Study On Synthesis Process Of Side-chain Of Docetaxel

Docetaxel,which obtained from the modified structure of paclitaxel,was considered as one of the most effective drugs used in cancer chemotherapy and had better anticancer activity than paclitaxel.It had broad-spectrum antitumor activity for leukemia and Solid Tumors.The total synthesis of Docetaxel was very hard because of its complex ring system and because of its many chiral centers.We could semisynthesize docetaxel by converting 10-deacetylbaccatinâ…¢which was extracted from the leaves of taxus to docetaxel via coupling with the appropriately protected the side chain.So synthesizing this side chain efficiently and lower cost became the key point of semisynthesizing docetaxel,this was very important to develop its industrialized route.The technological conditions has been optmized,the improved route was as follows. Firstly,theβ-lactam was synthesized with the material ofα-methylbenzylamine,benzaldehyde, glycollic acid and acetyl chloride.Then,ring opening product with two chiral centre was obtained by the reacion of deacetylation and ring cleavage reaction under acid catalysis.The ring opening product was debenzylated by H₂ under catalyzation with Pd-C.Then the aminogroup and hydroxide radical were protected with Di-tert-butyl dicarbonate and p-anisaldehyde dimethyl acetal.Finally,the precursor was accomplished by the hydrolyze reaction in the presence of KOH.Thin layer chromatography(TLC) was used to track the reaction.Mass spectrum(MS),nuclear magnetic resonance spectrum of hydrogen(1H-NMR) and nuclear magnetic resonance spectrum of carbon(13C-NMR) was used to analyse the product and identify the structure.Through single element experiment,we analysed the influence to yield when technological conditions(reaction temperature,reaction time,mole ratio,acidification reagent, variety and concentration of alkali,activator use level and so on) were changed,maked sure the most optimized conditions as follows.The technological parameters of synthesis of Schiff base were as follows:reaction temperature was 20℃,reaction time was 2.5h,drier was anhydrous sodium sulfate.The technological parameters of synthesis of acetoxy acetyl chloride were as follows:reaction temperature of water bath was 50℃,reaction time of water bath was 3h, reaction time of hot reflux was 2h.The technological parameters of synthesis ofβ-lactam were as follows:reaction time of ice bath was 2h,reaction time at room temperature was 7h, reaction temperature at room temperature was 20℃,eluant was mineral ether/aether(mineral ether:aether=10:1 was used to elute impurity,mineral ether:aether=2:1 was used to collect lactam).The technological parameters of synthesis of(3R,4S)-3-hydroxyl-N-(1'-phenly)ethyl-4-phenly-2-N heterocyclic butanone were as follows:solvent was acetonitrile,mole-to-volume ratio was 1:4,alkali for hydrolyze was 4mol/L KOH,reaction temperature was 20℃,reaction time was 2.5h,solvent for recrystallization was V(acetic ether):V(mineral ether)=4:1.The technological parameters of synthesis of(2R,3S)-2-hydroxyl-3-[(S)-(1-phenly)Ethylamino]-3-phenly-methyl propionate were as follows:mole-to-volume ratio was 1:3,reaction temperature was 20℃,reaction time was 50 minutes,acidification reagent was acetyl chloride.The technological parameters of synthesis of(2R,3S)-2-hydroxyl-3-amidocyanogen-3- phenly-methyl propionate were as follows:mole ratio was 1:4,mole-to-volume ratio was 10:1, reaction time was 8 h.The technological parameters of synthesis of(2R,3S)-2-hydroxyl-3-(N-Boc) -amidocyanogen-3- phenly- methyl propionate were as follows:reaction temperature was 20℃,reaction time was 5 h.The technological parameters of synthesis of(4S,5R)-N-BOC-2-(4'-methoxyl) phenly-4-phenly-1,3-oxygen and nitrogen heterocyclic penta-ring-5-formic acid were as follows:mole ratio of reactant-to-PPTS was 10:1,addition reaction temperature was 120℃,reaction temperature of water bath was 40℃,reaction time of water bath was 4 h, mole ratio of acetal-to-reactant was 4:1.After optimization,the total yield was 25.7%,the purity was greater than 95%,but the document had reported the total yield was 24.3%,the product was crude;the period could be controled in 36 hours,the period had shortened 14 hours.After optimization,synthesizing methodology of side-chain of docetaxel was more suitable for commercial process.