The Art of Process Chemistry E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 424

Veröffentlichungsjahr: 2010

Beschreibung

Providing must-have knowledge for the pharmaceutical industry and process chemists in industry, this ready reference offers solutions for saving time and money and supplying -- in a sustainable way -- valuable products. Application-oriented and well structured, each chapter presents successful strategies for the latest modern drugs, showing how to provide very fast bulk quantities of drug candidates. Throughout, the text illustrates how all the key factors are interwoven and dependent on one another in creating optimized methods for optimal products.

Leseprobe

Table of Contents

Cover

Table of Contents

Half title page

Related Titles

Title page

Copyright page

Preface

List of Contributors

1 Efavirenz®, a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), and a Previous Structurally Related Development Candidate

1.1 First Drug Candidate 2

1.2 Efavirenz®

1.3 Conclusion

Acknowledgments

2 CCR5 Receptor Antagonist

2.1 Project Development

2.2 Chemistry Development

2.3 Conclusion

Acknowledgments

3 5α-Reductase Inhibitors – The Finasteride Story

3.1 Project Development

3.2 Chemistry Development

3.3 Conclusion

Acknowledgments

4 Rizatriptan (Maxalt®): A 5-HT1D Receptor Agonist

4.1 Project Development

4.2 Chemistry Development

4.3 Conclusion

Acknowledgments

5 SERM: Selective Estrogen Receptor Modulator

5.1 Project Development

5.2 Chemistry Development

5.3 Conclusion

Acknowledgments

6 HIV Integrase Inhibitor: Raltegravir

6.1 Project Development

6.2 Further Chemistry Development

6.3 Conclusion

Acknowledgments

7 Cyclopentane-Based NK1 Receptor Antagonist

7.1 Project Development Compound 1

7.2 Chemistry Development

Acknowledgments

8 Glucokinase Activator

8.1 Project Development

8.2 Chemistry Development

8.3 Conclusion

Acknowledgments

9 CB1R Inverse Agonist – Taranabant

9.1 Project Development

9.2 Further Project Development

9.3 Conclusion

Acknowledgments

Index

Edited by

Nobuyoshi Yasuda

The Art of Process Chemistry

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The Editor

Dr. Nobuyoshi Yasuda

Process Research Department

Merck & Co. Inc.

126, E. Lincoln Ave.

Rahway, NJ 07065

USA

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© 2011 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

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Cover Design Grafik-Design Schulz, Fußgönheim

ISBN: 978-3-527-32470-5

ISBN: 978-3-527-63358-6 (ebk)

Preface

What is the definition of “Art”? According to Wikipedia, “Art is the process or product of deliberately arranging elements in a way that appeals to the senses or emotions.”

Music is one of the great art forms and provides listeners powerful emotions by twisting all ranges of human feelings, from earthy to heavenly and from physics to metaphysics. However, this principal applies in many human activities. When the appeal of a subject to the senses or emotions increases beyond a certain threshold, people find beauty in it and it becomes “Art”. For example, when Olympic athletes run in a 100 meter race, we feel the excitement of their performance and we sense the amazing movements of the human body, finding beauty in them. That is “Art”.

Of course, this definition can be applied to science and technology as well. In another example, as the shape of automobiles becomes more streamlined to increase speed, it becomes more attractive and awakens our emotions as we find beauty in it. Many people find beauty even inside the car.

All of this is also true of organic synthesis. As syntheses become highly innovative, creative and effective, the syntheses gain appeal to the senses and emotions of chemists who find beauty in them. In that moment, organic synthesis becomes “Art”.

It is logical to discover “Art” more frequently at the frontier of science, where most innovation and creativity takes place. For organic synthesis, pharmaceutical research is on one of the frontiers. In pharmaceutical research laboratories, synthetic organic chemistry plays a major role in two departments, namely Medicinal and Process Chemistry.

The objective for Medicinal Chemistry is the identification of the chemical structures for potential new medicines. Eventually, these new medicines will be launched into the market to address unmet medical needs and to improve the quality of life for all human beings. The marketing of new medicines is the lifeblood of the pharmaceutical industry. Due to the broad impact Medicinal Chemistry has in the drug discovery process, it is recognized as a top job for synthetic organic chemists.

To prepare the target compounds, Medicinal Chemists leverage their knowledge and skill in synthetic organic chemistry, but an understanding of pathology, pharmacology, and physiology are also important for making decisions on which compounds should be evaluated. Currently, Medicinal Chemists prepare small amounts of new chemicals for bio-assays and ADME (absorption, distribution, metabolism, and excretion) studies to identify the drug candidates through quantitative structure–activity relationships, and so on. With the advancement of computational biochemistry, we can imagine a time when Medicinal Chemists may only need to visualize chemical structures for in silico tests rather than prepare real substances for in vivo and/or in vitro studies. For the Medicinal Chemist, synthetic organic chemistry is only one of many competencies for their job.

The objective for Process Chemistry is to establish clean cost-effective manufacturing processes for new medicines identified by Medicinal Chemistry in a timely manner. At an absolute minimum, the reproducibility of the process and the quality of the final products has to meet established standards, such as the ICH guidelines.

To reach the ultimate goal, a process chemist seeks to reduce manufacturing costs of medicines and ensure the speed of supply of drug candidates to facilitate the drug discovery and development processes.

How does the Process Chemist reduce manufacturing cost? Manufacturing cost is made up of two components: operational cost and raw material cost. Operational cost consists of redemption of capital equipment, labor cost, overhead, vendor’s profits, and so on. Reducing the number of chemical steps in a process is directly tied to lower operational costs. A more convergent synthetic route is generally more efficient than a linear route. Keeping this in mind, details such as reaction time and work-up time (the so-called overall cycle time) are additional factors which affect the operational cost. Another important contributor to operational cost is associated with waste disposal. All waste from manufacturing processes must be disposed of properly. In order to protect our environment, the enforcement of laws regarding waste disposal is becoming more stringent with time and waste disposal cost is expected to increase year by year. Therefore, the concept of “Green Chemistry” is critical to modern Process Chemistry. The most straightforward solution to reduce the waste disposal cost is reduction of the amount of waste from a manufacturing process. The relative amount of waste versus product generated is measured by either the e-factor or PMI (process mass intensity). These indicators are critical benchmarks for the Process Chemist. Use of hazardous reagents not only costs more for their proper disposal but also adds more burden to analysis of products to ensure the quality of products under ICH guidelines. Again, this all leads to increased operational cost.

Lowering the starting material costs can be achieved by improving overall yield. The higher the overall yield, the less starting materials are required and the lower the raw materials cost. Furthermore, Process Chemists must collaborate with a procurement department to lower the supply cost. If the raw materials could be prepared in a simple process from commodity chemicals, in the long term, the raw material cost would simply depend on material demands. If demand is created, the price of the raw material can fall dramatically. One good example of these phenomena is the price of tert-butyldimethylsilyl chloride. Today, it is a common reagent available at very affordable prices. This low price is due to the high demand for acetoxyazetidinone, the key starting material for several carbapenem antibiotics.

Moreover, the Process Chemist can also have a major impact on supply cost through the development of better synthetic methods. This research by Process Chemists can impact the cost of raw materials.

Evidently, to create the most cost efficient process, the process chemist must utilize the most advanced organic chemistry, if not devise new transformations, to address all these competing concerns.

How does the Process Chemist ensure speed of drug candidates to facilitate the drug discovery and development processes? In the big picture, this objective could also be closely related to cost. To support all preclinical and clinical studies, including Phase I to III studies, the Process Chemist must prepare drug candidates under GMP guidelines. Timing for delivery of a drug candidate is critical for the development timeline. If the drug candidate is supplied earlier, it can be marketed sooner, resulting in benefits to patients as well as the company. The patent life of a new drug starts when a patent from Medicinal Chemistry is filed. The sooner the delivery is made, the faster clinical studies can be completed and the longer the patent coverage of the medicine during the marketing phase. If the development of the candidate is terminated early for any reason, the pharmaceutical company can avoid spending additional, unnecessary developmental costs. Thus, the quicker the supply of the drug candidate is available, the more cost effective the project.

What does “quicker” mean in terms of drug supply? How can the Process Chemist provide a drug candidate more quickly? Is it good enough to scale up the original Medicinal Chemistry route, despite problems with length or cost, simply because it has been demonstrated on a small scale? The answer differs from case to case. The Process Chemist must have keen chemical insight into which route could be suitable for optimization and which could be a potential manufacturing route. Time and effort spent on optimization of unsuitable routes are practically meaningless – a waste of resources. To conserve resources, this judgment should be made in a very short period of time, balancing short term goals and longer ones. This critical judgment clearly depends on the quality of organic chemists.

As this discussion makes clear, the demands of the drug development process for the Process Chemist are quite different from those of the Medicinal Chemist. The role of Process Chemistry is to devise and fully understand the most cost efficient total syntheses of new medicines with the most advanced methodologies. By far, synthetic organic chemistry is the most important skill for a Process Chemist. Synthetic organic chemistry impacts all parts of the job and guides all decision making in Process Chemistry. In a way, there is little difference between a Process Chemist in industry and a Synthetic Organic Chemist in academia. On a scientific level, their goals are the same and, therefore, Process Chemists must be innovative Synthetic Organic Chemists, striving for new, more efficient chemistry.

In this book, there are nine chapters, each of which is devoted to the syn­thetic chemistry of one candidate project. Some of these molecules have already become marketed drugs. Each chapter consists of two parts which reflects the two fundamental roles of Process Chemistry; the establishment of cost effective process and the discovery of new more effective chemistry. In Section 1 of each chapter, titled “Project Development”, the author(s) will discuss the first phase of Process Chemistry research. In each chapter, the Medicinal Chemistry route to the target compound is analyzed. To overcome the potential problems of this Medicinal Chemistry route, the original route can be optimized, new routes can be considered or some novel chemical transformations can be proposed. The shape of the process route may evolve depending on where the drug candidate is in the drug development process. Some chapters describe the manufacturing processes of marketed medicines. The process is reshaped to meet the ultimate goal of the drug development program. Through this optimization, innovations in the process will raise the synthesis to the level of “Art”.

As stated previously, these activities are only part of the job of the process chemist. As described in Section 2 of each chapter, titled “Chemistry Development”, the author(s) will focus on the advancement of synthetic organic chemistry discovered during the process development. In order to satisfy the Process Chemist’s scientific curiosity and to advance synthetic organic chemistry, further optimization followed by investigation of the scope and limitations of these reactions is explored. In order to ensure the robustness of the reaction and to optimize it in a more scientific way, elucidation of the reaction mechanism is undertaken. Mechanistic studies are very beneficial in improving our synthetic organic chemistry skills and provide opportunities to raise these reactions to a further dimension, again that of “Art”.

In recent years, the rate of change in the pharmaceutical industry has accelerated dramatically. Declining revenue growth due to patent expirations and the lower success rate for new medicines has forced the industry to make cost efficiency a top priority. Tighter research and development budgets may seem restrictive at first glance but have provided the opportunity to reshape research, making it more efficient. By further driving new research to higher levels of efficiency, the research becomes a form of “Art”.

This book is quite unique in addressing the major objectives of Process Chemistry in every chapter in two aspects. Please enjoy the projects described herein which I believe have attained the status of “Art”.

Nobuyoshi Yasuda

May 2010

List of Contributors

Cheng Chen

Guy R. Humphrey

Artis Klapers

Jeffrey T. Kuethe

Zhiguo Jake Song

Lushi Tan

Debra Wallace

Nobuyoshi Yasuda

Yong-Li Zhong

Merck Research Laboratories

Process Research

P.O. Box 2000

Rahway, NJ 07065

USA

Michael J. Williams

Merck Research Laboratories

Process Research

770 Sumneytown Pike

P.O. Box 4

West Point, PA 19468

USA