The way to get mometasone furoate

 

(57) Abstract:

The invention relates to an improved method of obtaining a known anti-inflammatory agents - furoate mometasone (I). (I) are obtained by direct complex esterification of the 17-hydroxyl group mometasone using 2-frailcare in the presence of a tertiary amine and an inert solvent, preferably dichloromethane, without prior protection of free 11-hydroxy-group. For removal of formed enolpyruvate perform additional processing hydrochloric acid. 7 C.p. f-crystals.

The invention relates to a method for mometasone furoate.

Furoate mometasone well known (Shapiro and Grove, USA 4/472/393 and Kwok, Tsi, Tan and Fu, WO 098/00437) as a strong anti-inflammatory steroid having the structure

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The U.S. patent And 4.472.393 describes two ways to get mometasone furoate. In example 12, the method I as the initial substance use 9, 11-epoxy-17, 21-dihydroxy-16-methyl-1,4-pregnadien-3,20-dione, whereas in method II uses 21-chloro-17-hydroxy-16-methyl-1,4,9(11)-pregnadien-3,20-dione.

Application WO 98/00437 describes an improved method coming from 9,11-epoxy-17, 21-dihydroxy-16-methyl-1,4-pregnadien-3,20-dio is in store complex esterification of the 17-hydroxy-group without prior protection 11-hydroxy-group.

A large number of clinically useful steroids, 17-hydroxy-group is difficult etherification and 11-hydroxy-group exists in a free form, well known as a clinically useful corticosteroids. Usually hard-ether group is introduced in the 17-position, while no other hydroxyl group is not present in the molecule, and other free hydroxyl groups are formed or gemaskerde later in the course of the synthesis. When there is another hydroxyl group, such as 11-hydroxy-group, use indirect ways. You can enter the 17-ester group by hydrolysis complex 17,21-orthoepical or by carrying out the complex esterification after protection of other hydroxyl groups in the molecule. For example, in order to achieve this, used protection 11-hydroxy-group in the form of trihalogenmenthanes of ester, in the form of trialkylsilyl ether or disguised in the form of 9,11-epoxide.

In this way, it was unexpectedly found that 17-hydroxy-group can be difficult to atrificial, without resorting to the protection of 11-hydroxy-group or disguised 11-hydroxy-group. In previous practice, the introduction of the 17-furoate group was always carried out with 9,11-epoxy group is the azone can be obtained in various ways.

It has been unexpectedly found that when mometazon undergoes reaction with 2-forargliga in the presence of a tertiary amine in an inert solvent, is obtained in good yield mometazon 17-(2-furoate). 2-Frailcare should preferably be used in excess, with the preferred amount of between 2.5 and 4 molar equivalents, but amounts outside this interval is also acceptable. There are no special restrictions with regard to the nature of the tertiary amine whose function is to activate 2-frailcare and neutralization of the hydrochloric acid released during the reaction, although preferred is triethylamine. The tertiary base is preferably used in an excess of from 3 to 6 molar equivalents, but you can use larger or smaller than these amounts. The solvent is preferably non-polar, is not miscible with water, the solvent should be such that all components of the reaction mixture, in particular any activated form Alliluyeva agent, were in solution during the reaction. It has been found that suitable solvent is dichloromethane, although you may be used and other solvents satisfying the above-formulated Crete is eriod a few hours although I can use a higher or lower temperature, which, respectively, can either reduce or increase the reaction time. When conducting the reaction in dichloromethane at 10oWith and using triethylamine she usually goes away completely within a period in the range of 10-15 hours

During the reaction can be formed by-products, such as furoate Enola on the provisions of 3 and 20. This in no way harmful affects neither the output nor the purity of the final product, because these compounds are easily converted into furoate mometasone by a short treatment of dilute aqueous hydrochloric acid. Usually after completion of complex esterification reaction solution after removal of the excess base with a short acid wash, within a few hours treated with an aqueous hydrochloric acid to convert by-products into the target mometasone furoate. This processing may be carried out in a two-phase system at a temperature of from 10 to 25oWith, although can be used for other temperature. In order to reduce the reaction time, the preferred thorough mixing and the use of a large volume of water chlorostoma">

Alternatively, you can add organic solvent, miscible with water and the solvent of the reaction, to increase the concentration of hydrochloric acid in the organic phase. For example, for this purpose can be used or ethanol or acetic acid in a ratio of from 0.5 to 2 volumes, and in this case, the reaction time at 25oWith typically ranges from 3 to 5 o'clock

Furoate mometasone can be isolated using standard techniques. Water flushing are used to remove water-soluble materials, after which dichloromethane is replaced by an alcohol of low molecular weight such as methanol or ethanol, from which the product crystallized in pure form and high yield. Can be carried out more techniques recrystallization from a number of other solvents suitable for the purification of pharmaceutical products, such as acetone, methanol and ethanol.

The following example explains, but in no way limits the present invention.

EXAMPLE

Getting 17-(2-furoate)mometasone

Mometazon (30 g) is suspended in methylene chloride (300 ml) and the resulting suspension is cooled to 0-5oC. At this temperature, add triethylamine (57 ml). Then slowly add the level of the present mometasone is lower than 0.2% according to HPLC (HPLC). Then the reaction solution is cooled to a temperature between -5 and 5oWith, and with stirring, water (120 ml). After stirring for 1 h at a temperature of from 10 to 15oThe mixture is cooled to a temperature between 0 and 5oWith and add concentrated hydrochloric acid to set the pH of the water layer between 1 and 2.

The phases are separated and the aqueous layer was extracted with methylene chloride (60 ml). To the combined organic layers add concentrated hydrochloric acid (90 ml) and acetic acid (30 ml) at a temperature of between 15 and 25oC. Then a two-phase reaction mixture is stirred at 20-25oFrom until, until there is less than 0.1% by-products by HPLC indications. The reaction mixture is cooled to a temperature of from 0 to 5oWith and add water (120 ml). The lower organic layer is separated and add water (120 ml) and 8 N. aqueous sodium hydroxide solution (about 30 ml) to bring the pH to between 5 and 6. After stirring for 2 h, the organic layer is separated and washed with water (120 ml).

The organic solution (containing 17-(2-furoate-mometasone) is concentrated by distillation to a volume of 120 ml Add additional metadot to a temperature between 20 and 25oC, then cooled to a temperature of between 0 and 5oC and stirred for 2 h Then filtered crude 17-(2-furoate)mometasone and washed with cold methanol (0 -oWith, 224 ml).

Cleaning 17-(2-furoate)mometasone

The wet cake is dissolved in acetone (395 ml) and add charcoal (3 g). After stirring at 15 - 25oWith at least within 24 h charcoal is filtered off and washed with acetone (90 ml). To the solution add charcoal (3 g), and the solution is stirred at a temperature of between 15 and 25oWith at least within 24 hours Then charcoal filtered and washed with acetone (75 ml).

The solution is concentrated by distillation to a volume of 120 ml During this concentration begins yet to crystallize 17-(2-furoate)mometasone. Add methanol (120 ml) and the solution again concentrated to 120 ml of This procedure is repeated twice.

The suspension is slowly cooled to a temperature between 20 and 25oC, then cooled to a temperature of between 0 and 5oC and stirred for about 2 h at this temperature. Then filter net 17-(2-furoate-mometasone and washed with cold methanol (0 to 5oWith, 224 ml). The product is dried with 6 PCs of mometasone with 2 forargliga in the presence of a tertiary amine in an inert solvent.

2. The method according to p. 1, in which the tertiary amine is triethylamine.

3. The method according to p. 1, in which the nonpolar solvent is not miscible with water, the solvent, such that any activated form 2-frailcare is in solution during the reaction.

4. The method according to p. 1 or 3, wherein the inert solvent is dichloromethane.

5. The method according to any of the preceding paragraphs, in which use 2.5 to 4 molar equivalents of 2-frailcare on the molar equivalent of mometasone.

6. The method according to any of the preceding paragraphs, in which you use from 3 to 6 molar equivalents of triethylamine in a molar equivalent to mometasone.

7. The method according to any of the preceding paragraphs, in which the reaction is carried out at a temperature of from 0 to 25oC.

8. The method according to any of the preceding paragraphs, further comprising processing the reaction products of aqueous hydrochloric acid to remove enolpyruvate formed in positions 3 and 20 mometasone.

 

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