Arylation of the indole prepared the chloropyridine 21.7, which was then reacted with the aniline 21.4 in the presence of excess p-toluenesulfonic acid to produce 21.8 (see Figure 7.3.2). The second SNAr reaction used the diamine 21.9, which was coprecipitated with water in DMF to give the amine 21.10 in 77% yield over a two-step reaction. Reduction of the nitro group using sodium sulfite gave the corresponding amine under metal-free and mild conditions. The crude aniline was then converted to the dihydrochloride salt 21.11, which was isolated as a solid in high purity (99.8%) and yield (94%) after slurrying in methanol and ethanol. Finally, a two-step approach was used to install the α,β-unsaturated amide, as opposed to the earlier route that used acryloyl chloride directly. The acylation reaction used the chloroacyl chloride 21.12 to give the alkyl chloride 21.13, which was isolated by filtration. Subsequently, an elimination reaction was carried out with triethylamine at reflux in acetonitrile to prepare alflutinib (21) in 93% yield and 99.2% purity.
