Preparation Of CDK Inhibitor Palbociclib And Its Key Intermediates

Cyclin-dependent kinases（CDKs）are a class of serine/threonine protein kinases that comprise of a catalytic subunit（Cdk）and a member of a family of regulatory subunits（Cyclin）.Cyclin-dependent kinases（CDKs）can regulate the cell cycle and thus control transcriptional process,which is important pathway for cell cycle regulatory machinery.Cyclin-dependent kinases 4 and 6（CDK4/6）are key regulators of the cell cycles.CDK4/6can control cellular progression from growth phase（G1）into DNA replications phases（S）.Increased CDK4/6 activity is frequently observed in estrogen receptor-positive（ER⁺）breast cancer.Palbociclib is a highly selective,reversible inhibitor of CDK4/6 and could block tumor cell proliferation.In February 2015,the United States Food and Drug Administration（FDA）approved Palbociclib for marketing under the name IBRANCE.It was approved for treating postmenopausal women with estrogen receptor-positive,human epidermal growth factor receptor 2-negative(ER⁺/HER^2-)advanced breast cancer in combination with Letrozole and Aromatase inhibitor.The synthetic process reported in the literature of Palbociclib was investigated and analyzed.And a new synthesis route of Palbociclib was designed.The key to producing Palbociclib is the synthesis of 6-bromo-8-cyclopentyl-5-methyl-2-（methylsulfinyl）pyrido[2,3-d]pyrimidin-7（8H）.This protocol started from thiouracil and involved methylation,nucleophilic substitution,bromination,nucleophilic substitution,Heck reaction,ring closure,oxidation and bromination to afford the product.Then Palbociclib was afforded after the nucleophilic substitution reaction,Heck reaction,aqueous workup.The main reactions were optimized and simplified to improve yield.The advantages of this developed synthetic strategy included inexpensive starting materials,readily controllable reaction conditions,and environmental friendship.The original research process of Palbociclib was also studied.It was started from2,4-dichloro-5-bromopyrimidine and prepared Palbociclib by six step reactions.The main reactions also optimized and simplified,and conducted a comparative analysis of the two routes.