Preface

Catalysis is everywhere!

It is an area of activity that has certainly improved our standard of living and the well-being of our planet as a whole. It impacts many areas of activity that include agriculture and the production of everyday common materials like plastics, polymers, and textiles. It also has a significant role in energy production and, of course, has an enormous role in the production of essential medicines, or, more appropriately, active pharmaceutical ingredients (s), which is the focus of this book.

More than 2400 APIs are known, and many of these are obtained using catalytic methods [1].

The "grand plan" of this book is to give the reader an insight into the key catalytic reactions which have been used to produce important APIs. This approach is different from other books, generally written by industrial chemists, where the focus is the actual API, where the processes giving the API are discussed. This is a book that, besides recounting the importance of the API, discusses in detail the importance of the principle catalytic processes involved in the API preparation. The key catalytic reactions discussed in our book are listed later, and include hydrogenation, epoxidation, cycloaddition reactions, metal-catalyzed couplings, biocatalysis, and phase-transfer catalysis. Both metal-based and organocatalysis are discussed at length. The book concentrates on the developments of APIs by both industrial and nonindustrial or academic laboratories.

Considering the fact that about 80% of the drugs on the market consist of a single enantiomeric species, naturally, a significant number of examples using asymmetric catalysis are described in this book. There has been a recent paradigm shift affecting the production of APIs by the pharmaceutical industry, where greater emphasis has been placed on process intensification, sustainability, and waste mitigation, and where catalysis has a central role. Catalytic methods coupled with continuous manufacturing processes like continuous-flow methods have become and will become vital, enabling technologies for accessing APIs.

This book provides the reader with an updated clear view of the current state of the challenging field of catalysis for API production. The book consists of 12 chapters seamlessly interwoven and spanning most of the spectrum of catalytic reactions used in modern API synthesis. Recent patent literature is also included for completeness; this facet will be of particular interest to industrial chemists.

The book's focus is on the application of catalytic methods for the synthesis of known APIs; however, for completeness, we also have covered important lead compounds that have got to clinical trials, but whose studies were discontinued for different reason (generally for safety reasons). We also have included some very promising molecules with demonstrated biological activities. We include, to a lesser extent, some examples of promising and interesting biologically active compounds.

This is a body of work written by a quartet of highly motivated chemists with diverse experience in the field of catalysis, which includes industrial catalysis, biocatalysis, asymmetric catalysis, metal-catalyzed coupling and organocatalysis, etc.

Chapters 1, 3, 4, and 8 were written by Anthony Burke; Chapters 5, 6, 9, and 10 by Carolina Marques; Chapters 2, 7, and 11 by Gesine Hermann; and Chapter 12 by Nicholas Turner. NT acknowledges the assistance he received from Dr. Scott France and Jin Xu from the School of Chemistry and the Manchester Institute of Biotechnology, University of Manchester for writing Chapter 12.

Chapter 1 is a general "review-type" chapter that explores the history of catalysis, which includes a time line of key discoveries and the impact it has had on the development of chemistry and on the chemical industry over the past 120 years. More importantly, it also addresses the importance it has had on the discovery of APIs by the pharmaceutical industry. To show its significance, a number of case examples are described, which include naproxen (obtained using a catalytic asymmetric hydrogenation), indinavir (obtained via a Jacobsen-Katsuki epoxidation), L-699,392 (from a Mizoroki-Heck coupling), and losartan (from a Suzuki-Miyaura reaction). This chapter also looks at the future of manufacturing of APIs by the pharmaceutical industry and emerging technologies such as continuous-flow processes.

Chapter 2 is a more specific chapter that looks at the factors involved in implementing one or more catalytic processes in the manufacture of an API. The factors that go into the planning of a catalytic process to be scaled up are considered, which include the option of conducting a homogeneous or heterogeneous catalysis, safety aspects, catalyst recycling, and removal issues including the control of residual metals, particularly when they are toxic, to ensure product safety and their effect on the environment, methods for improving the manufacturing process, like the use of design of experiment (DoE) and enabling technologies that allow better streamlining of the manufacturing process. In order to hammer home the concept and the application, case studies are given.

Chapter 3 deals with the catalytic hydrogenation, hydroformylation, and other reductions including hydrosilylation and the reduction of nitro groups (which is a very important undertaking considering the presence of amino groups in many APIs). Organocatalytic methods are discussed in the context of the hydrosilylation of imines. Asymmetric catalytic methods are strongly emphasized in this chapter.

Chapter 4 looks at catalytic oxidation methods, which includes the Sharpless-Katsuki reaction, the Jacobsen-Katsuki reaction, catalytic nucleophilic methods (which include the Juliá-Colonna-Roberts poly-Leucine method, the Sharpless dihydroxylation and amino-hydroxylation methods, including the formation of sulfones and sulfoxides that are present in many APIs, including omeprazole. Asymmetric catalytic methods are also strongly emphasized in this chapter.

Chapter 5 is a short chapter that looks at the impact both catalytic 1,2- and 1,4-additions have had on the manufacture of APIs. Some of the important reactions considered are the 1,4-addition of arylboronic acids to nitroolefins as in the case of Merck's synthesis of telcagepant, or the Nozaki-Hiyama-Kishi reaction which is a 1,2-addition used in Eisai's synthesis of the cancer drug eribulin, the use of the catalytic Henry reaction in the production of (R)-salmeterol, and the asymmetric Michael addition reaction in Abbott's process for ABT-546 used for cancer and congestive heart failure. Asymmetric catalytic methods are also strongly emphasized in this chapter.

Chapter 6 is the longest chapter in the book, and, of course, it looks at the application of metal-catalyzed coupling procedures, which include the "usual suspects" like the Heck-Mizoroki reaction (as is the case of montelukast and L-699,392 by Merck), the Suzuki-Miyaura reaction (as in the case of CI-1034 by Pfizer), the Buchwald-Hartwig reaction (AR-A2 by AstraZeneca), and the Sonogashira-Hagihara reaction (terbinafin by Sandoz) as well as, C─H activation processes that have been used for the synthesis of anacetrapib by Merck.

Chapter 7 is another short chapter that looks at catalytic metathesis reactions in the synthesis of APIs. Both Ru- and Mo-based catalysts have been used. In the case of the former, APIs such as relacatib (GSK), simeprevir (Medivir and Janssen), and vaniprevir (Merck, Sharp & Dohme) are obtained through a catalytic metathesis step, the latter-based catalyst has received much less interest for the synthesis of APIs, but nonetheless, has been used for the synthesis of balanol and KRN7000.

Chapter 8 is concerned with the application of catalytic cycloaddition reactions for accessing APIs. The most predominant methods used for API production have been the Diels-Alder () reaction (including the hetero-Diels-Alder () reaction) and 1,3-dipolar azomethine ylide cycloadditions. Some of the examples described include LY235959 by Eli Lilly (DA), MK-1256 by Merck (hDA) and vabicaserin by Pfizer (Wyeth) (1,3-dipolar azomethine ylide cycloadditions). The copper-catalyzed azide-alkyne (CuAAC) and the ruthenium-catalyzed azide-alkyne (RuAAC) reactions also feature in this chapter. Although few APIs have been produced to date with these methods, a vast array of interesting biologically active compounds have been obtained, and are discussed. Asymmetric catalytic methods are also emphasized in this chapter.

Chapter 9 addresses the issue of catalytic cyclopropanation reactions. This reaction is important considering the relevance of the cyclopropyl unit as a crucial pharmacophore in many APIs. Some of the examples include Eli Lilly's LY2140023, and Pfizer's TRPV1. Asymmetric catalytic methods are also emphasized in this chapter.

Chapter 10 deals with catalytic C─H insertion reactions or, more...