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. 此综述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、贵金属依赖高和工艺放大性差等挑战. 因此, 开发绿色、经济和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)-pyri- midin-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, 2026, 46(2): 315-355.

Jing Li, Feng Gao, Wanbin Zhang. Advances in the Synthesis Process of Antitumor Drugs CDK4/6 Inhibitors[J]. Chinese Journal of Organic Chemistry, 2026, 46(2): 315-355.

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图/表 70

图1. CDK4/6抑制剂化学结构式

Figure 1. Chemical structural formula of CDK4/6 inhibitors

图2. 哌柏西利结构

Figure 2. Structure of Palbociclib

图式1. 哌柏西利原研合成路线

Scheme 1. Original research synthesis route of Palbociclib

图式2. 哌柏西利合成路线1

Scheme 2. Synthesis route 1 of Palbociclib

图式3. 哌柏西利合成路线2

Scheme 3. Synthesis route 2 of Palbociclib

图式4. 哌柏西利合成路线3

Scheme 4. Synthesis route 3 of Palbociclib

图式5. 哌柏西利合成路线4

Scheme 5. Synthesis route 4 of Palbociclib

图式6. 哌柏西利合成路线5

Scheme 6. Synthesis route 5 of Palbociclib

图式7. 哌柏西利合成路线6

Scheme 7. Synthesis route 6 of Palbociclib

图式8. 哌柏西利合成路线7

Scheme 8. Synthesis route 7 of Palbociclib

图式9. 哌柏西利合成路线8

Scheme 9. Synthesis route 8 of Palbociclib

图式10. 哌柏西利合成路线9

Scheme 10. Synthesis route 9 of Palbociclib

图式11. 哌柏西利合成路线10

Scheme 11. Synthesis route 10 of Palbociclib

图式12. 哌柏西利合成路线11

Scheme 12. Synthesis route 11 of Palbociclib

图式13. 哌柏西利合成路线12

Scheme 13. Synthesis route 12 of Palbociclib

图式14. 哌柏西利合成路线13

Scheme 14. Synthesis route 13 of Palbociclib

图式15. 哌柏西利合成路线14

Scheme 15. Synthesis route 14 of Palbociclib

图式16. 哌柏西利合成路线15

Scheme 16. Synthesis route 15 of Palbociclib

图式17. 哌柏西利合成路线16

Scheme 17. Synthesis route 16 of Palbociclib

图式18. 哌柏西利合成路线17

Scheme 18. Synthesis route 17 of Palbociclib

图3. 达尔西利的结构

Figure 3. Structure of Dalpiciclib

图式19. 达尔西利原研合成路线

Scheme 19. Original research synthesis route of Dalpiciclib

图式20. 达尔西利合成路线1

Scheme 20. Synthesis route 1 of Dalpiciclib

图式21. 达尔西利合成路线2

Scheme 21. Synthesis route 2 of Dalpiciclib

图式22. 达尔西利合成路线3

Scheme 22. Synthesis route 3 of Dalpiciclib

图4. 瑞波西利结构

Figure 4. Structure of Ribociclib

图式23. 瑞波西利的合成策略

Scheme 23. Synthetic strategy of Ribociclib

图式24. 瑞波西利合成原研路线

Scheme 24. Original research synthesis route of Ribociclib

图式25. 瑞波西利合成路线1

Scheme 25. Synthesis route 1 of Ribociclib

图式26. 瑞波西利合成路线2

Scheme 26. Synthesis route 2 of Ribociclib

图式27. 瑞波西利合成路线3

Scheme 27. Synthesis route 3 of Ribociclib

图式28. 瑞波西利合成路线4

Scheme 28. Synthesis route 4 of Ribociclib

图式29. 瑞波西利合成路线5

Scheme 29. Synthesis route 5 of Ribociclib

图式30. 瑞波西利合成路线6

Scheme 30. Synthesis route 6 of Ribociclib

图式31. 瑞波西利合成路线7

Scheme 31. Synthesis route 7 of Ribociclib

图式32. 瑞波西利合成路线8

Scheme 32. Synthesis route 8 of Ribociclib

图式33. 瑞波西利合成路线9

Scheme 33. Synthesis route 9 of Ribociclib

图式34. 瑞波西利合成路线10

Scheme 34. Synthesis route 10 of Ribociclib

图5. 伏维西利结构

Figure 5. Structure of Fovinaciclib

图式35. 伏维西利原研合成路线

Scheme 35. Original research synthesis route of Fovinaciclib

图6. 阿贝西利结构

Figure 6. Structure of Abemaciclib

图式36. 阿贝西利原研合成路线

Scheme 36. Original research synthesis route of Abemaciclib

图式37. 阿贝西利合成路线1

Scheme 37. Synthesis route 1 of Abemaciclib

图式38. 阿贝西利合成路线2

Scheme 38. Synthesis route 2 of Abemaciclib

图式39. 阿贝西利合成路线3

Scheme 39. Synthesis route 3 of Abemaciclib

图式40. 阿贝西利合成路线4

Scheme 40. Synthesis route 4 of Abemaciclib

图式41. 阿贝西利合成路线5

Scheme 41. Synthesis route 5 of Abemaciclib

图式42. 阿贝西利合成路线6

Scheme 42. Synthesis route 6 of Abemaciclib

图式43. 阿贝西利合成路线7

Scheme 43. Synthesis route 7 of Abemaciclib

图式44. 阿贝西利合成路线8

Scheme 44. Synthesis route 8 of Abemaciclib

图式44. 阿贝西利合成路线9

Scheme 44. Synthesis route 9 of Abemaciclib

图式45. 阿贝西利合成路线10

Scheme 45. Synthesis route 10 of Abemaciclib

图式46. 阿贝西利合成路线11

Scheme 46. Synthesis route 11 of Abemaciclib

图式47. 阿贝西利合成路线12

Scheme 47. Synthesis route 12 of Abemaciclib

图式48. 阿贝西利合成路线13

Scheme 48. Synthesis route 13 of Abemaciclib

图式49. 阿贝西利合成路线14

Scheme 49. Synthesis route 14 of Abemaciclib

图7. 泰瑞西利结构

Figure 7. Structure of Tibremciclib

图式50. 泰瑞西利原研合成路线

Scheme 50. Original research synthesis route of Tibremciclib

图8. 曲拉西利的结构

Figure 8. Structure of Trilaciclib

图9. 来罗西利的结构

Figure 9. Structure of Lerociclib

图式51. 曲拉西利原研合成路线

Scheme 51. Original research synthesis route of Trilaciclib

图式52. 曲拉西利及其类似物合成路线1

Scheme 52. Synthesis route 1 of Trilaciclib and its analogues

图式53. 曲拉西利合成路线2

Scheme 53. Synthesis route 2 of Trilaciclib

图式54. 曲拉西利合成路线3

Scheme 54. Synthesis route 3 of Trilaciclib

图式55. 曲拉西利合成路线4

Scheme 55. Synthesis route 4 of Trilaciclib

图式56. 曲拉西利合成路线5

Scheme 56. Synthesis route 5 of Trilaciclib

图式57. 曲拉西利合成路线6

Scheme 57. Synthesis route 6 of Trilaciclib

图式58. 曲拉西利合成路线7

Scheme 58. Synthesis route 7 of Trilaciclib

图式59. 曲拉西利合成路线8

Scheme 59. Synthesis route 8 of Trilaciclib

图式60. 曲拉西利合成路线9

Scheme 60. Synthesis route 9 of Trilaciclib

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