Preparation And Characterization Of3-Hydroxy Desloratadine, Deuterium Labeled6α-Hydroxy Paclitaxel And Deuterium Labeled Simvastatin

Drug metabolism must be investigated when any new drugs are synthesized. The drug potencycan be determined by pharmacokinetics. The study on drug metabolism can provide assistance andinstructions for the design and structrural modification of drugs, and the exploitation of efficient andsafe drugs. On the other hand, the devlopement of gas chromatograhy-mass spectrography (GC-MS)or high performance liquid chromatograhy-mass spectrograph(HPLC-MS)in the higher sensitivityand specificity promotes the application of the stable isotope tracer technology in clinicalpharmacokinetic. The stable isotope labeled drugs normally used are mainly divided into "internalanalytical standard" and "internal biological standard" of drug metabolites. Therefore, we choosethree kinds of drugs: loratadine, paclitaxel and simvastatin, and intend to synthesize their metaboliteand isotope labeled molecules.Loratadine is a potent, long-acting second H1-antihistamine in clinical use. Many studies aimedat identifying the metabolites of loratadine reveal that the compound is first hydrolyzed todesloratadine and then hydroxylated at several positions. In these hydroxylated metabolites,3-hydroxy desloratatine is a major active hydroxy metabolite. Unfortunately, the total synthesis of3-hydroxy desloratdine has not been described in the literature. Thus, we designed a total route andsynthesized3-hydroxy desloratadine in twelve steps starting from3-methyl pyridine based on thesynthesis of loratadine and desloratadine. The method can be used to produce3-hydroxy desloratadinein a larger scale.Currently, taxol is one of the most popular anti-cancer drugs, while6α-hydroxy paclitaxel is amajor metabolite of paclitaxel in human. However, the synthesis of deuterium-labeled paclitaxel anddeuterium-labeled6α-hydroxy paclitaxel has not been described in detail. Hence, we proposed afour-step synthesis of five deuterium-labeled paclitaxel starting from five deuterium-labeled benzoicacid, baccatin Ⅲ and C-13chiral side chain based on the synthesis of paclitaxel. In addition, wedesigned a new route to synthesize five deuterium-labeled6α-hydroxy paclitaxel starting from fivedeuterium-labeled paclitaxel in a six-step reaction. After a ten-step reaction, five deuterium-labeledpaclitaxel and five deuterium-labeled6α-hydroxy paclitaxel can be obtained in high chemical purityand isotopic enrichment.Sivamstatin, used for lowering of serum cholesterol levels, is an agent of the3-hydroxy-3-methylglutary-coenzyme A (HMG-CoA) reducatase inhibitor groups of drugs. The synthesis ofdeuterium labeled simvastatin has not been disclosed. In this work, a new reaction procedure was designed to prepare simvastatin labeled with six deuteriums starting from acetone-d6and lovastatinbased on the synthesis of simvastatin. After a nine-step reaction, the desired compound was obtainedwith excellent chemical purity and isotopic enrichment.In summary,3-hydroxy desloratadine, paclitaxel-d5,6α-hydroxy paclitaxel-d5and sivamstatin-d6have been successfully prepared. These compounds can afford valuable references for theirpharmacokinetics research.