Applications of Transition Metal Catalysis in Drug Discovery and Development

An Industrial Perspective

Matthew L. Crawley, Barry M. Trost, Matthew L. Crawley, Barry M. Trost

• Publisher: Wiley
• Year: 2012
• Print ISBN:
  9780470631324
• eBook ISBN:
  9781118309834
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

This book focuses on the drug discovery and development applications of transition metal catalyzed processes, which can efficiently create preclinical and clinical drug candidates as well as marketed drugs.  The authors pay particular attention to the challenges of transitioning academically-developed reactions into scalable industrial processes. Additionally, the book lays the groundwork for how continued development of transition metal catalyzed processes can deliver new drug candidates. This work provides a unique perspective on the applications of transition metal catalysis in drug discovery and development – it is a guide, a historical prospective, a practical compendium, and a source of future direction for the field.

Chapter 1

Transition Metal Catalysis In The Pharmaceutical Industry

Carl A. Busacca, Daniel R. Fandrick, Jinhua J. Song, and Chris H. Senanayake

1.1 Overview of Catalysis

Catalysis typically provides the technology to enable the efficient and cost-effective synthesis of pharmaceutical products. By definition, catalysis increases the reaction rate by lowering the activation energy of the reaction, therefore allowing the chemical transformation to take place under much milder conditions over the uncatalyzed process. Furthermore, the catalyst typically imparts chemo-, regio-, or stereoselectivities over the course of the reaction to enable highly efficient syntheses of target molecules.

Catalysis is one of the principle drivers for the modern economy. Catalysis-based industries contribute more than 35% of the global GDP [1]. It has been estimated that about 90% of the chemicals are derived in some fashion from catalytic processes [2]. The annual worldwide demand for catalysts is approaching one million metric tons, and further growth in this sector was projected to continue [3]. Furthermore, catalysis is one of the 12 green chemistry principles [4]. The use of catalysis can significantly reduce waste streams, simplify synthetic processes, and reduce both cycle times and volume requirements, especially in chemical manufacturing. Catalysis often enables a business to enhance the value of the product while minimizing the overall carbon-footprint of their activities.

The significance of catalysis and its proven impact on the advancement of science was recognized by several Nobel Prizes in Chemistry. In 1909, Wilhelm Ostwald won the Nobel Prize for “his work on catalysis and for his investigation into the fundamental principles governing chemical equilibria and rates of reaction.” During the first decade of this century, four transition-metal catalyzed reactions were honored with Nobel Prizes in Chemistry: asymmetric hydrogenation and oxidation (2001; Knowles, Noyori, and Sharpless), metathesis (2005, Chauvin, Grubbs, and Schrock), and cross-coupling reactions (2010; Heck, Negishi, and Suzuki). These reactions not only have academic significance but also proved to be critical for the production of industrially important products.

Noyori's BINAP-Rh-catalyzed asymmetric allylic amine isomerization reaction was used to develop an industrial process for menthol (Scheme 1.1) [5]. Menthol is one of the most widely utilized natural products. In 2007, the total world production of menthol was >19,000 tons, over a quarter of which was used for pharmaceutical purposes, while the remainder was used for consumer products such as toothpaste, cosmetics, confectionary, and tobacco products [6]. Natural menthol is supplied via isolation from mint cultivated primarily in Asian countries. However, the market demand greatly exceeded the natural supply. In addition, the reliability of natural supply is affected by weather and climate of the mint-growing region. A need existed for an efficient and economical method for synthetic menthol to close the supply gap and also to alleviate the volatility of price on the market.

Scheme 1.1 Industrial menthol processes.

The new Takasago–Noyori menthol process commenced with the conversion of myrcene to geranyldiethylamine by treatment with lithium and diethylamine. Then asymmetric isomerization of the allylic amine with a cationic BINAP-Rh catalyst afforded a chiral enamine, which was hydrolyzed to (R)-citronellal (96–99%ee). Elaboration of (R)-citronellal to (−)-menthol was accomplished in two additional straightforward steps. This new process allowed Takasago to produce 1000–3000 tons of synthetic menthol every year for the past 30 years.

BASF recently disclosed a new menthol process using Chiraphos-Rh-catalyzed hydrogenation reaction as the key step [7]. They were able to achieve the direct asymmetric hydrogenation of neral to give (R)-citronellal with 87%ee. The projected production capacity of the BASF menthol process was 3000–5000 tons/year [8]. This menthol process described here clearly underscored the importance of catalysis to our everyday life.

1.2 Transition Metal Catalysis in the Pharmaceutical Industry

Transition metal catalyzed processes have been extensively utilized in the pharmaceutical industry for over the past 30 years. They have been employed for library preparations, discovery syntheses, and large-scale preparation of active pharmaceutical ingredients. This use relates to the efficiency to conduct a large number of chemical transformations with tolerance of numerous functional groups, and high enantio-, diastereo-, and chemoselectivities. The most commonly applied transition metal catalyzed applications relate to the transformations that result in a cross-coupling for the formation of carbon–carbon and carbon–heteroatom bonds, asymmetric hydrogenation, oxidation, asymmetric addition, and metathesis. The emergence of each technology, evolution into its current status, impact, and recent advances that are projected to provide additional value to the pharmaceutical industry deserve further discussion.

1.2.1 Cross-Couplings for the Formation of Carbon–Carbon Bonds

The importance of cross-couplings for the formation of carbon–carbon bonds to the chemical industry is best appreciated by awarding the 2010 Nobel Prize to Heck, Negishi, and Suzuki for “palladium-catalyzed cross-couplings in organic synthesis.” The basis of cross-coupling is the reductive elimination of two organic components from a high valent late transition metal for the formation of a C–C bond (Scheme 1.2) [9]. The utility of this reaction was realized by the development of suitable components for the selective formation of the mixed bis-organometallic intermediate. In 1971, Kochi demonstrated that a Fe(III) complex can catalyze the coupling of organo-magnesium reagents with haloalkenes [10]. The following year in 1972, Kumada, Tamao, and Corriu independently reported the cross-coupling of organo-magnesium reagents with alkenyl or aryl halides catalyzed by a Ni(II) complex [11]. Since these seminal reports, palladium and nickel complexes have emerged as the mainstream catalysts employing organo-boronates, silicon, tin, magnesium, and zinc reagents as the nucleophilic components wherein the corresponding cross-couplings are referred to as Suzuki-Miyaura [12], Hiyama [13], Stille [14], Kumada [15], and Negishi [16] couplings. The transmetallation operation can also be replaced by a migratory insertion with an olefin or carbon monoxide to achieve a Heck coupling [17] or carbonylation [18]. Since the advent of these technologies and by proper choice of reaction components, catalyst, and conditions, most carbon–carbon single bonds can be constructed through this process.

Scheme 1.2 General cross-coupling mechanism and extensions.

The utility of cross-couplings for the accessibility of bi-aryl, aryl-alkenyl, and aryl-alkynyl moieties has made these structures common synthetic intermediates for APIs and as pharmacophores rationally designed into numerous drugs and clinical candidates as exemplified by Losartan, Naratriptan, and Singulair (Fig. 1.1) [19]. A survey of reactions scaled in Pfizer's GMP facility at the Groton site showed a steady increase in the use of cross-couplings over the past two decades [20]. Of the 14% of reactions that generate a C–C bond, 4.3% were cross-couplings from 1985 to 1996, which increased to 14.5% for the period between 1997 and 2007. Further utility of cross-couplings will be due to advances in broadening the substrate scope for incorporation into a cross coupling. Extension to less reactive electrophiles such as aryl chlorides [21], phenolates [22], carbon-nitriles [23], and aryl ammonium salts [24] has greatly increased the flexibility for incorporating a...

Table of contents

• Cover
• Title Page
• Copyright
• Preface
• Contributors
• About the Authors
• Chapter 1: Transition Metal Catalysis in the Pharmaceutical Industry
• Chapter 2: Selected Applications of Transition Metal-Catalyzed Carbon–Carbon Cross-Coupling Reactions in the Pharmaceutical Industry
• Chapter 3: Selected Applications of Pd- and Cu-Catalyzed Carbon–Heteroatom Cross-Coupling Reactions in the Pharmaceutical Industry
• Chapter 4: Asymmetric Cross-Coupling Reactions
• Chapter 5: Metathesis Reactions
• Chapter 6: Transition Metal-Catalyzed Synthesis of Five- and Six-Membered Heterocycles
• Chapter 7: Oxidative Catalysis
• Chapter 8: Industrial Asymmetric Hydrogenation
• Index