Synthesis Of Novel Betulinic Acid Derivatives

Betulinic acid derivatives are a kind of three pentacyclic triterpenoids, most of them have anti-cancer, anti-inflammatory, anti septic, antimalarial, antibacterial, antiviral, anti insect and other significant biological activity, and has no toxicity and drug resistance of synthetic drugs. Because of its extensive sources and significant biological activity and its superior activity and novel mechanism of action and also very little physiological toxicity in the field of anti-tumor and anti AIDS, have attracted considerable research interests.In this paper, the synthesized novel betulinic acid derivatives have novel structure, and build the double interfacing carbonyl group at the C-28position is rare in the world; and the monoisomer obtained using the novel synthesis methods, that is condensation at C-3position, avoiding the isomers in the traditional method of open loop joint that brings separation difficulties; And introduction side chain carboxylic acid to the C-3position enhance the water solubility and biological activity of series of the derivatives.This paper first from the cheap, easy of betulin, via five steps of esterification, oxidation, rearrangement, selective deprotection and oxidation, we afforded the key synthesis block aldehyde, then obtained birch carboxylic acid derivatives through the two polarity reversal synthetic methods, and at last we complete the synthesis of betulinic acid and amide over four steps through condensation, hydrolysis, esterification and selective hydrolysis based on the last two synthetic methods16and12steps and with3.36%and4.68%yield.Then from the key intermediate of the hydroxyl group, via esterification, reduction of nitro group to amines, amino reductive alkylation, oxidation to obtain key keto amide intermediate, followed by deprotection, reductive alkylation, esterification of side chain and deprotection, finally completed the synthesis of the target product betulinic acid ketone amine derivatives over13steps with the yield of3.23%.Finally from the key intermediate of the hydroxy nitro, via hydroxy esterification, reduction elimination, oxidation of nitro group we got the key acetal intermediate, followed through the condensation with small molecular amine to obtained acetamide intermediates. After deprotection, the esterification of side chain and ester hydrolysis eventually completed the synthesis of the target product betulinic acid acetamide derivatives.