EP 1 896 425 B1 (19) )) a (12) (45) Date of publication and mention ofthe grant ofthe patent: 06.10.2010 Bulletin 2010/40 (21) Application number: 06772966. (22) Date of fling: 07.06.2008 (11) EP 1 896 425 B1 EUROPEAN PATENT SPECIFICATION (61) Inte C070 239/54 0620) (86) Intamational application number: PcT/us2006022026 (87) Intemational publication number: Wo 2006/135619 (21.12.2006 Gazette 2006/51) (64) PROCESS FOR THE SYNTHESIS OF 5-(METHYL- 1H-IMIDAZOL-1-YL) -3- (TRIFLUOROMETHYL) -BENZENEAMINE VERFAHREN ZUR SYNTHESE VON 5-(METHYL-1H-IMIDAZOL-1-YL)- 3-(TRIFLUORMETHYL)-BENZENEAMIN, PROCEDE DESTINE A LA SYNTHESE DE 5-(METHYL-1H-IMIDAZOL-1-YL)- 3-(TRIFLUOROMETHYL)-BENZENEAMINE. (84) Designated Contracting States: AT BE BG CH CY CZ DE DK EE ES FIFR GB GR HUJE IS IT LILTLU LV MC NL PL PT RO SE SI SkTR (80) Priority: 09.06.2005 Us 688920 P (43) Date of publication of apalication: 12.03.2008 Bulletin 2008/11 (73) Proprietors: * Novartis AG 4056 Basel (CH) Designated Contracting States: BE BG CH CY CZ DE DK EE ES FIFR GB GR HU IEISITLILTLULVMCNLPLPTROSESISKTR + Novartis Pharma GmbH 1230 Wien (AT) Dasignated Contracting States: aT (72) Inventors: * ACEMOGLU, Murat (CH-4082 Basel (CH) + SCHENKEL, Berthold 79576 Weil am Rhein (DE) + SHIEH, Wen-Chung Berkeley Heights, NJ 07922 (US) + XUE, Song Parsippany, NJ 07054 (US) + WIDMER, Erich (CH-4142 Minchenstein (CH) + GARCIA FUENTES, Pedro E-30817 Lorea, Murcia (ES) ‘+ MARTIN MEDINA, Jose -30890 La Nora, Murcia (ES) + VICENTE BANOS, Francisco E-30565 Las Torres de Cotillas, Murcia (ES) (74) Representative: Roth, Peter Richard et al Novartis AG Corporate Intellectual Property 4002 Basel (CH) (66) Reterences cited Wo-a1-2004/005281 Note: Within nine months ofthe publication of the mention ofthe 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 withthe Implementing Regulations. Notice of opposition shall not be deemed to have been fled untl the opposition fee has been paid. (Art. 99(1) European Patent Convention),EP 1 896 425 B1 Description kground of the Invention [0001] The present invention provides an efficient, safe and cost effective way to prepare 5-(4-methyl-1 Himidazol-1 )-(tiftuoremethy/)-oenzenamine ofthe following formula (): w FC NH [0002] The compound of formula () i an intermediate for the preparation of substituted pyrimidnylaminobenzamides of formula (il) a H i \ i we N re 0) oo) : ZN RI F F [0003] Compounds of formula (I) have been disclosed in W. Breitenstein et al., WO 04/0528: Al, the disclosure of ‘which is incorporated herein by reference. These compounds have been stiown to inhibit one or mare tyrosine kinases, such as c-Abl, Bor-Abl the receptor tyrosine kinases PDGF-A, FitS, VEGF-R, EGF-R and c-Kit. As such, compounds ‘of formula (I) can be used for he treatment of certain neoplastic diseases, such as leukemia. [0004] Previous synthesis of compound (I) involves @ 4 step synthetic route starting with an aromatic substitution reaction of compound (lla), 4-methyi-1H-Imidazole, with compound (IV), which requires employing high energy (150°C) (Scheme 1)EP 1 896 425 B1 ‘Scheme He. Hc. " XS games US ae + omrre 4 guonwe CD > N (ita) mw FC CN FC ‘COOH ™ wv) He. HE. l a erowrom, Briton y ‘00H i on FC N~ Yo 7 H crt FC" ‘NH, vm w [0005] Furthermore, transformation of compound (VI) to compound (Vil) via Curtius rearrangement utiizes an unsafe reagent, diphenylphosphorylazide. This reaction produces inconsistent product yields and qualty. In addition, emoving the resulting diphenylphosphorie acid by-produet is dificult. The carbamate product (Vil) needs to be purfied by chro: ‘matography, which is expensive and time consuming for commercial operations. [0006] tis an object ofthis invention to provide alternative processes to make the compound of formula (|) efficiently and in high yields. [0007] itis a further object of this invention to make compound (I) from lower cost staring materials and reagents, [0008] tis a stil further object of this invention to provide for a process to make the compound of formula (I) using safer reagents. [0009] The present invention overcomes the problems of the reaction shown in Scheme 1 above. ‘Summary of the Invention [0010] The present invention provides novel synthetic processes for the manufacture of 6-(4-methyl-1 Himiazol-1 )-(tituoromethy!)-eenzenamine having formula (0): 0 FC NH,EP 1 896 425 B1 [0011] The compound of formula () is an intermediate for the preparation of substituted pyrimidinylaminobenzemides ‘of formula (I) which have been disclosed in W. Breitenstein etal, WO 04/005281, which published on January 15, 2004, the disclosure of which is incorporated by reference. A preferred compound of formula ll) is 4-methyl-3[4-(S-pyriiny) 2 pyrimidinyljamino}-N{5-(4-methyl-1H-imidazol-t-y)-3-(tfluoremethyi}phenylbenzamide Detailed Description ofthe Invention [0012] The general reaction scheme of the invention can be illustrated in the following embodiments: [0013] In first embodiment, the present invention provides the general process of making compound (I) as follows: He, HAC NO, . | \ iN + & ‘ F W seduction Nox FOR Stpa ‘StepB Fe NO, FC NH, a) Y [0014] Step A involves a base and nucleophilic aromatic substitution forthe synthesis of 4-methy-1-(S-nitro-S-tnfluor- ‘omethyl-pheny))-1H-imidazole (Il). Step 8 is @ reduction leading to compound (). [0015] The base may be selected from an alkoxide, a hydride, a carbonate or @ phosphate. Preferably the base is a potassium alkoxide, sodium alkoxide, sodium hydride, potassium carbonate or potassium phosphate. The solvent used in Step Ais selected from N,.-dimethyiformamide (OMF), N,N-dimethy'acetamide (DMA), or 1-methyi-2-pyrroldinone (NMP) or mixtures thereot [0016] A second embodiment Involves coupling of dinirobenzotefluoride and 4-methyl-1H-imidazole folowed by a hydrogenation reaction He. HG, HC, r BOD rs Ny Ny a) Tsogeraion Nog F F FC NO, FC NH, «uty w [0017] In addition, a third embodiment involves a further step for each of the process descrived above optionally involving the transformation of compound (Il) nto a salt of the formula (V), for puication reasons, asilustrated by the following scheme:EP 1 896 425 B1 Scheme 7 N NN + acid | - ‘ \ cia —— on : ON’ t F qu (™ . [0018] Here a solution of compound (I) is treated with an acid, or a solution thereot in water or an organic solvent, followed by isolation ofthe salt (IV), e.g. by ftration, [0019] Compound) may then be obtained by treating sat (IV) with abase, preferably with aqueous sodium hydroxide solution, and isolating the free base (Il) by extraction or crystalization, [0020] |The coupling reaction works in several common polar aprotic solvents, including dimethyl sulfoxide (DMSO), OME, diglyme, THF, NMP and DMA. [0021] Ithas been found, in accordance withthe present invention thet the coupling reaction of methylimidazole and dinitrobenzotritiuoride works better in DMA. the solvent, ata temperature intherange of 80-150°C, preferably 90-140°C. When K;CO; or other bases are present, decomposition happens quite fast. Since the reaction mixture is not stable, reaction temperature and time should be reduced as much as possible. A faster heating and cooling cycle or shorter reaction time intervals, eg., using microwave or by addtional heat exchanger capacity in batch vessels or by using continuous reaction equipment wil lead to less decomposition and a cleaner reaction. [0022] KPO, has a similar performance compared to K,CO;, but the reaction is faster in the second case. A crude yleld of >40% can be obtained according to the procedure described herein [0023] Reduction ofthe nitroimidazol intermediate, compound (II), can be performed using hydrogen gas or hydrogen transfer agents such as formic acid or ammonium formate, in the presence of common supported transition Group VI ‘metal catalysts, such as palladium, platinum, nickel or any combination. The meta s incorporated on the support in an, ‘amount of from 0.1-20 weight percent, based on the total weight of the metal and suppor. A combination of catalysts ‘may also be used. Its within the scope of the present invention that the catalyst may also include a promoter or a co- promoter. The preferred reduction process, hydrogenation, uses hydrogen gas and palladium catalyst. The hydrogenation is usually performed at hydrogen pressure ranging 1-20 bar, preferably 5-10 ber. The crude product can also be isolated {as hydrochloride salt. The final purification is achieved by crystallization ofthe free base, compound (0). [0024] |The following examples more particulary ilustrate the present invention, utd notlimitthe invention inany way. Example 4 [0025] Ina200L vessel, 9kg of cintrobenzotrfluoride, 6.9 kg of potassium carbonate and 84.6 kg of DMA are placed. Aer 10 minutes, string for a good mixture (dark red coler), 3.8 kg of 4-methy/-1H-imidazole is charged, and the mixture is heated under stirring to 95°C for 15-20 hours until analysis shows no starting material. The derk red-brown mixture is cooled down to 30 °C, poured onto water under good sting, ftered and washed with water, to yield ca. Skg of crude product, as a dark-brown wet solid. Analysis shows 1:9 of the wrong isomer. This solid is treated with cyclohexane and ‘charcoal under heating, then the mixture is clad, the cake washed with hot cyclohexane. The combined fitrates are cooled down to room temperature and a beige soli preciptates. Expected yield: 2.6-3.6 kg; 25-35%. Example 2 Hydrogenation using Pa/C catalyst [0026] 34.4 gofthe nit intermediate Il), prepared according to Example 1, 1.72g, 8% Pd/C and 217 mL of methanol Were charged into a hydrogenation vessel, ter usual inetization, hydrogenation was performed at 70-75°C and 4.2-7.5 boar for 2 hours. Following reaction completion by gas chromatographic analyses, the catalyst was fitered off and then rinsed with methanol, The fitrates were combined and most of the solvents was distilled off under vacuum. 174 ml. ofEP 1 896 425 B1 ‘methanol and 626 mL of acetone were added to the solid residue, After the addition of 17 g of aqueous hydrochloric ‘acid, the hydrochloride sat precipitated out The suspension was cooled down to-10°C to -§°C and stirred for 30 minutes. ‘Then the salt was fitered and washed with 58 mL of acetone. 319 mL of methanol was added to the wet hydrochloride salt and the suspension was heated to 58-62 C. After the addition of 18 g of sodium bicarbonate and 756 g water, the solution is fitered and cooled to $-7"C. The crystallized product, compound (I), was filtered, washed with water and dried under vacuum at 60-75°C (yield: 19.1 g, 62% of theory, purity >99%). Example 3 [0027] The following involves a hydrogenation process using the Raney Nickel catalyst. The nitro intermediate (I) (7-5 kg), Raney Nickel (0.375 kg) and methanol (82.5 kg) are charged; and purged with nitrogen and vacuum several times and then with hydrogen plus vacuum 3 times. The pressure Is adjusted to 4 bar and then heated to 70°C. The pressure is Kept et 4 bar until no more hydrogen Is consumed: followed by string et this temperature for 2 addtional hours. The pressure and sample are released by the bottom valve. if reaction is not complete according to analysis, reheat to 70°C under 4 bar H gas and stir another hour. If reaction is complete, clarity the reaction mixture through cartridge fter. The solventis removed by vacuum distliation (maximum 60°C) and added to the residue toluene (44 kg) and acetone (121 kg). Over tis mixture hydrochloric acid (8.7 kg) is added dropwise. The white solid is centituged and washed with acetone. This sold is dissolved in methanol (85 kg) at 60°C, and to this solution another one of sodium bicarbonate (3.95 kg) in water (185 kg) is added keeping the temperature below 60°C. 0.7 kg of carbon are added and the mixture is stirred at 60°C for an hour. It is then clarified and cooled to 18-20°C, After stiring for one hour at this temperature, the mixture is centrifuged and washed twice with water, The sold is dried until the water content is below (0.5%, The expected amount it 5.5 kg (82.5 % yield), Claims 1. Aprocess for preparing 5-(4-methyl-t H-midazol-1-y)-S(triluoromethy))-benzenamine (I), comprising the steps of: 8) reacting, in a coupling reaction, the compound No, NO, with 4-methyl-1 Himidazole (lla) to prepare 4-methyl-t(G-nitro-5-triluoromethylpheny)-1H-imidazole (II); and ) reducing the resulting 4-methyi-1-(S-nitro-5tfluoremethyi-phenyl)-1H imidazole to produce the compound of formula (). The process according to Claim 1, wherein Step a) is performed ata temperature in the range of 80-180°C, 3, The process according to Claim 1, wherein Step a) is performed ata temperature in the range of 90-140°C, 4, Theprocess accordingto Claim 1, where the reduction reaction Step b) involves Group Villmeta catalysts, hydrogen gas or hydrogen transfer agents, ‘The process according to Ciaim 4, where the catalysts palladium, platinum or Reney Nickel or combinations thereot. 6. process for preparing 5-(4-methy-t H-midazol-1-y)-$(tiluoromethy)-benzenamine (I), comprising the steps of: ) reacting, ina suitable base using an appropriate solvent, the compoundEP 1 896 425 B1 No, No, with 4-methyl-1 Himidazole to prepare 4-methyi-1-(9-ritro-6-trfiuoromethyl-pheny)-1H-imidazole (Il); and ) hydrogenating the resuting 4-methyi-1-(3-nitro-5-trfluoromethy-pheny)-H-Imidazole (il) with hydrogen gas and a sultable catalyst using an appropriate solvent to produce the compound of formula (), 7. Aprocess according to Claim 6, wherein the base is an alkoxide, a hydride, a carbonate or a phosphate. ‘The process according to Claim 1 or 6, wherein Step a) utiizes a polar aprotic solvent selected trom dimethyl sulfoxide (DMSO), dimethylfomamide (DMF), diglyme, THF, N-methyl pyrrolidone (NMP) and dimethylacetamide (OMA). 9. Aprocess according to Claim 1, wherein microwaves are used, 10. A process according to Claim 1, wherein afaster heating and cooling cycle is achlevedby addtional heat exchanger capacity in batch vessels or by using continuous reaction equipment to obtain higher selectivity Patentanspriiche Verfahren zur Herstellung von §-(4-Methyi-1H-imidazol fen umfaset: yl-3-(tefluormethy)-benzamin (I), das die folgenden Stu 2) Umsetzen in einer Kupplungsreaktion der Verbindung No, Noy mit 4-Methylt H-imidazol (Ila) 2ur Herstellung von 4-Methy/-1-(3-nitro-5-trfluormethylphenyl)-1H-imidazol (I); und ) Reduzieten des erhaltenen 4-Methyi-1-(9-nitro-6-tifluormethyl-pheny!)-1H-Imidazols 2urHerstellung der Ver: bindung der Forel (I), 2. Verfahren nach Anspruch 1, wobei die Stufe a) bel einer Temperaturim Bereich von BOs 150°C durehgefllhn wit. 3. Verfahren nach Anspruch 1, wobei die Stute a) bel einer Temperaturim Bereich von 90bis 140°C durchgefuht wir. 4. Verfahren nach Anspruch 1, wobei die Reduktionereaktion der Stufe b) Metallketalysatoren der Gruppe Vl, Was: serstoffgas oder WasserstofiUbertrager umfasst. \Verfanren nach Anspruch 4, wobel der Katalysator Palladium, Platin oder Raney-Nickel oder eine Kombination hiervon ist. 6. Verfahren zur Herstellung von 5-(4-Methyl-1H-imidazol-1-y)-3-(trifluermethy)-benzamin (), das ale folgenden Stu:EP 1 896 425 B1 fen umfaset: 2) Umsetzen der folgenden Verbindung in einer geeigneten Base unter Verwendung eines geeigneten Lése- rmttels No, No, : F mit 4-Methyl-H-imidazol zur Herstellung von 4-Methyl-1-(S-itr-tfluormethyl-pheny!)-1H-imidazo Il}; und ) Hydrieren des erhaltenen 4-Methyl-1-(3-itro-Srifluormethyl-pheny!)-1H-nidazols (Il) mit Wasserstofgas Und einem geeigneten Katalysator unter Verwendung eines geeigneten Losemittels zur Herstellung der Ver- bindung der Forel 7. Verfahren nach Anspruch 6, wobei die Base ein Alkoxid, ein Hyckid, ein Carbonat oder ein Phosphat it 8. Verfahren nach Anspruch 1 oder 6, wobei die Stufe a) ein polares aprotsches Lisemittel verwendet, das aus Dimethylsufoxid (OMSO), Dimethyiformamid (OMF), Diglyme, THF, N-Methylpyrrolidon (NMP) und Dimethyiacet- ‘amid (DMA) ausgewabit ist. Verfahren nach Anspruch 1, wobei Mikrowellen verwendet werden, 10. Verfahren nach Anepruch 1, wobel ein schnellerer Erwérmungs- und Abkihizyklus durch 2usétzliche Warmeaus: ‘auscherkapazitét in ChargengeféBen oder durch Verwendung einer kontinuierichen Reaktionsgerstschaft zur Her beifthrung einer héheren Selektvitat ereicht wird. Revendications Procédé de préparation de la §-(4-méthyl-1 H-imidazol-1-y)--(tfluorométhy))benzéneamine (I), comprenant les tapes consistant & «) fare réagir, dane une réaction de couplage, le composé No, NO, F avec du 4-méthyl-1 H imidazole (lla) pour préparer le 4-méthyl- (8-nltro-5-tluorométhylphény)-1H imidazole (set by réduite le 4-méthyi-1-(@-ritro-6trfluorométhy/phény!)-1H-imidazole résutant pour produre le composé de formule (0). Procédé selon la revendication 1, dans lequel 'étape a) est réalisée & une température comprise dans Tintervalle de 80-150°C,EP 1 896 425 B1 Procédé selon la revendication 1, dans lequel 'étape a) est réalisée & une température comprise dans lintervalle de 90-140°C, 4. Procédé selon la revendication 1, oi 'étape réactionnelle de réduction b)implique des catalyseurs métalliques du Groupe Vill, de "hydrogene gazeux ou des agents de transfert dnydrogene. 5. Procédé selon la revencication 4, ol le catalyseur est du palladium, du platine ou du Nickel de Raney ou des ‘combinaisons de ceux-ci Procédé de préparation de la §-(4-méthyl-1 H-imidazol-1-y)--(tluorométhy)benzéneamine (0), comprenant les tapes consistant & «) fare réagir, dans une base appropriée en utlsant un solvant appropri, le composé No, Noy avec du 4-méthyl-1 H-imidazole pour préparer le 4-méthyl-1-(8-nitro-5trfluorométhylphény/)-1H imidazole (I); et by hydrogéner le 4-méthyl-1-@-niro-S-tituorométhy-phényi)-1H-imidazole (Il) résultant avec de Ihydrogéne .gazeux et un catalyseur approprié en uiilisant un solvant approprié pour produire le composé de formule (). 7. Procédé selon la revencication 6, dans lequel a base est un alcoxyde, un hydrure, un carbonate ou un phosphate. 8. Procédé selon la revendication 1 ou 6, dans lequel tape a) fat appel & un solvant polaire aprotique choisi parmi le diméthylsufoxyde (OMSO), le diméthyiformamide (OMF), le diglyme, le THF, la N-méthyipyrroidone (NMP) et le diméthylacétamide (DMA) 9. Procédé selon la revendication 1, dans lequel des micro-ondes sont utlisées, 10. Procédé selon la revendication 1, dans lequel un cycle de chauttage et de retroiissement plus rapide est obtenu (grace & une capacité d'échangeur de chaleur supplémentaire dans des récipients discontinus ou en utilisant un appareillage pour réaction continue afin dobtenir une sélectivté plus élevée.EP 1 896 425 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 ability in this regard. Patent documents cited in the description + WO 04005281 At, W. Breitenstein [0003] + WO 04005281 A, W. Breitenstein [0011] 10