Retrosynthesis in the Manufacture of Generic Drugs Selected Case Studies

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.

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.

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI

A note about the book and its use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XIII

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XV

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 process for Escitalopram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

4.12.3 Diol as a key intermediate in Escitalopram synthesis . . . . . . . . . . . . . . . . . . . . . . 115

4.12.4 Resolution of Citalopram and desmethyl analogues . . . . . . . . . . . . . . . . . . . . . . 119

4.12.5 Recovery of DPTTA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

4.12.6 Recycling of unwanted R-isomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

4.12.7 Key Diels-Alder cycloaddition in the synthesis of Escitalopram . . . . . . . . . . . . . 122

4.12.8 Escitalopram by asymmetric synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

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

5.2.1 Disconnecting the heterocycle first . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

5.2.2 Retrosynthetic analysis starting by transformation of the chiral amine . . . . . . . . . 146

5.2.3 Retrosynthetic analysis starting from haloaromatic ring . . . . . . . . . . . . . . . . . . . . 147

5.2.4 Retrosynthesis analysis summary and most efficient routes . . . . . . . . . . . . . . . . . . 147

5.3 The first reported Sitagliptin synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

5.4 The search for an industrial synthesis for Sitagliptin . . . . . . . . . . . . . . . . . . . . . . . . . . 149

5.4.1 Coupling the triazolopyrazine heterocycle at the end of the synthesis:

producing a key chiral β-amino acid intermediate . . . . . . . . . . . . . . . . . . . . . . . . . 151

5.4.2 Producing the chiral amine during the final stages of the synthesis . . . . . . . . . . . 168

5.4.3 Synthesis of Sitagliptin by attaching the 2,4,5-trifluorophenyl ring at the end

of the synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

5.4.4 Triazolopyrazine synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

5.5 Strategy comparison and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

5.5.1 Main strategies for asymmetric synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

5.5.2 The relative positions of the asymmetric step and the amide forming coupling

reaction in route selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

5.5.3 Preferred routes for the synthesis of Sitagliptin . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

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

6.2.1 The azetidin-2-one ring formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

6.2.2 Key structural features for the retrosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

6.2.3 Retrosynthesis using the Staudinger cycloaddition for the azetidin-2-one

synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

6.2.4 Retrosynthesis using the Kinugasa reaction to produce the azetidin-2-one . . . . . . 213

6.2.5 Retrosynthesis using a N to C2 ring closure to produce the azetidin-2-one . . . . . . 214

6.2.6 The (S)-hydroxyl benzylic group of Ezetimibe . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

6.2.7 Summary of the retrosynthesis analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

6.3 The first Ezetimibe syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

6.4 The search for an industrial synthesis of Ezetimibe . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

6.4.1 The synthesis of the C5 chain intermediates and the imines . . . . . . . . . . . . . . . . . 221

6.4.2 Using the Staudinger reaction in the azetedin-2-one ring formation . . . . . . . . . . 224

6.4.3 The Wacker oxidation route . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

6.4.4 The search for a selective β-lactam formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

6.4.5 Using Kinugasa cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

6.4.6 N-C2 ring closing strategy and the build-up sequence . . . . . . . . . . . . . . . . . . . . . . 230

6.4.7 N-C2 ring closure strategy: late attachment of the p-fluoroaromatic ring . . . . . . 231

6.4.8 N-C2 ring closure strategy: attaching the p-fluoroaromatic ring

at the beginning of the synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

6.4.9 N-C2 ring closing strategy: implementing the reduction at the beginning

of the route . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

6.4.10 Ezetimibe by alkylation of a C3 unsubstituted β-lactam . . . . . . . . . . . . . . . . . . . 252

6.4.11 Other β-lactam ring formations by N-C4 cyclization . . . . . . . . . . . . . . . . . . . . . . 254

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

7.2.1 Chirality issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277

7.2.2 The thiol side chain and the enantioselectivity of the synthetic process . . . . . . . . 278

7.2.3 Retrosynthetic analysis of the thiol side chain . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

7.3 Retrosynthetic outline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

7.4 The first reported Montelukast synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

7.5 The evolution of industrial chemical syntheses of Montelukast . . . . . . . . . . . . . . . . . 283

7.5.1 Processes to produce keto-ester intermediate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

7.5.2 Processes to convert the keto-ester intermediate to Montelukast . . . . . . . . . . . . . . 286

7.5.3 Montelukast synthesis using an incomplete thiol for the SN2 displacement . . . . . . 290

7.5.4 Montelukast synthesis using a Heck reaction as a key step . . . . . . . . . . . . . . . . . . 292

7.5.5 Montelukast synthesis using a carbonyl olefination reaction as a key step . . . . . . 294

7.5.6 Montelukast synthesis using a Michael addition as a key step . . . . . . . . . . . . . . . . 297

7.6 Synthesis of the thiol side chain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

7.6.1 Electrophilic side chain reactants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301

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

8.2.1 Starting material targeted retrosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

8.2.2 Retrosynthetic strategies of the Oseltamivir cyclohexene ring . . . . . . . . . . . . . . . . 324

8.2.3 Retrosynthetic analysis summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

8.3 The first reported Oseltamivir synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331

8.4 Routes from shikimic acid or quinic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332

8.4.1 First developments from shikimic acid or quinic acid . . . . . . . . . . . . . . . . . . . . . . 333

8.4.2 Azide free routes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

8.4.3 Other routes from (–)-shikimic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338

8.5 The supply problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342

8.5.1 Quinic and shikimic acid supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342

8.6 First non-shikimic or quinic acid synthetic routes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

8.6.1 The Diels-Alder furan approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

8.6.2 Oseltamivir by total hydrogenation of an aromatic ring . . . . . . . . . . . . . . . . . . . . . 343

8.7 Synthesis of Oseltamivir from cyclohexadiene derivatives . . . . . . . . . . . . . . . . . . . . . . 344

8.7.1 Meso aziridines desymmetrization routes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

8.7.2 Using iron diene carbonyl complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345

8.7.3 From cyclohexa-3,5-diene-1,2-diol derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347

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

8.8.1 Using a [4+2] cycloaddition to produce a trisubstituted six-membered

ring adduct . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350

8.8.2 Using a [4+2] cycloaddition to produce a monosubstituted six-membered

ring adduct . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356

8.8.3 Alternative syntheses for the Corey intermediate . . . . . . . . . . . . . . . . . . . . . . . . . . 356

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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