An improved synthetic strategy for the multigram-scale synthesis of DNA–PK inhibitor AZD7648

An efficient and feasible of the novel highly selective DNA–PK inhibitor AZD7648 was introduced. The route includes the following characteristics: (1) Intermediate (E)-N-hydroxy-N'-(4-methyl-5-nitropyridin-2-yl)formimidamide (4) was prepared from commercially available 4-methyl-5-nitropyridine-2-amine by “one-pot” method, and 7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (6) was prepared in two steps with an improved yield of 55.5%; (2) Building block 2-chloro-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (11) was changed to 7-methyl-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (17), obtained from 4-chloro-2-methylthiopyrimidine-5-carboxylate. This substitution avoided the formation of disubstituted products and eliminated the need for silica chromatography for purification. (3) The Buchwald–Hartwig cross-coupling reaction was replaced by a nucleophilic aromatic substitution reaction (SNAr) thus avoiding the expensive Pd catalyst and simplifying the work-up process. (4) This route achieves compliance with the strategy of “control from the root design” in organic process research and development, with the principles of efficient application of green and sustainable chemistry.