ITMI20090016A1 - PROCESS FOR THE PREPARATION OF CICLESONIDE - Google Patents
PROCESS FOR THE PREPARATION OF CICLESONIDE Download PDFInfo
- Publication number
- ITMI20090016A1 ITMI20090016A1 IT000016A ITMI20090016A ITMI20090016A1 IT MI20090016 A1 ITMI20090016 A1 IT MI20090016A1 IT 000016 A IT000016 A IT 000016A IT MI20090016 A ITMI20090016 A IT MI20090016A IT MI20090016 A1 ITMI20090016 A1 IT MI20090016A1
- Authority
- IT
- Italy
- Prior art keywords
- compound
- formula
- methanol
- epimeric
- ciclesonide
- Prior art date
Links
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 title claims description 27
- 229960003728 ciclesonide Drugs 0.000 title claims description 27
- 238000000034 method Methods 0.000 title claims description 27
- 238000002360 preparation method Methods 0.000 title claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 96
- 239000000203 mixture Substances 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000002955 isolation Methods 0.000 claims description 4
- 150000008282 halocarbons Chemical group 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000013517 stratification Methods 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 2
- 238000001640 fractional crystallisation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000005605 isobutyric acids Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- NJCJHGJZWVIYPY-ACXQXYJUSA-N [2-[(8s,9s,10r,13s,14s,17s)-10,13-dimethyl-3-oxo-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 NJCJHGJZWVIYPY-ACXQXYJUSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
†PROCESSO PER LA PREPARAZIONE DI CICLESONIDE†⠀ PROCESS FOR THE PREPARATION OF CYCLESONIDE⠀
DESCRIZIONE DESCRIPTION
La presente invenzione riguarda un processo per la preparazione di ciclesonide e, più in particolare, riguarda un processo di arricchimento epimerico per la preparazione di ciclesonide. The present invention relates to a process for the preparation of ciclesonide and, more particularly, it relates to an epimeric enrichment process for the preparation of ciclesonide.
Il composto di formula The compound of formula
O OR
O OR
O OR
H O I HAVE
OHO OHO
O OR
à ̈ un farmaco ad attività antinfiammatoria, noto con la denominazione comune internazionale ciclesonide, usato per via inalatoria nel trattamento dell’asma. Ciclesonide à ̈ l’epimero 22R. It is a drug with anti-inflammatory activity, known by the international common name ciclesonide, used by inhalation in the treatment of asthma. Ciclesonide is the 22R epimer.
I processi noti in letteratura per la preparazione di ciclesonide portano all’ottenimento di una miscela di epimeri R/S. E’ quindi necessario arricchire la miscela epimerica per ottenere ciclesonide con un contenuto di epimero 22S conforme, generalmente inferiore all’1%. The processes known in the literature for the preparation of ciclesonide lead to obtaining a mixture of R / S epimers. It is therefore necessary to enrich the epimeric mixture to obtain ciclesonide with a compliant 22S epimer content, generally lower than 1%.
US5482934 (Elmu SA) e US5733901 (Byk Gulden) descrivono la separazione degli epimeri di ciclesonide o di suoi analoghi per HPLC preparativa. US5482934 (Elmu SA) and US5733901 (Byk Gulden) describe the separation of ciclesonide epimers or its analogues by preparative HPLC.
US5728826 (Byk Gulden) descrive un processo per preparare ciclesonide che comprende l’arricchimento epimerico di una miscela R/S di silil derivati di ciclesonide per cristallizzazione frazionata fino ad ottenere un rapporto R/S>99/1. US5728826 (Byk Gulden) describes a process for preparing ciclesonide which comprises the epimeric enrichment of an R / S mixture of silyl derivatives of ciclesonide by fractional crystallization until an R / S ratio> 99/1 is obtained.
WO98/09982 (Byk Gulden) descrive l’arricchimento epimerico di ciclesonde per cristallizzazione frazionata da una miscela di acqua ed un solvente organico miscibile in acqua, in particolare etanolo. Partendo da miscele epimeriche R/S=90/10 si ottiene ciclesonide con rapporto epimerico R/S>99,5/0,5 dopo quattro cristallizzazioni. WO98 / 09982 (Byk Gulden) describes the epimeric enrichment of cyclesondes by fractional crystallization from a mixture of water and a water-miscible organic solvent, in particular ethanol. Starting from epimeric mixtures R / S = 90/10, ciclesonide is obtained with epimeric ratio R / S> 99.5 / 0.5 after four crystallizations.
WO2007/056181 (Sicor Inc.) descrive un metodo per aumentare il rapporto epimerico di ciclesonide per cristallizzazione da una soluzione di ciclesonide in uno o più solventi organici immiscibili con acqua. Per ottenere ciclesonide con rapporto epimerico 99,75/0,25 a partire da una miscela R/S=90/10 sono necessarie quattro cristallizzazioni. WO2007 / 056181 (Sicor Inc.) discloses a method of increasing the epimeric ratio of ciclesonide by crystallization from a solution of ciclesonide in one or more water-immiscible organic solvents. Four crystallizations are required to obtain ciclesonide with an epimeric ratio of 99.75 / 0.25 starting from a mixture R / S = 90/10.
WO2007/092574 (Sicor Inc.) descrive un metodo per aumentare il rapporto epimerico R/S di ciclesonide che consiste nel dissolvere ciclesonide in acetone scaldando a riflusso ed aggiungendo isottano mantenendo la soluzione a 90°C per poi raffreddare gradualmente. La procedura viene ripetuta quattro volte per ottenere ciclesonide con un rapporto epimerico R/S=99,75/0,25 partendo da una miscela R/S=90/10. WO2007 / 092574 (Sicor Inc.) describes a method for increasing the epimeric R / S ratio of ciclesonide which consists in dissolving ciclesonide in acetone by refluxing and adding isoctane while maintaining the solution at 90 ° C and then gradually cooling. The procedure is repeated four times to obtain ciclesonide with an epimeric ratio R / S = 99.75 / 0.25 starting from a mixture R / S = 90/10.
WO2008/015696 (Cadila Healthcare Ltd.) descrive un processo di preparazione di ciclesonide sostanzialmente priva di epimero S per trattamento cromatografico di una miscela R/S usando una fase stazionaria chirale. WO2008 / 015696 (Cadila Healthcare Ltd.) discloses a process of preparing substantially S epimer-free ciclesonide for chromatographic treatment of an R / S mixture using a chiral stationary phase.
Non à ̈ stato finora descritto in letteratura un metodo semplice e di facile applicazione industriale che consenta di ottenere ciclesonide in rapporto epimerico R/S superiore a 99/1. A simple and easy industrial application method which allows to obtain ciclesonide with an epimeric R / S ratio higher than 99/1 has not been described in the literature up to now.
Abbiamo ora sorprendentemente trovato che ciclesonide può essere ottenuta in forma epimerica R sostanzialmente pura per arricchimento di una miscela epimerica R/S di un composto di formula We have now surprisingly found that ciclesonide can be obtained in the epimeric form R substantially pure by enrichment of an epimeric mixture R / S of a compound of formula
OCOCH3OCOCH3
O OR
H O I HAVE
O OR
H(I) H (I)
O O O O
Costituisce pertanto oggetto della presente invenzione un processo per l’ottenimento di ciclesonide in forma epimerica R sostanzialmente pura che comprende il trattamento di una miscela epimerica R/S del composto di formula (I) con metanolo, l’isolamento del composto di formula (I) in forma epimerica R sostanzialmente pura, l’idrolisi del composto di formula (I) per rimuovere il gruppo acetile e la successiva esterificazione a ciclesonide per trattamento con un adatto derivato dell’acido isobutirrico. Therefore, the object of the present invention is a process for obtaining ciclesonide in substantially pure epimeric form R which comprises the treatment of an epimeric mixture R / S of the compound of formula (I) with methanol, the isolation of the compound of formula (I) in the epimeric form R substantially pure, the hydrolysis of the compound of formula (I) to remove the acetyl group and the subsequent esterification to ciclesonide by treatment with a suitable derivative of isobutyric acid.
Il composto di formula (I) à ̈ noto ed à ̈ stato descritto nel già citato US5482934. Il suo uso come intermedio per la preparazione di ciclesonide non à ̈ mai stato descritto in letteratura e costituisce pertanto un ulteriore oggetto della presente invenzione. The compound of formula (I) is known and has been described in the aforementioned US5482934. Its use as an intermediate for the preparation of ciclesonide has never been described in the literature and therefore constitutes a further object of the present invention.
Ulteriore oggetto della presente invenzione à ̈ un processo per l’arricchimento epimerico di miscele R/S del composto di formula (I) per trattamento con metanolo. A further object of the present invention is a process for the epimeric enrichment of R / S mixtures of the compound of formula (I) by treatment with methanol.
Nel presente contesto, in forma epimerica R sostanzialmente pura significa un composto con un rapporto epimerico R/S > 99/1. In the present context, in the epimeric form substantially pure R means a compound with an epimeric ratio R / S> 99/1.
L’aspetto caratterizzante della presente invenzione à ̈ rappresentato dalla possibilità di arricchire miscele epimeriche del composto di formula (I) per semplice trattamento con metanolo. The characterizing aspect of the present invention is represented by the possibility of enriching epimeric mixtures of the compound of formula (I) by simple treatment with methanol.
Il trattamento con metanolo consiste nella sospensione del composto di formula (I) in metanolo sotto agitazione ad una temperatura tra 15 e 35°C, preferibilmente tra 20 e 25°C per 0,5-3 ore. The treatment with methanol consists in the suspension of the compound of formula (I) in methanol under stirring at a temperature between 15 and 35 ° C, preferably between 20 and 25 ° C for 0.5-3 hours.
La sospensione può essere preparata trattando direttamente il composto di formula (I) solido con metanolo: in alternativa, la sospensione può essere preparata a partire da una soluzione concentrata del composto di formula (I) in un solvente organico in cui il composto di formula (I) à ̈ solubile, preferibilmente un idrocarburo alogenato, ancor più preferibilmente cloruro di metilene, per aggiunta di metanolo ed allontanamento del solvente organico. Inoltre, la sospensione del composto di formula (I) di cui si vuole aumentare il contenuto di epimero R può essere ottenuta per concentrazione delle acque madri metanoliche derivanti da precedenti trattamenti di arricchimento secondo la presente invenzione. The suspension can be prepared by directly treating the solid compound of formula (I) with methanol: alternatively, the suspension can be prepared starting from a concentrated solution of the compound of formula (I) in an organic solvent in which the compound of formula ( I) It is soluble, preferably a halogenated hydrocarbon, even more preferably methylene chloride, by addition of methanol and removal of the organic solvent. Furthermore, the suspension of the compound of formula (I) whose epimer R content is to be increased can be obtained by concentration of the methanolic mother liquors deriving from previous enrichment treatments according to the present invention.
Attraverso il processo oggetto della presente invenzione à ̈ possibile ottenere con due soli trattamenti con metanolo il composto di formula (I) in forma epimerica R sostanzialmente pura a partire da una miscela epimerica R/S=90/10. Lo stesso risultato si ottiene con tre soli trattamenti partendo da una miscela epimerica R/S=85/15. Through the process object of the present invention it is possible to obtain with only two treatments with methanol the compound of formula (I) in substantially pure epimeric form R starting from an epimeric mixture R / S = 90/10. The same result is obtained with just three treatments starting from an epimeric mixture R / S = 85/15.
L’elevata efficienza del processo oggetto della presente invenzione consente anche di arricchire miscele epimeriche R/S≤1/1, ad esempio le miscele epimeriche contenute nelle acque madri di un precedente trattamento di arricchimento. The high efficiency of the process object of the present invention also makes it possible to enrich R / Sâ ‰ ¤1 / 1 epimeric mixtures, for example the epimeric mixtures contained in the mother liquors of a previous enrichment treatment.
Il composto di formula (I) in forma epimerica R sostanzialmente pura viene poi trasformato in ciclesonide con la stessa purezza epimerica per idrolisi alcalina del gruppo acetossi e successiva riesterificazione con un derivato reattivo dell’acido isobutirrico. The compound of formula (I) in the substantially pure epimeric form R is then transformed into ciclesonide with the same epimeric purity by alkaline hydrolysis of the acetoxy group and subsequent reesterification with a reactive derivative of isobutyric acid.
Le elevate rese della reazione di idrolisi e di riesterificazione, unite al mantenimento della purezza epimerica ottenuta, rendono il processo oggetto della presente invenzione particolarmente vantaggioso dal punto di vista industriale rispetto ai metodo noti. The high yields of the hydrolysis and reesterification reaction, combined with the maintenance of the epimeric purity obtained, make the process object of the present invention particularly advantageous from an industrial point of view with respect to known methods.
In base alle osservazioni sperimentali effettuate, la fase di arricchimento epimerico per trattamento con metanolo oggetto della presente invenzione procede attraverso la formazione di un emimetanolato del composto di formula (I). On the basis of the experimental observations carried out, the epimeric enrichment step for treatment with methanol object of the present invention proceeds through the formation of a hemimethanolate of the compound of formula (I).
L’emimetanolato del 16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossipregna-1,4-diene-3,20-dione à ̈ un composto nuovo e costituisce un ulteriore oggetto della presente invenzione. The 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxypregna-1,4-diene-3,20-dione hemimethanolate is a new compound and constitutes a further object of the present invention.
Da un punto di vista pratico, tuttavia, l’isolamento dell’emimetanolato del composto di formula (I) non à ̈ necessario per ottenere l’arricchimento in epimero R secondo il processo oggetto della presente invenzione. From a practical point of view, however, the isolation of the hemimethanolate of the compound of formula (I) is not necessary to obtain the enrichment in epimer R according to the process object of the present invention.
La figura 1 riporta i profili di diffrazione (XRD) dell’emimetanolato del 16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossi-pregna-1,4-diene-3,20-dione (LF 195/7) e del corrispondente composto non solvato (LK195/25) Figure 1 shows the diffraction profiles (XRD) of 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione hemimethanolate (LF 195/7) and the corresponding unsolved compound (LK195 / 25)
Le figure 2a e 2b mostrano l’analisi termogravimetrica (TGA) e calorimetrica (DSC) rispettivamente dell’emimetanolato del 16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossi-pregna-1,4-diene-3,20-dione e del corrispondente composto non solvato Figures 2a and 2b show the thermogravimetric (TGA) and calorimetric (DSC) analysis of the 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxy-pregna-1,4-diene-3, respectively, 20-dione and the corresponding unsolved compound
Allo scopo di meglio illustrare la presente invenzione, senza tuttavia limitarla, vengono ora forniti i seguenti esempi. In order to better illustrate the present invention, without however limiting it, the following examples are now provided.
Esempio 1 Example 1
Preparazione di 16α,17-cicloesilmetilendiossi-11β,21-diidrossipregna-1,4-diene-3,20-dione Preparation of 16Î ±, 17-cyclohexylmethylenedioxy-11β, 21-dihydroxyregna-1,4-diene-3,20-dione
Ad una soluzione di acido bromidrico 48% (10 parti) raffreddato a 0°C/+2°C, sono stati aggiunti in sequenza 16-idrossiprednisolone, successivamente e lentamente cicloesancarbossaldeide (0,42 parti). La miscela di reazione à ̈ stata mantenuta sotto agitazione a 0°C/+2°C fino a conversione completa (15 ore). To a solution of 48% hydrobromic acid (10 parts) cooled to 0 ° C / + 2 ° C, 16-hydroxyprednisolone was added in sequence, subsequently and slowly cyclohexanecarboxaldehyde (0.42 parts). The reaction mixture was kept under stirring at 0 ° C / + 2 ° C until complete conversion (15 hours).
La miscela à ̈ stata versata in acqua purificata gelida (50 parti). Dopo circa 1 ora sotto agitazione a 5°C/+10°C, il solido à ̈ stato filtrato lavandolo con acqua purificata fino a neutralità . Il prodotto umido à ̈ stato caricato in un reattore contenente una miscela composta di metanolo (7,5 parti) ed acqua purificata (0,75 parti). La miscela à ̈ stata scaldata a riflusso per circa 1 ora, quindi, a dissoluzione avvenuta, à ̈ stata raffreddata fino a temperatura ambiente. Dopo aver raffreddato ulteriormente a circa 5°C, il solido à ̈ stato filtrato, lavato con una miscela acqua/metanolo=3/1 (4 parti) e seccato sotto vuoto a 60°C. The mixture was poured into icy purified water (50 parts). After about 1 hour under stirring at 5 ° C / + 10 ° C, the solid was filtered by washing it with purified water until neutral. The wet product was loaded into a reactor containing a mixture of methanol (7.5 parts) and purified water (0.75 parts). The mixture was heated under reflux for about 1 hour, then, once dissolved, it was cooled down to room temperature. After further cooling to about 5 ° C, the solid was filtered, washed with a mixture of water / methanol = 3/1 (4 parts) and dried under vacuum at 60 ° C.
Resa p/p = 112-120 % (teorico 125%) Yield p / p = 112-120% (theoretical 125%)
Rapporto epimerico R/S=90,3/9,7 Epimeric ratio R / S = 90.3 / 9.7
Esempio 2 Example 2
Preparazione di 16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossipregna-1,4-diene-3,20-dione Preparation of 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxypregna-1,4-diene-3,20-dione
In un reattore sono stati caricati piridina (5 parti) e 16α,17-cicloesilmetilendiossi-11β,21-diidrossipregna-1,4-diene-3,20-dione, preparato come descritto nell’esempio 1. Dopo raffreddamento a 0°C/+2°C, à ̈ stata aggiunta lentamente anidride acetica (5 parti). La miscela di reazione à ̈ stata mantenuta sotto agitazione a 0°C/+2°C fino a conversione completa (15 ore). Pyridine (5 parts) and 16Î ±, 17-cyclohexylmethylenedioxy-11β, 21-dihydroxyregna-1,4-diene-3,20-dione, prepared as described in example 1, were charged into a reactor. ° C / + 2 ° C, acetic anhydride (5 parts) was slowly added. The reaction mixture was kept under stirring at 0 ° C / + 2 ° C until complete conversion (15 hours).
Alla miscela di reazione à ̈ stato aggiunto ghiaccio (50 parti). Dopo circa 1 ora, la miscela di reazione à ̈ stata versata in acqua gelida (45 parti) ed acido solforico 50% (5 parti). La miscela à ̈ stata mantenuta sotto agitazione a 5°C/+10°C per circa 1 ora, quindi il solido à ̈ stato filtrato lavandolo con acqua purificata fino a neutralità ed ottenendo 16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossi-pregna-1,4-diene-3,20-dione grezzo con rapporto epimerico R/S=90,4/9,6. Ice (50 parts) was added to the reaction mixture. After about 1 hour, the reaction mixture was poured into cold water (45 parts) and 50% sulfuric acid (5 parts). The mixture was kept under stirring at 5 ° C / + 10 ° C for about 1 hour, then the solid was filtered by washing it with purified water until neutral and obtaining 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21 crude acetoxy-pregna-1,4-diene-3,20-dione with epimeric ratio R / S = 90.4 / 9.6.
Arricchimento epimero 22R 22R epimer enrichment
16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossi-pregna-1,4-diene-3,20-dione (R/S=90,4/9,6) umido, ottenuto come precedentemente descritto, à ̈ stato solubilizzato in diclorometano (5 parti). Dopo stratificazione l’acqua à ̈ stata separata e la fase organica à ̈ stata concentrata sotto vuoto fino ad olio. A questo punto à ̈ stato aggiunto metanolo (circa 30 parti), e la miscela à ̈ stata scaldata a riflusso distillando l’eventuale diclorometano ancora presente. Dopo aver raffreddato lentamente a temperatura ambiente, il prodotto precipitato à ̈ stato filtrato lavandolo in coda con metanolo gelido. 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione (R / S = 90.4 / 9.6) wet, obtained as previously described, à ̈ been solubilized in dichloromethane (5 parts). After stratification the water was separated and the organic phase was concentrated under vacuum to oil. At this point methanol (about 30 parts) was added, and the mixture was refluxed distilling any dichloromethane still present. After cooling slowly to room temperature, the precipitated product was filtered by washing it at the tail with freezing methanol.
Il prodotto ottenuto può essere ritrattato come precedentemente descritto o più semplicemente può essere trattato a temperatura ambiente con metanolo (12 parti). In entrambi i casi (ricristallizzazione o semplice sgranamento da alcole) à ̈ stato ottenuto il composto di formula (I) in elevata purezza HPLC >>99% e con rapporto epimerico 22R/22S come riportato in tabella The product obtained can be reprocessed as previously described or more simply it can be treated at room temperature with methanol (12 parts). In both cases (recrystallization or simple separation from alcohol) the compound of formula (I) was obtained in high purity HPLC >> 99% and with epimeric ratio 22R / 22S as shown in the table
epimero R epimero S epimer R epimer S
1° cristallizzato 97% 3% 1st crystallized 97% 3%
2° cristallizzato >99% <1% 2nd crystallized> 99% <1%
Sgranato >99% <1% Grained> 99% <1%
Resa p/p = 80-85 % (teorico 109%) Yield p / p = 80-85% (theoretical 109%)
Esempio 3 Example 3
Preparazione di (22R)-16α,17-cicloesilmetilendiossi-11β,21-diidrossipregna-1,4-diene-3,20-dione Preparation of (22R) -16Î ±, 17-cyclohexylmethylenedioxy-11β, 21-dihydroxyregna-1,4-diene-3,20-dione
Procedura A Procedure A
In un reattore sono stati caricati (22R)-16α,17-cicloesilmetilendiossi-11βidrossi-21-acetossi-pregna-1,4-diene-3,20-dione, preparato come descritto nell’esempio 2, diclorometano (5 parti) e metanolo (7,5 parti). La miscela à ̈ stata raffreddata a 0°C/+2°C, quindi lentamente sono stati aggiunti sodio idrossido 30% (0,175 parti) ed acqua (1,75 parti). La miscela di reazione à ̈ stata mantenuta sotto agitazione a 0°C/+2°C fino a conversione completa (1 ora). (22R) -16Î ±, 17-cyclohexylmethylenedioxy-11βhydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione, prepared as described in example 2, dichloromethane (5 parts ) and methanol (7.5 parts). The mixture was cooled to 0 ° C / + 2 ° C, then slowly 30% sodium hydroxide (0.175 parts) and water (1.75 parts) were added. The reaction mixture was kept under stirring at 0 ° C / + 2 ° C until complete conversion (1 hour).
Alla miscela di reazione à ̈ stato aggiunto acido acetico 80% (0,09 parti). Dopo chiarificazione effettuata per filtrazione, la miscela ottenuta à ̈ stata concentrata sotto vuoto fino a completa eliminazione del diclorometano. Il prodotto precipitato à ̈ stato isolato per filtrazione e lavaggio con una miscela acqua e metanolo. Il prodotto à ̈ stato essiccato sotto vuoto a 70°C per 14 ore. 80% acetic acid (0.09 parts) was added to the reaction mixture. After clarification carried out by filtration, the mixture obtained was concentrated under vacuum until the dichloromethane was completely eliminated. The precipitated product was isolated by filtration and washing with a mixture of water and methanol. The product was dried under vacuum at 70 ° C for 14 hours.
Isomero R Isomero S R isomer S isomer
Solido isolato >99% <1% Isolated solid> 99% <1%
Resa p/p = 80-83 % (teorico 91,8%) Yield p / p = 80-83% (theoretical 91.8%)
Procedura B Procedure B
In un reattore sono stati caricati (22R)-16α,17-cicloesilmetilendiossi-11βidrossi-21-acetossi-pregna-1,4-diene-3,20-dione, preparato come descritto nell’esempio 2, metanolo (20 parti) e, successivamente, sodio solfito (0,05 parti) sciolto in acqua (3 parti). La miscela di reazione à ̈ stata scaldata a riflusso fino a conversione completa (1 ora). (22R) -16Î ±, 17-cyclohexylmethylenedioxy-11βhydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione, prepared as described in example 2, methanol (20 parts ) and, subsequently, sodium sulphite (0.05 parts) dissolved in water (3 parts). The reaction mixture was heated under reflux until complete conversion (1 hour).
Alla miscela di reazione à ̈ stato aggiunto acido acetico 80% (0,09 parti). Dopo chiarificazione effettuata per filtrazione, la miscela ottenuta à ̈ stata concentrata sotto vuoto fino a completa eliminazione del diclorometano. Sempre a caldo à ̈ stata aggiunta acqua (7 parti) ed il metanolo à ̈ stato allontanato per distillazione. Dopo raffreddamento a temperatura ambiente, Il prodotto precipitato à ̈ stato isolato per filtrazione e lavaggio con acqua. Il prodotto à ̈ stato essiccato sotto vuoto a 70°C per 14 ore. 80% acetic acid (0.09 parts) was added to the reaction mixture. After clarification carried out by filtration, the mixture obtained was concentrated under vacuum until the dichloromethane was completely eliminated. Still hot, water (7 parts) was added and the methanol was removed by distillation. After cooling to room temperature, the precipitated product was isolated by filtration and washing with water. The product was dried under vacuum at 70 ° C for 14 hours.
Isomero R Isomero S R isomer S isomer
Solido isolato >99% <1% Isolated solid> 99% <1%
Resa p/p = 75-80 % (teorico 91,8%) Yield p / p = 75-80% (theoretical 91.8%)
Esempio 4 Example 4
Preparazione di ciclesonide Preparation of ciclesonide
(22R)-16α,17-cicloesilmetilendiossi-11β,21-diidrossi-pregna-1,4-diene-3,20-dione, preparato come descritto nell’esempio 3, à ̈ stato solubilizzato in piridina (5 parti) sotto agitazione a temperatura ambiente. Dopo raffreddamento a 0-2°C, à ̈ stata aggiunta lentamente anidride isobutirrica (0,5 parti) e la miscela di reazione à ̈ stata lasciata a temperatura ambiente per circa 15 h. (22R) -16Î ±, 17-cyclohexylmethylenedioxy-11β, 21-dihydroxy-pregna-1,4-diene-3,20-dione, prepared as described in example 3, was solubilized in pyridine (5 parts) under stirring at room temperature. After cooling to 0-2 ° C, isobutyric anhydride (0.5 parts) was slowly added and the reaction mixture was left at room temperature for about 15 h.
A reazione completa à ̈ stato aggiunto ghiaccio (1 parte). La miscela à ̈ stata mantenuta sotto agitazione per circa 30 minuti, poi à ̈ stata precipitata lentamente e sotto agitazione in acqua purificata gelida (45 parti) ed acido solforico 50% (5 parti). Dopo circa 2 ore, il prodotto cristallizzato à ̈ stato filtrato lavando fino a neutralità con acqua. Il prodotto umido così ottenuto à ̈ stato caricato nuovamente in un reattore ed addizionato con acetone (4 parti). Dopo chiarificazione la soluzione à ̈ stata versata lentamente in acqua raffreddata a 10-15°C. Dopo circa 1 ora sotto agitazione il solido à ̈ stato filtrato, lavato con acqua ed essiccato in stufa sotto vuoto a circa 70°C per 14 ore. When the reaction was complete, ice (1 part) was added. The mixture was kept under stirring for about 30 minutes, then it was precipitated slowly and under stirring in cold purified water (45 parts) and 50% sulfuric acid (5 parts). After about 2 hours, the crystallized product was filtered by washing until neutral with water. The wet product thus obtained was loaded again into a reactor and added with acetone (4 parts). After clarification, the solution was slowly poured into water cooled at 10-15 ° C. After about 1 hour under stirring, the solid was filtered, washed with water and dried in an oven under vacuum at about 70 ° C for 14 hours.
Resa p/p = 110%; purezza HPLC >99,7 (somma di 22R e 22S) Yield w / w = 110%; HPLC purity> 99.7 (sum of 22R and 22S)
Isomero R Isomero S R isomer S isomer
>99% <1% > 99% <1%
Esempio 5 Example 5
Arricchimento in epimero 22R 22R epimer enrichment
Una miscela epimerica R/S=83/17 di 16α,17-cicloesilmetilendiossi-11βidrossi-21-acetossi-pregna-1,4-diene-3,20-dione (4,3 g) à ̈ stata caricata in una beuta con metanolo (86 ml) sotto agitazione. La sospensione à ̈ stata scaldata a 50°C e mantenuta a tale temperatura per 15 minuti. Dopo aver raffreddato a temperatura ambiente, la sospensione à ̈ stata lasciata sotto agitazione per circa 2,5 ore. Il solido cristallino à ̈ stato filtrato, lavato con metanolo (8,6 ml) ed essiccato in stufa sotto vuoto a 70°C per circa 4 ore e poi a circa 55°C per 48 ore ottenendo una miscela epimerica con un contenuto di epimero R pari a 97,8% (3,2 g; resa 74,4%). An epimeric mixture R / S = 83/17 of 16Î ±, 17-cyclohexylmethylenedioxy-11βhydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione (4.3 g) was loaded into a flask with methanol (86 ml) while stirring. The suspension was heated to 50 ° C and kept at that temperature for 15 minutes. After cooling to room temperature, the suspension was left under stirring for about 2.5 hours. The crystalline solid was filtered, washed with methanol (8.6 ml) and dried in an oven under vacuum at 70 ° C for about 4 hours and then at about 55 ° C for 48 hours, obtaining an epimeric mixture with an epimer content R equal to 97.8% (3.2 g; yield 74.4%).
Esempio 6 Example 6
Preparazione di 16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossipregna-1,4-diene-3,20-dione Preparation of 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxypregna-1,4-diene-3,20-dione
In una beuta sono stati caricati, sotto agitazione e sotto azoto, piridina (45 ml) e 16α,17-cicloesilmetilendiossi-11β,21-diidrossipregna-1,4-diene-3,20-dione (9 g; rapporto R/S=85,8/14,2). Dopo raffreddamento a 0°C/+2°C, alla soluzione à ̈ stata aggiunta anidride acetica (4,5 ml). La miscela di reazione à ̈ stata poi mantenuta sotto agitazione a temperatura ambiente fino a conversione completa (5 ore). Pyridine (45 ml) and 16Î ±, 17-cyclohexylmethylenedioxy-11β, 21-dihydroxyregna-1,4-diene-3,20-dione (9 g; ratio R / S = 85.8 / 14.2). After cooling to 0 ° C / + 2 ° C, acetic anhydride (4.5 ml) was added to the solution. The reaction mixture was then kept under stirring at room temperature until complete conversion (5 hours).
Dopo aver aggiunto ghiaccio (9 ml), la miscela di reazione à ̈ stata mantenuta sotto agitazione per 30 minuti e quindi versata in acqua gelida (405 ml) ed acido solforico 50% (45 ml). La miscela à ̈ stata mantenuta sotto agitazione per circa 1,5 ore, quindi il solido à ̈ stato filtrato lavandolo con acqua purificata fino a neutralità ed ottenendo 16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossi-pregna-1,4-diene-3,20-dione grezzo con un contenuto di epimero R pari a 85,3%. After adding ice (9 ml), the reaction mixture was kept under stirring for 30 minutes and then poured into cold water (405 ml) and 50% sulfuric acid (45 ml). The mixture was kept under stirring for about 1.5 hours, then the solid was filtered by washing it with purified water until neutral and obtaining 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxy-pregna-1, Crude 4-diene-3,20-dione with an R epimer content of 85.3%.
Il grezzo à ̈ stato solubilizzato in diclorometano (90 ml)ed à ̈ stato aggiunto acido solforico 50% fino a pH 3-4. Dopo stratificazione l’acqua à ̈ stata separata e la fase organica à ̈ stata caricata in una soluzione di NaCl 10% mantenendo sotto agitazione a temperatura ambiente per 15 minuti. Dopo stratificazione, le fasi sono state nuovamente separate ed alla fase organica à ̈ stato aggiunto metanolo isolando infine per filtrazione un solido cristallino (8,2 g) con contenuto di epimero R=95,8%. The crude was solubilized in dichloromethane (90 ml) and 50% sulfuric acid was added up to pH 3-4. After stratification, the water was separated and the organic phase was charged in a 10% NaCl solution, stirring at room temperature for 15 minutes. After stratification, the phases were separated again and methanol was added to the organic phase, finally isolating by filtration a crystalline solid (8.2 g) with epimer content R = 95.8%.
Il prodotto cristallino così ottenuto à ̈ stato caricato in metanolo (135 ml), mantenendo la sospensione a leggero riflusso per circa 30 minuti. Dopo raffreddamento a 15°C, il solido à ̈ stato filtrato, lavato con metanolo gelido (18 ml) ed essiccato in stufa sotto vuoto a 70°C ottenendo 16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossi-pregna-1,4-diene-3,20-dione (7 g; resa 77,7% - rapporto R/S=99/1). The crystalline product thus obtained was charged in methanol (135 ml), keeping the suspension under slight reflux for about 30 minutes. After cooling to 15 ° C, the solid was filtered, washed with cold methanol (18 ml) and dried in an oven under vacuum at 70 ° C obtaining 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxy-pregna- 1,4-diene-3,20-dione (7 g; yield 77.7% - ratio R / S = 99/1).
Le acque madri metanoliche contenenti 16α,17-cicloesilmetilendiossi-11βidrossi-21-acetossi-pregna-1,4-diene-3,20-dione con un rapporto epimerico R/S=1/1 sono state concentrate fino ad un volume di circa 50 ml e poi lasciate sotto agitazione a temperatura ambiente. Dopo circa 15 minuti à ̈ iniziata la cristallizzazione. La sospensione à ̈ stata mantenuta sotto agitazione a temperatura ambiente per circa 90 minuti. il solido à ̈ stato filtrato, lavato con metanolo gelido (7 ml) ed essiccato in stufa sotto vuoto a 70°C ottenendo 16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossipregna-1,4-diene-3,20-dione (0,77 g) con rapporto epimerico R/S=83/17. Methanolic mother liquors containing 16Î ±, 17-cyclohexylmethylenedioxy-11βhydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione with an epimeric ratio R / S = 1/1 were concentrated to a volume of about 50 ml and then left under stirring at room temperature. Crystallization started after about 15 minutes. The suspension was kept under stirring at room temperature for about 90 minutes. the solid was filtered, washed with cold methanol (7 ml) and dried in an oven under vacuum at 70 ° C to obtain 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxypregna-1,4-diene-3.20 -dione (0.77 g) with epimeric ratio R / S = 83/17.
Esempio 7 Example 7
Isolamento dell’emimetanolato del 16α,17-cicloesilmetilendiossi-11βidrossi-21-acetossi-pregna-1,4-diene-3,20-dione Isolation of 16Î ±, 17-cyclohexylmethylenedioxy-11βhydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione hemimethanolate
In una pallone sono stati caricati cloruro di metilene (227,5 ml), metanolo (45,5 ml) e 16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossi-pregna-1,4-diene-3,20-dione (45,5 g; rapporto R/S=96,8/3,2). La sospensione à ̈ stata scaldata a leggero ricadere fino ad ottenere una soluzione, che à ̈ stata poi concentrata a pressione atmosferica fino ad un volume di 90-100 ml. Dopo diluizione con metanolo (227,5 ml), la miscela à ̈ stata nuovamente concentrata a pressione atmosferica fino ad una temperatura dei vapori di 64-64°C ed un volume interno finale di circa 125-135 ml. Il prodotto cristallino à ̈ stato raffreddato a 20°C e mantenuto a tale temperatura per circa 1 ora. Dopo filtrazione lavando con metanolo gelido (90 ml), il solido à ̈ stato essiccato in stufa sotto vuoto a 70°C per una notte ottenendo emimetanolato di 16α,17-cicloesilmetilendiossi-11β-idrossi-21-acetossi-pregna-1,4-diene-3,20-dione (44,1 g, resa 96,9%; rapporto R/S=99,3/0,7). Methylene chloride (227.5 ml), methanol (45.5 ml) and 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxy-pregna-1,4-diene-3.20 were loaded into a flask. -dione (45.5 g; R / S ratio = 96.8 / 3.2). The suspension was heated under light reflux until a solution was obtained, which was then concentrated at atmospheric pressure up to a volume of 90-100 ml. After dilution with methanol (227.5 ml), the mixture was again concentrated at atmospheric pressure up to a vapor temperature of 64-64 ° C and a final internal volume of about 125-135 ml. The crystalline product was cooled to 20 ° C and kept at this temperature for about 1 hour. After filtration by washing with cold methanol (90 ml), the solid was dried in an oven under vacuum at 70 ° C for one night obtaining hemimethanolate of 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxy-pregna-1, 4-diene-3.20-dione (44.1 g, 96.9% yield; R / S ratio = 99.3 / 0.7).
Claims (10)
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2009A000016A IT1397499B1 (en) | 2009-01-09 | 2009-01-09 | PROCESS FOR THE PREPARATION OF CICLESONIDE |
| ES09718667T ES2401057T3 (en) | 2008-03-13 | 2009-03-12 | Procedure for the preparation of pregnan derivatives |
| MX2010009303A MX2010009303A (en) | 2008-03-13 | 2009-03-12 | Process for the preparation of pregnane derivatives. |
| EP09718667A EP2262823B1 (en) | 2008-03-13 | 2009-03-12 | Process for the preparation of pregnane derivatives |
| US12/866,577 US20100331539A1 (en) | 2008-03-13 | 2009-03-12 | Process for the preparation of pregnane derivatives |
| CA2714653A CA2714653A1 (en) | 2008-03-13 | 2009-03-12 | Process for the preparation of pregnane derivatives |
| PCT/EP2009/052945 WO2009112557A2 (en) | 2008-03-13 | 2009-03-12 | Process for the preparation of pregnane derivatives |
| JP2010550203A JP2011513469A (en) | 2008-03-13 | 2009-03-12 | Process for producing pregnane derivatives |
| PT97186670T PT2262823E (en) | 2008-03-13 | 2009-03-12 | Process for the preparation of pregnane derivatives |
| IL207557A IL207557A0 (en) | 2008-03-13 | 2010-08-12 | Process for the preparation of pregnane derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2009A000016A IT1397499B1 (en) | 2009-01-09 | 2009-01-09 | PROCESS FOR THE PREPARATION OF CICLESONIDE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ITMI20090016A1 true ITMI20090016A1 (en) | 2010-07-10 |
| IT1397499B1 IT1397499B1 (en) | 2013-01-16 |
Family
ID=40825252
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ITMI2009A000016A IT1397499B1 (en) | 2008-03-13 | 2009-01-09 | PROCESS FOR THE PREPARATION OF CICLESONIDE |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1397499B1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2004085460A1 (en) * | 2003-03-27 | 2004-10-07 | Altana Pharma Ag | Process for preparing crystalline ciclesonide with defined particle size |
| US20070117974A1 (en) * | 2005-06-21 | 2007-05-24 | Zhejiang Xianju Pharmaceutical Co., Ltd. | One-pot processes for preparing prednisolone derivatives |
| WO2008035066A2 (en) * | 2006-09-19 | 2008-03-27 | Cipla Limited | Processes for the preparation of ciclesonide and its crystal form |
-
2009
- 2009-01-09 IT ITMI2009A000016A patent/IT1397499B1/en active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2004085460A1 (en) * | 2003-03-27 | 2004-10-07 | Altana Pharma Ag | Process for preparing crystalline ciclesonide with defined particle size |
| US20070117974A1 (en) * | 2005-06-21 | 2007-05-24 | Zhejiang Xianju Pharmaceutical Co., Ltd. | One-pot processes for preparing prednisolone derivatives |
| WO2008035066A2 (en) * | 2006-09-19 | 2008-03-27 | Cipla Limited | Processes for the preparation of ciclesonide and its crystal form |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1397499B1 (en) | 2013-01-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2007298770B2 (en) | Processes for the preparation of ciclesonide and its crystal form | |
| WO2016004704A1 (en) | Gastrodin production process | |
| ITMI20121344A1 (en) | PROCESS OF PREPARATION OF URSODESOSICOLICO ACID WITH HIGH PURITY | |
| US10875835B2 (en) | Method for producing 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione | |
| JP5955985B2 (en) | New method for producing ciclesonide | |
| EP2262823B1 (en) | Process for the preparation of pregnane derivatives | |
| CN101993447A (en) | Method for synthesizing Prasugrel artificially | |
| WO2013123878A1 (en) | Acetatic abiraterone trifluoroacetate and preparation method and application of same | |
| US20070135638A1 (en) | Process for the manufacture of lysergic acid | |
| WO2008087667A1 (en) | Preparative process for artesunate from artemisinin | |
| US8119793B2 (en) | Process for preparing budesonide | |
| ITMI20090016A1 (en) | PROCESS FOR THE PREPARATION OF CICLESONIDE | |
| JPH07224077A (en) | Production of 9-(z)-retinoic acid | |
| CN114478290A (en) | Synthetic method of oseltamivir intermediate | |
| WO2006008302A2 (en) | Improved process for the manufacture of mirtazapine | |
| CN115504864A (en) | Method for obtaining high-purity cannabidiol from industrial cannabis sativa | |
| WO2012020417A1 (en) | Process for the preparation of estradiol and its derivatives | |
| KR101815332B1 (en) | Method for purifying a fused pyrrolocarbazole derivative | |
| IT201800002347A1 (en) | INTERMEDIATES AND PROCEDURE FOR THE PREPARATION OF A CRYSTALLINE FORM OF A TOPICAL ANTI-INFLAMMATORY DRUG | |
| KR100600520B1 (en) | Process for the manufacture of solanesol | |
| CN112300226A (en) | Method for preparing beta-tetraacetyl-L-ribose | |
| CN117430653A (en) | Preparation method of hydrocortisone acetate | |
| MXPA04008944A (en) | Process for producing triterpene derivative. | |
| ITMI20081429A1 (en) | PROCESS FOR THE STEREOSELECTIVE SYNTHESIS OF THE 22-R EPIMERO DI CICLESONIDE | |
| JPH0474175A (en) | Purification of 4-cyanoquinuclidine sulfuric acid adduct |