Synthesis Of Deuterium-labelled Drug Standards: Diclofenac And Fluvastatin Sodium

Drug standards are referred to the standard materials which are used in bioassay, the measurement of the content or the titer of antibiotics and biochemicals. We could obtain stable isotope drug standards through labelling the isotopes, such as 2H,13C,15N and 18O into drug compounds using chemical synthesis.The outsourcing market for drug synthesis is increasing evey year, so is drug standards. Meanwhile, the research of stable isotope drug standards in China is still in its early stage. In this paper, we choosed two kinds of drugs: Diclofenac and Fluvastatin Sodium. We focoused on the synthesis of the stable isotope labelled drug standards of these two drugs.Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) belongs to phenyl acetic acid type, which is used for the treatment of mild to moderate pain, fever and inflammation. In this thesis, on the basis of the previous research, we designed a new reaction route to synthesize four-deuterium-labelled diclofenac. It was started from five-deuterium-labelled phenyl acetic acid. After a four-step reaction, we could obtain four-deuterium-labelled diclofenac with high chemical purity and isotopic enrichment. In addition, we explored the synthesis of deuterium labeled 4'-OH diclofenac, which was the main metabolite of diclofenac.Fluvastatin sodium, an antihypercholesterolemic HMG CoA reductase inhibitor, is the first antihypercholesterolemic drug synthesized by Novartis. The synthesis of deuterium labeled fluvastatin sodium has not been reported yet. In this thesis, a seven-step synthesis of six-deuterium-labelled (3S, 5R)-fluvastatin sodium starting from six-deuterium-labelled 2-bromopropane and aniline had been described. The successful synthesis of this compound also provides an important reference for the synthesis of other isomers of fluvastatin sodium.In this thesis, we synthesized deuterium labeled diclofenac and (3S, 5R)-fluvastation sodium successfully, and it also offers valuable reference for the synthesis of other deuterium-labeled drug standards.