Synthesis Process Of Palbociclib

Palbociclib is novel oral selective inhibitor of Cyclin-dependent 4/6(CDK 4/6).It was developed by the Pfizer.In February 3rd 2015,palbociclib was approved by the accelerated approval process of the US FDA.In clinical practice it indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor(ER)-positive,human epidermal growth factor receptor 2(HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease.In this paper,a synthetic route of arotinolol hydrochloride was chosen from all the reportedprocesses,2-chloro-8-cyclopentyl-5-methyl-8H-pyridine[2,3-D]pyrimidine-7-keto ne(PD-9)and4-(6-aminopyridine-3-piperazine-1-carboxylic acid tert-butyl ester(PD-4)as the starting material,after substitution,Herk coupling reaction,hydrolysis reaction,rearrangement reaction and deprotection to final formation of the final product palbociclib.After the optimization of reaction conditions,so that the total yield was up to33.07%,significantly higher than the yield of the reported.the purity of the product was higher than 99.7%,and the content of single impurity was less than 0.1%..The chemical structure of arotinolol hydrochloride had been characterized by means of 1H-NMR and MS.Based on the structures of 10 imprities which may be present,the sources of their generations were analyzed.Then the synthetic routes were designed and tried,finally 5impurities of them were obtained and the chemical structures were comfirmed by1H-NMR.Based on the results of the small-scale experiments,the synthesis process of the pilot-scale experiments were followed and it was proved to be validated.The stability and maneuverability of the synthesis process in industrial scale production was further to verified in a plant trial production,the results proved feasible and laid technical foundation for the commercial batch production of arotinolol hydrochloride.