Synthesis Of The Related Substances Of Statin Hypolipidemic Drugs

The study of the related substances of APIs is related to the clinical safety and effectiveness of drugs,and is the key focus of the quality control.There is a topic"Research on Key Technologies and Standards for Drug Consistency Evaluation"(numbered2017ZX09101001)in the The National Thirteenth Five-Year New Drug Innovation Great Project,this article is part of the sub-subject of this topic"Research on Separation and Analysis Technology of Drug Impurity Spectrometry System and Establishment of Standards".Rosuvastatin calcium,atorvastatin calcium and lovastatin represent the HMG-Co A reductase inhibitor statin hypolipidemic drugs and they are the mainstream products for clinical treatment of hyperlipidemia.Atorvastatin calcium has been honored for many years as the Champion of the world's best-selling drugs.Their patents have expired,so they become generic drugs.It is very important to establish or improve their quality standards,and one of the important steps is to obtain the related substances of these drugs.Referring to the European Pharmacopoeia 9.0,the related substances of three statin drugs(rosuvastatin calcium,atorvastatin calcium and lovastatin)were synthesized in the paper so as to provide the reference products for the quality research,the consistency evaluation of their preparations and the improvement of pharmacopoeia quality standards.In this article,twelve compounds were synthesized,including five related substances of rosuvastatin,which are the related substances B,C,D and F of the European Pharmacopoeia(corresponding to compounds 1,2,3,5 in this article)and compound 4,five related substances of atorvastatin,which are the related substances A,B,C,D of the European Pharmacopoeia(corresponding to compounds 6,7,8,9 in this article),and related substances F(compound 10)of the United States Pharmacopoeia,together with two related substances of lovastatin,which are the related substances B and C in the European Pharmacopoeia(corresponding to compounds 11,12).The structure of these twelve compounds were confirmed by MS and ~1H-NMR,and their melting points and specific rotations were determined.The specific rotation of all compounds and the melting points of seven compounds are reported for the first time in this article.Detected by HPLC,the purity of all compounds is greater than 95%,and the retention time relative to the standard is consistent with the provisions of the European Pharmacopoeia 9.0 version.The synthesis route of related substance 4 has not been reported in the literature.During the synthesis of related substance 2,the oxidation reaction of compound b into c with DDQ has not been reported.During the synthesis of related substances 6 and 8,the conditions for the Michael-Stetter conversion of 6b to 6c and 8b to 8c were optimized and have not been reported in the literature,the yield was increased from 32%to 42%.