WO2008015696A2 - Procédé pour préparer le ciclésonide - Google Patents

Procédé pour préparer le ciclésonide Download PDF

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Publication number
WO2008015696A2
WO2008015696A2 PCT/IN2007/000206 IN2007000206W WO2008015696A2 WO 2008015696 A2 WO2008015696 A2 WO 2008015696A2 IN 2007000206 W IN2007000206 W IN 2007000206W WO 2008015696 A2 WO2008015696 A2 WO 2008015696A2
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WIPO (PCT)
Prior art keywords
ciclesonide
isomer
compound
acetal intermediate
preferably less
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PCT/IN2007/000206
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English (en)
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WO2008015696A3 (fr
Inventor
Sanjog Ramdharane
Manoj Kumar Singh
Gautam Pal
Malav Gautambhai Shah
Soumitra Banerjee
Ashish Kumar Sarkar
Anant Kumar Manilal Patel
Virendra Kumar Agrawal
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Cadila Healthcare Limited
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Publication of WO2008015696A2 publication Critical patent/WO2008015696A2/fr
Publication of WO2008015696A3 publication Critical patent/WO2008015696A3/fr

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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
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17

Definitions

  • the present invention relates to process for preparing Ciclesonide or its pharmaceutically acceptable salts, solvates.
  • Ciclesonide which is the generic name for the compound of formula (I), (R)-I lbeta,16alpha,17,21-Tetrahydroxypregna-l,4-diene- 3,20-dione cyclic 16,17-acetal with cyclohexanecarboxaldehyde, 21-isobutyrate.
  • the present invention further provides substantially pure Ciclesonide.
  • the present invention further provides Ciclesonide substantially free from compounds of formula 4.
  • Ciclesonide is a non-halogenated corticosteroid prodrug with anti-inflammatory activity delivered via a metered-dose inhaler (MDI), as a treatment for asthma.
  • MDI metered-dose inhaler
  • Inhaled synthetic glucocorticosteroids are widely used in the therapy of bronchial asthma, for which they are the most effective agents available, particularly in patients with persistent mild-to-moderate disease.
  • Regular treatment with inhaled glucocorticoids improves asthma control and lung function, and reduces asthma exacerbations.
  • This improvement in asthma control is associated with attenuation of markers of airway inflammation, such as airway responsiveness to provocative stimuli, sputum eosinophilia and exhaled nitric oxide (NO) concentration.
  • Poor patient compliance is a perennial problem with prophylactic anti-asthma drugs, and inhaled glucocorticoids suffer particularly from this.
  • inhaled steroids A further obstacle to the use of inhaled steroids is the occasional occurrence of local side effects, such as dysphonia and oral candidiasis, and of more serious systemic effects, such as suppression of the hypothalamo-pituitary-adrenal (HPA) axis.
  • HPA hypothalamo-pituitary-adrenal
  • New drugs have, therefore, been developed with the aim of minimizing systemic actions of inhaled steroids by increasing the ratio of local to systemic availability. Drugs that have very low bioavailability but achieve high local concentrations at the site of topical application are most suitable, and the synthesis of steroids that meet this requirement was the subject of the research program at Recordati Elmu SL that produced ciclesonide.
  • Ciclesonide is a non-halogenated inhaled steroid ester prodrug that is metabolized intracellularly to form the active drug, which binds to cytoplasmic glucocorticoid receptors.
  • a chiral center exists in the cyclic aldehyde group: the R stereoisomer is preferred and currently on the market.
  • Ciclesonide exhibits anti- inflammatory actions in vivo that are comparable to those of budesonide, and it has been studied for potential therapeutic efficacy in allergic rhinitis, asthma and chronic obstructive pulmonary disease (COPD).
  • Ciclesonide was first time reported in US patent no. 5,482,934 and exist in two diastereoisomeric forms as R epimer (I) and S epimer (II) as shown in below formula:
  • Ciclesonide is reported to be pharmaceutically acceptable with diastereoisomer containing R-configuration at C-22 position.
  • the enrichment of S-isomer is reported up to 99% by chromatographic method using Cl 8 Lichrosorb column as stationary phase and eluting by ethanol / water mixture.
  • the elution using such aqueous phases as eluent is commercially not viable at large scale.
  • US patent no 5,733,901 discloses the process for preparing pure form of R isomer of Ciclesonide by selective cystallization followed by chromatographic purification. The result indicates the purer form achieved by the process in the epimer ratio of R isomer: S isomer is
  • US Patent No. 6,787,533 discloses the process for obtaining other approach to obtain enriched R isomer of Ciclesonide by repeated fractionally crystallization.
  • the fractional crystallization involves dissolving the R/S-epimer mixture of the Ciclesonide in a suitable, water-miscible organic solvent, expediently at elevated temperature, in particular at the boiling point of the solvent used.
  • the subsequent addition of water is expediently carried out with stirring and whilst maintaining the elevated temperature, in particular at the boiling point; after the water has been added, the mixture is cooled, preferably to room temperature, with vigorous stirring in order to obtain as finely crystalline a product as possible.
  • Chiral separation is always a big challenge for the scientists worldwide.
  • one enantiomer or diastereoisomer is frequently more active or has fewer side effects than the other.
  • Obtaining the desired-enantiomer or diastereoisomer as selectively as possible and as pure as possible is therefore of great importance in the case of chirally active molecules.
  • U.S Patent No. 6,787,533 reports preparation of ciclesonide with a mixture of approximately 90% R-isomer and approximately 10% S-isomer at C-22 position. The mixture further undergoes to repeated fractional crystallization with water and water miscible organic solvents. Crystallization method as reported in US 6,787,533 accomplished by using repeated crystallization in water/ethanol mixture to enhance the (22-R)-isomer up to 99% from 90% by sacrificing 50% of yield. Thus to enhance the (22-R)-isomer content by 10% there is a substantial loss of approximately 50% of product. Further, U.S Patent No.
  • 5,733,901 discloses the separation of both the isomers of (ll ⁇ , 16 ⁇ ) -16,17-[(cyclohexylmethylene)bis(oxy)]-l l,21-dihydroxy-l,4- pregnadiene-3,20-dione (2) at 200mg scale, by preparative HPLC, using Hypersil C18, 12 ⁇ m column of 250 x 20 mm dimensions.
  • Sample solution is prepared with 20 times dilution in a mixture of DMSO : Ethanol (3 : 19), and elution takes place with a mixture of water (59%) and ethanol (41%), to get both the isomers independently in more than 99% of isomeric purity at C-22 position.
  • the separation method mentioned in the above patents is using reverse phase eluting system and is not suitable for the commercialisation at plant scale.
  • the separation of both the isomers of acetal intermediate (2) are performed in view to use it for batch process of preparative HPLC chromatography, super-critical or sub-critical chromatography and / or continuous preparative separations such as simulated moving bed, etc to get single isomers at C-22 position and free from other impurities.
  • the amount of other epimers in its pure isomer at C-22 is to be preferably less than 1.0% and more preferably below detection limit.
  • one stereoisomer for example an epimer, is often more effective or associated with fewer side effects than the other.
  • Ciclesonide of formula (I) It is an object of the present invention to provide a process for preparing Ciclesonide of formula (I).
  • Another object of the invention of the invention is to provide a process for preparing Ciclesonide of formula (I), substantially free form (S) isomer. Description of the invention
  • Ciclesonide is reported to be pharmaceutically acceptable with diastereoisomer containing R-configuration at C-22 position. Ciclesonide is first reported in US 5,482,934 as an equal mixture of R and S diastereoisomers at C-22 position. The enrichment of S-isomer is reported up to 99% by chromatographic method using Cl 8 Lichrosorb column as stationary phase and eluting by ethanol / water mixture. The isolation of product from aqueous eluent is commercially not viable at large scale.
  • the ciclesonide synthesis is reported in approximately 50% to 90% of pharmacologically acceptable (22-R)-isomer; hence there is a requirement of purification of ciclesonide substantially free from (22-S)-isomer below 1.0% to below detection limit.
  • Optically pure (R) Ciclesonide or optically pure (R) isomer of Ciclesonide or (R) isomer of Ciclesonide is substantially free of the (S)- isomer of Ciclesonide is meant to have content of (S)- isomer of Ciclesonide in (R) isomer of Ciclesonide less then 10%, preferably less then 5%, more preferably less then 1%, most preferably less then 0.5.
  • a process for increasing the proportion of R-isomer of Ciclesonide in R/S-isomer mixture of Ciclesonide which comprises subjecting the R/S-isomer mixture of Ciclesonide to chromatography using a chiral stationary phase.
  • a process for increasing the proportion of R-isomer of Ciclesonide in R/S-isomer mixture of Ciclesonide which comprises subjecting the R/S-isomer mixture of Ciclesonide to chromatography using a chiral stationary phase and concurrent removal of 22-S- Ciclesonide from 22-R-Ciclesonide, recovering 22-R-Ciclesonide by removing solvents and isolating substantially pure 22-R-Ciclesonide.
  • liquid chromatography or super or sub critical chromatography can be used by using a chiral stationary phase.
  • the chiral stationary phase may comprise an optically active high molecular compound, e.g. a polysaccharide derivative, such as esters or carbamates of cellulose or amylose, a polyacrylate derivative (e.g. a methacrylate derivative, such as poly(triphenylmethylmethacrylate)) or a polyamide derivative, a protein with an asymmetric or disymmetric chain (bovine serum albumin bonded to silica, cellulase covalently bonded to aldehyde silica), polymers with an asymmetric centre in its side chains etc.
  • a polysaccharide derivative such as esters or carbamates of cellulose or amylose
  • a polyacrylate derivative e.g. a methacrylate derivative, such as poly(triphenylmethylmethacrylate)
  • a polyamide derivative e.g. a protein with an
  • a chiral stationary phase comprising a low molecular compound having optical resolution capability, e.g. crown ethers ((S) or (R)-18-crown- 6-ether on silica) and cyclodextrin derivatives (alpha cyclodextrin bonded to silica).
  • chiral separation factors which may be comprised by the chiral stationary phase are amino acids and derivatives thereof, esters or amide of amino acids, acetylated amino acids and oligopeptides.
  • Still another possibility is a particulate polysaccharide material, e.g., macrocrystalline cellulose triacetate.
  • Chiral stationary phases including polysaccharide derivatives and polyamides useful for separation of enantiomers are described in EP 0 147 804, EP 0 155 637, EP 0 157 365, EP 0 238 044, WO 95/18833, WO 97/04011, EP 0656 333 and EP 718 625.
  • the chiral stationary phase comprises a carbohydrate derivative, more preferred a polysaccharide derivative and most preferred an amylose or cellulose derivative.
  • the polysaccharide adsorbed on the silica gel carry groups such as phenylcarbamoyl, 3,5-dimethyl- phenylcarbamoyl, 4-chlorophenylcarbamoyl, 3,5- dichloro-phenylcarbamoyl, acetyl, benzoyl, cinnamoyl, 4-methyl- benzoyl or S-alpha- phenylethyl carbamoyl.
  • groups such as phenylcarbamoyl, 3,5-dimethyl- phenylcarbamoyl, 4-chlorophenylcarbamoyl, 3,5- dichloro-phenylcarbamoyl, acetyl, benzoyl, cinnamoyl, 4-methyl- benzoyl or S-alpha- phenylethyl carbamoyl.
  • the carbohydrate derivative comprises phenyl carbamate substituents, which optionally may be substituted with one or more C, 4- alkyl groups, preferably methyl groups.
  • the chiral compound which is the chiral separating factor of the stationary phase, may suitably be adsorbed on a carrier, such as silica gel.
  • a carrier such as silica gel.
  • the chiral stationary phase is ChiralpakTM AD-H, a silica gel supported amylose derivative wherein the majority of the hydroxyl groups are substituted with 3,5-dimethylphenyl carbamate groups, or ChiralcelTM OD, a silica gel supported cellulose derivative wherein the majority of the hydroxyl groups are substituted with 3,5- dimethylphenyl carbamate groups.
  • ChiralpakTM AD-H and ChiralcelTM OD Exemplary of such chiral stationary phases is ChiralpakTM AD-H.
  • any liquid chromatographic separation method may be used for the separation of the diastearomers.
  • the chromatographic separation method comprises a continuous chromatographic technology, suitably simulated moving bed technology, preparative HPLC.
  • the eluent is typically selected from the group comprising acetonitrile, alcohols, such as methanol, ethanol or isopropanol, and C5-C8 alkanes which may be linear or branched aliphatic or cyclic alkanes and selected from cyclo pentane, cyclohexane, hexane, heptane, octane, and mixtures thereof.
  • An acid such as formic acid, acetic acid and trifluoroacetic acid and/or a base such as diethylamine, triethylamine, propylamine, isopropylamine and dimethyl- isopropyl-amine optionally may be added to the eluent.
  • super or sub critical carbon dioxide containing a modifier may be used as eluent.
  • the modifier is selected from lower alcohols such as methanol, ethanol, propanol and isopropanol.
  • An amine such as diethylamine, triethylamine, propylamine, isopropylamine and dimethyl-isopropyl-amine and optionally an acid, such as formic acid, acetic acid and trifluoroacetic acid may be added.
  • the chromatographic method used is a liquid chromatographic method.
  • a suitable eluent according to this embodiment of the invention is alcohol such as ethanol, isopropanol in mixture with alkanes such as cyclo pentane, cyclo hexane, hexane.
  • a suitable mixture contains alkanes 70% vol to 95% vol and alcohol 30% vol to 5%.
  • the present invention provides separation and subsequent removal of (S)- Ciclesonide from (R)-Ciclesonide to obtain (R)-Ciclesonide, substantially free from (S)-Ciclesonide on commercial scale thereby getting better isolated yield of (R)- Ciclesonide with desired HPLC purity, and thus avoiding substantial loss of the product in repeated crystallizations.
  • the present invention further provides substantially pure (R)-Ciclesonide.
  • Another embodiment of the invention encompasses methods to analyze (R)-
  • Ciclesonide purity comprising assaying (R)-Ciclesonide to determine the presence and an amount, if any, of (R)-Ciclesonide impurities.
  • Yet another embodiment of the invention encompasses methods to determine (R)-Ciclesonide stability comprising assaying (R)-Ciclesonide to determine the presence and amount, if any, of (R)- Ciclesonide impurities.
  • Yet another embodiment of the invention encompasses methods to analyze (R)-Ciclesonide purity, stability to degradation, or both comprising assaying a sample of (R)-Ciclesonide by HPLC, and determining the presence and/or amount of (R)-Ciclesonide impurities identified by an HPLC.
  • the present invention relates to analytical methods to determine the purity and level of impurities of (R)-Ciclesonide, which comprises assaying an amount of (R)- Ciclesonide; determining the presence of impurities; identifying the impurities including (S)-Ciclesonide; and quantifying the amount of impurities by an HPLC.
  • Amylose tris(3,5 ⁇ dimethylcarbamate) coated on 5 micron silica gel substrate is selected as chiral stationary phase for separation of 22-R- Ciclesonide and 22-S-Ciclesonide.
  • Mobile phase is a mixture of n-heptane and ethanol in varying proportions.
  • Flow rate is adjusted from 0.5mL per minute onwards. Detection is done at 244nm. Resolution factor of 4.0 is achieved between the peaks due to (R)-Ciclesonide and (S)-Ciclesonide and asymmetry of both the peaks is less than
  • Retention time of (R)-Ciclesonide varies between 9.2 -11.0 minutes and that of (S)-Ciclesonide is 12 - 13.4 minutes. Retention time of (R)-Ciclesonide and (S)- Ciclesonide is further adjusted as per the requirement by varying mobile phase composition and flow rate as described above.
  • the present invention further provides separation and subsequent removal of (22-S)-Isomer from (22-R)-isomer of acetal intermediate (2) to get (22-R)-isomer of acetal intermediate (2) substantially free from its epimers at C-22 position on commercial scale thereby getting better isolated yield of (22-R)-isomer at C-22 position of acetal (2) with desired HPLC purity, and thus avoiding substantial loss of the product in repeated crystallizations.
  • the present invention provides separation and subsequent removal of (22 -R)-
  • composition of mobile phase is such that after getting pure (22-R)-isomer or (22-S)-isomer in said mobile phase composition; solvent removal and subsequent product recovery are achieved by simple operations.
  • the separation of both the isomers of intermediate 2 are performed in view to use it for batch process of preparative HPLC chromatography super-critical or sub-critical chromatography and/or continuous preparative separations such as simulated moving bed, etc to get (22-R)-2 substantially free from (22-S)-2.
  • the amount of (22-S)-2 present in (22-R)-2 is to be preferably less than 1.0% and more preferably below detection limit.
  • the separation of both the isomers of intermediate 2 are performed in view to use it for batch process of preparative HPLC chromatography, super-critical or sub-critical chromatography and / or continuous preparative separations such as simulated moving bed, etc to get (22-S)-2 substantially free from (22-R)-2.
  • the amount of (22-R)-2 present in (22-S)-2 is to be preferably less than 1.0% and more preferably below detection limit.
  • Amylose tris(3,5-dimethylcarbamate) coated on 5 micron silica gel substrate is selected as chiral stationary phase for separation of (22- R)-2 and (22-S)-2.
  • Mobile phase is a mixture of n-hexane and ethanol in varying proportions. Flow rate is adjusted from 0.5mL per minute onwards. Detection is done at 244nm. Retention time of (22-R)-2 varies between 18.1 - 20.4 minutes and that of (22- S)-2 is 24.6 - 26.44 minutes. Retention time of (22-R)-2 and (22-S)-2 is further adjusted as per the requirement by varying mobile phase composition and flow rate as described above.
  • Phenomenex Cl 8 column is selected as achiral stationary phase for separation of (22-R)-2 and (22-S)-2.
  • Mobile phase is a mixture of 0.1% TFA in water and 0.1% TFA in acetonitrile in varying proportions.
  • Flow rate is adjusted from 0.5mL per minute onwards. Detection is done at 243nm.
  • Retention time of (22-R)-2 varies between 19.1 - 21.5 minutes and that of (22-S)-2 is 20.5 - 23.1 minutes.
  • Retention time of (22-R)-2 and (22-S)-2 is further adjusted as per the requirement by varying mobile phase composition and flow rate as described above.
  • another objective of the present invention relates to the separation of both the isomers of 2 at C-22 position by using achiral stationary phase for batch process of preparative FIPLC chromatography, super-critical or sub-critical chromatography and / or continuous preparative separations such as simulated moving bed, etc to get (22-R)-2 and (22-S)-2 independently in their pure form and free from each other epimers.
  • optically pure (22-R)-cicIesonide or optically pure (22-R)- isomer of ciclesonide is meant the (22-R)-isomer of ciclesonide is substantially free of the (22-S)-isomer of ciclesonide.
  • Optically pure (22-R)-ciclesonide or optically pure (22-R)-isomer of ciclesonide is substantially free of the (22-S)-isomer of ciclesonide is meant to have content of (22-S)-isomer of ciclesonide in (22-R)-isomer of ciclesonide less than 10%, preferably less than 1%, more preferably less than 0.5% and most preferably less than below detection limits.
  • a process for increasing the proportion of (22-R)-isomer of acetal intermediate (2) in its R/S-isomer mixture which comprises subjecting the R/S-isomer mixture of acetal intermediate (2) to chromatography using a chiral and/or achiral stationary phases.
  • the chirally pure single isomer of acetal intermediate (2) further undergoes to the acylation with to afford pure ciclesonide as the single isomer and substantially free from its epimers at C-22 position.
  • the chiral stationary phase may comprise an optically active high molecular compound, e.g. a polysaccharide derivative, such as esters or carbamates of cellulose or amylose, a polyacrylate derivative (e.g.
  • a methacrylate derivative such as poly(triphenylmethylmethacrylate)) or a polyamide derivative
  • a protein with an asymmetric or disymmetric chain bovine serum albumin bonded to silica, cellulase covalently bonded to aldehyde silica
  • a chiral stationary phase comprising a low molecular compound having optical resolution capability, e.g. crown ethers ((S) or (R)-18-crown- 6-ether on silica) and cyclodextrin derivatives (alpha cyclodextrin bonded to silica).
  • chiral separation factors which may be comprised by the chiral stationary phase, are amino acids and derivatives thereof, esters or amide of amino acids, acetylated amino acids and oligopeptides.
  • present invention relates to an efficient process for the preparation of ciclesonide in its pure form and free from its epimers at C-22 position.
  • acetal intermediate (2) is isolated in its pure form with its epimers at C-22 position less than 7%, preferably less than 1%, more preferably less than 0.5% and most preferably below quantification limits.
  • the pure and single isomer of acetal intermediate (2) undergoes condensation with isobutyric anhydride at C-21 hydroxy group, in the presence of a base to afford ciclesonide as a pure and single isomer at C-22 position and free from its epimers.
  • the contents of the other epimers in pure form of single isomer of ciclesonide at C-22 position is less than 10%, preferably less than 1%, more preferably less than 0.5% and most preferably below quantification limits.
  • the present invention also relates to the process for the preparation of 22-R-ciclesonide as a single isomer, according to process, intermediate (22-R)-2 is isolated in its pure form with (22-S)-2 less than 10%, preferably less than 1%, more preferably less than 0.5% and most preferably below quantification limits.
  • the pure and single isomer of acetal intermediate (22-R)-2 undergoes condensation with isobutyric anhydride at C-21 hydroxy group, in the presence of a base to afford (22-R)-ciclesonide as a pure and single isomer at C-22 position and free from (22-S)-ciclesonide.
  • the contents of the (22-S)-ciclesonide in pure form of single isomer of (22-R)-ciclesonide at C-22 position is less than 10%, preferably less than 1%, more preferably less than 0.5% and most preferably below quantification limits.
  • intermediate (22-S)-2 is isolated in its pure form with (22-R)-2 less than 10%, preferably less than 1%, more preferably less than 0.5% and most preferably below quantification limits.
  • the pure and single isomer of acetal intermediate (22-S)-2 undergoes condensation with Isobutyric anhydride at C-21 hydroxy group, in the presence of a base to afford (22-S)-ciclesonide as a pure and single isomer at C-22 position and free from (22 -R)- ciclesonide.
  • the contents of the (22-R)-ciclesonide in pure form of single isomer of (22-S)-ciclesonide at C-22 position is less than 10%, preferably less than 1%, more preferably less than 0.5% and most preferably below quantification limits.
  • cyclohexane carboxylic acid present in trace amount also reacts with C-21 hydroxy groups in 16 ⁇ -hydroxyprednisolone (1), to form a new derivative of pregna-l,4-diene- 3,20-dione, which is characterized by IH-NMR, 13C-NMR and Mass as the compound of structural formula 4.
  • the structure of compound 4 is further established by its synthesis by the reaction of acetal intermediate (2) with cyclohexane carboxylic anhydride in presence of a base in a suitable solvent.
  • the present invention relates to the novel derivative of pregna-l,4-diene-3,20-dione of structural formula 4, and a process for the preparation of same.
  • the present invention further provides the process for the preparation of ( 11 ⁇ , 16 ⁇ )- 16, 17-[[(R)-cyclohexylmethylene]bis(oxy)]- 11 -hydroxy-21 -(2-methyl- 1 - oxopropoxy)pregna-l,4-diene-3,20-dione of formula (I), substantially free from compound of structural formula 4, preferably less than 1.0%, preferably less than 0.1%, more preferably less than 0.05% and more preferably below quantification limits.
  • Another objective of the present invention relates to the preparation of acetal intermediate 2 substantially free from compound of structural formula 4, preferably less than 1.0% more preferably less than 0.1% and most preferably below quantification limits.
  • the inventors of the present invention has observed that an acetal intermediate (2) with cyclohexane carboxylic acid in presence of 70% perchloric acid and found the enrichment of compound of structural formula (4) as a major related substance in acetal intermediate (2).
  • the present invention provides a process for removal of traces of cyclohexane carboxylic acid from acetal intermediate 2, by washing with suitable solution of a base and then treating the washed solution with isobutyric anhydride to achieve ciclesonide free from related substance 4, preferably less than 1.0%, more preferably less than 0.1% and most preferably below quantification limits.
  • the inventors of the present invention have surprisingly found that when acetal intermediate is treated with cyclohexane carboxylic acid in presence of basic condition in acetone, only a little trace of formation of compound 4 is observed in the reaction mixture.
  • acetal intermediate 2 is completely converted to compound 4 when cyclohexane carboxylic anhydride is used instead of cyclohexane carboxylic acid.
  • the next objective of the present invention relates to the removal of cyclohexane carboxylic acid from the acetal intermediate 2 by washing with suitable base and then reacting intermediate 2 with isobutyric anhydride in presence of a base in a suitable solvent to achieve ciclesonide free from related substance 4, preferably less than 1.0%, more preferably less than 0.1% and more preferably below quantification limits.
  • the term "about” indicates variations in the measured quantity as would be expected by the skilled artisan making the measurements or determination and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring apparatus being used.
  • Ciclesonide having approximately 62% (R)-Ciclesonide and 38% (S)-Ciclesonide in n-heptane and ethanol in the ratio of 93% and 7% respectively was injected on CHIRALPAK AD-H and the mobile phase composition is same throughout analysis with flow rate 1.0 mL per minute with detection at 244nm, (R)-Ciclesonide eluted at 9.21 minute and (S)-Ciclesonide at 11.93 minute and resolution between two peaks is approximately 4. Asymmetry of both the peaks is less than 1.5.
  • Example - 2
  • Ciclesonide having approximately 62% (R)-Ciclesonide and 38% (S)-Ciclesonide in n-heptane and ethanol in the ratio of 85% and 15% respectively was injected on CHIRALPAK AD-H and the mobile phase composition is same throughout analysis with flow rate 0.5 mL per minute with detection at 244nm, (R)-Ciclesonide eluted at 11.02 minute and (S)-Ciclesonide at 13.42 minute and resolution between two peaks is approximately 4.3. Asymmetry of both the peaks is less than 1.5.
  • Example - 3 Separation of Diastereoisomers of 2 using chiral stationary phase 500 ppm of 2 having approximately 90% (22-R)-2 and 10% (22-S)-2 in n- hexane and ethanol in the ratio of 85% and 15% respectively was injected on CHIRALPAK AD-H and the mobile phase composition is same throughout analysis with flow rate 0.5 mL per minute with detection at 244nm, (22-R)-2 eluted at 19.62 minute and (22-S)-2 at 25.06 minute.
  • Example - 4 Example - 4
  • Example - 7 Preparation of acetal intermediate (2) with Enriched Compound (4) In a 250 mL R. B. Flask acetal intermediate 2 (5.0 g) was dissolved in dichloromethane (200 mL); and 70% perchloric acid (4.6g, 3.0 eq.) and cyclohexane carboxylic acid (1.63g, 1.2 eq.) were added to the solution.

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Abstract

L'invention concerne un procédé pour réaliser un enrichissement énantiomérique du (R)-ciclésonide. Le procédé comprend l'opération consistant à adresser un mélange de (R)-ciclésonide : (S)-ciclésonide à une chromatographie utilisant une phase stationnaire chirale.
PCT/IN2007/000206 2006-05-23 2007-05-22 Procédé pour préparer le ciclésonide WO2008015696A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IN785/MUM/2006 2006-05-23
IN785MU2006 2006-05-23
IN1093MU2006 2006-07-10
IN1093/MUM/2006 2006-07-10
IN1196MU2006 2006-07-28
IN1196/MUM/2006 2006-07-28

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WO2008015696A3 WO2008015696A3 (fr) 2008-05-29

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008035066A3 (fr) * 2006-09-19 2009-02-26 Cipla Ltd Méthodes de préparation de ciclésonide et sa modification cristalline
WO2010054158A2 (fr) * 2008-11-07 2010-05-14 Auspex Pharmaceuticals, Inc. Modulateurs stéroïdiens du récepteur des glucocorticoïdes
JP2011513469A (ja) * 2008-03-13 2011-04-28 ファルマビオス ソシエタ ペル アチオニ プレグナン誘導体の製造法
WO2013124395A1 (fr) 2012-02-23 2013-08-29 Boehringer Ingelheim International Gmbh Nouveau procédé de préparation du ciclésonide
CN106883283A (zh) * 2015-12-15 2017-06-23 天津金耀集团有限公司 环索奈德一水合物及其晶型与制备方法
CN107778343A (zh) * 2016-08-30 2018-03-09 天津太平洋制药有限公司 一种环索奈德的制备方法
CN109293730A (zh) * 2018-10-23 2019-02-01 山东泰华生物科技股份有限公司 一种环索奈德的制备方法
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
CN113117653A (zh) * 2021-04-19 2021-07-16 中国科学院兰州化学物理研究所 一种羧酸改性环糊精手性色谱固定相材料的制备和应用

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WO2008035066A3 (fr) * 2006-09-19 2009-02-26 Cipla Ltd Méthodes de préparation de ciclésonide et sa modification cristalline
US8158780B2 (en) 2006-09-19 2012-04-17 Cipla Limited Processes for the preparation of ciclesonide and its crystal modification
AU2007298770B2 (en) * 2006-09-19 2013-01-31 Cipla Limited Processes for the preparation of ciclesonide and its crystal form
JP2011513469A (ja) * 2008-03-13 2011-04-28 ファルマビオス ソシエタ ペル アチオニ プレグナン誘導体の製造法
WO2010054158A2 (fr) * 2008-11-07 2010-05-14 Auspex Pharmaceuticals, Inc. Modulateurs stéroïdiens du récepteur des glucocorticoïdes
WO2010054158A3 (fr) * 2008-11-07 2010-08-19 Auspex Pharmaceuticals, Inc. Modulateurs stéroïdiens du récepteur des glucocorticoïdes
WO2013124395A1 (fr) 2012-02-23 2013-08-29 Boehringer Ingelheim International Gmbh Nouveau procédé de préparation du ciclésonide
CN106883283A (zh) * 2015-12-15 2017-06-23 天津金耀集团有限公司 环索奈德一水合物及其晶型与制备方法
US10668167B2 (en) 2016-06-02 2020-06-02 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
CN107778343A (zh) * 2016-08-30 2018-03-09 天津太平洋制药有限公司 一种环索奈德的制备方法
US10772970B2 (en) 2017-12-01 2020-09-15 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
CN109293730A (zh) * 2018-10-23 2019-02-01 山东泰华生物科技股份有限公司 一种环索奈德的制备方法
CN113117653A (zh) * 2021-04-19 2021-07-16 中国科学院兰州化学物理研究所 一种羧酸改性环糊精手性色谱固定相材料的制备和应用
CN113117653B (zh) * 2021-04-19 2022-03-25 中国科学院兰州化学物理研究所 一种羧酸改性环糊精手性色谱固定相材料的制备和应用

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