3 (en) * 2006-05-23 2008-05-29 Cadila Healthcare Ltd Process for preparing ciclesonide
CN106290695A (en) * 2015-06-25 2017-01-04 重庆华邦制药有限公司 Desonide and the separation of related impurities and assay method
US10668167B2 (en) 2016-06-02 2020-06-02 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
US10772970B2 (en) 2017-12-01 2020-09-15 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof

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