Development of Rapid and Modular Continuous Flow Synthesis of Lumacaftor, A Treatment for Cystic Fibrosis and A Potential Inhibitor of SARS-CoV-2

Cystic fibrosis (CF) is a rare and life-threatening genetic disease that causes damages to mostly the lungs and other organs in the body. Lumacaftor is an FDA-approved pharmaceutical for treatment of CF by acting as a modulator of F508del-CFTR (cystic fibrosis transmembrane conductance regulatory) protein. Recently, drug repurposing studies and computational simulations discovered that Lumacaftor is a potential inhibitor of SARS-CoV2, the coronavirus that caused the COVID-19 global pandemic. Despite being a promising therapeutic candidate targeting SARS-CoV-2 and a major treatment for CF, the annual cost is prohibitive to many patients due to the high production cost. A multitude of challenges were identified with the preparation of this drug, namely (1) lengthy synthetic route that was labor-intensive, time-consuming, and costly; (2) laborious synthetic and purification steps that required specialized techniques; (3) use of hazardous and toxic reagents; (4) poor reaction scalability; and (5) limited and difficult derivatization of structural patterns. In view of viral mutations of SARS-CoV-2 and further optimization towards a more potent treatment for CF, there is a definite need to develop a new method to access Lumacaftor and its analogues in a safe, efficient, eco-friendly, and modular manner. Continuous flow chemistry is a powerful technique in organic synthesis that provides many advantages relative to traditional organic synthesis. We herein propose a new 3-step synthetic route and a continuous flow system towards the preparation of Lumacaftor and structurally diverse analogues. Our sequence uses a combination of techniques including palladium-catalyzed C−C and C−N bond formations while the proposed flow system will address persistent challenges. Preliminary results have verified the plausibility of the proposed study, in which the carbonitrile intermediate was successfully prepared using our proposed pathway and prototype flow reactions provided promising yield of intermediate. The potential of our flow system would be fully explored in this project, including the scope of the palladium processes, streamlined synthesis of Lumacaftor analogues, and demonstration of addressing solvent compatibility and solubility issues between individual reaction steps. The fundamental and technical knowledge obtained during the development of flow reactions and exploration of palladium chemistries will be of significant value to academic interest and industrial applications. The demonstrated technology will serve as a representative model for future designs of streamlined continuous flow synthesis. Currently, flow chemistry is still underdeveloped in Hong Kong and our study would attract considerable attention on continuous flow production and help transform the fine chemical manufacturing and pharmaceutical industry.