Synthesis of Bempedoic Acid

Bempedoic Acid (ETC-1002) is synthesised using ethyl isobutyrate as raw material by chemical reaction. The specific synthesis steps are as follows:

The preparation of bempedoic acid started with ethyl isobutyrate 147 containing 317 kg. Alkylation with alkyl bromide 148 followed by a Finkelstein reaction afforded alkyl iodide 149. This material was then reacted with 0.5 equiv of toluenesulfonyl isocyanide (TosMIC) under basic conditions to facilitate a double alkylation of iodide 149 to arrive at intermediate isonitrile 150. This intermediate was not isolated but instead subjected to acidic conditions in isopropyl acetate. After pH adjustment, ketone 151 was produced in excellent yield on the basis of the mass of the intermediate 150. The utility of the TosMIC reagent as a ketone surrogate on this scale highlights the versatility of this reagent in organic synthesis. 149 Reduction of the ketone with sodium borohydride followed by saponification provided the crude API, which was further isolated after a series of crystallization steps to afford bempedoic acid in excellent overall yield. Notably, this sequence has been exemplified on >300 kg scale.

Introduction of Bempedoic Acid

Bempedoic acid is a nonstatin antihyperlipidemic drug developed by Esperion Therapeutics and was approved by the USFDA in 2020 for the treatment of hypercholesterolemia. Bempedoic acid upregulates LDL receptors and decreases LDL-C for adult patients with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease for patients who require further lowering of LDL-C and are unable to reach the desired goals with the maximum tolerated statin dose.