Study On Synthesis Of Pemetrexed And Semisynthetic Cabazitaxel Intermediates

Pemetrexed disodium,as a new multi-target folate antagonist,can inhibite many target enzymes,so it is not easy to produce drug resistance than other single enzyme inhibitors.It's widely used in malignant pleural mesothelioma(MPM)and non-small-cell lung cancer.The prospect of its development and application is still a research hotspot in China.In this paper,a new synthetic route of pemetrexed disodium is established by using tolunene and succinic anhydride as raw materials,through the reaction of Friedel-Crafts acylation,oxidation,hydrogenation,esterifycation and brominating the reaction involved is optimized.The optimized route is easy to operate and easy to industrialize.As the third generation of paclitaxel deriatives,cabazitaxel has some advantages in some cancer cell systems,especially in prostate cancer than in the previous two generations.Because of the limitation of natural paclitaxel extraction,semisynthetic cabazitaxel is particularly important.In this paper,the route of synthesis of the target compound cabazitaxel by 4 steps using(4S,5R)-3-(tributyloxycarbonyl)-2,2-dimethyl-4-pHenyl oxazolidine acid as the side chain was proposed and the total yield of the trial was 62.1%.At the same time,the synthesis process of key intermediates was optimized,so that the reaction could be carried under room temperature and pressure.The difficulty of reducing the water-free condition of the reaction was reduced and the yield of 70%was obtained.The purity of the crude product was up to 94%.