Nicholas M. Thomson

Pharmaceutical Process Chemistry: Evolution of a Contemporary Data-Rich Laboratory Environment

Over the past 20 years, the industrial laboratory environment has gone through a major transformation in the industrial process chemistry setting. In order to discover and develop robust and efficient syntheses and processes for a pharmaceutical portfolio with growing synthetic complexity and increased regulatory expectations, the round-bottom flask and other conventional equipment familiar to a traditional organic chemistry laboratory are being replaced. The new process chemistry laboratory fosters multidisciplinary collaborations by providing a suite of tools capable of delivering deeper process understanding through mechanistic insights and detailed kinetics translating to greater predictability at scale. This transformation is essential to the field of organic synthesis in order to promote excellence in quality, safety, speed, and cost efficiency in synthesis.

Electron-Deficient Phosphines Accelerate the Heck Reaction of Electronrich Olefins in Ionic Liquid

Using various substrates and ligands, we show that electron-deficient, bidentate phosphines are the ligands of choice for palladium-catalyzed arylation of electron-rich olefins. This is in contrast to the reaction of electron-deficient olefins, which benefit from electron-rich monodentate phosphines. A tentative explanation is offered based on DFT calculations.

Chapter 4:Rapid Early Development of Potential Drug Candidates

Process chemistry plays an extremely valuable role in the rapid development of potential small-molecule drug candidates from compound identification through to clinical proof-of-concept (POC). In all aspects of process chemistry enabling in this early development phase, the aim is not to develop the ultimate commercial route with in-depth process understanding and exquisite quality control. Rather it is to develop a fit-for-purpose process capable of supporting multikilogram synthesis with adequate control in a rapid timeframe to accelerate critical toxicology and clinical studies. A potential drug candidate can fail for many reasons during the early development phase, including safety, toleration and efficacy. Thus, a fit-for-purpose enabling paradigm is critical to drive speed and efficiency, providing a vibrant environment for the process chemistry community. This chapter outlines the key criteria and triggers for early process enabling in order to meet legislated safety, environmental, legal and control requirements, in addition to other key business efficiency requirements such as economic and throughput considerations. Through the use of effective criteria to trigger enabling activities, combined with rapid technologies to execute enabling packages, process chemists can play a critical role in delivering material rapidly to support toxicology and clinical studies. Once confidence in the drug candidate is achieved through a successful POC clinical study, the role of the process chemist then changes, as described in subsequent chapters.