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WO 2010/122096 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 28 October 2010 (28.10.2010) WO 2010/122096 Al (51) International Patent Classification: dos, s/n, E-37008 Salamanca (ES). GUTIERREZ C07J 7/00 (2006.01) C07J 71/00 (2006.01) FUENTES, Luis Gerardo [ES/ES]; Ragactives, S.l.u., C07J 51/00 (2006.01) Parque Tecnolόgico de Boecillo, parcelas 2 y 3, E-4715 1 Boecillo - Valladolid (ES). (21) International Application Number: PCT/EP20 10/055333 (74) Agent: ARIAS SANZ, Juan; ABG Patentes, S.L., Aveni- da de Burgos, 16D, Edificio Euromor, E-28036 Madrid (22) International Filing Date: (ES). 22 April 2010 (22.04.2010) (81) Designated States (unless otherwise indicated, for every (25) Language: English Filing kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (30) Priority Data: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 09382055.3 23 April 2009 (23.04.2009) EP HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (71) Applicant (for all designated States except US): CRYS¬ KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, TAL PHARMA, S.L.U. [ES/ES]; Parque Tecnolόgico de ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, Boecillo, parcela 105A, E-4715 1 Boecillo - Valladolid NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (ES). SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors; and (75) Inventors/Applicants (for US only): LORENTE (84) Designated States (unless otherwise indicated, for every BONDE-LARSEN, Antonio [ES/ES]; Ragactives, S.l.u., kind of regional protection available): ARIPO (BW, GH, Parque Tecnolόgico de Boecillo, parcelas 2 y 3, E-4715 1 GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, Boecillo - Valladolid (ES). IGLESIAS RETUERTO, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Jesύs Miguel [ES/ES]; Ragactives, S.l.u., Parque Tec TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, nolόgico de Boecillo, parcelas 2 y 3, E-4715 1 Boecillo - ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Valladolid (ES). HERRAIZ SIERRA, Ignacio [ES/ES]; MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Ragactives, S.l.u., Parque Tecnolόgico de Boecillo, parce ML, MR, NE, SN, TD, TG). las 2 y 3, E-4715 1 Boecillo - Valladolid (ES). BERME- JO GONZALEZ, Francisco [ES/ES]; Universidad De Published: Salamanca, Facultad de Ciencias Quimicas, Plaza de los — with international search report (Art. 21(3)) Caidos, s/n, E-37008 Salamanca (ES). MARCOS ES- CRIBANO, Jose Andres [ES/ES]; Universidad De Sala manca, Facultad de Ciencias Quimicas, Plaza de los Cai (54) Title: PROCESS FOR OBTAINING FLUOROMETHOLONE AND INTERMEDIATES THEREFOR 1 (57) Abstract: The present invention relates to a process for obtaining compounds of formula (I) and (V), wherein R is Ci-C 6 2 3 4 3 4 alkyl; and R is OR , OC(=O)R or O-(HPG), wherein R is H, Ci-C 6 alkyl or C6-Ci4 aryl; R is H or Ci-C 6 alkyl; and HPG is a hy dro xyl protecting group, intermediates useful in the synthesis of some steroids, for example, fluorometholone and derivatives thereof. The invention also relates to other intermediates useful in synthesis. PROCESS FOR OBTAINING FLUOROMETHOLONE AND INTERMEDIATES THEREFOR FIELD OF THE INVENTION The present invention relates to a process for obtaining derivatives of steroids or solvates thereof, as well as to intermediates useful in said process. More particularly, it relates to a process for preparing derivatives useful for obtaining fluorometholone and derivatives thereof, such as fluorometholone acetate. BACKGROUND OF THE INVENTION The active ingredient fluorometholone and its corresponding acetate in position 17, referred to as fluorometholone acetate, are corticosteroids with anti-inflammatory properties useful in dermatology and ophthalmology since they do not affect intraocular pressure. The chemical structure of these active ingredients is shown in Scheme 1 Fluorometholone, R=H Fluorometholone acetate, R=Ac Scheme 1 in which the numbers that are usually assigned to the carbons of the molecules of said family is also indicated, which numbers are followed in this description. Fluorometholone was first described in US 2,867,637, a document in which several processes for obtaining it are also described. A first process allows obtaining fluorometholone by means of the elimination, in three synthetic steps, of the 21-hydroxyl group of the compound 9α-fluoro-l l β,17,21 - trihydroxy-6 α-methyl-l,4-pregnadiene-3,20-dione (1). Compound 1 is a very advanced starting product, obtained in turn in 5 synthetic steps from methylprednisolone 21- acetate (J. Am. Chem. Soc. 1957, 79, 1515). Therefore, the formation of fluorometholone involves a total of 8 synthetic steps starting from a commercial product, as shown in Scheme 2. Scheme 2 A second process disclosed in Example 6 of US 2,867,637 starts from l l β,17- dihydroxy-6α-methyl-l,4-pregnadiene-3,20-dione (2), a compound which is not commercially available and for which the synthesis thereof is not described. Therefore, this fluorometholone synthesis process, in addition to the transformations necessary for obtaining compound 2, requires 5 synthetic steps to convert said compound into fluorometholone, as shown in Scheme 3. Scheme 3 Patent US 2,867,638 uses l l β,17-dihydroxy-6α-methyl-4-pregnene-3,20-dione (3) as a starting product, performing in the last step a dehydrogenation in position 1-2 by fermentation, making difficult the industrial application of the process. A large number of steps are also required in this case, since the starting product 3 is not easily available either (see Scheme 4). Scheme 4 FR 1 330 110 uses 17-α-hydroxyprogesterone, as a starting product, but 12 synthetic steps are needed to obtain fluorometholone. Therefore, although the starting product is commercially available, the synthesis is long (see Scheme 5), and furthermore l l β-hydroxylation and 1,2-dehydrogenation are carried out b y fermentation, which limits its industrial application. Fluorometholone Scheme 5 Another alternative for obtaining fluorometholone is provided in FR 2 223 364. In this case the starting product is 9α-fluoro-l l β,17-dihydroxy-l,4-pregnadiene-3,20- dione (4), on which the methyl group is introduced in position 6 and it is finally dehydrogenated in position 1-2 by fermentation or using 2,3-dicyano-5,6- dichloroparabenzoquinone (DDQ) in dioxane under reflux (see Scheme 6). Fluorometholone Scheme 6 However, the main difficulty of the final dehydrogenation with DDQ of the previous process is the possible low regioselectivity in the reaction, positions 1-2 and 5- 6 being able to compete. Furthermore, under these conditions, the recrystallization mentioned in the patent is not sufficient, and the crude reaction product obtained requires purification by means of a chromatography column. As an additional problem, 9α-fluoro-l l β,17-dihydroxy-4-pregnene-3,20-dione is a non-commercially available starting product. Its formation is necessary, and therefore the number of steps for obtaining fluorometholone from a commercial product increases. In relation to fluorometholone acetate, the acetylation of fluorometholone is described in J. Org. Chem. 1960, 25_, 1675. More recently, patent US 4,346,037 describes base-catalyzed acylations using enol esters, such as isopropenyl acetate, on substrates of a steroid nature. It is therefore necessary to develop an alternative process for obtaining fluorometholone and derivatives thereof (for example, fluorometholone acetate) overcoming all or part of the problems associated to known processes. In particular, said alternative process must start from a commercial product, must take place in few synthetic steps and prevent fermentation processes which make its industrialization difficult. SUMMARY O F THE INVENTION The present invention provides an efficient process for obtaining derivatives o f 6α-alkyl-4,9(l l)-diene-pregna-3,20-dione o f general formula (V) or solvates thereof, forming synthetic intermediates useful in the preparation o f steroids, particularly o f fluorometholone and derivatives thereof, such as fluorometholone acetate. According to a first aspect, the present invention is aimed at a process for obtaining a compound o f formula (V) R 1 (V) wherein 1 R is Ci-C 6 alkyl; and R 2 is -OR \ -OC(=O)R 4 or -O-(HPG) wherein 3 R is H , Ci-C 6 alkyl o r C 6 -Ci 4 aryl; R 4 is H o r Ci-C alkyl; and HPG is a hydro xyl protecting group; or a solvate thereof, comprising the catalytic hydro genation o f a compound o f formula (III) (III) wherein R 2 is aass ddeeffiinneedd aabboovvee,, aarnd R 5 is hydrogen or C1-C5 alkyl, or a solvate thereof, An additional aspect of the invention relates to said compounds of formula (III) or solvates thereof, intermediates useful in the synthesis of steroids, for example, in the synthesis of fluorometholone or the acetate thereof in position 17. An additional aspect relates to a process for preparing a compound of formula (III) or a solvate thereof, comprising subjecting a compound of formula (II) (H) wherein R2 is as defined above, or a solvate thereof, to a vinylogous Mannich reaction.
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