Synthesis Of Anticancer Drug Docetaxel And .the Study Of Enlargemental Test

As is known that Paclitaxel (Taxol, (fig 1)), isolated from the bark of the Pacific yew, is considered one of the most promising new drugs in cancer chemotherapy and has recently been approved for treatment of various types of cancers. Docetaxe.(fig 1),which obtained from the modified structure of paclitaxe ,is currently considered as one of the most effective drugs used in cancer chemotherapy and has better anticancer activity than paclitaxel. It has broad-spectrum antitumor activity for leukemia and Solid Tumors and was approved by Food and Drug Administration for the treatment of the lung,breast and ovarian cancer in 1996. Docetaxel is not a natural product and has complex structure. The total synthesis of Docetaxel is very hard because of its complex ring system and because of its many chiral centers. So semisynthesis is the most effective means of produce the docetaxel. 10-deacetylbaccatin III (fig.1) ,which is extracted from the leaves of taxus, has the similar structure with paclitaxel and docetaxel. But its anti-cancer activity is not as effective as paclitaxel.and docetaxel. Fortunately, 10-deacetylbaccatin III has been converted to docetaxel via coupling with the appropriately protected the (2R, 3S)-N-t-Butylcarbonyl-3- phenylisoserine side chain (C13)(fig.1).The more readily available docetaxel precursor 10-deacetylbaccatin III can be easily obtained (1g/kg) by extraction from the leaves of taxus (European yew) with a high yield and can be supplied continuously without threatening the survival of the yew species Thus, the development of short and practical synthetic routes to the docetaxel C13 side chain, which are adaptable for Industrial-scale production, have become very important.In this paper , We accomplished synthesis of docetaxel C13 side chain with high yield on the basis of the Sharpless asymmetric dihydroxylation (AD) reaction of olefins. Then it was coupled with protected 10-deacetylbaccatinⅢ,followed by deprotection to afford docetaxel.The chiral osmium catalyst is generated in situ by the chiral ligand complexing with OsO4 in the reaction. Although AD reaction can be widely applied to the synthesis of pharmaceuticals, natural products and fine chemicals, the high cost of osmium and chiral ligands has restricted its use in industry. So exploration of the recovery and reuse of the ligands for AD and AA reaction is urgent. This project aims at the development of economical, simple and highly effective recoverable and reusable free ligands for the AD reaction of olefins, and use it to synthetic the docetaxel.This thesis mainly focuses on the following three aspects.1.Design,synthesis and Evaluation of ligand. (1).Design and synthesis of recoverable and reusable free cinchona alkaloid derivativesWith quinine which is cheap and readily available as starting material, Ligand I(fig1)was synthesized through five steps.(2). Evaluation of free cinchona alkaloid derivatives Ligand I was applied to the homogeneous AD reaction of six olefins respectively in tBuOH-H2O (1:1) and in Me2CO-H2O (9:1) system and inspected its recoverable ability. The results can be summarized as follows:a) Evaluation of catalytic activity of Ligand I.In tBuOH-H2O (1:1) / K3[Fe(CN)6]system.Ligand 1 deliver excellent enantioselectivity (89~99%ee) and good yield (85~94%) for six olefins. In Me2CO-H2O (9:1) /NMO system.Ligand 1 deliver excellent enantioseletivity (83~99%ee) and Good yields(81~95%) for six olefinsb) Evaluation of recoverable ability of Ligand I.With ethyl trans-cinnamate as substrate of the AD reaction, the recovered ligand I was reused in tBuOH-H2O (1:1) / K3[Fe(CN)6] system. No significant decrease in activity and enatioselectivity was observed within the first three recycles. Recovery rate was 92~95%.And in Me2CO-H2O(1:1) /NMO system for nine times to show very good yields and excellent enantioselectivity. The results indicated that found that ligand I has better stereoselectivity in tBuOH-H2O (1:1) / K3[Fe(CN)6] system than Me2CO-H2O (9:1) /NMO system,but the catalytic activity and recoverable ability of ligand I are opposite. Especially , the recovery and reusing of ligand I are more readily and effective in Me2CO-H2O (9:1) /NMO system than in tBuOH-H2O (1:1) / K3[Fe(CN)6] system.2. Synthesis of docetaxelWith trans-ethyl cinnamic as starting material, chiral docetaxel C13 side chain was synthesized in 76% yield and 99%ee through asymmetric dihydroxylation (AD), epoxidation,diazotization and hydrogeneration. Then after being protected it was coupled with protected baccatinⅢin the presence of dicyclohexylcarbod- iimide (DCC) and 4-dimethylaminopyridine (DMAP),followed by deprotection to afford target compound–docetaxel with 76% yield.The purity of docetaxel is above 99.5% through inspecting by HPLC.Through the study on semisynthesis of the docetaxel ,we did some new work.(1) we choosed 4-methoxyl benzaldehyde and 2,2,2,-trichloroethoxyl chloroformate as the best protecting group for. the docetaxel C13 side chain and 10-deacetylbaccatin III and got the product with high yield through optimizing the reactive condition. (2)For monitoring the reaction,we established the method of monitoring reaction and detecting product's purity through HPLC for the key reaction of this route. Through the monitoring of HPLC,we not only increase the yield ,but also ensure the purity of product. It provide the means of monitoring for industrial-scale production.(3) to grope a new mothod for getting high purity docetaxol. After repeated study indicate that the route have some advantages such as short steps,convenient operation and easy purified et. At the same time, the expensive cinchona alkaloid derivatives was recycled, which dramatically decreased the reaction cost.so this route is adaptable for industrial-scale production.3.The study of enlargemental testAfter successfully synthesized the docetaxel with small-scale experiment ,we enlarge the experimental scale in order to inspect the feasibility and reproducibility of the route The result of mass detection of three batch products indicated that this synthesis route has stable chemical and optical yield and stable quality of the product in the study of enlargemental test which establish stable foundation for middle test.