The Route Design And Synthesis Of Novel Water-soluble Docetaxel Derivative

Objective:The route design and synthesis of novel water-soluble docetaxel derivative LK-196.Methods : By using α-(S)hydroxy-γ-phthalimido butyric acid as the starting material,through esterification reaction,fluorination reaction,hydrolysis reaction and Leuckart reaction,(R)-4-dimethylamino-2-fluoro-butanoic acid hydrochloride(5a)was obtained first of all;Then,7,10-O-dibenzyloxy oxygen acyl-docetaxel(4b)was obtained through esterification reaction,condensation reaction and selective deprotection of 10-deacetylbaccatin III as the starting material.This key intermediate 4b was further reacted with 5a,and followed by hydrogenolysis in the presence of palladium on carbon to obtain the target docetaxel derivative(LK-196).Results:The target product and key intermediates were characterized by means of 1HNMR,13 CNMR and HRMS.Conclusion:The synthetic route was benefited from simple operation,overall yield of 64.1%(lit.45%)and purity of over 99%(lit.96.8%).Compared to the synthetic method in literature,the yield and purity were increased by 19% and 3% respectively.This study provided strong support for the pre-clinical study on docetaxel derivative.