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Abstract <p>An optimized synthesis of the enzyme-cleavable Val-Cit dipeptide linker, a critical component in antibody–drug conjugates (ADCs) is reported. By substituting HATU for EEDQ as condensing agent, the revised synthetic route effectively suppresses side oxazolone formation and eliminates racemization, thereby significantly enhancing the yield. Additionally, the influence of various deprotecting agents was systematically evaluated, revealing that diethylamine and piperidine exhibit superior efficiency. MC-Val-Cit-PAB-MMAE was successfully synthesized in eight steps with an overall yield of 14%, which represents an 8% improvement in the key step compared to previously reported values. This study thus offers a more efficient and reliable method for ADC linker synthesis.</p>

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Process Optimization for the Synthesis of Enzyme-Cleavable Val-Cit Dipeptide Linker in Antibody–Drug Conjugate Production

  • 期刊论文

  • 发表日期：

    2025年12月1日

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  • Jia-Sen Ren,
  • Qing-Wen Dong,
  • Sheng-Yu Liu,
  • Yue-Ping Kang,
  • Wen-Tao Liu,
  • Ai-Ling Wang

摘要

Abstract

An optimized synthesis of the enzyme-cleavable Val-Cit dipeptide linker, a critical component in antibody–drug conjugates (ADCs) is reported. By substituting HATU for EEDQ as condensing agent, the revised synthetic route effectively suppresses side oxazolone formation and eliminates racemization, thereby significantly enhancing the yield. Additionally, the influence of various deprotecting agents was systematically evaluated, revealing that diethylamine and piperidine exhibit superior efficiency. MC-Val-Cit-PAB-MMAE was successfully synthesized in eight steps with an overall yield of 14%, which represents an 8% improvement in the key step compared to previously reported values. This study thus offers a more efficient and reliable method for ADC linker synthesis.