(613g) A Modular Continuous Manufacturing Platform for Fine Chemicals Via Lithium-Halogen Exchange and Electrophilic Substitution

Functionalized aromatic species represent a key class of materials that are present in more than 200 active pharmaceutical ingredients (APIs). It is necessary to develop bottoms-up manufacturing capabilities for key raw materials from chemical feedstocks to ensure a robust pharmaceutical supply chain in the United States. Production of these materials via continuous flow in a modular and reconfigurable way is desirable to mitigate critical supply chain issues. Three arylbromide starting materials have been identified that can be converted into a variety of fine chemical targets using multiple electrophiles and minimal reconfiguration. The starting materials initially undergo lithium-halogen exchange under cryogenic conditions followed by a functionalization step with an electrophile. This synthetic sequence introduces a wide range of molecular complexity, producing high value functionalized compounds that serve as advanced intermediates in many areas of chemical production. We have developed and optimized a continuous manufacturing platform capable of producing these materials, including workup and isolation steps for the product via liquid-liquid extraction, distillation, or crystallization. This system is designed so that while only one synthetic process is being run at a time, all routes are possible through rapid rearrangement of the manufacturing equipment. We demonstrated scalability (>1 kg/day) of four fine chemical targets within five days to validate the modularity of the reactor system. The process equipment is suitable for modular fabrication approaches, which facilitates installation at multiple, strategic chemical processing locations.