抗肿瘤药物CDK4/6抑制剂合成工艺研究进展

doi:10.6023/cjoc202509021

摘要/Abstract

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.

关键词: CDK4/6抑制剂, 抗癌药物, 多环结构, 绿色化学

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.

Key words: CDK4/6 inhibitors, anticancer drugs, polycyclic structures, green chemistry

引用此文

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, doi: 10.6023/cjoc202509021.

Li Jing, Gao Feng, Zhang Wanbin. Advances in the Synthesis Process of Antitumor Drugs CDK4/6 Inhibitors[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202509021.

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