Preparation procedure for (11 ß, 16a) -9-fluoro-11-hydroxy-16,17- [1-methylene-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitrooxymethyl ) benzoxy]] preña-1,4-dien-3,20-dioneDESCRIPTIONField of techniqueThe present invention relates to a new process for the preparation of the compound (11β, 16a) -9-fluoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitrooxymethyl) benzoxy]] prena-1,4-dien-3,20-dione, useful as a topical anti-inflammatory.
State of the artThe compound (11β, 16a) -9-fluoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitrooxymethyl) benzoxy]] prena- 1,4-dien-3,20-dione of formula (I) is a corticosteroid previously described in the application WO2007025632 (Example 1). It is a compound especially useful in the treatment of certain inflammatory diseases such as dermatosis sensitive to corticosteroids, 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 application WO2007025632 by 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 Scheme 1.
Scheme 1The yield of this reaction is 34.4%, which makes it unfeasible industrially. In addition, the price of the diimide used (IV) is also a drawback for use in industrial processes.
Thus, it is necessary to have another procedure that provides industrially the compound (I) with a high yield and that 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) by the cheaper N, N'-diisopropylcarbodiimide (VI), . 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 step of controlled precipitation that provides the final product with a suitable particle size for the preparation of topical formulations.
Compendium of the inventionIn a single aspect, the invention provides a new industrial process for the preparation of (11β, 16a) -9-fluoro-11-hydroxy-16,17- [1-methylene-ethylidenebis (oxy)] - 21- [ 1-oxo- [4- (nitrooxymethyl) benzoxy]] prena-1,4-dien-3,20-dione (I), in good yield, starting from economically available products and providing a final product with purity and size of suitable particle.
Detailed description of the inventionThe process for the preparation of (11β, 16a) -9-fluoro-11-hydroxy-16,17- [1-methyl-ethylidenebis (oxy)] - 21- [1-oxo- [4- (nitrooxymethyl) benzoxy] ]] preña-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?,? '- diisopropylcarbodiimide (VI)in an inert solvent, followed by the elimination by filtration or centrifugation of the formed solid, constituted mainly by?,? '- diisopropilurea, acidification of the liquid phase, neutralization and washing of the same with water, addition of an anti-solvent d. inert 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 dimethyl sulfoxide, 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, trifluoroacetic acid and formic acid , sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, and other similar acids, and mixtures thereof. Preferably the acid is hydrochloric acid.
In another preferred embodiment, the neutralization is carried out with a base selected from the group consisting of alkaline bicarbonates such as sodium bicarbonate and potassium bicarbonate, and alkaline 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-d Similar solvents, 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 asethyl acetate and isopropyl acetate, nitriles 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 tetrahyde oxide, ketones such as acetone and methyl isobutyl ketone, nitriles 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 d-C4 alkanols as ethanol, methanol and isopropanol, and similar anti-solvents, and their mixtures. Preferably the anti-solvent is heptane.
ExamplesExample 1Synthesis of (1 1ß, 16a) -9-fluoro-11-hydroxy-16,17-ri-methyl-ethylidenebis (oxm-21-ri-oxo- [4- (nitrooxymethyl) benzoxy-1-4-diene) 3,20-dione (I)Scheme 2(i) ReactionTo 284 L of dichloromethane, 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 L of α, β'-diisopropylcarbodiimide were added. (SAW). The solution was brought to room temperature and kept stirring until the reaction was complete. 13 L of dichloromethane were added.
The formed solid (?,? '- diisopropylurea) was filtered off and the filter was washed with dichloromethane.
The dichloromethane extracts were combined and 203 L of 0.5 N HCl were added. 20 L of 0.5 N HCl and then 129 L of 0.25 N NaHCO 3 were added to the organic phase. It 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 come to 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). Performance = 85.5%. Purity HPLC = 98.41%. -(ii) Crystallization15.56 Kg of the solid obtained in the previous step were 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 come to room temperature and 560 L of ethanol were added.
The suspension was filtered and the wet solid was washed with ethanol.
The wet solid was dried in vacuo.(iii) Precipitation11.21 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. HEfiltered the solution through a 0.2 μ 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 2Particle 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 pm; d (0.5) = 5.26 pm; and d (0.1) = 2.34 pm.