Research and Development of a Novel Process for Nilotinib: A Bcr-Abl Inhibitor

Abstract

In this study, an efficient, economic and novel process for the production of highly pure nilotinib (1), a Bcr-Abl inhibitor in described. The synthesis comprises the chlorination of 4-methyl-3-nitro benzoic acid (2) to get 4-methyl-3-nitro benzoyl chloride (2A). Condensation of compound ( 2) with 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzeneamine (11) to obtain 4-methyl-N-[3-(4-methyl-1Himidazol-1-yl-5-(trifluoromethyl)phenyl]-3-nitro-benzamide hydrochloride (3). Reducing compound (3) with stannous chloride (or) raney nickel to obtain 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-amino-benzamide (4). Reaction of compound (4) with cyanamide to obtain 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-guanidino-benzamide (5). Condensation of the compound (5) with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (8) to obtain nilotinib (1).

A Practical Preparation of Imatinib Base

“…Besides using noble-metal platinum and palladium as catalysts not only enhanced the production cost but also led to the highly toxic metal residual in final product, which should be strictly controlled in the medicine synthesis. Amala et al, 4 Szakács et al, 5 Szczepek et al, 6 and Kompella et al 7 then improved the above synthetic routes, but there are still shortcomings such as the use of excess moles of tin(II) chloride/Raney nickel and hydrazine hydrate reagents for the reduction of the nitropyrimidine intermediate to prepare the corresponding amino compound 6. In 2012, Lee et al tried to improve the last step of Loiseleur's routes using polystyrene-supported CuO as catalyst, but resulted in very low yield of the product imatinib base (15%).…”

Synthesis and Characterization of 1-(2-(Dimethylamino)ethyl)-6,6a,7,11-tetrahydro- 3H,9H-oxazolo[3,4-b]pyrrolo[2,3-h]isoquinolin-9-one: A Zolmitriptan Related Impurity

“…To this reaction mass in methanol lot-2 ethylformate was added was added in 0.5 h and reaction mass was stirred for 2 h. After completion of the reaction (vide TLC) cooled to 25-35 ºC and methanol was saturated with excess water. Extracted with ethyl acetate followed by total solvent was evaporated under vacuum at below 60 ºC to afford 7-nitro-1,5,10,10a-tetrahydro [1,3]oxazolo [3,4- Compound 12 was added into mixture of water and aq. HCl and cooled to -20-(-10 ºC).…”

“…Reaction mass was cooled to 0-5 ºC followed by thionyl chloride (49 mL) was added in 1h and heated to reflux for 4 h. After completion of the reaction (vide TLC) the excess methanol was distilled under vacuum at below 60 ºC and isolated from IPA to afford 9. m.p. 120-123 ºC; 1 Ethyl 3-(hydroxymethyl)-7-nitro-3,4-dihydro isoquinoline-2(1H)-carboxylate (10): Compound-9 added into methanol and water mixture followed by cooled to 0-5 ºC. Sodium borohydride was added at 0-5 ºC in 5 equal lots.…”

Trace level detection and quantification of genotoxic impurities 3‐amino‐4‐methylbenzoate, 3‐amino‐4‐methylbenzoic acid, and 3‐(4‐methyl‐1H‐imidazol‐1‐yl)‐5‐(trifluoromethyl) aniline in Nilotinib dihydrochloride active pharmaceutical ingredient using liquid chromatography‐tandem mass spectrometry

“…The MRM experiment advantage is specifying the parent mass followed by the MS/MS fragment of the product ion. Some of the articles published and discussed the RP-HPLC method for establishing the quality by design experiments, and degradation impurities, also mentioned the development and validation of the PR-HPLC method for estimation of Nilotinib hydrochloride and its dosage form [10][11][12][13]. Another article disclosed the ultra-fast LC method development and quantification of Nilotinib [14].…”