Pedro Paulo Santos, William Heggie

Retrosynthesis in the Manufacture of Generic Drugs

Selected Case Studies

• Gebundenes Buch

Produktbeschreibung

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: https://www.wiley.com/go/santos/retrosynthesis

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.

Produktdetails

• Verlag: Wiley / Wiley & Sons
• Artikelnr. des Verlages: 1W119155530
• 1. Auflage
• Seitenzahl: 432
• Erscheinungstermin: 9. November 2020
• Englisch
• Abmessung: 288mm x 222mm x 28mm
• Gewicht: 1384g
• ISBN-13: 9781119155539
• ISBN-10: 1119155533
• Artikelnr.: 59963269

Autorenporträt

Pedro Paulo Santos, PhD, is Professor in Organic Chemistry at Universidade de Lisboa. He collaborates with Portuguese pharmaceutical companies--supporting the development and launching of new generic drugs and in auditing of plants, synthetic processes, and DMFs. As a patent expert and witness, he has been involved in more than 50 court litigation processes referring to more than 30 different APIs. Dr Santos also published two textbooks and one exercise book covering the basic organic chemistry. William Heggie, PhD, was the Chief Scientist at Hovione before his retirement. He is author of more than 25 patents dealing with various aspects of process chemistry for the production of drug substance together with several other scientific publications. He has more than 30 years' experience designing, developing, and overseeing chemical processes from laboratory through pilot to industrial scale and developed more than 20 processes for drug substances, both Generics and NCEs.

Inhaltsangabe

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

2.2.1 Using the primary amine for retrosynthesis 7

2.2.2 Rearrangement as a key synthetic step: taking advantage of symmetrical intermediates 8

2.2.3 Avoiding the rearrangement and obtaining the amine by a reduction step 10

2.2.4 Disconnecting only one carbon chain from the cyclohexane ring 10

2.2.5 Using an aromatic ring to produce the saturated cyclohexane ring 11

2.3 The first reported synthesis of gabapentin 13

2.4 The evolution of the chemical synthesis of gabapentin 14

2.4.1 Initial development of synthetic routes to Gabapentin using a rearrangement step 14

2.4.2 Routes to the spiro-anhydride or spiro-imide intermediates 16

2.4.3 Synthetic routes of Gabapentin using a one carbon atom nucleophile 18

2.4.4 The 1,4-dicarbonyl intermediate routes 23

2.4.5 Synthetic processes based on a Birch reduction 25

2.4.6 Re-visiting the rearrangement as a key step 26

2.4.7 Other synthetic routes 26

2.4.8 Purifying the product 27

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

3.2.1 Chirality and Clopidogrel 41

3.2.2 Retrosynthetic analysis 44

3.3 The first reported synthesis of Clopidogrel 49

3.4 The evolution of chemical synthesis of Clopidogrel 50

3.4.1 Synthetic routes using a resolution step 50

3.4.2 Asymmetric synthesis in Clopidogrel production 66

3.4.3 Other synthetic processes 67

3.4.4 Synthesis of the Thiophene building block 69

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

4.3.1 Disconnection of the propylamine side chain 88

4.3.2 The aromatic nitrile group 89

4.3.3 Retrosynthesis of the trisubstituted aromatic intermediate 89

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

4.8.1 Two Grignard route using 5-bromophthalide as starting material 98

4.8.2 Two Grignard route using 5-cyanophthalide as starting material 102

4.8.3 Coupling the hydrofuran ring formation with the second Grignard reaction 103

4.8.4 A two Grignard route not using 3-dimethylamino propyl Grignard 103

4.8.5 Phthalide synthesis 104

4.8.6 The non-Grignard C3 nucleophilic route 105

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

4.12.1 The chiral switch 113

4.12.2 The first proce