Abstract

Synthetic Biology meets Continuous Processing: Towards a Novel Synthesis of Levomilnacipran

Amanda Evans, Assistant Professor, California State University Fullerton

The union of continuous flow technology and engineered enzyme chemistry is here applied towards a novel five step synthesis of an active pharmaceutical ingredient (API), levomilnacipran. This drug is currently prescribed to treat the symptoms of both major depressive disorder (MDD) and fibromyalgia syndrome (FMS). Levomilnacipran, the single-enantiomer form of milnacipran, is a selective serotonin- and norepinephrine-reuptake inhibitor (SNRI) recently approved for treatment of patients with MDD and FMS. However, the published batch syntheses of this drug require at least nine days to perform and have not been renovated for over a decade as synthetic techniques have evolved. Chirally-pure formulations of the levo-isomer of milnacipran have been demonstrated to increase SNRI activity: a critical component of this synthesis therefore involves the enantioselective formation of the central cyclopropane ring, a common scaffold found in many bioactive molecules. The work presented here demonstrates the utility of applying continuous processing and bioprocessing technologies to showcase a novel five step continuous synthesis of levomilnacipran. Biochemical catalytic strategies are deployed to enantioselectively install the central cyclopropane ring while utilizing efficient and sustainable reaction conditions throughout API synthesis. The advantages of flow chemistry include higher yields, faster reaction times, reduced waste, sustainable practices and access to chemistry previously considered impossible under batch protocols. By incorporating continuous bioprocessing as well as continuous processing into innovating API synthesis, a new technological platform for the use of continuous synthesis of key APIs can be developed.