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

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)-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

Cite this article

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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Fig. & Tab. 70

Figure 1. Chemical structural formula of CDK4/6 inhibitors

Figure 2. Structure of Palbociclib

Scheme 1. Original research synthesis route of Palbociclib

Scheme 2. Synthesis route 1 of Palbociclib

Scheme 3. Synthesis route 2 of Palbociclib

Scheme 4. Synthesis route 3 of Palbociclib

Scheme 5. Synthesis route 4 of Palbociclib

Scheme 6. Synthesis route 5 of Palbociclib

Scheme 7. Synthesis route 6 of Palbociclib

Scheme 8. Synthesis route 7 of Palbociclib

Scheme 9. Synthesis route 8 of Palbociclib

Scheme 10. Synthesis route 9 of Palbociclib

Scheme 11. Synthesis route 10 of Palbociclib

Scheme 12. Synthesis route 11 of Palbociclib

Scheme 13. Synthesis route 12 of Palbociclib

Scheme 14. Synthesis route 13 of Palbociclib

Scheme 15. Synthesis route 14 of Palbociclib

Scheme 16. Synthesis route 15 of Palbociclib

Scheme 17. Synthesis route 16 of Palbociclib

Scheme 18. Synthesis route 17 of Palbociclib

Figure 3. Structure of Dalpiciclib

Scheme 19. Original research synthesis route of Dalpiciclib

Scheme 20. Synthesis route 1 of Dalpiciclib

Scheme 21. Synthesis route 2 of Dalpiciclib

Scheme 22. Synthesis route 3 of Dalpiciclib

Figure 4. Structure of Ribociclib

Scheme 23. Synthetic strategy of Ribociclib

Scheme 24. Original research synthesis route of Ribociclib

Scheme 25. Synthesis route 1 of Ribociclib

Scheme 26. Synthesis route 2 of Ribociclib

Scheme 27. Synthesis route 3 of Ribociclib

Scheme 28. Synthesis route 4 of Ribociclib

Scheme 29. Synthesis route 5 of Ribociclib

Scheme 30. Synthesis route 6 of Ribociclib

Scheme 31. Synthesis route 7 of Ribociclib

Scheme 32. Synthesis route 8 of Ribociclib

Scheme 33. Synthesis route 9 of Ribociclib

Scheme 34. Synthesis route 10 of Ribociclib

Figure 5. Structure of Fovinaciclib

Scheme 35. Original research synthesis route of Fovinaciclib

Figure 6. Structure of Abemaciclib

Scheme 36. Original research synthesis route of Abemaciclib

Scheme 37. Synthesis route 1 of Abemaciclib

Scheme 38. Synthesis route 2 of Abemaciclib

Scheme 39. Synthesis route 3 of Abemaciclib

Scheme 40. Synthesis route 4 of Abemaciclib

Scheme 41. Synthesis route 5 of Abemaciclib

Scheme 42. Synthesis route 6 of Abemaciclib

Scheme 43. Synthesis route 7 of Abemaciclib

Scheme 44. Synthesis route 8 of Abemaciclib

Scheme 44. Synthesis route 9 of Abemaciclib

Scheme 45. Synthesis route 10 of Abemaciclib

Scheme 46. Synthesis route 11 of Abemaciclib

Scheme 47. Synthesis route 12 of Abemaciclib

Scheme 48. Synthesis route 13 of Abemaciclib

Scheme 49. Synthesis route 14 of Abemaciclib

Figure 7. Structure of Tibremciclib

Scheme 50. Original research synthesis route of Tibremciclib

Figure 8. Structure of Trilaciclib

Figure 9. Structure of Lerociclib

Scheme 51. Original research synthesis route of Trilaciclib

Scheme 52. Synthesis route 1 of Trilaciclib and its analogues

Scheme 53. Synthesis route 2 of Trilaciclib

Scheme 54. Synthesis route 3 of Trilaciclib

Scheme 55. Synthesis route 4 of Trilaciclib

Scheme 56. Synthesis route 5 of Trilaciclib

Scheme 57. Synthesis route 6 of Trilaciclib

Scheme 58. Synthesis route 7 of Trilaciclib

Scheme 59. Synthesis route 8 of Trilaciclib

Scheme 60. Synthesis route 9 of Trilaciclib

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抗肿瘤药物CDK4/6抑制剂合成工艺研究进展