ES2359708B1 - 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. - Google Patents

Abstract

Preparation procedure for (11 {be}, 16 {al}) - 9-fluoro-11-hydroxy-16.17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitrooxymethyl) benzoxy]] prena-1,4-dien-3,20-dione. # The present invention relates to a new method of preparing (11 {be}, 16 {al}) - 9-fluoro- 11-hydroxy-16.17 - [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitroxymethyl) benzoxy]] prena-1,4-dien-3,20-dione, which It comprises the steps of (i) reacting triamcinolone acetonide with 4- (nitroxymethyl) benzoic acid, 4-dimethylaminopyridine and N, N’-diisopropylcarbodiimide, (ii) crystallization, and (iii) controlled precipitation.

Description

Preparation procedure for (11β, 16α) -9- fl uoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4 (nitrooxymethyl) benzoxy]] pregna -1,4-dien-3,20-diona.

Technical field

The present invention relates to a new process for preparing the compound (11β, 16α) -9- fl uoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitroxymethyl) benzoxy]] pregna-1,4-dien-3,20-dione, useful as a topical anti-inflammatory.

State of the art

The compound (11β, 16α) -9- fl uoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitroxymethyl) benzoxy]] pregna-1 , 4-dien-3,20-dione, of formula (I), is a corticosteroid previously described in application WO2007025632 (Example 1). It is an especially useful compound in the treatment of certain inflammatory diseases such as corticosteroid sensitive dermatosis, atopic dermatitis, contact dermatitis, psoriasis and seborrheic dermatitis.

Said compound is applied topically preferably by creams, ointments, lotions and gels, and similar formulations.

The compound of formula (I) is obtained in example 1 of the application WO2007025632 by reacting triamcinolone acetonide (II) with 4- (nitroxymethyl) benzoic acid (III) in the presence of 1-ethyl-3- (3-dimethylaminopropyl ) carbodiimide (IV) and 4-dimethylaminopyridine (V), according to Scheme 1.

(Scheme goes to next page) Scheme 1

The yield of this reaction is 34.4%, which makes it industrially unfeasible. In addition, the price of the diimide used (IV) is also inconvenient for use in industrial processes.

Thus, it is necessary to have another process that industrially provides the compound (I) with high performance and uses cheaper starting products.

The authors of the present invention have achieved a new industrial process for obtaining (I), which leads to the product with much higher yield and also replaces the diimide (IV) with the N, N'-diisopropylcarbodiimide (VI), cheaper . On the other hand, it has been found that the resulting product is of high purity. In addition, the new process also comprises a final controlled precipitation stage that provides the final product with a particle size suitable for the preparation of topical formulations.

Compendium of the invention

In a single aspect, the invention provides a new industrial process for the preparation of (11β, 16α) -9 fl uoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitroxymethyl) benzoxy]] pregna-1,4-dien-3,20-dione (I), with good performance, starting from economically affordable products and providing a final product with adequate purity and particle size.

Detailed description of the invention

The preparation process for (11β, 16α) -9- fl uoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo [4- (nitrooxymethyl) benzoxy]] pregna-1,4-dien-3,20-dione (I), which constitutes the only aspect of the invention, comprises 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, followed by removal by filtration or centrifugation of the solid formed, consisting mostly of N, N'-diisopropylurea, acidification of the liquid phase, neutralization and washing thereof with water, addition of an inert anti-solvent to the organic phase and separation by filtration or centrifugation of the compound (I) thus formed;

(ii) crystallization of the compound (I) formed in step (i) in a mixture of a solvent and an anti-solvent; Y

(iii) precipitation of the compound (I) crystallized in step (ii) in a mixture of a solvent and an anti-solvent.

In a preferred embodiment, the solvent of step (i) is selected from the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofuran, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, nitriles such as acetonitrile, sulfoxides such as dimethylsulfoxide, and similar solvents, and mixtures thereof. Preferably the solvent is dichloromethane.

In another preferred embodiment, the acidification is carried out with an acid selected from the group consisting of mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, carboxylic acids such as acetic acid, tri-fluoroacetic acid and formic acid. , sulfonic acids such as methanesulfonic acid, tri-fluoromethanesulfonic acid and p-toluenesulfonic acid, and other similar acids, and mixtures thereof. Preferably the acid is hydrochloric acid.

In another preferred embodiment, neutralization is carried out with a base selected from the group consisting of alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, and alkali carbonates such as sodium carbonate and potassium carbonate. Preferably the base is sodium bicarbonate.

In another preferred embodiment, the anti-solvent of step (i) is selected 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 anti-solvents similar, and their mixtures. Preferably the anti-solvent is ethanol.

In another preferred embodiment, the solvent of step (ii) is selected from the group consisting of halogenated hydrocarbons such as dichloromethane, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofuran, ketones such as acetone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, nitrites such as acetonitrile, sulfoxides such as dimethyl sulfoxide, and similar solvents, and mixtures thereof. Preferably the solvent is dichloromethane.

In another preferred embodiment, the anti-solvent of step (ii) is selected 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 anti-solvents similar, and their mixtures. Preferably the anti-solvent is ethanol.

In another preferred embodiment, the solvent of step (iii) is selected from the group consisting of esters such as ethyl acetate and isopropyl acetate, amides such as dimethylformamide and dimethylacetamide, cyclic ethers such as tetrahydrofuran, ketones such as acetone and methyl isobutyl ketone, nitrites such as acetonitrile, halogenated hydrocarbons such as dichloromethane, and sulfoxides such as dimethyl sulfoxide, and similar solvents, and mixtures thereof. Preferably the solvent is ethyl acetate.

In another preferred embodiment, the anti-solvent of step (iii) is selected from the 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 as ethanol, methanol and isopropanol, and similar anti-solvents, and mixtures thereof. Preferably the anti-solvent is heptane.

Examples

Example 1

Synthesis of (11β, 16α) -9- fl uoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitroxymethyl) benzoxy]] pregna-1 , 4-dien-3,20-diona (I)

Scheme 2

(i) Reaction To 284 L of dichloromethane, 12.92 Kg of triamcinolone acetonide (II), 6.50 Kg of 4- (nitroxymethyl) benzoic acid (III), 401 g of 4-dimethylaminopyridine (V) and 5.8 L of N were added, N'-diisopropylcarbodiimide (VI). The solution was brought to room temperature and kept under stirring until the reaction was complete. 13 L of

dichloromethane

The solid formed (N, N’-diisopropylurea) was removed by filtration and the fi lter was washed with dichloromethane.

The dichloromethane extracts were combined and 203 L of 0.5 N HCl was added. They were added to the organic phase.

203 L of 0.5 N HCl and then 129 L of 0.25 N NaHCO3 was washed with water until the pH of the aqueous phase was similar to that of the added water. 465 L of absolute ethanol were added to the organic phase and distilled at atmospheric pressure to a final volume between 465 L and 504 L, and allowed to reach room temperature. The suspension was filtered and the wet solid was washed with ethanol. The wet solid was dried in vacuo to obtain 15.59 kg of the compound (I). Yield = 85.5%. HPLC purity = 98.41%.

(ii) Crystallization 15.56 Kg of the solid obtained in the previous step was added to 467 L of dichloromethane. It was heated to reflux and distilled at atmospheric pressure to a final volume of 47 L. It was allowed to reach room temperature and added

560 L of ethanol. The suspension was filtered and the wet solid was washed with ethanol. The wet solid was dried in vacuo.

(iii) Precipitation

11.21 Kg of the solid obtained in the previous step was added to 516 L of ethyl acetate. It was heated to reflux and stirred until dissolved. It was cooled to 40-50 ° C. 538 L of heptane were added and brought to room temperature. The solution was filtered through a 0.2 μm filter. It was washed with ethyl acetate and stirred for at least 3 hours at room temperature.

The suspension was filtered and the wet solid was washed with heptane.

The wet solid was dried in vacuo.

Example 2

Particle size distribution of (I)

The particle size distribution of the product obtained in the final stage of Example 1 presented a Gaussian distribution characterized by the values d (0.9) = 10.79 μm; d (0.5) = 5.26 μm; and d (0.1) = 2.34 μm.

Claims (18)

1. Preparation procedure for (11β, 16α) -9- fl uoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo [4- (nitrooxymethyl) benzoxy] ] pregna-1,4-dien-3,20-diona (I) which comprises the following stages: (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 centrifugation of the solid formed, acidification of the liquid phase, neutralization and washing thereof with water, addition of an inert anti-solvent to the organic phase and separation by filtration or centrifugation of the compound (I ) so formed; (ii) crystallization of the compound (I) formed in step (i) in a mixture of a solvent and an anti-solvent; Y (iii) precipitation of the compound (I) crystallized in step (ii) in a mixture of a solvent and an anti-solvent.

2.

Process according to claim 1, wherein the solvent of step (i) is selected from the group consisting of dichloromethane, dimethylformamide, tetrahydrofuran, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethylsulfoxide.

3. Process according to claim 2, wherein the solvent is dichloromethane.

Four.

Process according to claim 1, wherein the acidification is carried out with an acid selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, tri-fluoroacetic acid, hydrobromic acid, formic acid, methanesulfonic acid, tri-fluoromethanesulfonic acid and p-toluenesulfonic acid.

5. Process according to claim 4, wherein the acid is hydrochloric acid.

6.

Process according to claim 1, wherein the neutralization is carried out with a base selected from the group consisting of sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.

7. Method according to claim 6, wherein the base is sodium bicarbonate.

8.

Process according to claim 1, wherein the anti-solvent of step (i) is selected from the group consisting of ethanol, methanol, isopropanol, toluene and water.

9. Process according to claim 8, wherein the anti-solvent is ethanol.

10.

Process according to claim 1, wherein the solvent of step (ii) is selected from the group consisting of dichloromethane, dimethylformamide, tetrahydrofuran, acetone, acetonitrile, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethylsulfoxide.

11. Process according to claim 10, wherein the solvent is dichloromethane.

12.

Process according to claim 1, wherein the anti-solvent of step (ii) is selected from the group consisting of ethanol, methanol, isopropanol, toluene and water.

13. Process according to claim 12, wherein the anti-solvent is ethanol.

14.

Process according to claim 1, wherein the solvent of step (iii) is selected from the group consisting of ethyl acetate, dimethylformamide, tetrahydrofuran, acetone, acetonitrile, dichloromethane, isopropyl acetate, methyl isobutyl ketone, dimethylacetamide and dimethylsulfoxide.

15. Process according to claim 14, wherein the solvent is ethyl acetate.

16.

Process according to claim 1, wherein the anti-solvent of step (iii) is selected from the group consisting of heptane, isopropyl ether and isopropanol.

17. Method according to claim 16, wherein the anti-solvent is heptane. SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 200930999 SPAIN Date of submission of the application: 16.11.2009 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: C07J41 / 00 (01.01.2006) RELEVANT DOCUMENTS

Category

Documents cited Claims Affected

TO

WO 2007025632 A2 (NICOX AND FERRER INTERNATIONAL) 08.03.2007, example 1; claims 18-30. 1-17

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 22.02.2011

Examiner M. Fernández Fernández Page 1/4

REPORT OF THE STATE OF THE TECHNIQUE Application number: 200930999 Minimum documentation sought (classification system followed by classification symbols) C07J Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENES, EPODOC, WPI, CAS State of the Art Report Page 2/4  WRITTEN OPINION Application number: 200930999 Date of Completion of Written Opinion: 02.22.2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-17 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-17 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/4  WRITTEN OPINION Application number: 200930999 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

WO 2007/025632 A2 (NICOX AND FERRER INTERNATIONAL) 03.03.2007

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The application relates to a process for the preparation of the pregna-3,20-dione derivative of formula (I) of claim 1, which comprises the reaction of triamcinolone acetonide of formula (II) with 4- (nitrooxymethyl) acid benzoic acid (formula (III), 4-dimethylaminopyridine (formula (V) and N, N-diisopropylcarbodiimide (formula VI). Finally, compound (I) is purified by crystallization and precipitation. Document D1 is the closest to the state of the art, discloses the synthesis of compound (I) from the compound of formula (II), however the experimental conditions described in the application vary with respect to those disclosed in D1 and that in D1 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC) is used (see example 1 of D1) and in the subsequent phase of purification of compound (I) the application procedure avoids purification by chromatography using crystallization and precipitation to adapt the experimental conditions on a larger scale and achieve the final product with the desired purity and particle size characteristics. Consequently, it is considered that the procedure described in the application is new and inventive as it would not be possible for a person skilled in the art to deduce that said experimental conditions are favorable without the corresponding experimentation. Consequently, claims 1-17 of the application are considered to meet the conditions of novelty and inventive activity set forth in Articles 6.1 and 8.1 of Patent Law 11/1986. State of the Art Report Page 4/4