CA2780139A1 - Process for preparing (11.beta., 16.alpha.)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione - Google Patents
Process for preparing (11.beta., 16.alpha.)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione Download PDFInfo
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- C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
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Abstract
This invention relates to a new process for preparing (11 ß, 16a)-9-fluoro-11 - hydroxy-16,17-[1 -methyl -ethyl idenebis(oxy)]-21 -[1 -oxo-[4- (nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione, comprising the steps of (i) reaction of triamcinolone acetonide with 4-(nitrooxymethyl)benzoic, 4- dimethylaminopyridine and N-N'-diisopropylcarbodiimide, (ii) crystallisation, and (iii) controlled precipitation.
Description
Process for preparing (1113, 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione Field of the invention This invention relates to a new process for the preparation of the compound (1113, 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione, used as a topic anti-inflammatory drug.
Background art Compound (11 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione with formula (I) is a corticosteroid previously described in application W02007025632 (Example 1). This compound is especially useful in the treatment of certain inflammatory diseases such as corticosteroid-sensitive dermatosis, atopic dermatitis, contact dermatitis, psoriasis and seborrhoeic dermatitis.
a`O CH3 HO O
F
(I) Said compound is applied topically, preferably using creams, ointments, lotions and gels and similar formulations.
Background art Compound (11 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21 -[1 -oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione with formula (I) is a corticosteroid previously described in application W02007025632 (Example 1). This compound is especially useful in the treatment of certain inflammatory diseases such as corticosteroid-sensitive dermatosis, atopic dermatitis, contact dermatitis, psoriasis and seborrhoeic dermatitis.
a`O CH3 HO O
F
(I) Said compound is applied topically, preferably using creams, ointments, lotions and gels and similar formulations.
The compound of formula (I) is obtained in example 1 of application W02007025632 by the reaction of triamcinolone acetonide (II) with 4-(nitrooxymethyl)benzoic acid (III) in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (IV) and 4-dimethylaminopyridine (V) according to Diagram 1.
O
HO
N N
/ (III) (IV) CH3 (V) F H
O
(II) a`O CH3 HO O
F H
(I) Diagram I
The yield of this reaction is of 34.4%, which makes it industrially unviable. Also, the price of the diimide used (IV) is also a drawback for use in industrial processes.
It is therefore necessary to find a different process for the industrial production of compound (I) with a high yield and using cheaper starting products.
O
HO
N N
/ (III) (IV) CH3 (V) F H
O
(II) a`O CH3 HO O
F H
(I) Diagram I
The yield of this reaction is of 34.4%, which makes it industrially unviable. Also, the price of the diimide used (IV) is also a drawback for use in industrial processes.
It is therefore necessary to find a different process for the industrial production of compound (I) with a high yield and using cheaper starting products.
The authors of the present invention have achieved a new industrial process to obtain (I) that produces the product with a much higher yield and also replaces diimide (IV) with N,N'-diisopropylcarbodiimide (VI), which is cheaper. On the other hand, we have found that the resulting product is of very high purity. Moreover, the new process also comprises a final step of controlled precipitation, which provides the end product with a suitable particle size for the preparation of topical formulations.
Summary of the invention In a single aspect, the invention provides a new industrial process for preparing (11P, 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl -ethyl idenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione (I) with a good yield, starting from cost effective products and providing an end product with suitable purity and particle size.
Detailed description of the invention The process for preparing 11P, 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethyl idenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione (I), which is the single aspect of the invention, comprises the following steps:
(i) reaction of triamcinolone acetonide (II) HO
.`O CH3 HO
F H
O
(II) with 4-(nitrooxymethyl)benzoic acid (III), 4-dimethylaminopyridine (V) and N,N'-diisopropylcarbodiimide (VI) COOH H3C'~' CH ,CH3 N
N
61w~/NO2 N H
O
(III) (V) (VI) in an inert solvent, followed by the elimination by filtration or centrifuging of the solid formed, which consists mainly of N,N'-diisopropylurea, acidification of the liquid phase, neutralising and washout thereof with water, adding an inert anti-solvent to the organic phase and separating the compound (I) thus formed by filtration or centrifuging;
(ii) crystallisation of compound (I) formed in step (i) in a mixture of a solvent and an anti-solvent; and (iii) precipitation of the compound (I) crystallised in step (ii) in a mixture of a solvent and an anti-solvent.
In a preferred embodiment, the solvent of step (i) is chosen from the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, 5 esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably dichloromethane.
In another preferred embodiment, the acidification is performed with an acid chosen from the group consisting of mineral acids such as hydrochloric acid, sulphuric acid, phosphoric acid and hydrobromic acid, carboxylic acids such as acetic acid, trifluoroacetic acid and formic acid, sulphonic acids such as methane sulphonic acid, trifluoromethane sulphonic acid and p-toluene sulphonic acid and other similar acids and mixtures thereof. The acid is preferably hydrochloric acid.
In another preferred embodiment, the neutralisation is performed with a base chosen from the group consisting of alkaline bicarbonates such as sodium bicarbonate and potassium bicarbonate and alkaline carbonate such as sodium carbonate and potassium carbonate. The base is preferably sodium bicarbonate.
In another embodiment preferred, the anti-solvent of step (i) is chosen from the group consisting of C1-C4 alkanols such as ethanol, methanol and isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as water and other similar anti-solvents and mixtures thereof. The anti-solvent is preferably ethanol.
In another preferred embodiment, the solvent of step (ii) is chosen from the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably dichloromethane.
In another preferred embodiment, the anti-solvent of step (ii) is chosen from the group consisting of C1-C4 alkanols such as ethanol, methanol and isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as water and other similar anti-solvents and mixtures thereof. The anti-solvent is preferably ethanol.
In another preferred embodiment, the solvent of step (iii) is chosen from the group consisting of esters such as ethyl acetate and isopropyl acetate, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane and sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably ethyl acetate.
In another preferred embodiment, the anti-solvent of step (iii) is chosen from a group consisting of C6-C9 aliphatic hydrocarbons such as heptane, aliphatic ethers such as isopropyl ether and ethyl ether, the group consisting of C1-C4 alkanols such as ethanol, methanol and isopropanol, and similar anti-solvents and mixtures thereof. The anti-solvent is preferably heptane.
Examples Example 1 Synthesis of (1113, 16a)-9-fluoro-11-hydroxy-16,1741-methyl-ethyl idenebis(oxy)1-21-f1-oxo-[4-(nitrooxymethyl)benzoxyllpregna-1,4-dien-3,20-dione (I) COOH H3C'~' CH /CH, O CH3 \
~.O CH3 HO N
(III) (VI) (V) F H
(II) a`O CH3 HO O
F H
O
(I) Diagram 2 (i) Reaction 12.92 Kg of triamcinolone acetonide (II), 6.50 Kg of 4-(nitrooxymethyl)benzoic acid (III), 401 g of 4-dimethylaminopyridine (V) and 5.8 I of N,N'-diisopropylcarbodiimide (VI) were added to 284 I of dichloromethane. The solution was placed at ambient temperature and maintained with stirring until the reaction was completed. 13 I of dichloromethane were added.
The solid formed (N,N'-diisopropylurea) was removed by filtration and the filter was washed with dichloromethane.
The dichloromethane extracts were placed together and 203 I of 0.5 N HCI
were added. 203 1 of 0.5 N HCI were added to the organic phase, followed by 129 I of 0.25 N NaHCO3. It was washed with water until the pH of the aqueous phase was similar to that of the water added.
465 I of absolute ethanol were added to the organic phase and it was distilled at atmospheric pressure to a final volume of between 465 I and 504 I, and it was left to reach room temperature.
The suspension was filtered and the wet solid was washed with ethanol.
The wet solid was dried under vacuum, producing 15.59 Kg of compound (I).
Yield = 85.5%. HPLC Purity = 98.41 %.
(ii) Crystallisation 15.56 Kg of the solid obtained in the previous step were added to 467 I of dichloromethane. This was heated to reflux and distilled at atmospheric pressure to a final volume of 47 I. It was left to reach ambient temperature and 560 I of ethanol were added.
The suspension was filtered and the wet solid was washed with ethanol.
The wet solid was dried under vacuum.
(iii) Precipitation 11.21 Kg of the solid obtained in the previous step were added to 516 I of ethyl acetate. It was heated to reflux and stirred until solution. It was cooled to 40-50 C. 538 I of heptane were added and it was taken to ambient temperature. The solution was filtered through a 0.2 pm filter. It was washed with ethyl acetate and stirred at least for 3 hours at ambient temperature.
The suspension was filtered and the wet solid was washed with heptane.
Summary of the invention In a single aspect, the invention provides a new industrial process for preparing (11P, 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl -ethyl idenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione (I) with a good yield, starting from cost effective products and providing an end product with suitable purity and particle size.
Detailed description of the invention The process for preparing 11P, 16a)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethyl idenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione (I), which is the single aspect of the invention, comprises the following steps:
(i) reaction of triamcinolone acetonide (II) HO
.`O CH3 HO
F H
O
(II) with 4-(nitrooxymethyl)benzoic acid (III), 4-dimethylaminopyridine (V) and N,N'-diisopropylcarbodiimide (VI) COOH H3C'~' CH ,CH3 N
N
61w~/NO2 N H
O
(III) (V) (VI) in an inert solvent, followed by the elimination by filtration or centrifuging of the solid formed, which consists mainly of N,N'-diisopropylurea, acidification of the liquid phase, neutralising and washout thereof with water, adding an inert anti-solvent to the organic phase and separating the compound (I) thus formed by filtration or centrifuging;
(ii) crystallisation of compound (I) formed in step (i) in a mixture of a solvent and an anti-solvent; and (iii) precipitation of the compound (I) crystallised in step (ii) in a mixture of a solvent and an anti-solvent.
In a preferred embodiment, the solvent of step (i) is chosen from the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, 5 esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably dichloromethane.
In another preferred embodiment, the acidification is performed with an acid chosen from the group consisting of mineral acids such as hydrochloric acid, sulphuric acid, phosphoric acid and hydrobromic acid, carboxylic acids such as acetic acid, trifluoroacetic acid and formic acid, sulphonic acids such as methane sulphonic acid, trifluoromethane sulphonic acid and p-toluene sulphonic acid and other similar acids and mixtures thereof. The acid is preferably hydrochloric acid.
In another preferred embodiment, the neutralisation is performed with a base chosen from the group consisting of alkaline bicarbonates such as sodium bicarbonate and potassium bicarbonate and alkaline carbonate such as sodium carbonate and potassium carbonate. The base is preferably sodium bicarbonate.
In another embodiment preferred, the anti-solvent of step (i) is chosen from the group consisting of C1-C4 alkanols such as ethanol, methanol and isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as water and other similar anti-solvents and mixtures thereof. The anti-solvent is preferably ethanol.
In another preferred embodiment, the solvent of step (ii) is chosen from the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably dichloromethane.
In another preferred embodiment, the anti-solvent of step (ii) is chosen from the group consisting of C1-C4 alkanols such as ethanol, methanol and isopropanol, aromatic hydrocarbons such as toluene and xylenes, as well as water and other similar anti-solvents and mixtures thereof. The anti-solvent is preferably ethanol.
In another preferred embodiment, the solvent of step (iii) is chosen from the group consisting of esters such as ethyl acetate and isopropyl acetate, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofurane, ketones such as acetone and methyl isobutyl ketone, nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane and sulphoxides such as dimethyl sulphoxide and similar solvents and mixtures thereof. The solvent is preferably ethyl acetate.
In another preferred embodiment, the anti-solvent of step (iii) is chosen from a group consisting of C6-C9 aliphatic hydrocarbons such as heptane, aliphatic ethers such as isopropyl ether and ethyl ether, the group consisting of C1-C4 alkanols such as ethanol, methanol and isopropanol, and similar anti-solvents and mixtures thereof. The anti-solvent is preferably heptane.
Examples Example 1 Synthesis of (1113, 16a)-9-fluoro-11-hydroxy-16,1741-methyl-ethyl idenebis(oxy)1-21-f1-oxo-[4-(nitrooxymethyl)benzoxyllpregna-1,4-dien-3,20-dione (I) COOH H3C'~' CH /CH, O CH3 \
~.O CH3 HO N
(III) (VI) (V) F H
(II) a`O CH3 HO O
F H
O
(I) Diagram 2 (i) Reaction 12.92 Kg of triamcinolone acetonide (II), 6.50 Kg of 4-(nitrooxymethyl)benzoic acid (III), 401 g of 4-dimethylaminopyridine (V) and 5.8 I of N,N'-diisopropylcarbodiimide (VI) were added to 284 I of dichloromethane. The solution was placed at ambient temperature and maintained with stirring until the reaction was completed. 13 I of dichloromethane were added.
The solid formed (N,N'-diisopropylurea) was removed by filtration and the filter was washed with dichloromethane.
The dichloromethane extracts were placed together and 203 I of 0.5 N HCI
were added. 203 1 of 0.5 N HCI were added to the organic phase, followed by 129 I of 0.25 N NaHCO3. It was washed with water until the pH of the aqueous phase was similar to that of the water added.
465 I of absolute ethanol were added to the organic phase and it was distilled at atmospheric pressure to a final volume of between 465 I and 504 I, and it was left to reach room temperature.
The suspension was filtered and the wet solid was washed with ethanol.
The wet solid was dried under vacuum, producing 15.59 Kg of compound (I).
Yield = 85.5%. HPLC Purity = 98.41 %.
(ii) Crystallisation 15.56 Kg of the solid obtained in the previous step were added to 467 I of dichloromethane. This was heated to reflux and distilled at atmospheric pressure to a final volume of 47 I. It was left to reach ambient temperature and 560 I of ethanol were added.
The suspension was filtered and the wet solid was washed with ethanol.
The wet solid was dried under vacuum.
(iii) Precipitation 11.21 Kg of the solid obtained in the previous step were added to 516 I of ethyl acetate. It was heated to reflux and stirred until solution. It was cooled to 40-50 C. 538 I of heptane were added and it was taken to ambient temperature. The solution was filtered through a 0.2 pm filter. It was washed with ethyl acetate and stirred at least for 3 hours at ambient temperature.
The suspension was filtered and the wet solid was washed with heptane.
The wet solid was dried under vacuum.
Example 2 Particle size distribution for (I) The particle size distribution of the product obtained in the final step of Example 1 showed a Gaussian distribution characterised by values d(0.9) _ 10.79 pm; d(0.5) = 5.26 pm; and d(0.1) = 2.34 pm.
Example 2 Particle size distribution for (I) The particle size distribution of the product obtained in the final step of Example 1 showed a Gaussian distribution characterised by values d(0.9) _ 10.79 pm; d(0.5) = 5.26 pm; and d(0.1) = 2.34 pm.
Claims (17)
1. A process for preparing (11 .beta., 16.alpha.)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione (I) comprising the following steps:
(i) reaction of triamcinolone acetonide (II) with 4-(nitrooxymethyl)benzoic acid (III), 4-dimethylaminopyridine (V) and N,N'-diisopropylcarbodiimide (VI) in an inert solvent, elimination by filtration or centrifuging of the solid formed, acidification of the liquid phase, neutralising and washout thereof with water, adding an inert anti-solvent to the organic phase and separating the compound (I) thus formed by filtration or centrifuging;
(ii) crystallisation of compound (I) formed in step (i) in a mixture of a solvent and an anti-solvent; and (iii) precipitation of the compound (I) crystallised in step (ii) in a mixture of a solvent and an anti-solvent.
(i) reaction of triamcinolone acetonide (II) with 4-(nitrooxymethyl)benzoic acid (III), 4-dimethylaminopyridine (V) and N,N'-diisopropylcarbodiimide (VI) in an inert solvent, elimination by filtration or centrifuging of the solid formed, acidification of the liquid phase, neutralising and washout thereof with water, adding an inert anti-solvent to the organic phase and separating the compound (I) thus formed by filtration or centrifuging;
(ii) crystallisation of compound (I) formed in step (i) in a mixture of a solvent and an anti-solvent; and (iii) precipitation of the compound (I) crystallised in step (ii) in a mixture of a solvent and an anti-solvent.
2. The process according to claim 1, wherein the solvent of step (i) is chosen from the group consisting of dichloromethane, dimethylformamide, tetrahydrofurane, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethyl sulphoxide.
3. The process according to claim 2, wherein the solvent is dichloromethane.
4. The process according to claim 1, wherein the acidification is performed with an acid chosen from the group consisting of hydrochloric acid, sulphuric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, formic acid, methane sulphonic acid, trifluoromethane sulphonic acid and p-toluene sulphonic acid.
5. The process according to claim 4, wherein the acid is hidrochloric acid.
6. The process according to claim 1, wherein the neutralising is performed with a base chosen from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
7. The process according to claim 6, wherein the base is sodium bicarbonate.
8. The process according to claim 1, wherein the anti-solvent of step (i) is chosen from the group consisting of ethanol, methanol, isopropanol, toluene and water.
9. The process according to claim 8, wherein the anti-solvent is ethanol.
10.The process according to claim 1, wherein the solvent of step (ii) is chosen from the group consisting of dichloromethane, dimethylformamide, tetrahydrofurane, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethyl sulphoxide.
11.The process according to claim 10, wherein the solvent is dichloromethane.
12.The process according to claim 1, wherein the anti-solvent of step (ii) is chosen from the group consisting of ethanol, methanol, isopropanol, toluene and water.
13.The process according to claim 12, wherein the anti-solvent is ethanol.
14.The process according to claim 1, wherein the solvent of step (iii) is chosen from the group consisting of ethyl acetate, dimethylformamide, tetrahydrofurane, acetone, acetonitrile, dichloromethane, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethyl sulphoxide.
15. The process according to claim 14, wherein the solvent is ethyl acetate.
16.The process according to claim 1, wherein the anti-solvent of step (iii) is chosen from the group consisting of heptane, isopropyl ether and isopropanol.
17. The process according to claim 16, wherein the anti-solvent is heptane.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200930999A ES2359708B1 (en) | 2009-11-16 | 2009-11-16 | PREPARATION PROCEDURE OF THE (11BETA, 16ALFA) -9-FLUORO-11-HIDROXI-16,17- [1-METHYL-ETHYLENEBIS (OXI)] - 21- [1-OXO- [4- (NITROOXIMETILE) BENZOXI]] PREÑA-1,4-DIEN-3,20-DIONA. |
| ESP200930999 | 2009-11-16 | ||
| PCT/EP2010/067443 WO2011058161A2 (en) | 2009-11-16 | 2010-11-15 | Process for preparing (11beta, 16alpha)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2780139A1 true CA2780139A1 (en) | 2011-05-19 |
Family
ID=43896867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2780139A Abandoned CA2780139A1 (en) | 2009-11-16 | 2010-11-15 | Process for preparing (11.beta., 16.alpha.)-9-fluoro-11-hydroxy-16,17-[1-methyl-ethylidenebis(oxy)]-21-[1-oxo-[4-(nitrooxymethyl)benzoxy]]pregna-1,4-dien-3,20-dione |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP2501710A2 (en) |
| JP (1) | JP2013510826A (en) |
| KR (1) | KR20120084788A (en) |
| CN (1) | CN102612522A (en) |
| AR (1) | AR078909A1 (en) |
| AU (1) | AU2010317895A1 (en) |
| BR (1) | BR112012011552A2 (en) |
| CA (1) | CA2780139A1 (en) |
| ES (1) | ES2359708B1 (en) |
| MX (1) | MX2012005616A (en) |
| PE (1) | PE20121315A1 (en) |
| RU (1) | RU2012124815A (en) |
| TW (1) | TW201130861A (en) |
| UY (1) | UY33032A (en) |
| WO (1) | WO2011058161A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632562B (en) * | 2015-10-30 | 2020-02-18 | 天津法莫西医药科技有限公司 | Fluorometholone refining process |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1238912B (en) * | 1964-01-31 | 1967-04-20 | Thomae Gmbh Dr K | Process for the preparation of new esters of triamcinolone-16alpha, 17alpha-acetonide |
| US4323512A (en) * | 1981-05-13 | 1982-04-06 | Schering Corporation | Process for the preparation of steroidal 17α-arylcarboxylates |
| GB9919693D0 (en) * | 1999-08-19 | 1999-10-20 | Rhone Poulenc Rorer Ltd | Process |
| US6696592B2 (en) * | 2001-05-22 | 2004-02-24 | Nicox-S.A. | Methods of making 21-[4′-(nitrooxyalkyl)benzoate] corticosteroid derivatives and intermediates useful in the synthesis thereof |
| EP1336602A1 (en) * | 2002-02-13 | 2003-08-20 | Giovanni Scaramuzzino | Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases |
| NZ566128A (en) * | 2005-09-02 | 2011-03-31 | Nicox Sa | Nitrooxy derivatives of glucocorticoids |
| EP1964550A1 (en) * | 2007-03-01 | 2008-09-03 | NicOx S.A. | Glucocorticoid-nitrooxyderivative compositions |
| ES2324007A1 (en) * | 2007-10-25 | 2009-07-28 | Ferrer Internacional, S.A. | Amorphous form of (11beta,16alpha)-9-fluoro-11-hydroxy-16,17-[(1-methylethyliden)bis(oxy)]-21-[[4- [(nitrooxy)methyl]benzoyl]oxy]-pregna-1,4-dien-3,20-dione |
-
2009
- 2009-11-16 ES ES200930999A patent/ES2359708B1/en not_active Expired - Fee Related
-
2010
- 2010-10-19 TW TW099135537A patent/TW201130861A/en unknown
- 2010-11-04 AR ARP100104079A patent/AR078909A1/en unknown
- 2010-11-15 MX MX2012005616A patent/MX2012005616A/en not_active Application Discontinuation
- 2010-11-15 CN CN2010800517342A patent/CN102612522A/en active Pending
- 2010-11-15 RU RU2012124815/04A patent/RU2012124815A/en unknown
- 2010-11-15 EP EP10776364A patent/EP2501710A2/en not_active Withdrawn
- 2010-11-15 BR BR112012011552A patent/BR112012011552A2/en not_active IP Right Cessation
- 2010-11-15 WO PCT/EP2010/067443 patent/WO2011058161A2/en active Application Filing
- 2010-11-15 CA CA2780139A patent/CA2780139A1/en not_active Abandoned
- 2010-11-15 UY UY0001033032A patent/UY33032A/en unknown
- 2010-11-15 PE PE2012000618A patent/PE20121315A1/en not_active Application Discontinuation
- 2010-11-15 JP JP2012538352A patent/JP2013510826A/en active Pending
- 2010-11-15 AU AU2010317895A patent/AU2010317895A1/en not_active Abandoned
- 2010-11-15 KR KR1020127015331A patent/KR20120084788A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU2010317895A1 (en) | 2012-05-24 |
| WO2011058161A2 (en) | 2011-05-19 |
| UY33032A (en) | 2011-05-31 |
| EP2501710A2 (en) | 2012-09-26 |
| WO2011058161A3 (en) | 2011-07-07 |
| PE20121315A1 (en) | 2012-10-06 |
| RU2012124815A (en) | 2013-12-27 |
| MX2012005616A (en) | 2012-10-15 |
| KR20120084788A (en) | 2012-07-30 |
| TW201130861A (en) | 2011-09-16 |
| JP2013510826A (en) | 2013-03-28 |
| ES2359708A1 (en) | 2011-05-26 |
| AR078909A1 (en) | 2011-12-14 |
| CN102612522A (en) | 2012-07-25 |
| BR112012011552A2 (en) | 2015-10-06 |
| ES2359708B1 (en) | 2012-03-30 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |
Effective date: 20141117 |