Nilotinib
From The Cure For The Needy
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Nilotinib (Tasigna)
Effective Against
Drug-resistant CML - Chronic myelogenous leukemia
Nilotinib is a selective Bcr/Abl tyrosine kinase inhibitor. Tyrosine kinase inhibitors interfere with cell communication and growth. They have been of great interest to scientists in recent years who hope to use them as an option to treat cancer.
Cost
From LC Laboratories: 129 USD (25mg)
Reported Routes of Synthesis
The condensation of 3-fluoro-5-(trifluoromethyl)benzonitrile (I) with 2-methylimidazole (II) in hot N,N-dimethylacetamide affords the imidazolyl benzonitrile (III), which is hydrolyzed to the corresponding benzoic acid (IV) employing NaOH in aqueous dioxan. Subsequent Curtius rearrangement of acid (IV) in tert-butanol in the presence of diphenylphosphoryl azide, followed by acidic hydrolysis of the resulting tert-butyl carbamate (V), yields 3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)aniline (VI). The condensation of 3-amino-4-methylbenzoic acid ethyl ester (VII) with cyanamide in refluxing ethanolic HCl gives the 3-guanidinobenzoate (VIII) (1). Claisen condensation of 3-acetylpyridine (IX) with ethyl formate by means of sodium metal in hot toluene, followed by treatment with dimethylamine, gives the enamino ketone (X) (2), which is cyclized with guanidine (VIII) in refluxing ethanolic NaOH to produce the pyridylpyrimidine (XI). After saponification of ethyl ester (XI) with NaOH in hot aqueous ethanol, the 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]benzoic acid (XII) obtained is finally coupled with aniline (VI) employing diethyl cyanophosphate to furnish the corresponding amide nilotinib (1).
Davies, S.L., Bolos, J., Serradell, N., Bayes, M. Nilotinib. Drugs of the Future 2007, 32(1): 17
Novartis AG. Pyrimidine derivatives and process for their preparation. EP 0564409, JP 1994087834, US 5521184
Novartis AG, Novartis Pharma GmbH. Inhibitors of tyrosine kinases. WO 2004005281, US 2006167015, EP 1532138, JP 2005533827, US 2007093506, US 7169791, JP 2008044968, US 2008188451
Cost of Starting Materials and Intermediates:
3-Fluoro-5-(trifluoromethyl)benzonitrile from Melford Laboratories Ltd: 112.50 € or appr. 158 .50 USD (10g) (custom synthesis)
3-Amino-4-methylbenzoic acid ethyl ester:
3-Acetylpyridine from Sigma-Aldrich: 106.00 (100 g)
4-methylinidazole from Sigma-Aldrich : 221 USD (500g)
Dimethylamine from Sigma-Aldrich: 143 USD (100g)
Ethyl formate from Sigma-Aldrich: 33.60 USD (500mL)
Diphenylphosphoryl azide, polymer-bound (DPPA) from Sigma-Aldrich: 337.5 USD (5g)
The condensation of the methyl benzoate derivative (I) with the aniline derivative (II) by means of potassium tert-butoxide in THF gives the target Nilotinib.
Novartis AG, Novartis Pharma GmbH. Process for the synthesis of 5-(methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzeneamine. WO 2006135641, EP 1924574, CA 2610105, US 2008188656, JP 2008545786
The intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (V) (see scheme 38617801a, intermediate (VI)) has been obtained by several ways: 1.- The bromination of 3-nitro-benzotrifluoride (I) by means of DBDH and H2SO4 gives 3-bromo-5-nitro benzotrifluoride (II), which is condensed with 4-methyl-1H-imidazole (III) by means of a Cu, Pd or Ni catalyst to yield 3-(4-methyl-1H-imidazol-1-yl)-5-nitro benzotrifluoride (IV). Finally the nitro group of (IV) is reduced by means of H2 over Pd/C to obtain the target intermediate 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (V). 2.- The nitration of 2-bromo-5-fluorobenzotrifluoride (VI) by means of KNO3 and H2SO4 yields 2-bromo-5-fluoro-3-nitro benzotrifluoride (VII), which is treated with H2 over Pd/C to afford 3-fluoro-5-(trifluoromethyl)aniline (VIII). Finally this compound is condensed with 4-methyl-1H-imidazole (III) as before to obtain the target intermediate the aniline (V).
Novartis AG, Novartis Pharma GmbH. Process for the synthesis of organic compounds. US 2008200692, JP 2008546645, WO 2006135640, EP 1896426
The condensation of 3-bromo-5-fluoro benzotrifluoride (IX) with 4-methyl-1H-imidazole (III) by means of NaH gives 3-bromo-5-(4-methyl-1H-imidazol-1-yl) benzotrifluoride (X), which is condensed with benzophenone imine (XI) by means of Pd(OAc)2 to yield the adduct (XII). Finally this compound is hydrolyzed by means of aq. HCl and KHCO3 to obtain the target intermediate the aniline (V)(see scheme 38617801a, intermediate (VI)) .
Novartis AG, Novartis Pharma GmbH. Process for the synthesis of organic compounds. US 2008200692, JP 2008546645, WO 2006135640, EP 1896426
The condensation of 3,5-dinitro benzotrifluoride XIII) with 4-methyl-1H-imidazole (III) by means of K2CO3 gives 3-(4-methyl-1H-imidazol-1-yl)-5-nitro benzotrifluoride (XIV), which is finally hydrogenated with H2 over Pd/C to obtain the target intermediate the aniline (V) (see scheme 38617801a, intermediate (VI)) .
Novartis AG, Novartis Pharma GmbH. Process for the synthesis of 5-(methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzeneamine. US 2008200691, WO 2006135619, CA 2610402, EP 1896425, JP 2008545782