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(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

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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):

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):

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[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):

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[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 pharmacological 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:

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:

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[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. [0014] Another method presented in the abovementioned patent consists of the reaction of hydrazonoyl chloride [VI] with nitriles via a nitrilium ion (generated from [VI] and aluminum chloride):

[0015] Although this method gives the desired material at a good yield, it is more complicated (high number of steps, commercially unavailable starting materials and intermediates which require further isolation and purification). [0016] Consequently, there is a long-felt need for a process for the preparation deferasirox which not only overcomes 40 the problems in the art processes as mentioned above, but is also safe, cost effective, and industrially feasible. [0017] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like deferasirox may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal 45 behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC"), which have been used to characterize crystal forms. A new form of a compound may possess physical properties that differ from, and are advantageous over, those of other crystalline or amorphous forms. These include, packing properties such as molar volume, density and hygroscopicity; thermody- namic properties such as melting temperature, vapor pressure and solubility; kinetic properties such as dissolution rate 50 and stability under various storage conditions; surface properties such as surface area, wettability, interfacial tension and shape; mechanical properties such as hardness, tensile strength, compatibility, handling, flow and blend; and better filtration properties. Variations in any one of these properties affect the chemical and pharmaceutical processing of a compound as well as its bioavailability and may often render the new form advantageous for medical use. [0018] Several polymorphs of deferasirox are known in the art. Publication number IPCOM000 146862D describes a 55 crystalline form of deferasirox, designated form I, characterized by X-ray powder diffraction having peaks at about 13.2, 14.1 and 16.6 6 0.2 degrees 2 θ. Form I may be further characterized by X-ray powder diffraction having peaks at about 6.6, 10.0, 10.6, 20.3, 23.1, 25.7 and 26.2 6 0.2 degrees 2θ. [0019] WO 2008/094617, filed by Teva Pharmaceuticals USA, describes three crystalline forms of deferasirox, des-

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ignated Forms II, III and IV (a THF solvate). WO 2008/065123, filed by Novartis, describes other crystalline forms of deferasirox, designated Forms A, B, C and D, as well as an amorphous form of deferasirox, and deferasirox solvates designated Forms SA and SB. WO 2009/016359, filed by Pliva Hrvatska D.O.O, describes five crystalline forms of deferasirox, designated Forms I-V, and four amorphous forms designated Forms I-IV. 5 [0020] There still remains an unmet need for advantageous solid state forms of deferasirox having good physiochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters.

SUMMARY OF THE INVENTION

10 [0021] The present invention provides a process for the preparation of deferasirox, which is useful as an oral iron chelator. [0022] Inone embodiment, the present invention provides a process for preparinga compound of formula I(deferasirox). This process is exemplified in Scheme 6 below:

[0023] The process includes the following steps: 50 a) converting salicylic acid (8) to its acyl chloride (3):

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10 b) reacting salicyl chloride (3) with an amidating reagent selected from the group consisting of disilazanes of general 1 2 3 1 2 1 2 3 formula (R R R Si)2NH and cyclosilazanes of general formula (R R SiNH)n, wherein n is 3 or 4 and R , R and R are each independently alkyl or aryl; to produce a deferasirox intermediate of formula (4):

25 and

c) reacting intermediate (4) with 4-hydrazinobenzoic acid (6) to form deferasirox (1):

55 1 2 3 [0024] The amidating reagent in step (b) may be a disilazane of general formula (RR R Si)2NH. Alternatively, the 1 2 1 2 amidating reagent in step (b) may be a cyclosilazane of general formula (R R SiNH)n, wherein n is 3 or 4 and R , R and R3 are each independently alkyl (e.g., C1-C6 alkyl) or aryl. In a currently preferred embodiment, the amidating

7 EP 2 509 423 B1

reagent is hexamethyldisilazane. [0025] In some embodiments, step (b) is conducted in a solvent. The nature of the solvent can vary, and it is preferably selected from the group consisting of hydrocarbons and their halogenated derivatives, aromatic hydrocarbons and their halogenated derivatives, esters, ethers, carboxylic acid amides such as DMF, acetonitrile, and suitable mixtures of these 5 solvents. Each possibility represents a separate embodiment of the invention. In a currently preferred embodiment, the solvent is toluene. [0026] In some embodiments, in step (b) the reaction between salicyl chloride and the amidating reagent is conducted in the presence of a catalyst. In some embodiments, the catalyst is a tertiary amine such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, DBU, DBN, DABCO or picoline, preferably pyridine, or an amide 10 such as DMF and dimethylacetamide. Each possibility represents a separate embodiment of the invention. In one currently preferred embodiment, the catalyst is pyridine. In another currently preferred embodiment, the catalyst is DMF. [0027] Advantageously, step (a) and step (b) of the process of Scheme 6 are combined as a one-pot synthesis. Preferably these steps are conducted in the same solvent, which is preferably toluene. [0028] In other embodiments, step (c) of the process of Scheme 6 is performed in a solvent in the presence of acid. 15 The nature of the solvent can vary, and it is preferably selected from the group consisting of alcohols, ethers, DMF, NMP, DMSO, water and mixtures thereof. In a currently preferred embodiment, the solvent is ethanol. [0029] The acid in step (c) can be an inorganic acid such as hydrochloric acid, hydrobromic, phosphoric or sulfuric acid. Alternatively, the acid can be an organic acid such as formic acid, acetic acid, trifluoroacetic, methanesulfonic or propionic acid. In a currently preferred embodiment, the acid is trifluoroacetic acid. 20 [0030] Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

25 [0031] The present invention provides a synthetic process for the preparation of deferasirox. [0032] In one embodiment of the present invention, the applicants provide a new process, by which deferasirox may be prepared on an industrial scale from the compound of formula (8) in three steps (Scheme 6 above). The process is described in details in the discussion and examples below. [0033] Salicylic acid, 4-hydrazinobenzoic acid and hexamethyldisilazane, which are used here as raw materials, are 30 commercially available reagents. [0034] The present invention relates to a process for preparing a deferasirox intermediate (3), which comprises the steps of converting salicylic acid to its acyl chloride by reaction with chlorinating reagent, preferably in the presence of a catalyst in an organic solvent. [0035] Suitable chlorinating agents can be thionyl chloride, oxalyl chloride, phosgene, POCl3, PCl3, PCl5, cyanuric 35 chloride, combination of triorganophosphine, such as triphenylphosphine with carbon tetrachloride and the like. Each possibility represents a separate embodiment of the present invention. In one currently preferred embodiment, the chlorinating agent is thionyl chloride. [0036] The catalyst can be a tertiary amine such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, DBU, DBN, DABCO and picoline, preferably pyridine or amide, such as DMF and dimethylacetamide. 40 [0037] Further disclosed is a process for preparing a deferasirox intermediate (4), which comprises reacting salicyl 1 2 3 chloride (3) with amidating reagent selected from the group consisting of disilazanes of general formula (R R R Si)2NH 1 2 1 2 3 and cyclosilazanes of general formula (R R SiNH)n, wherein n =3,4, and each of R , R and R is alkyl (e.g., C1-C6 alkyl) or aryl. [0038] In one currently preferred embodiment, the amidating agent is hexamethyldisilazane. The unique role of hex- 45 amethylsilazane in this reaction is due to the multifunctional nature of silazanes. These can be amidating reagents and can also serve as a hydrogen chloride acceptors and protecting groups for OH-groups, thus overcoming the problems in the art processes, i.e. formation of polyesters side products as well as corrosive and hazardous HCl gas. Furthermore, the reaction can proceed efficiently at lower temperatures (e.g. 5-10°C). [0039] Preferably, salicyl chloride reacts with hexamethyldisilazane to form trimethylsilylamide (9) and trimethylchlo- 50 rosilane. Trimethylchlorosilane reacts with the OH-group of compound (9), forming a protected compound (10) while liberating HCl, which is trapped by hexamethyldisilazane forming the inactive ammonium chloride as an insoluble solid. It is contemplated that protection of the hydroxyl group of compound (9) prevents formation of linear and cyclic polyesters, such as compound (7). Further reaction of protected compound (10) with salicyl chloride (3) gives protected amide (11), which is converted by conventional work-up to the desired amide (4) (Scheme 7): 55

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[0040] The reaction is conducted in any suitable solvent, which may, for example, be selected from the group consisting of aliphatic hydrocarbons and their halogenated derivatives, aromatic hydrocarbons and their halogenated derivatives, 35 esters, ethers, nitriles, ketones, carboxylic acid amides, as DMF, acetonitrile, and suitable mixtures of these solvents. Each possibility represents a separate embodiment of the present invention. A currently preferred solvent is hexane or toluene. [0041] The reaction may be catalyzed by addition of tertiary amines such as triethylamine, diisopropylethylamine, N- methylmorpholine, pyridine, lutidine, N-ethylpiperidine, DBU, DBN, DABCO and picoline, preferably pyridine or amide, 40 such as DMF and dimethylacetamide. [0042] If required, the reaction may be performed in an inert gas atmosphere such as argon or nitrogen. [0043] Typically, the salicyl chloride is added to the solvent system at a suitable temperature (for example room temperature), and this mixture is added to a solution of an amidating agent such as hexamethyldisilazane in the same solvent. The progress of the reaction can be monitored by a variety of techniques, for example by chromatographic 45 techniques as described above for process A. Typically, the reaction between salicyl chloride and hexamethyldisilazane is completed after about 2 hour to about 12 hours. If during this time the reaction is not completed, the reaction mixture is heated to reflux. The reflux temperature depends on the choice of the solvent used for this reaction. When the reaction is completed, the product (4) can be isolated from the reaction mixture by standard work-up procedures, for example by filtering the reaction mixture followed by evaporation of the filtrate. If desired, the product can then be purified by any 50 standard technique, for example by crystallization or flash chromatography over silica. [0044] The present invention further provides a process for preparing a deferasirox intermediate (4), in which the steps of salicyl chloride preparation and reaction of such chloride with hexamethyldisilazane can be performed as "one-pot" process. In this case the solvent using at the step (a) can be the same as at the step (b), for example, it can be toluene. [0045] The present invention comprises the reaction of amide (4) with 4-hydrazinobenzoic acid (6). The conditions for 55 such reaction can be determined by a person of skill in the art. Generally, condensation of hydrazines with diacylamines is well known in the literature [Potts, Chemical Reviews, 1961, 61(2): 87-127]. Such reactions occur in the absence of solvents at high temperatures and are termed Pellizzari reactions [Pellizzari, Gazztta, 1911, 41, II, 20]. [0046] The applicants found that the reaction of the amide (4) with 4-hydrazinobenzoic acid (6) can be performed in

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solvents in the presence of acid yielding the required triazole (1). Suitable solvents to be used in such reaction include, but are not limited to alcohols, ethers, DMF, NMP, DMSO, water or suitable mixtures of these solvents. Each possibility represents a separate embodiment of the present invention. Preferred solvents are alcohols, such as methanol, ethanol, isopropanol or their mixtures with water, more preferable, ethanol. 5 [0047] Suitable acids are inorganic acids, such as hydrochloric acid, hydrobromic, phosphoric or sulfuric acid; or organic acids, such as formic acid, acetic acid, trifluoroacetic, methanesulfonic or propionic acid. Preference is given to organic acids, such as acetic acid, trifluoroacetic, methanesulfonic acids and special preference is given to trifluoroacetic acid. [0048] The product may be isolated from the reaction mixture by ordinary methods, and it can be easily purified in 10 terms of impurities, byproducts, contaminants, and the like by means of separation, for example, crystallization or chromatography. [0049] The solvent or mixture of solvents for the purification step can be selected in such manner that any desired polymorphic form of the compound of Formula I is provided by crystallization or precipitation from such solvent or mixture of solvents. 15 [0050] The deferasirox product can be in polymorphic, pseudopolymorphic or amorphous forms, or any mixtures thereof.

Chemical Definitions:

20 [0051] An "alkyl" group as used herein refers to any saturated aliphatic hydrocarbon, including straight-chain, branched- chain and cyclic alkyl groups (cycloalkyl). In one embodiment, the alkyl group has 1-12 carbons designated here as C1-C12-alkyl. In another embodiment, the alkyl group has 1-6 carbons designated here as C1-C6-alkyl. In another embodiment, the alkyl group has 1-4 carbons designated here as C1-C4-alkyl. The alkyl group may be unsubstituted or substituted by one or more groups including, but not limited to from halogen, hydroxy, alkoxy, aryloxy, carbonyl, amido, 25 alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl. [0052] A "cycloalkyl" group refers to a non-aromatic mono- or multicyclic ring system. In one embodiment, the cycloalkyl grouphas 3-10carbon atoms.In anotherembodiment, thecycloalkyl group has 5-10 carbon atoms. Exemplary monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and the like. An alkylcycloalkyl is an alkyl group as defined herein bonded to a cycloalkyl group as defined herein. The cycloalkyl group can be unsubstituted or substituted with 30 any one or more of the substituents defined above for alkyl. [0053] An "aryl" group refers to an aromatic ring system containing from 6-14 ring carbon atoms. The aryl ring can be a monocyclic, bicyclic, tricyclic and the like. Nonlimiting examples of aryl groups are phenyl, naphthyl including 1-naphthyl and 2-naphthyl, and the like. The aryl group can be unsubstituted or substituted through available carbon atoms with one or more groups defined hereinabove for alkyl. 35 [0054] A "silyl" group refers to a group SiRRR, wherein each R is independently, alkyl or aryl as described above. [0055] An "acyl" group refers to a C(=O)R group wherein R is alkyl or aryl as described above. [0056] The principles of the present invention are demonstrated by means of the following non-limitative examples.

EXAMPLES 40 [0057] The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. [0058] Unless otherwise noted, the materials used in the examples were obtained from readily available commercial 45 suppliers or synthesized by standard methods known to one skilled in the art of chemical synthesis. The work-up treatment in each step can be applied by a typical method, wherein isolation and purification is performed as necessary by selecting or combining conventional methods, such as crystallization, recrystallization, distillation, partitioning, silica gel chromatography, preparative HPLC and the like.

50 Example 1

Preparation of Salicyloyl chloride

[0059] Salicylic acid (5.0 g, 36.2 mmol) was suspended in dry hexane (40ml) and thionyl chloride (4.52 g, 38 mmol) 55 was added under nitrogen atmosphere followed by one drop of pyridine. The mixture was refluxed for two hours while stirring. The clear yellow solution was cooled and concentrated in vacuum, giving a dense oil to be used in the next step.

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Preparation of 2-hydroxy-N-(2-hydroxybenzoyl)benzamide [(di(salycyl)imide] (4)

6 salicylchloride + 5 (Me3Si)2NH → 3 di(salicyl)imide + 4 Me3SiCl + 2NH4Cl

5 [0060] The previously prepared salicyl chloride was dissolved in dry toluene (10 ml) and added dropwise to a solution of hexamethyldisilazane (4.954 g, 30.8 mmol) in dry toluene (20 ml). The mixture was stirred at 0-10°C under nitrogen atmosphere for 1 hour. The mixture was then filtered and the filtrate concentrated under reduced pressure. Ethanol was added to the residue and the reaction mixture was refluxed. After cooling, the precipitate was filtered and dried in vacuum, giving a white to off-white solid with 50% yield. Separation from mother liquid gave an additional amount of compound 10 (4) with 75% overall yield. m.p. 197-199°; lit. m.p. 188-190° [J.Chem.Soc.,1958, 23, 893-896] 1 H NMR (500 MHz, DMSO- d6): δ: 7.831 (dd, J=7.5, 2 Hz, 1H), 7.745 (td, J=7.5, 1.5 Hz, 1H), 7.388 (s, 1 H), 7.286 (s, 1 H), 7.184 (s, 1 H), 7.077 (d, J=8.5 Hz, 1H), 6.975 (t, J=7.5Hz 1H). ESIMS(+): [M+H]=257.9; ESIMS(-): [M-H]= 256.1 15 Preparation of 4-[3,5-Bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox)

[0061] Disalicylimide (4) (3.7 g, 14.32 mmol) and 4-hydrazinobenzoic acid (2.6 g, 17.14 mmol) were suspended in ethanol (50 ml) and refluxed, adding TFA in portions until most of the reagents were dissolved (6% v/v), monitoring the 20 reaction progress by HPLC. After 4h no more starting material was present. The mixture was cooled and concentrated. After cooling the precipitate was filtered. The solid was recrystallized from ethanol-water, filtered, washed with mixture ethanol-water and dried for 24 h in vacuum to give desired compound with 85% yield. 1 H NMR (400 MHz, DMSO- d6): δ: 6.87 (d, J=8.4 Hz, 1H), 7.045-6.97 (m, 3H), 7.24 (m, 2H), 7.405 (qd, J=7.6, 1.6 Hz, 2H), 7.558 (d, J=10 Hz, 3H), 7.98 (d, J=8.4 Hz, 2H), 8.059 (dd, J=7.6, 2 Hz, 1H), 10.059 (s, OH), 10.812 (s, OH). 25 EI-MS calcd for C21H15N3O4 MW 373.11, found m/z 373.11 Anal. Calcd for C21H15N3O4 (373.36): C, 67.56; H, 4.05; N, 11.25 Found: C, 67.48; H, 4.0; N, 10.98.

Claims 30 1. A process for the preparation of deferasirox (1), comprising the steps of:

a) converting salicylic acid (8) to its acyl chloride (3):

45 b) reacting salicyl chloride (3) with an amidating reagent selected from the group consisting of disilazanes of 1 2 3 1 2 general formula (R R R Si)2NH and cyclosilazanes of general formula (R R SiNH)n, wherein n is 3 or 4 and R1, R2 and R3 are each independently alkyl or aryl, so as to produce a deferasirox intermediate of formula (4):

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and c) reacting intermediate (4) with 4-hydrazinobenzoic acid (6) to form deferasirox (1):

2. The process according to claim 1, wherein the amidating reagent is hexamethyldisilazane.

3. The process according to claim 1, wherein step (b) is conducted in a solvent, wherein the solvent is preferably 45 selected from the group consisting of hydrocarbons and their halogenated derivatives, aromatic hydrocarbons and their halogenated derivatives, esters, ethers, carboxylic acid amides such as DMF, acetonitrile, and suitable mixtures of these solvents, more preferably wherein the solvent is toluene.

4. The process according to claim 1, wherein in step (b) the reaction between salicyl chloride and the amidating reagent 50 is conducted in the presence of catalyst, wherein the catalyst is preferably selected from the group consisting of tertiary amine such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, DBU, DBN, DABCO and picoline, preferably wherein the catalyst is pyridine or amide such as DMF and dimethylacetamide, more preferably wherein the catalyst is pyridine or DMF.

55 5. The process according to claim 1, wherein step (a) and step (b) are combined as a one-pot synthesis, preferably in the same solvent which is preferably toluene.

6. The process according to claim 1, wherein step (c) is performed in a solvent in the presence of acid.

12 EP 2 509 423 B1

7. The process according to claim 6, wherein the solvent is selected from the group consisting of alcohols, ethers, DMF, NMP, DMSO, water and mixtures thereof, preferably wherein the solvent is ethanol.

8. The process according to claim 6, wherein the acid is an inorganic acid, such as hydrochloric acid, hydrobromic, 5 phosphoric or sulfuric acid; or an organic acid such as formic acid, acetic acid, trifluoroacetic, methanesulfonic or propionic acid, preferably wherein the acid is trifluoroacetic acid.

Patentansprüche 10 1. Verfahren zur Herstellung von Deferasirox (1), welches die Schritte umfasst :

a) Umwandeln von Salicylsäure (8) in dessen Acylchlorid (3):

25 b) Umsetzen des Salicylchlorids (3) mit einem Amidierungsreagenz, ausgewählt aus der gruppe bestehend aus 1 2 3 1 2 Disilazanen der allgemeinen Formel (R R R Si)2NH und Cyclosilazanen der allgemeinen Formel (R R SiNH)n, worin n 3 oder 4 ist und R1, R2 und R3 jeweils unabhängig Alkyl oder Aryl sind, um so ein Deferasirox-Zwi- schenprodukt der Formel (4) zu bilden: 30

and c) Umsetzen des Zwischenprodukts (4) mit 4-Hydrazinbenzoesäure (6) um Deferasirox (1) zu bilden:

13 EP 2 509 423 B1

2. Verfahren nach Anspruch 1, worin das Amidierungsreagenz Hexamethyldisilazan ist.

30 3. Verfahren nach Anspruch 1, worin Schritt (b) in einem Lösungsmittel durchgeführt wird, worin das Lösungsmittel vorzugsweise ausgewählt ist aus der Gruppe bestehend aus Kohlenwasserstoffen und deren halogenierten Deri- vaten, aromatischen Kohlenwasserstoffen und deren halogenierten Derivaten, Estern, Ethern, Carboxylsäureami- den, wie DMF, Acetonitril und geeigneten Gemischen dieser Lösungsmittel, mehr bevorzugt worin das Lösungsmittel Toluol ist. 35 4. Verfahren nach Anspruch 1, worin in Schritt (b) die Reaktion zwischen Salicylchlorid und dem Amidierungsreagenz in der Anwesenheit eines Katalysators durchgeführt wird, worin der Katalysator vorzugsweise ausgewählt ist aus der Gruppe bestehend aus tertiären Aminen, wie Triethylamin, Diisopropylethylamin, N-Methylmorpholin, Pyridin, Lutidin, DBU, DBN, DABCO und Picolin, vorzugsweise worin der Katalysator Pyridin ist oder Amid, wie DMF und 40 Dimethylacetamid, mehr bevorzugt worin der Katalysator Pyridin oder DMF ist.

5. Verfahren nach Anspruch 1, worin Schritt (a) und Schritt (b) als eine Eintopf-Synthese kombiniert werden, vorzugsweise in dem gleichen Lösungsmittel, das vorzugsweise Toluol ist.

45 6. Verfahren nach Anspruch 1, worin Schritt (c) in einem Lösungsmittel in Anwesenheit von Säure durchgeführt wird.

7. Verfahren nach Anspruch 6, worin das Lösungsmittel ausgewählt ist aus der Gruppe bestehend aus Alkoholen, Ethern, DMF, NMP, DMSO, Wasser und Gemischen davon, vorzugsweise worin das Lösungsmittel Ethanol ist.

50 8. Verfahren nach Anspruch 6, worin die Säure eine anorganische Säure ist, wie Chlorwasserstoffsäure, Bromwas- serstoffsäure, Phosphor- oder Schwefelsäure, oder eine organische Säure, wie Ameisensäure, Essigsäure, Triflu- oressigsäure, Methansulfonsäure oder Propionsäure, vorzugsweise worin die Säure Trifluoressigsäure ist.

55 Revendications

1. Un procédé pour la préparation de déférasirox (1), comprenant les étapes suivantes :

14 EP 2 509 423 B1

a) convertir l’acide salicylique (8) à son chlorure d’acyle (3) :

b) mettre en réaction le chlorure salicylique (3) avec un réactif d’amidation sélectionné du groupe consistant 15 2 3 2 en disilazanes à formule générale (R’R R Si)2NH et cyclosilazanes à formule générale (R’R SiNH)n, où n est 3 ou 4 et R 1, R2 et R3 sont chacun indépendamment alkyl ou aryl, afin de produire un intermédiaire déférasirox à formule (4) :

30 et c) mettre en réaction l’intermédiaire (4) avec 4-acide hydrazinobenzoïque (6) pour former le déférasirox (1) :

15 EP 2 509 423 B1

2. Le procédé d’après la revendication 1, où le réactif d’amidation est l’améthyldisilazane.

3. Le procédé d’après la revendication 1, où l’étape (b) est réalisée dans un solvant, où le solvant est préférablement sélectionné d’un groupe consistant en hydrocarbonés et leur dérivés halogénés, hydrocarbonés aromatiques et 5 leur dérivés halogénés, esters, éthers, amides d’acide carboxylique tels que DMF, acétonitrile, et des mélanges appropriés de ces solvants, plus préférablement où le solvant est le toluène.

4. Le procédé d’après la revendication 1, où dans l’étape (b) la réaction entre le chlorure salicylique et le réactif d’amidation est réalisée en présence d’un catalyseur, où le catalyseur est préférablement sélectionné d’un groupe 10 consistant en amine tertiaire tels que triéthylamine, diisopropyléthylamine, N-méthylmorpholine, pyridine, lutidine, DBU, DBN, DABCO et picoline, préférablement où le catalyseur est la pyridine ou l’amide tels que DMF et dimé- thylacétamide, plus préférablement où le catalyseur est la pyridine ou le DMF.

5. Le procédé d’après la revendication 1, où l’étape (a) et l’étape (b) sont combinées en une synthèse monotope, 15 préférablement dans le même solvant qui est préférablement le toluène.

6. Le procédé d’après la revendication 1, où l’étape (c) est réalisée dans un solvant en présence d’acide.

7. Le procédé d’après la revendication 6, où le solvant est sélectionné du groupe consistant en alcools, éthers, DMF, 20 NMP, DMSO, eau et mélanges de ceux-ci, préférablement où le solvant est l’éthanol.

8. Le procédé d’après la revendication 6, où l’acide est un acide inorganique, tel qu’acide hydrochlorique, hydrobro- mique, phosphorique ou acide sulfurique ; ou un acide organique tel qu’acide formique, acide acétique, trifluoroa- cétique, méthanésulfonique ou acide propionique, préférablement où l’acide est l’acide trifluoroacétique. 25

16 EP 2 509 423 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

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