(19) TZZ Z ¥_T (11) EP 2 509 423 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 249/08 (2006.01) C07D 291/06 (2006.01) 27.01.2016 Bulletin 2016/04 (86) International application number: (21) Application number: 10835601.5 PCT/IL2010/000074 (22) Date of filing: 28.01.2010 (87) International publication number: WO 2011/070560 (16.06.2011 Gazette 2011/24) (54) PROCESSES FOR THE PREPARATION OF DEFERASIROX, AND DEFERASIROX POLYMORPHS VERFAHREN ZUR HERSTELLUNG VON DEFERASIROX UND DEFERASIROX-POLYMORPHE PROCÉDÉS POUR LA PRÉPARATION DU DÉFÉRASIROX, ET POLYMORPHES DE DÉFÉRASIROX (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A1-2009/016359 WO-A2-2008/065123 HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL WO-A2-2008/094617 US-A- 5 318 959 PT RO SE SI SK SM TR US-A1- 2001 037 020 US-B1- 6 465 504 US-B1- 6 465 504 (30) Priority: 07.12.2009 US 267096 P • JAMES R. BOWSER ET AL: "Cleavage of silicon- (43) Date of publication of application: nitrogen bonds by acid chlorides: an unusual 17.10.2012 Bulletin 2012/42 synthetic route to amides", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 48, no. 22, 1 (73) Proprietor: Mapi Pharma Limited November 1983 (1983-11-01), pages 4111-4113, 74140 Ness Ziona (IL) XP055064579, ISSN: 0022-3263, DOI: 10.1021/jo00170a050 (72) Inventors: • VONGCHAN ET AL.: ’Anticoagulant Activities of • MIZHIRITSKII, Michael the Chitosan Polysulfate Synthesized from 76217 Rehovot (IL) Marine Crab Shell by Semi-hetergenous • MAROM, Ehud Conditions’ SCIENCE ASIA vol. 29, 2003, pages 44308 Kfar Saba (IL) 115 - 120 • RUBNOV, Shai • TOPUZYAN ET AL.: ’Derivatives of ?,?-Dehydro 65214 Tel Aviv (IL) Amino Acids: III. Reaction of 4-Arylmethylidene- 4,5-dihydro-1,3-oxazol-5- ones with Hexamethyl- (74) Representative: Becker Kurig Straus disilazane’ RUSSIAN JOURNAL ORGANIC Patentanwälte CHEMISTRY vol. 43, 2007, pages 868 - 871 Bavariastrasse 7 • STEINHAUSER ET AL: "Complex formation of 80336 München (DE) ICL670 and related ligands with FeIII and FeII", EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, WILEY-VCH VERLAG, WEINHEIM, DE, no. 21, 1 January 2004 (2004-01-01), pages 4177-4192, XP002484059, ISSN: 1434-1948, DOI: 10.1002/EJIC.200400363 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 509 423 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 509 423 B1 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to a process for the preparation of deferasirox, an oral iron chelator developed to treat chronic iron overload due to, e.g., multiple blood transfusions. BACKGROUND OF THE INVENTION 10 [0002] Patients with chronic anemias such as thalassemia or sickle cell anemia often require regular red blood cell transfusions. Repeated transfusions result in toxic, and eventually fatal, accumulation of iron as insoluble ferritin in various tissues of the body. This chronic iron overload occurs due to the body’s inability to actively eliminate iron. Chronic iron overload is a serious condition and organ failure can occur due to the resulting iron deposits. When the heart or liver are affected, the condition may be life threatening. Iron overload is treated by administration of iron chelators, which 15 mobilize the iron deposits into soluble complexes that can be excreted from the body. The currently available first-line iron chelator, deferoxamine (Desferal®), requires intravenous or slow subcutaneous infusion over a period of 8-12 h, 5-7 times per week. This has resulted in low patient compliance of the product. Deferoxamine can also cause local and systemic reactions. An orally available iron chelator, deferiprone, also has a short duration of action and may be associated with serious side effects. Novartis therefore embarked on a major research program to identify oral iron chelators, which 20 ultimately led to a completely new class of compounds, the bishydroxyphenyltriazoles. The best compound from this class was found to be deferasirox (ICL-670A), an orally active tridentate compound which is FDA approved and is marketed under the trade name Exjade® for the treatment of transfusion-dependent chronic iron overload (transfusional hemosiderosis) [Drugs of the Future 2004, 29(4): 331-335]. [0003] Deferasirox has the chemical name 4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid, and is rep- 25 resented by the following structural Formula (1): 30 35 40 45 [0004] Steinhauser et.al. (Eur. J. Inorg. Chem, 2004, 21, 4177-4192) discloses the complex formation of deferasirox and related ligands with FeIII and FeII. Steinhauser discloses a process for preparing deferasirox which comprises two steps: (1) preparation of the intermediate 2-(2-Hydroxyphenyl)-benzo-4H-[1,3]-oxazin-4-one by condensing salicyloyl chloride (formed in-situ from salicylic acid and thionyl chloride) and salicylamide under reflux. The yield reported for this step is 55%. (2) preparation of 4-[3,5-Bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox) by reacting 2-(2- 50 Hydroxyphenyl)-benzo-4H-[1,3]-oxazin-4-one with 4-hydrazino-benzoic acid under reflux. The yield reported for this step is 80%. The overall yield of the process is 44%. [0005] U.S. Pat. No. 6,465,504 discloses substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators. This patent describes a process for the preparation of 4-[3,5-Bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1- yl]benzoic acid (deferasirox) (1) that involves the condensation of salicylamide (2) with salicyloyl chloride (3) by heating 55 at 170 °C yielding 2-(2-hydroxyphenyl)-benz[e][1,3]oxazin-4-one (5), which reacts with 4-hydrazinobenzoic acid (6) in refluxing ethanol to give (1) (Scheme 1): 2 EP 2 509 423 B1 5 10 15 20 25 30 [0006] High reaction temperature (170°C), evolution of corrosive and hazardous HCl gas and low overall yield (<50%) makes this process expensive and not feasible on an industrial scale. [0007] U.S. Appln. Publication No. 2005/080120 provides another method for the preparation of deferasirox analogues. 35 This process is also described in Eur. J. Inorg. Chem. 2004, 4177-4192, and consists of two stages. The first stage, formation of 2-(2-hydroxyphenyl)-benzo-4 H-[1,3]-oxazin-4-one, involves a reaction of salicylic acid and salicylamide with thionyl chloride in the presence of pyridine under reflux in xylene or toluene with vigorous stirring over a period of 4 h. An intense evolution of SO2 and HCl was noted. At the end of the addition, the product started to crystallize. Stirring was continued for an additional 30 min, and the solvent was removed by distillation at reduced pressure. The resulting 40 solid residue was suspended in EtOH and acetic acid. The mixture was heated gently and then allowed to cool to 20°C. The precipitate was filtered and recrystallized from 2-methoxyethanol, providing the desired compound with 50-55 % yield. The second stage proceeded according to previously mentioned patent (US 6,465,504) and consists of reaction of 2-(2-hydroxy phenyl)-benzo-4 H-[1,3]-oxazin-4-one with 4-hydrazinobenzoic acid in boiling ethanol. The reported yield of this stage was 80%. 45 [0008] Although this process is more technological than the one based on molding salicylamide in salicyloyl chloride, the overall yield is still moderate (40-45%). The moderate yield can be attributed to the formation of by-products - a mixture of the linear and cyclic polyesters (for example, (7)) as a result of intermolecular reaction of salicyloyl chloride [Chinese J. Struct. Chem., 2003, 22(5): 512-516] (Scheme 2): 50 55 3 EP 2 509 423 B1 5 10 15 20 [0009] Therefore, there is a need for a process, in which no significant heating is required and the formation of polyesters as well as corrosive and hazardous gases such as HCl is minimized or avoided. 25 [0010] Deferasirox belongs to the family of substituted 1,2,4-triazoles, heterocycles possessing important pharmaco- logical activities such as antifungal and antiviral activities. Methods for the synthesis of 1,2,4-triazoles are well described in literature [See, for example, review "1,2,4-TRIAZOLES: SYNTHETIC APPROACHES AND PHARMACOLOGICAL IMPORTANCE" in Chemistry of Heterocyclic Compounds, 2006, 42(11): 1377-1403], but most of these methods are not suitable for the construction of 1, 3, 5-substituted 1, 2, 4-triazoles. 30 [0011] A preparation of substituted 3,5-diphenyl-1,2,4-triazoles [I] structurally close to deferasirox can be found in European Patent No. 0572142, and can be achieved by a reaction between an alkyl N-acyl(thio) imidate derivative, having a general formula [II], and a hydrazine derivative of a general formula [III] in an inert solvent, according to the following scheme: 35 40 45 [0012] The starting compound of the general formula [II] was prepared by reacting the imine [IV] with the halogen anhydride [V] in the presence of a base according to the following scheme: 50 55 4 EP 2 509 423 B1 5 10 [0013] This process involves usage of more complicated starting materials than those used in deferasirox processes. Such materials are not commercially available and their preparation enlarges the number of steps and needs for inter- 15 mediate isolation at each step.