综述与进展

抗肿瘤药物CDK4/6抑制剂合成工艺研究进展

  • 李静 ,
  • 高峰 ,
  • 张万斌
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  • a上海交通大学化学化工学院 上海市手性药物分子工程重点实验室 化学生物协同物质创制全国重点实验室 变革性分子前沿科学中心 上海 200240;
    b上海上药第一生化药业有限公司 上海 200240

收稿日期: 2025-09-18

  修回日期: 2025-10-01

  网络出版日期: 2025-10-29

基金资助

上海市科技重大专项、上海市青年科技启明星计划(No. 24QB2705200)、国家自然科学基金(No. 22571195)和上海市自然科学基金(No. 25ZR1401173)资助项目.

Advances in the Synthesis Process of Antitumor Drugs CDK4/6 Inhibitors

  • Li Jing ,
  • Gao Feng ,
  • Zhang Wanbin
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  • aFrontiers Science Center for Transformative Molecules, State Key Laboratory of Synergistic Chem-Bio Synthesis, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240;
    bSPH No. 1 Biochemical & Pharmaceutical CO., LTD., Shanghai 200240

Received date: 2025-09-18

  Revised date: 2025-10-01

  Online published: 2025-10-29

Supported by

the Shanghai Municipal Science and Technology Major Project, the Shanghai Rising-Star Program (No. 24QB2705200), the National Natural Science Foundation of China (No. 22571195), Natural Science Foundation of Shanghai (No. 25ZR1401173).

摘要

CDK4/6抑制剂作为第三代细胞周期蛋白依赖性激酶抑制剂, 凭借其低毒性和高体内活性的优势, 已成为治疗乳腺癌、肺癌等癌症的关键药物. 本文结合药物上市时间与结构相似性, 系统评述哌柏西利与达尔西利、瑞波西利与伏维西利、阿贝西利与泰瑞西利、曲拉西利与来罗西利等8种代表性药物的合成路径, 重点分析新反应体系与合成策略对工艺效率的提升作用. 这类分子多以N-(吡啶-2-基)嘧啶-2-胺为核心骨架, 其合成依赖金属催化交叉偶联(C-N键构建)与缩合反应(嘧啶骨架构建), 面临区域选择性控制难、贵金属依赖高、工艺放大性差等挑战. 因此, 开发绿色、经济、高效的新型合成工艺, 是该领域未来核心优化方向.

本文引用格式

李静 , 高峰 , 张万斌 . 抗肿瘤药物CDK4/6抑制剂合成工艺研究进展[J]. 有机化学, 0 : 202509021 . DOI: 10.6023/cjoc202509021

Abstract

As third-generation cyclin-dependent kinase inhibitors, CDK4/6 inhibitors have become pivotal therapeutic agents in the treatment of breast cancer, lung cancer, and other malignancies due to their favorable safety profile and high in vivo efficacy. This review provides a systematic examination of the synthetic routes of eight representative compounds—palbociclib and dalpiciclib, ribociclib and volbociclib, abemaciclib and tericiclib, as well as trilaciclib and lerociclib—selected based on their time of market authorization and structural homology. Special emphasis is placed on the role of novel reaction systems and advanced synthetic strategies in enhancing process efficiency. These agents predominantly share an N-(pyridin-2-yl)pyrimidin-2-amine core scaffold, with their synthesis primarily dependent on metal-catalyzed cross-coupling reactions for C-N bond formation and condensation reactions for pyrimidine ring construction. Key challenges remain, including difficulties in regioselectivity control, significant reliance on precious metal catalysts, and limited scalability of current processes. Consequently, the development of greener, more cost-effective, and efficient synthetic methodologies represents a critical direction for future optimization in this domain.

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