US 2013 0211069A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0211069 A1 Cherniak et al. (43) Pub. Date: Aug. 15, 2013 (54) PROCESS FOR THE PREPARATION OF Publication Classification 17-DESOXY-CORTCOSTEROIDS (51) Int. Cl. (75) Inventors: Simon Cherniak, Haifa (IL); Rosa C07J 7/00 (2006.01) Cyjon, Haifa (IL); Ilana Ozer, Yokneam C07J 7L/00 (2006.01) lit (IL); Igor Nudelman, Haifa (IL) (52) U.S. Cl. CPC .............. C07, 7/08 (2013.O1): CO7 7L/005 (73) Assignee: Taro Pharmaceutical Industries Ltd., ( ); (2013.01) Haifa Bay (IL) USPC .............................. 540/89; 552/588; 552/574 (21) Appl. No.: 13/811,141 (57) ABSTRACT (22) PCT Filed: Jul. 20, 2011 (86). PCT No.: PCT/IL11AO058O The present invention provides an improved process for the preparation of 17-desoxy corticosteroid derivatives in a S371 (c)(1), single chemical step by reacting the 17-hydroxy starting (2), (4) Date: Mar. 28, 2013 material with an excess of Trimethylsilyl Iodide. The present Related U.S. Application Data invention is specifically advantageous in preparing 17-des .S. App oxy corticosteroid derivatives having one or more halogen 60) ProvisionalrOV1S1Onal applicationapol1Cat1On No.NO. 61/365,950,s , filedIlled. onOn Jul.Jul groupsroups at positionspoS1t1ons 2, 6, 7 or 9 of theth cort1costero1did suchSuch as 20, 2010. Clocortolone of Desoximetasone. US 2013/021 1069 A1 Aug. 15, 2013 PROCESS FOR THE PREPARATION OF provides high region-selectivity of hydroxyl removal at posi 17-DESOXY-CORTCOSTEROIDS tion 17 of the corticosteroid while one or more halogen groups at positions 2, 6, 7 and 9 remain intact. The region FIELD OF THE INVENTION selectivity of the process enables the use of this process for 0001. The present invention is directed to a novel process facile preparation of biologically active 17-desoxy corticos for the preparation of 17-desoxy-corticosteroids. teroids having one or more halogen groups at positions 2, 6, 7 and 9. BACKGROUND OF THE INVENTION 0007. In one embodiment, the present invention relates to 0002 The corticosteroids are a particular type of steroids the preparation of a corticosteroid derivative having the gen having the basic carbon skeletal formula which contains 21 eral Formula I: carbon atoms in 4 rings. A thru D. Formula I 0003 Corticosteroids are known to have anti-inflamma tory and immunomodulatory properties useful in the treat wherein R is OH and R is H, or R and R form together a ment of numerous diseases, including autoimmune and double bond with O. R. is Hand R is CH, or R is CH and inflammatory diseases. R is H, and wherein at least one of Xs is independently Cl, 0004 A large number of 21-hydroxy-20-oxo-17-desoxy Br or F. pregnane compounds are known as therapeutically valuable Substances with the action of natural corticoids, i.e. ofadreno 0008. The preparation process of the present invention cortical hormones, or they can be used as intermediates for comprises reacting the corticosteroid derivative of general obtaining such active substances. These compounds have Formula II principally been obtained by removing the hydroxyl group in carbon 17. The removal of the hydroxyl group is normally carried out in several steps, usually by a direct or indirect Formula II exchange of the hydroxyl group for an hydrogen atom. Numazawa et al. (J. Chem. Soc. Chem. Commun., 1984 and Chem. Pharm. Bull., v.34(9), pp. 3722-3726 (1986)) disclose the deoxygenation of the Dihydroxyacetone moiety at C-17 by using Iodotrimethylsilane for the preparation of Hydro cortisone, Cortisone, Prednisolone and Prednisone. German Patent NOS. 11694.44 and 121 1194 disclose a multistep syn thesis of 17-Desoxicorticosteroids. 0005. The processes described above suffer from various disadvantages. Therefore, there is an unmet need for an improved process for the preparation of 17-desoxy-corticos teroids in a single chemical step from commercially available starting materials. wherein R-R and X-Xs areas defined above with an excess of Trimethylsilyl Iodide in the presence of an aprotic solvent SUMMARY OF THE INVENTION to yield the 17-desoxy corticosteroid derivative of Formula I. 0006. The present invention provides an improved process 0009. The process of the present invention does not have for the preparation of 17-desoxy corticosteroid derivatives in the drawback referred to the known processes since it pro a single chemical step. The present invention is specifically vides 17-desoxy corticosteroid derivatives in a single chemi advantageous in preparing 17-desoxy corticosteroid deriva cal step. The process of the present invention does not require tives having one or more halogen groups at positions 2, 6, 7 the protection of the halogen groups which are present in the and 9 of the corticosteroid. In a preferred embodiment, the starting material against undesired reactions with the Trim present invention provides an improved process for the prepa ethylsilyl Iodide reagent. The process of the present invention ration of Diflucortolone, Desoximetasone, Clocortolone, employs easy to handle reagents and the reaction proceeds Fluocortolone, 7C.-Chloro-11B,21-dihydroxy-16C.-methyl with high yield of the 17-desoxy corticosteroid derivative. pregna-1,4-diene-320-dione and 2-Bromo-6(3,9-difluoro Particular halogen groups which are present in the starting 11,21-dihydroxypregna-1,4-diene-320-dione. It was Sur material are fluorine, bromine or chlorine atoms in one or prisingly found that the process of the present invention more of positions 2, 6, 7 and 9 of the corticosteroid. US 2013/021 1069 A1 Aug. 15, 2013 DETAILED DESCRIPTION OF THE PRESENT 0019. Following the extraction, the reaction is completed INVENTION by washing the organic layer, preferably with a solution of a 0010. In the following detailed description, numerous spe weak inorganic base such as Sodium bicarbonate and a satu cific details are set forth in order to provide a thorough under rated solution of salt such as sodium chloride and evaporating standing of the invention. However, it will be understood by the solution to dryness to yield the 17-desoxy corticosteroid those skilled in the art that the present invention may be of the invention. In other embodiments, standard chemical practiced without these specific details. In other instances, procedures for isolation of the corticosteroid may be well-known methods, procedures, and components have not employed Such as extraction or filtration. been described in detail so as not to obscure the present 0020. The present invention may preferably be used for invention. the preparation of Diflucortolone, Desoximetasone, Clocor 0011. The term “17-desoxy corticosteroid derivatives' as tolone, Fluocortolone, 7C.-Chloro-113,21-dihydroxy-16C.- used herein, refers to corticosteroid derivatives having no methylpregna-1,4-diene-320-dione and 2-Bromo-6(3,9-dif hydroxyl group in the 17 position and having at least one luoro-1 1,21-dihydroxypregna-1,4-diene-320-dione. More halogen group at position 2, 6, 7 or 9 of the corticosteroid. preferably, the present invention is used for the preparation of 0012. It has surprisingly been found that it is possible to prepare 17-desoxy corticosteroid derivatives having at least Clocortolone and Desoximetasone. In a preferred embodi one halogen group at position 2, 6, 7 or 9 of the corticosteroid ment, Clocortolone may be further converted to Clocortolone in a single chemical step by reacting the 17-hydroxy starting Pivalate by using methods known in the art. material with an excess of Trimethylsilyl Iodide. The process 0021. The present invention further relates to a method of of the present invention does not require the protection of the preparing Clocortolone having the structure of Formula III, halogen groups present in the starting material against undes ired reactions with the Trimethylsilyl Iodide reagent. 0013 The preparation of 17-desoxy corticosteroid deriva tives involves reacting the starting material of Formula II with an excess of Trimethylsilyl Iodide in the presence of an apro tic solvent. The molar ratio between Trimethylsilyl Iodide Formula III and the 17-hydroxy starting material is between about 2:1 to about 10:1, preferably between about 2:1 to about 6:1. 0014. The aprotic solvent suitable for the reaction may be for example Acetonitrile, chlorinated solvents, or aromatic solvents, and is preferably methylene chloride or acetonitrile or a combination thereof. Minor amounts of a polar protic co-solvent such as water or C-C-alcohol may be added to the reaction in order to enhance the reaction yield. In a pre ferred embodiment, between about 0.05% to about 1.0% (v/v) of the polar protic co-solvent may be added to the reaction, 2. more preferably, between about 0.1% to about 0.5% (v/v) of F the polar protic co-solvent may be added to the reaction. A preferred polar protic co-solvent which may be used is metha nol or isopropyl alcohol. the method comprising the steps of 0015 The 17-hydroxy starting materials of Formula II are 0022 (a) Reacting a 17-hydroxy epoxide of Formula IV known compounds which may be obtained commercially. These include for example FlumetaSone, DexametaSone, Paramethasone, Betamethasone, 9-Chloro-6C-fluoro-11, 17, 21-trihydroxy-16C.-methylpregna-1,4-diene-320-dione, Halopredone or Alclometasone. Formula IV 0016. The reaction temperature employed for the reaction between Trimethylsilyl Iodide and the 17-hydroxy starting material is in the range from between about -30°C. and about +30°C., more preferably in the range of between about -20° C. and about +20° C. 0017 Depending on the respective conditions (tempera ture, concentration of Trimethylsilyl Iodide and the starting material, the solvent etc.), the reaction time is from about 15 minutes to about 3 hours, more preferably from about 15 minutes to about 2 hours.