合成路线1

Iodination of 6-nitroindazole (I) utilizing iodine in the presence of NaOH provides 3-iodo-6-nitroindazole (II). Subsequent protection of indazole (II) with 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) under phase-transfer conditions, followed by Suzuki coupling of the SEM-protected compound (III) with styrylboronic acid, gives the styryl indazole (IV). The nitro group of (IV) is reduced by means of SnCl2 to produce amine (V), which is then converted to the iodoindazole analogue (VI) by diazotization followed by reaction with I2 and KI. Ozonization of the styryl moiety of (VI) and further reductive work-up leads to the aldehyde (VII), which is subjected to Wittig reaction with 2-picolyl triphenylphosphonium chloride (VIII) to produce the pyridylvinylindazole (IX). Displacement of the iodoindazole (IX) with methyl 2-mercaptobenzoate (X) in the presence of Cs2CO3 and palladium catalyst gives the thioether (XI). After alkaline hydrolysis of the methyl ester (XI), the resulting carboxylic acid (XII) is coupled with methylamine in the presence of HATU to furnish the N-methyl amide (XIII). Axitinib is then obtained by removal of the SEM protecting group of (XIII) by means of tetrabutylammonium fluoride and ethylenediamine (1). Scheme 1.