Study On Synthesis Process Of AT13387 As Hsp90 Inhibitor

Heat shock proteins?Hsps?are a group of protein molecules that are synthesized by the body under stress.Their major functions are maintaining correct fold of their client proteins and enabling them in the desired conformation for physiological functions.Therefore Hsps play important roles in regulating synthesis,degradation balance and localization of proteins.As a member of the Hsps family,Hsp90 plays a significant role in the assembly,operation,fold and degradation of its client proteins which are expression products of oncogenes.Moreover,some of the client proteins have been well-defined as anti-tumor drug targets clinically.Non-ansamycin?AT13387?as a novel Hsp90 inhibitor has been used intensively in clinical research for the treatment of advanced tumors especially for refractory ones due to its potent and persistent pharmacological activity in vitro.AT13387 is synthesized via condensation and reduction by the two key intermediates2,4-dibenzyloxy-5-isopropenylbenzoic acid?A?and 5-??4-methyl-1-piperazinyl?methyl?isoindoline?B?.In this dissertation,the synthetic process of A and B were studied to offer a suitable and effective synthetic strategy for large-scale production of AT13387.It will provide theoretical and experimental foundation for investigations of AT13387 in domestication.Study on the synthetic process of 2,4-dibenzyloxy-5-isopropenylbenzoic acid?A?.Based on the literatures,the compound A was prepared via“one pot method”of Friedel-Crafts acylation and Fries rearrangement reaction,nucleophilic substitution,Wittig reaction and hydrolysis using the methyl 2,4-dihydroxybenzoate as starting material.The compound A was obtained in the yield of 65.8%with a purity of99.6%.In order to find the optimal conditions,the effects of the reaction system,the rate of ingredients,reaction temperature,solvent and terminational temperature of crystallization on the yield of compound A were investigated.The use of the"one pot method"not only simplified the operations,but also improved the product yields.Study on the synthesis process of 5-??4-methyl-1-piperazinyl?methyl?isoindoline?B?.Founded on the literatures,the compound B was prepared by the debenzylation of N-Bn-piperazinyl-isoindoline.As a key intermediate,N-Bn-piperazinyl-isoindoline was synthesized via aminolysis,condensation and reduction using the trimellitic anhydride as starting material.It also was synthesized via aminolysis,reduction,sulfonylation and nucleophilic substitution.In order to find the optimal conditions,the effects of the reaction system,the rate of ingredients,reaction temperature and solvent on the yield of B were investigated.The synthetic method of compound B has the advantages of readily available materials,lower cost and shorter routes,etc.Finally,AT13387 was obtained by condensation and reduction between compound A and compound B.The structures of all compounds were confirmed by¹H NMR,¹³C NMR and MS spectra.