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<p>Adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>AR) antagonists have emerged as promising candidates for cancer immunotherapy. In our previous work, we developed benzo[4, 5]imidazo[1, 2‑a]pyrazin-1-amine-3-amide derivatives, including compound <b>12o</b>, which demonstrated promising pharmacodynamic properties but suffered from poor metabolic stability, with a microsomal half-life of approximately 30&#xa0;min. To enable structural optimization of <b>12o</b> and improve lead compound identification, we sought to streamline its lengthy 10-step synthetic route, which had hindered further analog development. Guided by step-economy principles, we developed a new 7-step synthesis of the central carboxylic acid intermediate, achieving a 33% increase in overall yield and reducing the E-factor by approximately four-fold. Key improvements included a one-step transformation of an acyl-protected hydroxymethyl group into a carboxylic acid using 1-hydroxycyclohexyl phenyl ketone (1-HCPK) and the replacement of the Boc protecting group with a more efficient PMB group. These modifications significantly enhanced the synthetic efficiency and sustainability of the route, providing a more robust platform for the development of stable and potent A<sub>2A</sub>AR antagonists.</p> Graphical abstract <p></p>

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Synthesis optimization of A2AAR antagonists: shortening the route to accelerate discovery

  • 期刊论文

  • 发表日期：

    2025年6月5日

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  • Wenjiang Liu,
  • Jianyong Ye,
  • Shuhao Liu,
  • Taoda Shi,
  • Wenhao Hu

摘要

Adenosine A2A receptor (A2AAR) antagonists have emerged as promising candidates for cancer immunotherapy. In our previous work, we developed benzo[4, 5]imidazo[1, 2‑a]pyrazin-1-amine-3-amide derivatives, including compound 12o, which demonstrated promising pharmacodynamic properties but suffered from poor metabolic stability, with a microsomal half-life of approximately 30 min. To enable structural optimization of 12o and improve lead compound identification, we sought to streamline its lengthy 10-step synthetic route, which had hindered further analog development. Guided by step-economy principles, we developed a new 7-step synthesis of the central carboxylic acid intermediate, achieving a 33% increase in overall yield and reducing the E-factor by approximately four-fold. Key improvements included a one-step transformation of an acyl-protected hydroxymethyl group into a carboxylic acid using 1-hydroxycyclohexyl phenyl ketone (1-HCPK) and the replacement of the Boc protecting group with a more efficient PMB group. These modifications significantly enhanced the synthetic efficiency and sustainability of the route, providing a more robust platform for the development of stable and potent A2AAR antagonists.

Graphical abstract