Development of green purification process for piperazine-type drugs: a case study of quetiapine process development

Abstract

A thorough study was conducted on the sequential synthesis route of quetiapine fumarate. In this process, a general approach was developed to enhance the quality of a key intermediate of quetiapine. This approach utilized ACD software to calculate the pH values of the intermediate and its impurities, and design distribution experiments according to the pK_a values. Subsequent experimental results demonstrated the feasibility of this strategy, wherein the precise pH control could effectively eliminate impurities and significantly improve the product's quality. Notably, this process could be carried out on the hundred-kilogram scale in the workshop. The multi-batch production has demonstrated the stability and great application value of this process.