ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

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

Tian Cai, Xuebo Yang, Xuena Wang, Huanhuan Qin, Binghao Kang, Bo Li, Kun Xing, Min Huang, and Linxiang Zhao

Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China

E-mail: huangcrazye@sina.com

Received: 6 September 2023  Accepted: 3 January 2024

Abstract:

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.

Keywords: DNA–PK inhibitor; AZD7648; Process optimization; Sulfone; Chemo selectivity

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-024-03306-8

Chemical Papers 78 (5) 3213–3222 (2024)