Synthesis Of Taxol Analogues Amidated On C3'-N

As diet and life style changes, cancer was high in the world situation. But there is not yet an effective way to prevent cancer, so the treatment of cancer is particularly important. Among cancer treatment drugs, for its unique therapeutic mechanism and significant effect, taxol has been widely accepted and recognized. However, its side effect and high price constrainted to clinical application. In this paper,10-DABⅢwas chosed as starting materials, which was aboundon in yew branches. Based on the structure-activity relationship, two routs of synthesizing taxol analogues in high efficiency and low cost was attempted, which could be a scientific basis for new drug development.Conclusions were summered below:(1) Rout 1:Because of low convertion ratio, poor putity, or huge stereospecific blockade, the yield of target product was very low, so rout 1 was given up. However, two kinds of pro-substituted products were synthesized, trisubstituted alkenes and hexasubstistuted-cyclooctane. The results was summerised below:①Twelve intermediated pro-substituent products (trisubstituted alkenes) from benzaldehyde analogues and ethyl acetoacetate were synthesized by Kneovenagel reaction, with a high yield (>60%), and the structures were confirmed by 1H NMR, 13C NMR and MS. Reaction solvent DCM, catalyst AlCl3 (20 mmol%), room temperature, reaction time 2～3h.②Hexasubstistuted-cyclooctane was synthesized from acetoneacetate and benzaldehyde, by double Michael addition reaction, with yield 85%. The structure was confirmed by MS and 1H NMR spectra. Reaction solvent EtOH, catalyst NaOH (200 mmol%), refluxed on 50℃, reaction time 2 h. (2) Rout 2:10-DABⅢand (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carboxylic acid were chosed as starting materials, following protecting of 7,10-OH group in the side chain, removing the amino protection of side chain, amidating with saturated fatty acid,unsaturated fatty acid,aromaticity acid, and so on, and then 8 paclitaxel derivatives wre got. The new analogues were confirmed by 1H NMR, in the yield 30%～77%. Reaction conditions of key synthesis were optimized and determined:①Synthesis of 7,10-di-Troc-DABⅢ. Reaction solvent anhydrous pyridine, V(TrocCl):V(anhydrous pyridine)=200:1500, M(TrocCl):M(10-DABⅢ)=4:1, reaction time 1.5 h, room temperature. The yield of target product is 85%.②Condensation of 7,10-di-Troc-DABⅢand side chain. Reaction solvent toluene, M(7,10-di-Troc-DABⅢ):M(side chain)=1:1.1, dehydrating agent DIC, M(DIC):M(7,10-di-Troc-DABⅢ)=1.7:1, reaction time 15 min, room temperature. The yield of target product is 90% after column chromatography.③Deprotecting of side chain. Reaction of solvent methylene dichloride, catalyst trifluoroacetic acid(TFA), V(TFA):V(methylene)=1:1, reaction temperature -12～-8℃, reaction time 4 h. The yield of target product is 95% after column chromatography.④Synthesis of taxol analoges amidated on C3'-N. Reaction solvent methylene dichloride, M(-COOH):M(-NH2)=3:1, reaction time 2 h, room temperature. The yield of target product is 30%-77%.(3) Twenty-one compounds were designed and synthesized in this paper. Thirteen of them are intermediates, and eight of them are Taxol derivatives. Thirteen intermediates were from Rout1 (11 new compounds).