A Facile Total Synthesis of Imatinib Base and Its Analogues

Abstract

Imatinib and its analogues were successfully synthesized by an improved method in 19.5-46.2% total yield of six main steps. Pyrimidinyl amine was prepared by the reaction of enaminone and guanidine nitrate without the use of a toxic cyanamide. N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine as a key intermediate for the synthesis of imatinib was prepared by coppercatalyzed N-arylation of heteroarylamine in 82% yield. The copper salts were used instead of the expensive palladium compounds in this C-N bond-forming reaction. The intermediate nitro compound was reduced by a N 2 H 4 • H 2 O/FeCl 3 /C system using water as a solvent in good yield.

Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs

“…Specifically, the reported sequence for the conversion of 1 a to imatinib ( Im ‐ 1 ) suffered from problems due to palladium impurities in the final step ( 4 + 5 → Im ‐ 1 , Scheme A), while the reductive amination of 1 a ( 1 a + 2 → 1 b , Scheme A) was not easily applicable to the aldehydes involved in the present work due to harsh conditions (i.e., anticipated decomposition and, in some cases, epimerization). In addition, the expected decreased stability and reactivity of the required alkyl halides in the projected nucleophilic substitutions according to the reported routes for activated benzylic and/or benzoyl chlorides ( 7 + 1 c or 1 d ; then 2 → Im ‐ 1 , Scheme B) . complicated the situation even further.…”

“…A brief investigation in order to circumvent these problems led to the finding that reductive amination of methyl 4‐formylbenzoate ( 1 a ) with 1‐methylpiperazine ( 2 ), induced by sodium triacetoxyborohydride (step f, Scheme C), furnished piperazine derivative 1 b in 98 % yield, which compares favorably to the yield (70 %) obtained under the conditions employed in an earlier report for the synthesis of 1 b (Pt/C, H 2 (5 bar), 80 °C, 20 h; Scheme A). Furthermore, the final coupling of methyl ester piperazine derivative 1 b with aniline derivative 7 (prepared in four steps from 6 ; Scheme B) proceeded smoothly under the influence of trimethylaluminum (step g, Scheme C; see also 1 b + 3 → 4 , Scheme A) to afford easily purified imatinib ( Im‐1 ) in 74 % yield (unoptimized). This sequence proved overall more convenient and efficient for our purposes than those previously reported …”

Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives

“…The pharmacophore 6-methyl-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine (8), was synthesized by using a route that partially follows the reported preparation of imatinib (Scheme 1) [29]. The reaction of 3-acetylpyridine 2 with an excess of dimethylformamide dimethyl acetal (DMF DMA) in xylene gave the enaminone 3.…”

A Practical Preparation of Imatinib Base

“…Further reaction with guanidine nitrate gave 4-(pyridin-3-yl)pyrimidin-2-amine (12) in good yield (Scheme 5). 9 Thus, in our procedures, all of the materials were industrially available and their prices were below $100/kg (in China).…”