ITMI20090016A1 - PROCESS FOR THE PREPARATION OF CICLESONIDE - Google Patents

Description

â € PROCESS FOR THE PREPARATION OF CYCLESONIDEâ €

DESCRIPTION

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.

The compound of formula

OR

OR

OR

I HAVE

OHO

OR

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.

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) and US5733901 (Byk Gulden) describe the separation of ciclesonide epimers or its analogues by preparative HPLC.

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) 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.) 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.) 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.) discloses a process of preparing substantially S epimer-free ciclesonide for chromatographic treatment of an R / S mixture using a chiral stationary phase.

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.

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

OCOCH3

OR

I HAVE

OR

H (I)

O O

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.

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.

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.

In the present context, in the epimeric form substantially pure R means a compound with an epimeric ratio R / S> 99/1.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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)

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

In order to better illustrate the present invention, without however limiting it, the following examples are now provided.

Example 1

Preparation of 16Î ±, 17-cyclohexylmethylenedioxy-11β, 21-dihydroxyregna-1,4-diene-3,20-dione

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).

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.

Yield p / p = 112-120% (theoretical 125%)

Epimeric ratio R / S = 90.3 / 9.7

Example 2

Preparation of 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxypregna-1,4-diene-3,20-dione

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).

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.

22R epimer enrichment

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.

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

epimer R epimer S

1st crystallized 97% 3%

2nd crystallized> 99% <1%

Grained> 99% <1%

Yield p / p = 80-85% (theoretical 109%)

Example 3

Preparation of (22R) -16Î ±, 17-cyclohexylmethylenedioxy-11β, 21-dihydroxyregna-1,4-diene-3,20-dione

Procedure A

(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).

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.

R isomer S isomer

Isolated solid> 99% <1%

Yield p / p = 80-83% (theoretical 91.8%)

Procedure B

(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).

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.

R isomer S isomer

Isolated solid> 99% <1%

Yield p / p = 75-80% (theoretical 91.8%)

Example 4

Preparation of ciclesonide

(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.

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.

Yield w / w = 110%; HPLC purity> 99.7 (sum of 22R and 22S)

R isomer S isomer

> 99% <1%

Example 5

22R epimer enrichment

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%).

Example 6

Preparation of 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxypregna-1,4-diene-3,20-dione

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).

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%.

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%.

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).

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.

Example 7

Isolation of 16Î ±, 17-cyclohexylmethylenedioxy-11βhydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione hemimethanolate

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)

CLAIMS 1) A process for obtaining ciclesonide in substantially pure R epimeric form which comprises the treatment of an R / S epimeric mixture of the compound of formula with methanol, the isolation of the compound of formula (I) in a substantially pure epimeric form R, 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. 2) A process according to claim 1 wherein 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. 3) A process according to claim 2 in which the treatment is carried out at a temperature between 20 and 25 ° C. 4) A process according to claim 2 wherein the suspension is prepared by directly treating the solid compound of formula (I) with methanol. 5) A process according to claim 2 wherein the suspension is prepared starting from a concentrated solution of the compound of formula (I) in an organic solvent in which the compound of formula (I) is soluble. 6) A process according to claim 5 wherein the organic solvent is a halogenated hydrocarbon. 7) A process according to claim 6 wherein the halogenated hydrocarbon is methylene chloride. 8) Use of the compound of formula (I) as an intermediate for the preparation of ciclesonide. 9) A process for the epimeric enrichment of R / S mixtures of the compound of formula (I) by treatment with methanol. 10) 16Î ±, 17-cyclohexylmethylenedioxy-11β-hydroxy-21-acetoxy-pregna-1,4-diene-3,20-dione hemimethanolate.