TosMIC-free synthesis of bempedoic acid, a hypercholesterolemia drug

Abstract

A novel concise and convergent approach for the preparation of bempedoic acid, a new group of non-statin LDL-lowering drug has been developed starting from pentane-1,5-diol in 8 steps with an overall yield of 20%. Result: The synthesis of a key precursor i.e. 1,11-dihydroxyundecan-6-one, has been accomplished through the ring opening of  - caprolactone with alkyl Grignard reagent. This method doesn’t require the use of p - toluenesulfonylmethylisocyanaide (TosMIC) for the construction of dihyroxyketone, a key intermediate of bempedoic acid. The key steps involved in this approach are the bromination of dihydroxyketone and base-catalyzed alkylation of methyl isobutyrate with 1,11-dibromoundecan-6-ol followed by the hydrolysis of dimethyl ester into bempedoic acid.