合成路线1

A related procedure consists of the iodination of 6-iodoindazole (XXIII) with I2 and KOH to give 3,6-diiodoindazole (XXIV), which is coupled with 2-mercapto-N-methylbenzamide (XXI) in the presence of Pd2(dba)3 and Xantphos diphosphine ligand to yield the diaryl thioether (XXV). Alternatively, intermediate (XXV) can be prepared by coupling of 6-iodoindazole (XXIII) with mercaptobenzamide (XXI), followed by iodination of the resulting indazolyl thioether (XXVI). Optionally, the indazolyl derivative (XXV) is protected as the N-Boc (XXVIIa) or the N-tetrahydropyranyl derivative (XXVIIb) by treatment with Boc2O and DMAP or with dihydropyran and p-TsOH, respectively. Palladium-catalyzed coupling of the protected iodoindazoles (XXVIIa) and (XXVIIb) with 2-vinylpyridine (XV) then leads to the respective N-protected axitinib derivatives (XXII) and (XXVIII), which are finally deprotected utilizing p-TsOH in MeOH or TFA, respectively. Alternatively, axitinib can be obtained by direct coupling of unprotected iodoindazole (XXV) with 2-vinylpyridine (XV) in the presence of palladium diacetate, tri-o-tolylphosphine, LiBr and 1,8-bis(dimethylamino)naphthalene (proton sponge) in hot NMP (3). Scheme 3.