US patent no. 4,472,393 describes a process for the preparation of mometasone furoate and WO 98/00437 describes an improved process.

Mometasone furoate is obtained by both processes without the need to prepare mometasone per se. Thus, the process described in US patent no. 4, 472,393 first prepares the 17- (2-furoate) of 21-chloro-9 (3, 11 (3-epoxy-17a-hydroxy-16a-methyl- 1, 4-pregnadiene-3,20-dione or further uses 16a-methyl-1, 4,9 (11)-pregnatriene- 17a, 21-diol-3, 20-dione as a raw material to prepare the 17-furoate, without passing through mometasone. WO 98/00437 describes a process starting from 9 , 11- epoxy-17a, 21-dihydroxy-16a-methyl-1, 4-pregnadiene-3,20-dione.

These processes introduce the 17-furoate group and substitute the 21- hydroxyl by chlorine before formation of the hydroxyl group in CI I, since it is feared that otherwise important adverse reactions may occur. However, we have unexpectedly found that the 21-hydroxyl group can be substituted by 21-chlorine, even in the presence of the unprotected 11 -hydroxyl. From this observation, it can be concluded that the presence of the chlorine atom in the 9a-position ensures a a greater stability of the neighbouring hydroxyl group, rendering it non-reactive under the conditions in which the 21-hydroxyl is substituted by an atom of halogen.

In one aspect, the present invention provides a process for preparing 9a, 21-dichloro-11, 17a-dihydroxy-16a-methyl-pregna-1, 4-diene-3,20-dione momestasone), which comprises reacting 9a-chloro-llp, 17a, 21-trihydroxy-16a- methyl-pregna-1, 4-diene-3,20-dione (icomethasone) with a sulfonyl chloride of the formula R-CI02S wherein R is CH3 or p-CH3C6H4, in the presence of a tertiary amine and solvent ; and reacting the 21-sulfonate so obtained with a source of chloride ions in an inert solvent.

We have further found that mometasone per se, which is not described in the prior art, is a potent anti-inflammatory agent and is also very useful as a starting compound or intermediary in the preparation of the 17-furoate and other 17-esters, as well as in the preparation of other derivatives.

In a second aspect, therefore, the invention provides mometasone per se.

In one embodiment, the process of the invention comprises 21-mesylation of icomethasone in the presence of a tertiary amine, followed by reaction of the compound thus obtained with a chloride salt, such as for instance lithium or sodium chloride, in an inert solvent, to obtain mometasone. In another embodiment, icomethasone is reacted with a slight excess of p-toluenesulfonyl chloride in the presence of a tertiary amine, preferably triethylamine, in an inert solvent. Preferably, a lower aliphatic alcohol, such as methanol or ethanol, is subsequently added to the reaction mixture to destroy the excess p-toluenesulfonyl chloride. On heating the reaction mixture at 40°C for a few hours, the tosylate undergoes decomposition in the presence of chloride ions, thus yielding mometasone. The chloride ions can conveniently be provided by the hydrochlorides of the amines used in the tosylation reaction, such as triethylammonium chloride when triethylamine is used as a base. In this manner, it is possible to carry out the transformation of icomethasone into mometasone of a high purity in a single reactor, without isolating the 21-tosylate of icomethasone, the yield being near to stoichiometric.

To obtain a high quality mometasone in a high yield, it is preferred to use highly pure icomethasone starting material. This is readily available nowadays, with a purity above 98%. Special care should preferably be taken to ensure that there is no water in the starting material, and that the reaction solvent, a tertiary amine, is anhydrous.

The mesylation reaction is preferably carried out at low temperature, most preferably between-2°C and +2°C, in pyridine which is used as a base as well as a solvent. When the reaction is carried out at lower temperatures, the reaction time is longer and when higher temperatures are used, a lower quality product is obtained. The addition of mesyl chloride usually takes from 1 to 2 hours, e. g. about Ih 30m, and the reaction time, after adding the reagent at 0°C, is usually approximately 4 hours. The 21-mesylate of icomethasone can thus be obtained highly pure and practically free of traces of substitution in the 11- position. The transformation of the 21-mesylate of icomethasone to mometasone is preferably carried out in N, N-dimethylformamide, using an excess of an alkali metal chloride. Sodium chloride is preferred since it gives an excellent yield and does not require any special care to maintain the mixture free of water as is the case when lithium chloride, a hygroscopic compound, is used.

The process of the invention to make mometasone can be carried out in a single reaction vessel without isolation of the sulfonate obtained in the first step. For example, icomethasone can be added to dichloromethane (the water content of which should be lower than 0.03% by K. F.) and the 21-tosylate can be prepared by performing the reaction with an excess of p-toluenesulfonyl chloride under inert nitrogen conditions. The reaction is carried out, preferably, at a temperature of-1°C, with good stirring. After the addition of the chloride, triethylamine is added for example, and the temperature is preferably not allowed to rise above 0°C. Usually, the amine is added over 2 to 3 hours, e. g. about 2h 30m. After the addition, the mixture is stirred at 0°C for a further period, e. g. 7 hours, to complete the tosylation reaction. At the end of the reaction, excess p-toluenesulfonyl chloride is destroyed by adding (at 0°C) an amount of methanol or ethanol equivalent to the excess of the chloride used. The 21-tosylate of mometasone thus obtained is subsequently converted into mometasone, by heating the reaction mixture, for example to between 35°C and 40°C, and regularly controlling the reaction progress, e. g. by thin layer chromatography or high performance liquid chromatography. The reaction is usually complete after about 6 to 7 hours. The chloride ions necessary for the reaction come from the triethylammonium chloride formed during the tosylation. Mometasone can be isolated by various procedures. For instance, to isolate the product, the solvent can be completely distilled under vacuum and the residue dissolved in dimethylformamide. Mometasone can be subsequently precipitated by adding the solution dropwise to a mixture of ice and water.

The mometasone thus obtained can then be filtered, washed in iced water until the filtrate is free of chloride ions, and dried at 50°C to constant weight.

The mometasone can be transformed directly into any 17-ester by the process described in Portuguese Patent 102.343.

The following examples serve to illustrate the invention and are not, in any way, to be considered a limitation thereof.

EXAMPLE 1 A 3g of icomethasone are added to 18 ml of dried pyridine at a temperature between 20°C and 25°C, under stirring. After complete dissolution, the solution is cooled down to between-2°C and +2°C, whilst excluding humidity. 1.02 ml of methanesulfonyl chloride is subsequently added, the reaction mixture being maintained at a temperature between-2°C and +2°C.

The end of the reaction is detected by thin layer chromatography.

[Stationary phase: silica gel, Merck Art. 554; eluent CHC13/MeOH/H20 (90: 7.5: 0.5). Sampling: 5p1 of a solution of 8 mg/ml of CHC13/MeOH (9: 1); U. V. peak at 254 nm]. For the reaction to be complete, it is necessary to stir for about 3.5 to 4 hours. The reaction mixture is subsequently added, under good stirring, to a mixture containing 108 ml of water, 72g of ice and 15.9 ml of concentrated hydrochloric acid. It is then stirred for 1 hour, after which the precipitated product is filtered and washed with iced water (about 2 x 20 ml) until neutral pH. After drying to constant weight at 50°C under good air circulation, 3.57 g of icomethasone 21-mesylate were obtained, [a] D°°206 (in dioxane), El'% m309 at 240 nm in methanol ; melting point 196-202°C with decomposition.

B 2g of the icomethasone 21-mesylate obtained above are added to 20 ml of dimethylformamide, under good stirring. When the mesylate is completely dissolved, 2g of sodium chloride are added. The mixture is then heated in a water-bath between 60°C and 65°C until the reaction is complete, which takes 3 to 4 hours. The reaction mixture is then cooled down to 20°C and added to a mixture containing 140 ml of water and 60g of ice, under good stirring. The precipitate is filtered and washed with 150 ml of iced water until the mother-liquors do not contain chloride ions. It is subsequently dried at 50°C to constant weight, yielding 1.7g of mometasone. Melting point 233°C, [a] 20° 127 (C, 1 in dioxane), ElCzm 354 at 240 nm in methanol (see accompanying single-Figure drawing which is an infrared curve of mometasone).

EXAMPLE 2 The reaction as described above in Example 1-B is repeated but using 1.49g of lithium chloride instead of 2g sodium chloride, yielding 1.6g of mometasone, identical to the product obtained in said Example.

EXAMPLE 3 2.5g of icomethasone are added under nitrogen to 15 ml of dichloromethane and cooled down to-1°C. A solution containing 2.05g of p-toluenesulfonyl chloride in 15 ml of dichloromethane is then added dropwise, maintaining the temperature at -1°C. After stirring for 30 minutes, 2.8 ml of triethylamine are added dropwise, maintaining the temperature at-1°C, which takes about 2.5 to 3 hours. The reaction progress is followed by thin-layer chromatography. After the reaction is complete, which takes about 7 hours, the reaction mixture is added to a mixture containing 0.2 ml of methanol and 2 ml of dichloromethane. The resulting mixture is then heated to 40°C, under good stirring. The reaction takes 6 to 7 hours and its completion is controlled by thin-layer chromatography. Usually, the reaction is complete after 6 to 7 hours. The solvent is then evaporated under vacuum and 3 ml of dimethylformamide are added. The mometasone product is precipitated by dropwise addition of the solution thus obtained to 50 ml of iced water, under good stirring. The crystalline product is then filtered off and washed with distilled iced water until the mother-liquors do not contain chloride ions. The mometasone thus obtained weighs, after drying, 2.56g.