The Synthesis Research Of Docetaxel

Docetaxel,5β,20-epoxy-1,2α,4.7β,10β,13α-hexahydroxy taxane-11-en-9-ketone-4,10-diacetate-2-benzoate-13-[(2'R,3'S)-N-benzoyl-3-phenylisoserine ester, is a novel anticancer and has been broadly used in the treatment of various cancers. The action mechanism is to promote tubulin assembly into microtubules and prevent microtubule depolymerize, thereby inhibiting cancer cell mitosis and proliferation. In 1996, the FDA confirmed its curative effect to lung cancer, breast cancer and colon cancer. Docetaxel belong to a kind of paclitaxel drugs, and its anticancer activity is much higher than that of paclitaxel. For its unique anticancer mechanism and broad-spectrum anticancer activity, it has good application prospect in the market.In this thesis,7,10-bis(trichloro-ethoxycarbonyl)-10-DABⅢwas synthesized from10-DeacetylbaccatinⅢ(10-DABⅢ) by using the 2,2,2-trichloro-ethoxy chloride to protect the reaction activity relatively of 7,10-hydroxy. The reaction temperature was below 5℃. The reaction time was 30-60min. By using n-BuLi as a catalyst, the ester couple reaction was carried between 7,10-bis (trichloro-ethoxycarbonyl)-10-DABⅢwith three ethyl silicone base protecting the hydroxyl of racemic four membered ring side chain, to preparing 2'-three ethyl silicon-7,10-two-triclosan ethoxy carbonyl-docetaxel. The molar ration of 7,10-bis(trichloro-ethoxycarbonyl)-10-DABⅢ:catalyst:racemic four membered ring side chain should be 1:1.2:2.5. The reaction temperature was-40～45℃. Zinc in acetic acid and methanol was used as reducing agent to take off the protection substrate for the synthesis of docetaxel crude. Pure docetaxel products was gotten with column chromatography and purified precess. The total yield of the product was more than 30%. The reaction process was carefully investigated, and the optimum reaction conditions were gotten.The target compounds and intermediates were indentified by FTIR, MS, elemental analysis, H1-NMR. C13-CNM, HPLC and thin layer chromatography.The results showed that the production process has many advantages such as easily available raw materials, mild reaction condition, easy separation and purification, high yield. So it is suitable for industrialized production.