Robust Processes for Polymer Modification and Pharmaceutical Synthesis

Abstract

Chapter 1: Continuous Dimethyldioxirane Generation for Polymer Epoxidation Post-polymerization modification of commodity polymers yields new applications for materials already produced industrially. Incorporation of small amounts of epoxides into unsaturated polymers such as polybutadiene expands their use for grafting and compatibilization applications, but controlled epoxidation of these polymers in a safe, scalable manner presents a challenge. Herein we describe the development of a reactor for the continuous flow generation and use of dimethyldioxirane and its application to the low-level epoxidation of unsaturated polymers. A continuous stirred tank reactor prevents reactor clogging by allowing solid precipitates to settle, enabling the pumping of a homogeneous solution of oxidant. Modification of relative concentrations, flow rates, and temperatures achieves variable epoxidation levels. This method has been demonstrated on gram scale.

Chapter 2: Large-Scale Synthesis of Molnupiravir from Cytidine Molnupiravir (Lagevrio®, MK-4482, EIDD-2801) is an orally bioavailable medication for COVID-19. We report the development of a supply-centered and chromatography- free synthesis of molnupiravir from cytidine, consisting of a selective enzymatic acylation followed by transamination to yield the final drug product. Both steps have been successfully performed on a decagram scale: the first step at 200 g and the second step at 80 g. Overall, molnupiravir has been obtained in a 41% isolated yield over two steps compared to a maximum 17% isolated yield over five steps in the patented route.

Chapter 3: Diastereoselectivity Is In the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline Bedaquiline fumarate (Sirturo®)is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi-lab reproducibility led to optimized reaction conditions that feature an unusual base-salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication.

Chapter 4: Progress Towards a Diazepam Precursor for Telescoped Flow Synthesis Diazepam (Valium®) is an important medication for the treatment of various central nervous system symptoms and disorders. On-demand flow synthesis of this molecule presents many benefits, but previously reported telescoped syntheses use expensive, advanced starting materials. We demonstrate proof of concept for the synthesis of a crucial diazepam precursor from commodity chemicals. Our synthesis uses a directed metallation approach to selectively acylate a protected aniline in up to 39% yield in two minutes in continuous flow. We anticipate that further optimization of this reaction will enable a fully telescoped synthesis of diazepam from commodity chemicals.