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Retrosynthesis in the Manufacture of Generic Drugs. Selected Case Studies. Edition No. 1

  • ID: 5179027
  • Book
  • December 2020
  • 432 Pages
  • John Wiley and Sons Ltd
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Offers a compendium of information on retrosynthesis and process chemistry, featuring innovative "reaction maps" showing synthetic routes of some widely used drugs

This book illustrates how the retrosynthetic tool is applied in the Pharmaceutical Industry. It considers and evaluates the many viable synthetic routes that can be used by practicing industrialists, guiding readers through the various steps that lead to the "best" processes and the limits encountered if these are put into practice on an industrial scale of seven key Active Pharmaceutical Ingredient (API). It presents an evaluation of the potential each process has for implementation, before merging the two points of view - of retrosynthesis and process chemistry - in order to show how retrosynthetic analysis assists in selecting the most efficient route for an industrial synthesis of a particular compound whilst giving insight into the industrial process. The book also uses some key concepts used by process chemists to improve efficiency to indicate the best route to select.

Each chapter in Retrosynthesis in the Manufacture of Generic Drugs Selected Case Studies is dedicated to one drug, with each containing information on: worldwide sales and patent status of the Active Pharmaceutical Ingredient (API); structure analysis and general retrosynthetic strategy of the API; first reported synthesis; critical analysis of the processes which have been developed and comparison of the synthetic routes; lessons learned; reaction conditions for Schemes A to X; chemical "highlights" on key reactions used during the synthesis; and references. Drugs covered include: Gabapentin, Clopidogrel, Citalopram and Escitalopram, Sitagliptin, Ezetimibe, Montelukast, and Oseltamivir. 

  • Show how the retrosynthetic tool is used by the Pharmaceutical Industry
  • Fills a gap for a book where retrosynthetic analysis is systematically applied to active pharmaceutical ingredients (APIs)
  • Features analyses and methodologies that aid readers in uncovering practical synthetic routes to other drug substances, whether they be NCEs (New Chemical Entities) or generic APIs (Active Pharmaceutical Ingredients)
  • Presents information from both the patent and academic literature for those who wish to use as a basis for further study and thought
  • Features the use of "reaction maps" which display several synthetic processes in the same scheme, and which allow easy comparisons of different routes that give the same molecule or intermediate.
    A selection of these maps are available to download from: [external URL]

Retrosynthesis in the Manufacture of Generic Drugs Selected Case Studies is an ideal book for researchers and advanced students in organic synthetic chemistry and process chemistry. It will also be of great benefit to practitioners in the pharmaceutical industry, particularly new starters, and those new to process chemistry.

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Preface XV

A note about the book and its use XVII

Abbreviations XIX

1 Introduction 1

2 GABAPENTIN 5

2.1 Worldwide sales and patent status 6

2.2 Gabapentin structure and general retrosynthetic strategy 7

2.3 The first reported synthesis of gabapentin 13

2.4 The evolution of the chemical synthesis of gabapentin 14

2.5 Strategy comparison and conclusions 28

2.6 Lessons from the gabapentin case 29

2.7 Reaction conditions for schemes A to D 31

2.8 References 34

3 CLOPIDOGREL 39

3.1 Worldwide sales and patent status 40

3.2 Clopidogrel structure and general retrosynthetic strategy 41

3.3 The first reported synthesis of Clopidogrel 49

3.4 The evolution of chemical synthesis of Clopidogrel 50

3.5 Strategy comparison and conclusions 71

3.6 Lessons from the Clopidogrel case 73

3.7 Reaction conditions for schemes C to J 73

3.8 References 78

4 CITALOPRAM AND ESCITALOPRAM 85

4.1 Worldwide sales and patent status 86

4.2 Escitalopram/Citalopram structure 87

4.3 Retrosynthetic analysis of Citalopram 88

4.4 Escitalopram retrosynthesis 93

4.5 The first reported synthesis of Citalopram 95

4.6 The evolution of chemical synthesis of Citalopram 96

4.7 A quick glimpse of Escitalopram 97

4.8 The two Grignard phase in Citalopram synthesis 98

4.9 The phthalane route - alkylation of a phthalane with an electrophilic side chain 107

4.10 Other synthetic routes to Citalopram 112

4.11 Strategy comparison and conclusions for the synthesis of Citalopram 113

4.12 The evolution of Escitalopram synthesis 113

4.13 Best processes for Escitalopram 126

4.14 Lessons from the Citalopram/Escitalopram case 127

4.15 Reaction conditions for schemes A to H 128

4.16 References 135

5 SITAGLIPTIN 141

5.1 Worldwide sales and patent status 142

5.2 Sitagliptin structure and general retrosynthetic analysis 143

5.3 The first reported Sitagliptin synthesis 149

5.4 The search for an industrial synthesis for Sitagliptin 149

5.5 Strategy comparison and conclusions 184

5.6 Lessons from the Sitagliptin case 189

5.7 Reaction conditions for schemes A to J 191

5.8 References 200

6 EZETIMIBE 207

6.1 Worldwide sales and patent status 208

6.2 Ezetimibe structure and general retrosynthetic analysis 209

6.3 The first Ezetimibe syntheses 219

6.4 The search for an industrial synthesis of Ezetimibe 221

6.5 Comparison of strategies and conclusions 255

6.6 The best syntheses 259

6.7 Lessons from the Ezetimibe case 261

6.8 Reaction conditions for schemes A to M 262

6.9 References 269

7 MONTELUKAST 275

7.1 Worldwide sales and patent status 275

7.2 Montelukast structure and general retrosynthetic analysis 277

7.3 Retrosynthetic outline 279

7.4 The first reported Montelukast synthesis 282

7.5 The evolution of industrial chemical syntheses of Montelukast 283

7.6 Synthesis of the thiol side chain 297

7.7 Strategy comparison and conclusions 301

7.8 Lessons from the Montelukast case 305

7.9 Reaction conditions for schemes A to F 307

7.10 References 312

8 OSELTAMIVIR 319

8.1 Worldwide sales and patents status 320

8.2 Oseltamivir structure and general retrosynthetic analysis 321

8.3 The first reported Oseltamivir synthesis 331

8.4 Routes from shikimic acid or quinic acid 332

8.5 The supply problem 342

8.6 First non-shikimic or quinic acid synthetic routes 343

8.7 Synthesis of Oseltamivir from cyclohexadiene derivatives 344

8.8 Building the carboxylic ring of Oseltamivir by a Diels-Alder reaction 350

8.9 Oseltamivir ring by a [3,3] sigmatropic rearrangement 360

8.10 Oseltamivir synthesis by a Michael addition-Horner-Wadsworth-Emmons cascade sequence 360

8.11 Aldol type condensations as key ring-forming step 365

8.12 Metathesis as key-ring forming step 365

8.13 Strategy comparison and conclusions 374

8.14 Lessons from the Oseltamivir case 378

8.15 Reaction conditions for schemes B to R 378

8.16 References 390

9 A Final Word 395

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William Heggie
Pedro Paulo Santos
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