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Nilotinib Intermediates and Preparation Thereof

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Nilotinib Intermediates and Preparation Thereof (19) & (11) EP 2 305 667 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 06.04.2011 Bulletin 2011/14 C07D 401/14 (2006.01) (21) Application number: 11151589.6 (22) Date of filing: 17.07.2009 (84) Designated Contracting States: • Kansal, Vinod, Kumar AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 121003, Faridabad Haryana (IN) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • Zhu, Jirang PT RO SE SI SK SM TR Pudong Shanghai (CN) Designated Extension States: • Lifshitz-Liron, Revital AL BA RS Herzlia (IL) • Mistry, Dhirenkumar, N. (30) Priority: 17.07.2008 US 81464 P 393145, Rajpipla Gujarat (IN) 24.07.2008 US 83424 P • Vasoya, Sanjay, L. 20.08.2008 US 90368 P 360002, Dist-rajkot Gujarat (IN) 24.11.2008 US 117478 P • Ariyamuthu, Sundaraselvan 19.03.2009 US 161670 P 627006, Tirunelveli Tamilnada (IN) 13.05.2009 US 168822 P • Pilarski, Gideon 22.05.2009 US 171706 P 58417 Holon (IL) • He, Xungui (62) Document number(s) of the earlier application(s) in 201204 Pudong Shanghai (CN) accordance with Art. 76 EPC: 09790590.5 (74) Representative: Wong, Kit Yee D Young & Co LLP (71) Applicant: Teva Pharmaceutical Industries Ltd. 120 Holborn 49131 Petah Tiqva (IL) London EC1N 2DY (GB) (72) Inventors: Remarks: • Wang, Yanling This application was filed on 20-01-2011 as a Pudong Shanhai (CN) divisional application to the application mentioned • Li, Jie under INID code 62. Pudong Shanghai (CN) (54) Nilotinib intermediates and preparation thereof (57) Nilotinib•3HCl and its crystalline forms are described, and processes for the preparation of the same. EP 2 305 667 A2 Printed by Jouve, 75001 PARIS (FR) EP 2 305 667 A2 Description CROSS-REFERENCE TO RELATED APPLICATIONS 5 [0001] This application claims the benefit of U.S. Provisional Patent Application Serial. Nos. 61/081,464, filed July 17, 2008; 61/083,424, filed July 24, 2008; 61/090,368, filed August 20, 2008; 61/117,478, filed November 24, 2008; 61/161,670, filed March 19, 2009; 61/171,706, filed April 22, 2009; 61/168,822, filed April 13, 2009, which are incorporated herein by reference. 10 FIELD OF INVENTION [0002] The present invention is directed to preparation of Nilotinib by a one-pot process, intermediates of Nilotinib, Nilotinib·3HC1 and its crystalline forms. 15 BACKGROUND OF THE INVENTION [0003] Nilotinib, 4- methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-benzamide, having the following formula 20 25 30 is a tyrosine kinase inhibitor used for the treatment of drug-resistant chronic myelogenous leukemia (CML), and in particular, for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia (CML) in adult patients whose disease has progressed on or who cannot tolerate other therapies that included 35 imatinib. Nilotinib is administered as a hydrochloride salt in forms of capsules that are marketed in the USA and the EU under the name Tasigna®. [0004] US patent no. 7,169,791 ("US ’791 ") and its parallel PCT publication WO 2004/005281, the journal article in Synthesis, 2007, vol 14, pp 2121-2124, as well as PCT publication nos.: WO 2006/135640, WO 2006/135641 ("WO ’641 "), WO 2007/018325 and WO 2007/017734, report processes for preparing Nilotinib intermediate, 3-(trifluoromethyl)- 40 5-(4-methyl-1H-imidazole-1-yl)-benzeneamine of formula I 45 50 by reacting 3-bromo-5-trifluoromethylaniline of formula II and 4-methylimidazole of formula III in the presence of a non- 55 alkaline hydroxide inorganic base, such as potassium carbonate, cesium carbonate and sodium hydride, a copper (I) salt, such as copper iodide and a complexing amine ligand, such as ethylene diamine. The process can be illustrated by the following scheme: 2 EP 2 305 667 A2 5 10 15 [0005] The journal article in Synthesis, 2007, Vol 14, pp 2121-2124, describes a purification process of 3-(trifluorome- thyl-5-(4-methyl-1H-imidazole-1-yl)-beuzeneamine of formula I. [0006] US ’791 describes processes for preparing Nilotinib and its different intermediates, using di- ethyl cyano phos- phate, as described in the following scheme: 20 25 30 35 40 45 50 55 3 EP 2 305 667 A2 5 10 15 20 25 30 35 40 45 [0007] WO ’641 further describes a process for preparing Nilotinib according to the following scheme: 50 55 4 EP 2 305 667 A2 5 10 15 [0008] The present invention provides improved processes to prepare and/or purify 3-(trifluoromethyl)-5-(4-methyl- 1H-imidazole-1-yl)-benzeneamine of formula I without requiring the use of column chromatography, and thus can be easily applied to large scale manufacture, as well as new intermediates of Nilotinib, which result in higher yields in the preparation of Nilotinib. 20 [0009] PCT publications WO 2007/015870 ("WO’870") and WO 2007/015871 1 ("WO’871") describe several Nilotinib salts including crystalline forms of nilotinib free base, Nilotinib hydrochloride and Nilotinib Sulfate. [0010] The present invention also relates to the solid state physical properties of Nilotinib•3HCl, 4-methyl-N-[3-(4- methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide trihydrochloride. These properties can be influenced by controlling the conditions under which Nilotinib-3HC1 is obtained in solid form. 25 Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must necessitate the use of glidants such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate. [0011] Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. 30 The rate of dissolution of an active ingredient in a patient’s stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally administered active ingredient can reach the patient’s bloodstream. The rate of dissolution is also a consideration in formulation syrups, elixirs, and other liquid medicaments. The solid state form of a compound can also affect its behavior on compaction and its storage stability. [0012] These practical physical characteristics are influenced by the conformation and orientation of molecules in the 35 unit cell, which define a particular polymorphic form of a substance. The polymorphic form can give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC") and can be used to distinguish some polymorphic forms from others. A particular polymorphic form can also give rise to distinct spectroscopic properties that can be detectable by powder rayx- crystallography, solid 40 state l3C NMR spectroscopy, and infrared spectrometry. [0013] Generally, a crystalline solid has improved chemical and physical stability over the amorphous form, and forms with low crystallinity. Crystalline forms may also exhibit improved solubility, hygroscopicity, bulk properties, and/or flow- ability. [0014] The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity 45 to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. [0015] There is a need in the art for new intermediates of Nilotinib and processes for their preparation, new processes for preparing Nilotinib and new crystalline forms of Nilotinib•3HCl salt and processes for the preparation thereof. 50 SUMMARY OF THE INVENTION [0016] In one embodiment, the present invention provides a process for preparing 3-(trifluoromethyl)- 5-(4-methyl-1H- imidazole-1-yl)-benzeneamine of formula I, 55 5 EP 2 305 667 A2 5 10 comprising reacting 3-bromo-5- trifluoromethylaniline of formula II, 15 20 25 4-methylimidazole of formula III, 30 35 40 a base selected from a group consisting of: an alkaline metal hydroxide, an alkaline earth metal hydroxide and ammonium hydroxide; and a water absorbing agent. [0017] In another embodiment, the present invention provides a process for crystallizing the compound of formula I from a mixture of ethyl acetate and petroleum ether comprising dissolving 3-(trifluoromethyl- 5-(4-methyl-1H-imidazole- 1-yl)-benzeneamine of formula I in ethyl acetate; adding petroleum ether to obtain a suspension and isolating. 45 [0018] In yet another embodiment, the present invention further provides a process for purifying the intermediate of formula I by recrystallizing it from a mixture of IPA and water or a mixture of ethanol and water. [0019] In one embodiment, the present invention provides a process for preparing Nilotinib and salt thereof of the following formula 50 55 6 EP 2 305 667 A2 5 10 comprising: preparing 3-(trifluoromethyl)-5-(4-methyl-1H-imidazole-1-yl)-benzeneamine of formula I according to the 15 processes of the present and converting it to Nilotinib or a salt thereof wherein, n is either 0 or 1, and HA is an acid, preferably, HCI. [0020] In another embodiment, the present invention provides N-(3- Bromo-5-trifluoromethylphenyl)-4-methyl-3-[[4-(3- pyridinyl)-2-pyrimidinyl]amino]benzamide, a Nilotinib intermediate of formula IV, having the following structure: 20 25 30 [0021] In another embodiment, the present invention provides an isolated N-(3-Bromo-5-trifluoromethylphenyl)-4- methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide, a Nilotinib intermediate of formula IV.
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