Synthetic Process And Quality Study Of Palbociclib

Palbociclib is a selective cyclin dependent kinase 4/6 inhibitor that can be taken orally.Because of its good targeting effect,it was approved by FDA in 2015.As the world’s first listed CDK4/6 inhibitor,it is used to treat breast cancer with positive result of estrogen receptor and negative result of human epidermal growth factor receptor 2.Herein,based on the analysis of five main synthetic routes of Palbociclib,we design a set of commercial synthesis processes of Palbociclib that has achieved patent interpenetration.Starting with changing the starting material,the cheaper 4-chloro-2-methylthio-5-cyanopyrimidine is used as the raw material to undergo nucleophilic substitution reaction with cyclopentamine.After methylation reaction,Wittig-Horner reaction,NBS bromination,SNAR reaction,and Heck coupling,Boc is removed under acidic conditions to obtain Palbociclib.The main steps were optimized based on the route.The structures of the intermediates were confirmed by ¹H-NMR,¹³C-NMR and HRMS.The synthetic route has lesser steps,lower cost,and simpler operation,and is suitable for industrial production.To verify the stability,safety,and controllability of the quality of Palbociclib obtained by this synthetic route,this paper studies the quality of three batches of Palbociclib samples made by ourselves based on the Chinese Pharmacopoeia and ICH guidelines.The structure and crystal form of the sample were comprehensively confirmed by elemental analysis,infrared spectrum,ultraviolet spectrum,nuclear magnetic resonance spectrum,high resolution mass spectrometry and powder X-ray diffraction;The physical and chemical properties of the sample were studied by appearance,solubility,melting point,moisture,particle size,thermal analysis and microscopic analysis;Inorganic impurities were detected,and their ignition residue and heavy metal elements were detected in accordance with the general principles of the fourth part of the Chinese Pharmacopoeia;To determine its organic impurities and establish a method for the simultaneous determination of seven different organic impurities,of which the single impurity is less than 0.10%and the total impurity is less than 1.0%;The method development and methodology validation of seven solvents used in the production process were carried out,and the seven solvents all met the ICH standards for residual solvents;The content determination method of Palbociclib was established and the methodology validation was carried out.The content of three batches of samples was above 99%,and the inter-batch RSD was less than 1%,indicating that the product content was qualified and the inter-batch process was stable.In this paper,the synthesis process and quality of Palbociclib were systematically developed to provide a technical basis for the industrial imitation of Palbociclib.