Method for producing alclometasone dipropionate and intermediates thereof

Abstract

Disclosed is a process for the preparation of a compound of formula (VI) comprising: a) conversion of a compound of formula (VII) to the compound of formula (XII) wherein A is a silyl group of formula -Si(R)3 b) bromination reaction of a compound of formula (XII), and c) subsequent HBr elimination reaction with formation of a compound of formula (VI). The invention also provides a method for preparing alclometasone dipropionate of formula (I), which comprises the use of the compound of formula (VI) as starting product.

Description

[0001] METHOD FOR PRODUCING ALCLOMETASONE DIPROPIONATE AND

[0002] INTERMEDIATES THEREOF

[0003] Field of invention

[0004] The present invention relates to a method for obtaining alclometasone dipropionate and intermediates thereof useful in synthesis.

[0005] Background to the invention

[0006] Alclometasone dipropionate [7a-chloro-16a-methyl-l,4-pregnadiene-l 11β, 17α, 21 -tri 01- 3,20-dione 17,21 -dipropionate] of formula (I) is a synthetic corticosteroid that possesses anti- inflammatory, anti-pruritic and vasoconstriction properties.

[0007] Alclometasone dipropionate

[0008] Alclometasone dipropionate is the active ingredient of medicaments approved for topical dermatological use.

[0009] The synthesis of alclometasone dipropionate of formula (I) is known from the scientific and patent literature.

[0010] Green et aL in patent US4076708, described the synthesis of 7α-halogen derivative compounds for the first time. In particular, alclometasone dipropionate of formula (I) is prepared by adding gaseous HC1 on the C6-C7 double bond of the compound of formula (II),

[0011] Scheme 1.

[0012] Scheme 1 The compound of formula (II), in turn, can be prepared from the compound 16a- methylprednisolone 21-acetate (IV) by oxidation reaction with 2,3-dichloro-5,6-dicyano-l,4- benzoquinone (DDQ) in the C6-C7 position, as reported by Green et al. in patent US4124707 (Scheme 2). Said oxidation reaction gives rise to the compound of formula (III) bearing the conjugated double bond in C6-C7 which, after manipulation of the hydroxyl functions in Cl 7 and C21 into propionate esters, provides the compound of formula (II), the synthesis intermediate of alclometasone dipropionate of formula (I).

[0013] Scheme 2

[0014] However, neither the yields of the individual steps nor the total process yield are stated in said patent.

[0015] The same inventors, in patents US4076708 and US4124707, further disclose that adding HC1 to the compound of formula (VI) bearing the ketone function at Cl 1 (Scheme 3), instead of to the analogue thereof of formula (II) having a hydroxyl functional group, produces a considerably better yield. Although obtaining alclometasone dipropionate of formula (I) from a compound of formula (V) necessitates a further ketone reduction reaction in Cl l, the total process yield to produce alclometasone dipropionate of formula (I) is more advantageous if the HC1 addition reaction is conducted on the compound containing the ketone function at Cl 1 of formula (VI).

[0016] Scheme 3 When the authors of the present invention repeated the procedure described in Scheme

[0017] 3, also conducting the ketone reduction reaction at Cl 1 of the compound of formula (V), they isolated alclometasone dipropionate of formula (I) with a yield twice that obtained by direct addition to the analogue of formula (II) having a hydroxyl functional group at Cl l, thus experimentally confirming the findings disclosed by Green et al. Preparation of the compound of formula (VI), characterised by the presence of the ketone function at Cl l, which is essential for preparation of alclometasone dipropionate of formula (I), is known in the literature.

[0018] For example, 2 preparations are specified in patent US4124707. In preparation 10D, the patent reports the synthesis of the compound of formula (VI) by oxidation of the compound of formula (VII) with DDQ, very similarly to the method used to prepare the compound of formula (II), Scheme 4.

[0019]

[0020] Scheme 4

[0021] However, in preparation 10D, neither the details of the experimental procedure nor the oxidation yield are supplied. Moreover, it should be noted that the oxidising agent DDQ is toxic and the derivatives thereof are difficult to remove from the crude end-of-reaction products, requiring lengthy, tedious purifications; the use thereof on an industrial scale in oxidation reactions is therefore not recommended.

[0022] In preparation 5, however, it is stated that following the bromination reaction at C6 of a compound of formula (X) with 7V-bromosuccinimide (NBS), a compound of formula (IX) is obtained. After elimination of HBr, a compound of formula (VIII) is obtained, containing the double bond in the C6-C7 position which, after the known modifications in C17 and C21, provides the key intermediate of formula (VI), Scheme 5. Once again, the inventors of US4124707 do not supply the bromination yield, but provide extensive information about the experimental details.

[0023]

[0024] Scheme 5

[0025] The authors of the present invention used the same bromination conditions on the compound of formula (VII), already bearing the propionate esters in the C17 and C21 position, for the remainder of the molecule very similar to the compound of formula (X) described in US4124707 wherein the manipulation has not yet been carried out. The bromination reaction with NBS of the compound of formula (VII) to give the brominated derivative of formula (XI) did not begin, however, and no conversion of the starting product was observed. In this case NBS is a good brominating agent also used on an industrial scale, but the fact that the reaction does not proceed effectively to give the key intermediate of formula (VI) means that bromination is not an alternative to the use of DDQ.

[0026] However, preparation of the brominated derivative of formula (XI) was described by

[0027] Shapiro et al in US4440690, by bromination of the compound of formula (VII) using molecular bromine instead of NBS as brominating agent, Scheme 6.

[0028] Scheme 6

[0029] US4440690 does not provide the bromination reaction yield; however, molecular bromine is a highly toxic oxidizing gas, such that 0.2 ppm is sufficient to cause irritation of the eyes and respiratory tract. Using molecular bromine on an industrial scale in the bromination reaction of a compound of formula (VII) is therefore not the best choice of synthesis method for the key intermediate of formula (VI). On an industrial scale, it would be preferable to use brominating agents that are less hazardous and more easily handled, especially solids.

[0030] Despite the various processes described in the prior art relating to synthesis of a compound of formula (VI) for use as a key intermediate in the synthesis of alclometasone dipropionate of formula (I), and our attempts to use the reported methods on intermediates, such as the compound of formula (VII), which should produce the compound of formula (VI) with fewer synthesis steps and using industrially safe brominating agents, alclometasone dipropionate of formula (I) could never be obtained using a process that was safe and efficient in terms of yield and purity.

[0031] There is therefore a need for a method of preparation of alclometasone dipropionate of formula (I) and the key intermediates thereof that is reproducible on an industrial scale, robust, safe and economical, without the use of methods which involve hazardous oxidation or bromination reagents like bromine, or lengthy, difficult purifications.

[0032] Description of the invention

[0033] The subject of the present invention is a process for the preparation of the compound of formula (VI)

[0034] comprising: a) conversion of a compound of formula (VII) to the compound of formula (XII) wherein A is a silyl group of formula -Si(R)3, wherein R is selected independently from the group comprising (C1-C4)alkyl, (C6-C10)aryl, (C1-C4)alkyl-(C6-C10)aryl and (C6- C10)aryl-(C1-C4)alkyl b) bromination reaction of a compound of formula (XII), and c) subsequent HBr elimination reaction with formation of a compound of formula (VI).

[0035] According to a preferred aspect of the invention, group A is a silyl group of formula - Si(R)s, selected from the group comprising trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tri-isopropylsilyl, diphenyltertbutylsilyl, diphenylmethyl silyl and phenyldimethylsilyl. More preferably, a silyl group of formula -Si(R)3 is the tert-butyldimethylsilyl group.

[0036] The conversion of a compound of formula (VII) to a compound of formula (XII) described in step a) of the present invention can be conducted by reacting the compound of formula (VII) with a silylating agent of formula A-X, wherein A is as defined above and X is (i) a leaving group preferably selected from the group of alkyl sulphonates of formula PSO3 , wherein P is a (C1-C6) alkyl group, optionally substituted with one or more halides, preferably fluoride; in certain embodiments, an alkyl sulphonate of formula PS Or is methanesulphonate or trifluoromethanesulphonate; or (ii) a leaving group selected from the group of halides, particularly chloride, bromide and iodide. Preferably the reaction is conducted in a solvent and in the presence of a base.

[0037] The reaction between a compound of formula (VII) and the silylating agent of formula A-X, wherein A and X are as defined above, can be conducted under stirring at a temperature ranging between 0°C and the reflux temperature of the solvent, preferably between 0°C and 10°C. On completion of the silylation reaction, the reaction mixture can undergo common aqueous washes, and the product of formula (XII) can be recovered from the resulting organic solution by evaporation of the solvent or crystallisation (Scheme 7). The compound of formula (XII) can be used directly in the subsequent bromination reaction described in step b) without any further purifications.

[0038] Scheme 7

[0039] The silylating agent of formula A-X, wherein A and X are as defined above, is preferably trimethyl silyl tritiate, tert-butyldimethylsilyl tritiate or trimethyl silyl chloride and te / 7-butyl di methyl si lyl chloride, more preferably tert-butyldimethylsilyl tritiate.

[0040] The reaction between a compound of formula (VII) and the silylating agent of formula A-X, wherein A and X are as defined above, can be conducted in a solvent selected from the group comprising ether solvents such as dioxane, tetrahydrofuran, isopropyl ether, 1,2- dimethoxyethane and tert-butyl methyl ether, preferably tetrahydrofuran, or chlorinated solvents such as dichloromethane, chlorobenzene and chloroform, preferably di chi or om ethane . The base used in the reaction between a compound of formula (VII) and the silylating agent of formula A-X, wherein A and X are as defined above, can be an organic or inorganic base. An organic base can be a tertiary aliphatic or aromatic amine, for example selected from the group comprising 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, N,N- diisopropylethylamine (DIPEA), methylimidazole, imidazole and tri ethylamine. Preferably, the organic base is triethylamine. An inorganic base can be selected from the group comprising a hydroxide or an alkali metal or alkaline earth carbonate, preferably potassium carbonate.

[0041] The bromination reaction of a compound of formula (XII) described in step b) of the process according to the invention can be conducted by methods well known to the skilled person under electrophilic substitution or radical substitution conditions by reacting a compound of formula (XII), wherein A is as defined above, with a brominating agent in a solvent, and possibly in the presence of a catalyst or base.

[0042] The brominating agent can be selected from NBS, 1, 3 -dibromo-5, 5 -dimethylhydantoin (DBDMH), molecular bromine, V-brornophthalimide and A-bromoacetamide, or from the group comprising tribromides of quaternary ammonium salts, such as tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, pyridinium tribromide, 4-dimethylaminopyridinium tribromide and l-butyl-3- methylimidazolium tribromide; the brominating agent is preferably selected from the group of tribromides, and even more preferably the brominating agent is pyridinium tribromide.

[0043] The solvent can be selected from the group comprising ether solvents, such as dioxane, tetrahydrofuran, isopropyl ether, 1,2-dimethoxy ethane and tert-butyl methyl ether, preferably tetrahydrofuran, or chlorinated solvents, such as dichloromethane, chlorobenzene and chloroform, preferably dichloromethane.

[0044] The bromination reaction can be conducted under electrophilic substitution conditions by reacting a compound of formula (XII), wherein A is as defined above, with a brominating agent in the presence of a base, which can be an organic or inorganic base. The organic base can be a tertiary aliphatic or aromatic amine, for example selected from the group comprising 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, VA-diisopropylethylamine (DIPEA), methylimidazole, imidazole and tri ethylamine. Preferably, the organic base is triethylamine. An inorganic base can be selected from the group comprising a hydroxide or an alkali metal or alkaline earth carbonate, preferably potassium carbonate.

[0045] The bromination reaction can be also conducted under radical substitution conditions by reacting a compound of formula (XII), wherein A is as defined above, with a brominating agent in the presence of a catalyst that acts as radical initiator, which can be selected from the group comprising azobisisobutyronitrile (AIBN), l-razobis(cyclohexanecarbonitrile), di- / c / 7- butyl peroxide, benzoyl peroxide and methyl ethyl ketone peroxide; preferably, the catalyst is AIBN.

[0046] The compound of formula (XI) containing bromine at C6, or the compound of formula (XIII) containing bromine at C7, or a mixture of the two compounds, can be obtained, depending on the bromination conditions (Scheme 8).

[0047] Scheme 8

[0048] The bromination reaction temperature can range between -30°C and the reflux temperature of the solvent, preferably between 0°C and 10°C. To complete the bromination reaction, the reaction mixture can undergo common aqueous washes, and the compound of formula (XI), or the compound of formula (XIII), or a mixture of the two compounds, can be recovered from the resulting organic solution by evaporation of the solvent or crystallisation. The compound of formula (XI), or the compound of formula (XIII), or the mixture of the two compounds, can be used directly in the subsequent HBr elimination reaction described in paragraph c) of the present invention, without any further purifications.

[0049] The HBr elimination reaction with formation of a compound of formula (VI) described in step c) of the subject of the present invention can be conducted by reacting a compound of formula (XI) or formula (XIII) or a mixture thereof in a solvent in the presence of a base, and optionally of a catalyst. According to a preferred aspect of the invention, the HBr elimination reaction can be conducted by reacting the compound of formula (XI) or formula (XIII) or a mixture thereof in a solvent which can be selected from a polar aprotic solvent such as acetone, tetrahydrofuran, dioxane, dimethyl sulphoxide and dimethylformamide, preferably dimethylformamide, and a chlorinated solvent such as dichloromethane, chlorobenzene and chloroform, preferably chlorobenzene.

[0050] The base used in the HBr elimination reaction can be an organic or inorganic base. An organic base can be a tertiary aliphatic or aromatic amine, for example selected from the group comprising 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, A,A-diisopropylethylamine (DIPEA), methylimidazole, imidazole and triethylamine. Preferably, the organic base is triethylamine. An inorganic base can be selected from the group comprising a hydroxide or an alkali metal or alkaline earth carbonate, preferably lithium carbonate.

[0051] The HBr elimination reaction can optionally be conducted in the presence of a catalyst, which can be a lithium salt, such as a lithium halide, preferably lithium bromide. The catalyst optionally used in the HBr elimination reaction can be in excess or in sub stoichiometric amounts. The excess or sub stoichiometric amount of catalyst is calculated compared with the molar amount of the compound of formula (XI) or formula (XIII), or with the sum of the molar amounts of said compounds in admixture.

[0052] The HBr elimination reaction with formation of a compound of formula (VI) can be conducted under stirring at a temperature ranging between 25°C and the reflux temperature of the solvent, preferably between 70°C and 90°C. On completion of the HBr elimination reaction, the reaction mixture can undergo common aqueous washes, and the product of formula (VI) can be recovered from the resulting organic solution by evaporation of the solvent or crystallisation (Scheme 9). The compound of formula (VI) can be used directly in the preparation of alclometasone dipropionate of formula (I) without any further purifications.

[0053]

[0054] Scheme 9

[0055] Surprisingly, the authors of the present invention have found that by conducting the bromination and subsequent elimination reaction on a compound of formula (XII), the compound of formula (VI) can be obtained with a good yield regardless of the brominating agent used, and can be isolated with a purity exceeding 90% with no need for chromatographic purifications.

[0056] The compound of formula (XII), wherein A is as defined above, represents a further subject of the present invention.

[0057] When the bromination reaction of a compound of formula (XII) described in step b) of the present invention was conducted with a brominating agent included in the tribromide group, the bromination yield obtained was always very high. Surprisingly, by using pyridinium tribromide, the inventors obtained a mixture of the compound of formula (XI) and the compound of formula (XIII) with 93% purity and an estimated yield of around 87%. The purity data were obtained from the HPLC analysis of the reaction products, and are expressed as area%. As a result of said excellent bromination yield and the fact that the conversion reaction of a compound of formula (VII) to a compound of formula (XII) and the HBr elimination reaction proceed with almost quantitative yields, the yield with which the compound of formula (VI) was obtained according to the subject of the invention is 82%, much higher than the average obtained with the other brominating agents and than any yield ever reported in the prior art for conversion of a compound of formula (VII) to a compound of formula (VI). Therefore, in a preferred embodiment, the bromination reaction described in step b) of the process according to the invention is conducted using pyridinium tribromide as brominating agent.

[0058] The compound of formula (VII) illustrated in Scheme 7, which is subjected to the process according to the present invention, can be prepared by procedures known to the prior art, such as those reported by Green et al. in US4124707, preparation 10.

[0059] The compound of formula (VI), obtained by the process according to the present invention, is conveniently used as starting product in a process for the preparation of alclometasone dipropionate of formula (I).

[0060] In particular, the compound of formula (VI) can be subjected to an HC1 addition reaction to give a compound of formula (V) by methods known to the prior art, for example as described by Green et al. in US4076708.

[0061] According to a particular embodiment, the compound of formula (VI) can be reacted with gaseous HC1 in a solvent (Scheme 10).

[0062] Scheme 10

[0063] The solvent used in the HC1 addition reaction can be selected from an ether solvent such as dioxane or tetrahydrofuran, preferably tetrahydrofuran, and a chlorinated solvent such as dichloromethane.

[0064] The HC1 addition reaction can be conducted at a temperature ranging between -10°C and 30°C, preferably between 10°C and 20°C.

[0065] The compound of formula (V), as a solid, can be recovered by known techniques such as filtration or centrifugation, and dried.

[0066] The resulting compound of formula (V) can undergo a ketone reduction reaction in Cl l to give alclometasone dipropionate of formula (I), using methods known to the skilled person, for example as described in patent US4124707.

[0067] According to a particular embodiment, the compound of formula (V) is reacted with sodium borohydride in a mixture of tetrahydrofuran and water (Scheme 11).

[0068] Scheme 11

[0069] The reduction reaction can be conducted at a temperature ranging between 0°C and 30°C.

[0070] The resulting alclometasone dipropionate of formula (I) can be purified by techniques known to the skilled person, such as crystallisation.

[0071] A further subject of the present invention is therefore a process for the preparation of alclometasone dipropionate of formula (I) starting with a compound of formula (VI), obtained according to the subject of the invention.

[0072] Examples

[0073] Analysis methods

[0074] The instrument used to conduct the HPLC analyses was an Agilent 1290 Infinity II chromatograph equipped with an Agilent 1290 Infinity II Diode array detector. An XSELECT CSH Phenyl-Hexyl column (50 mm x 2.1 mm) and an Xselect Premier CSH C18 column (100 mm x 4.6 mm) were used as stationary phases. The mobile phase used was prepared with variable gradients of water / acetonitrile mixtures.

[0075] The spectroscopic analysis of Nuclear Magnetic Resonance (NMR) was conducted with a Bruker-600 instrument (600 MHz) with DMSO-de as solvent, setting a delay time of 2

[0076] Example 1. Preparation of the compound of formula (XI)

[0077] 0.1 g of AIBN and 0.10 g of NBS were added to a solution obtained by dissolving 3.0 g of the compound of formula (VII) in 30 ml of methylene chloride. The solution was stirred at 0 / 5°C for 30 minutes and analysed by TLC, which did not detect any conversion of the starting material. The reaction mixture was then heated to reflux temperature and maintained under stirring for 2 hours. The reaction mixture was again analysed by TLC which, however, did not detect any conversion of the starting material of formula (VII). The reaction mixture was then quenched with a solution of 100 ml of Na2S20s, the resulting biphasic mixture obtained was stirred at a temperature of 20 / 25°C, and the organic phase was separated from the aqueous phase. The solvent was removed by evaporation under vacuum, obtaining 2.9 g of the compound of formula (VII).

[0078] Example 2. Preparation of a compound of formula (XII)

[0079] 80 ml of tert-butyldimethylsilyl triflate was added to a solution obtained by dissolving 100 g of the compound of formula (VII) in 1000 ml of methylene chloride and 80 ml of triethylamine at a temperature of less than 5°C. After the addition, the suspension was stirred at 0 / 5°C for at least 0.5 hours. A solution of 1000 ml of NaHCCh was then added, the resulting biphasic mixture was stirred at a temperature of 20 / 25°C, and the organic phase was separated from the aqueous phase. The solvent was removed by evaporation under vacuum, obtaining 132 g of the compound of formula (XII), which was used in the bromination reactions without any further purifications.

[0080] MS positive: 599.0 [M+H]+; 621.0 [M+Na]+; 1219.0 [2M+Na]+;

[0081] 1H-NMR (600MHz, DMSO-d6) δ 6,438 (d, 1H, J = 10,2 Hz), 5,655 (dd, 1H, J = 2,4 Hz e 9,6 Hz), 5,304-5,243 (m, 2H), 4,819 (d, 1H, J = 15,6), 4,710 (d, 1H, J = 15,6 Hz), 3,280- 3,238 (m, 1H), 2,862 (d, 1H, J = 12,6 Hz), 2,491-2,390 (m, 6H), 2,850-2,250 (m, 2H), 2,105- 2,048 (m, 2H), 1,467-1,401 (m, 2H), 1,311 (s, 3H), 1,197-1,167 (m, 6H), 1,015 (m, 3H, J = 7,2 Hz), 0,934 (s, 9H), 0,777 (s, 3H), 0,158 (s, 6H). Example 3. Bromination of the compound of formula (XII) with pyridinium tribromide

[0082] 60.6 g of pyridinium tribromide was added to a solution obtained by dissolving 132 g of the compound of formula (XII), obtained in Example 2, in 2000 ml of methylene chloride and 30 ml of triethylamine. The solution was stirred at 0 / 5°C for at least 0.5 hours. A solution of 1000 ml of Na2S20s was then added, the resulting biphasic mixture was stirred at a temperature of 20 / 25°C, and the organic phase was separated from the aqueous phase. The solvent was removed by evaporation under vacuum, obtaining 116.7 g of a mixture of the compound of formula (XIII) and the compound of formula (XI) which, when analysed by HPLC, exhibited 93% purity, expressed as the sum of the percentage peak areas of the 2 compounds. The yield of the mixture of the two brominated products was estimated at around 87%.

[0083] Compound of formula (XIII): MS positive: 564,7 [M+H]+; 586,8 [M+Na]+; 1148,5 [2M+Na]+. 1H-NMR (600MHz, DMSO-d6) δ 7,661 (d, 1H, J = 10,2 Hz), 6,397 (s, 1H), 6,175 (dd, 1H, J = 1,8 Hz e 10,8 Hz), 5,467 (dd, 1H, J = 2,4 Hz e 4,2 Hz), 4,950 (d, 1H, J = 16,8 Hz), 4,758 (d, 1H, J = 16,8 Hz), 3,299-3,261 (m, 1H), 2,979 (d, 1H, J = 12,6 Hz), 2,568 (d, 1H, J = 10,8 Hz), 2,478-2,454 (m, 1H), 2,443-2,400 (m, 4H), 2,334-2,272 (m, 1H), 2,233- 2,199 (m, 1H), 2,172 (d, 1H, J = 12,6 Hz), 2,073-2,022 (m, 1H), 1,835 (q, 1H, J = 12,0 Hz), 1,651 (s, 3H), 1,419-1,377 (m, 1H), 1,073 (t, 3H J = 7,2 Hz), 1,052 (t, 3H J = 7,2 Hz), 0,912 (d, 3H J = 7,0 Hz), 0,763 (s, 3H).

[0084] Compound of formula (XI): MS positive: 564,7 [M+H]+; 586,8 [M+Na]+; 1148,5 [2M+Na]+;1H-NMR (600MHz, DMSO-d6) δ 7,581 (d, 1H, J = 10,2 Hz), 6,440 (s, 1H), 6,181 (dd, 1H, J = 1,8 Hz e 10,2 Hz), 5,382-5,350 (m, 1H), 4,967 (d, 1H, J = 16,8 Hz), 4,734 (d, 1H, J = 16,8 Hz), 3,288-3,242 (m, 1H), 2,948 (d, 1H, J = 12,4 Hz), 2,520-2,466 (m, 2H), 2,442- 2,384 (m, 1H), 2,409 (t, 4H, J = 7,8 Hz), 2,280-2,217 (m, 1H), 2,092 (d, 1H, J = 12,4 Hz), 1,893-1,834 (m, 1H), 1,773 (q, 1H, J = 12,0 Hz), 1,417 (s, 3H), 1,379-1,338 (m, 1H), 1,606 (t, 3H, J = 7,2 Hz), 1,045 (t, 3H, J = 7,8 Hz), 0,905 (d, 3H, J = 6,6 Hz), 0,708 (s, 3H).

[0085] A solution obtained by dissolving 116.7 g of a mixture of the compound of formula (XIII) and the compound of formula (XI), obtained in Example 3, was dissolved in 1300 ml of DMF, and 90.75 g of LiBr and 80.45 g of LiCCh were then added at a temperature of 20 / 25°C. The suspension was stirred at a temperature of 80 / 85°C for at least 2 hours. The reaction mixture was then cooled to a temperature of 20 / 25°C, and quenched by adding water. The resulting mixture was stirred at 20 / 25°C for at least 1 hour and filtered. The wet solid was suspended in 4000 ml of water and treated with 120 ml of acetic acid. The mixture was stirred at 20 / 25°C for at least 1 hour and filtered. The wet solid was then dried at 50°C, obtaining 90.5 g of the compound of formula (VI) which, when analysed by HPLC, exhibited 92% purity. In view of the purity value, the yield of the compound of formula (VI), starting from the compound of formula (VII), is about 82% in 3 steps. The compound of formula (VI) was used in the subsequent HC1 addition reaction without any further purifications.

[0086] MS positive: 483,0 [M+H]+; 505,0 [M+Na]+;1H-NMR (600MHz, DMSO-d6) δ 7,648 (d, 1H, J = 10,2 Hz), 6,408 (dd, 1H, J = 2,8 Hz e 10,0 Hz), 6,155 (dd, 1H, J = 2,0 Hz e 10,2 Hz), 6,089 (dd, 1H, J = 2,0 Hz e 10,0 Hz), 6,041 (s, 1H), 4,972 (d, 1H, J = 16,8 Hz), 4,744 (d, 1H, J = 16,8 Hz), 3,328-3,282 (m, 1H), 3,062 (d, 1H, J = 12,0 Hz), 2,750 (d, 1H, J = 11,0 Hz), 2,648-2,601 (m, 1H), 2,551-2,512 (m, 1H), 2,446-2,403 (m, 4H), 2,084-1,980 (m, 2H), 1,535- 1,494 (m, 1H), 1,288 (s, 3H), 1,070 (t, 3H, J = 7,6 Hz), 1,040 (t, 3H, J = 7,6 Hz), 0,934 (d, 3H, J = 7,0 Hz), 0,778 (s, 3H).

[0087] Example 5. Preparation of the compound of formula (V)

[0088] 1270 ml of THF was cooled to 0-5°C and treated with HC1 gas until saturation. 90.5 g of the compound of formula (VI), obtained in Example 4, was added to the saturated solution, and the resulting solution was stirred at a temperature of 10 / 15°C for at least 2 hours. The end-of-reaction mixture was then treated with water, and the resulting dispersion was stirred at 20 / 25°C for at least 10 min and filtered. The wet solid was dispersed in 4000 ml of water, and the pH of the suspension was corrected with a solution of NaHCCf until neutral. The final dispersion was stirred at a temperature of 20 / 25°C for 1 hour and filtered. The solid was then dried at a temperature of 50°C, obtaining 84.5 g of crude compound of formula (V) which, when analysed by HPLC, exhibited 83% purity.

[0089] MS positive: 518,9 [M+H]+; 540,9 [M+Na]+; 556,9 [M+K]+; 1055,9 [2M+Na]+; 'H- NMR (600MHz, DMSO-d6) δ 7,641 (d, 1H, J = 10,2 Hz), 6,150 (dd, 1H, J = 2,0 Hz e 10,2 Hz), 6,052 (s, 1H), 4,982 (d, 1H, J = 16,8 Hz), 4,746 (d, 1H, J = 16,8 Hz), 4,635-4,623 (m, 1H), 3,321-3,273 (m, 1H), 3,203-3,170 (m, 1H), 2.994 (d, 1H, J = 12,8 Hz), 2,630 (dd, 1H, J = 3,0 Hz e 14,6 Hz), 2,556-2,512 (m, 3H), 2,456-2,385 (m, 4H), 2,134 (d, 1H, J = 12,8 Hz), 1,970-1,913 (m, 1H), 1,429-1,355 (m, 1H), 1,386 (s, 3H), 1,069 (t, 3H, J = 8,0 Hz), 1,039 (t, 3H, J = 8,0 Hz), 0,918 (d, 3H, J = 7,0 Hz), 0,743 (s, 3H).

[0090] Example 6. Preparation of alclometasone dipropionate (I)

[0091] 84.5 g of the compound of formula (V), obtained in Example 5, was dissolved in a mixture containing 1000 ml of THF and 100 ml of water; 6 g of sodium borohydride was then added. The suspension was stirred at a temperature of 0 / 5°C for at least 2 hours, and the end- of-reaction mixture was quenched by adding 40.9 ml of acetone and 3 ml of acetic acid. The mixture was then treated with water and the resulting dispersion was stirred at 20 / 25°C for 1 hour, and finally filtered. The wet solid was dried at a temperature of 50°C, obtaining 75.2 g of crude alclometasone dipropionate of formula (I) which, when analysed by HPLC, exhibited 84% purity.

[0092] MS positive: 543,211 [M+Na]+; 559,210 [M+K]+. 'H-NMR (600MHz, DMSO-d6) 6 7,322 (d, 1H, J = 10,2 Hz), 6,198 (dd, 1H, J = 1,8 Hz e 9,6 Hz), 5,950 (s, 1H), 4,890-4,864 (m, 2H), 4,749 (d, 1H, J = 16,2 Hz), 4,656-4,641 (m, 1H), 4,384-4,361 (m, 1H), 3,247-3,173 (m, 2H), 2,587 (dd, 1H, J = 3,0 Hz e 15,0 Hz), 2,438-2,350 (m, 5H), 1,991-1,940 (m, 1H), 1,888-1,829 (m, 2H), 1,724 (dd, 1H, J = 2,4 Hz e 13,8 Hz), 1,415 (s, 3H), 1,367 (dd, 1H, J = 3,6 Hz e 11,4 Hz), 1,305-1,266 (m, 1H), 1,072 (t, 3H, J = 7,2 Hz), 1,022 (s, 3H), 1,001 (t, 3H, J = 7,8 Hz), 0,834 (d, 3H, J = 6,6 Hz).

Claims

CLAIMS1. A process for the preparation of a compound of formula (VI)comprising: a) conversion of a compound of formula (VII) to the compound of formula (XII):wherein A is a silyl group of formula -Si(R)3, wherein R is selected independently from the group consisting of (C1-C4)alkyl, (C6-C10)aryl, (C1-C4)alkyl-(C6-C10)aryl and (C6-C10)aryl-(C1-C4)alkyl; X is a leaving group b) bromination reaction of the compound of formula (XII) to give (XIII) and (XI), according to the following scheme:c) subsequent HBr elimination reaction with formation of a compound of formula (VI):

2. Process according to claim 1, wherein A is selected from the group consisting of trimethyl silyl, triethylsilyl, / crt-butyldimethylsilyl, tri-isopropylsilyl, diphenyltertbutylsilyl, diphenylmethyl silyl and phenyldimethyl silyl, preferably tert- butyldimethylsilyl.

3. Process according to claims 1 and 2, wherein the conversion of the compound of formula (VII) to the compound of formula (XII) according to step a) is preferably carried out with tert-butyldimethylsilyltriflate.

4. Process according to claims 1 and 2, wherein the bromination reaction according to step b) is carried out with a brominating agent selected from the group consisting of tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, pyridinium tribromide, 4-dimethylaminopyridinium tribromide and l-butyl-3-methylimidazolium tribromide.

5. Process according to claim 4, wherein said bromination reaction is carried out with pyridinium tribromide.

6. Process according to claims 1 and 4-5, wherein the bromination reaction is carried out at a temperature ranging between -30°C and the reflux temperature of the solvent, preferably ranging between 0°C and 10°C.

7. Process according to claim 1, wherein the HBr elimination reaction according to step c) is carried out with lithium carbonate.

8. Process according to claim 7, wherein said HBr elimination reaction is also carried out in the presence of lithium bromide, in excess or in sub stoichiometric amounts, preferably in sub stoichiometric amounts, relative to the molar amount of compound XIII or compound XI, or to the sum of the molar amounts of said two compounds in admixture.

9. Compound of formula (XII)wherein A is as defined in claims 1-2, preferably tert-butyldimethylsilyl.

10. Process for the preparation of alclometasone dipropionate of formula (I), comprising preparation of the compound of formula (VI) according to claims 1-8 and subsequent conversion of said compound (VI) to alclometasone dipropionate of formula (I):

11. Process according to claim 10, wherein said conversion of compound (VI) to alclometasone dipropionate of formula (I) is carried out according to the following steps:b)

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