An Introduction to drug synthesis / Graham L. Patrick.

Enhanced descriptions from Syndetics:

An Introduction to Drug Synthesis explores the central role played by organic synthesis in the process of drug design and development. Written by an experienced and talented author to complement his existing An Introduction to Medicinal Chemistry, the book illustrates how organic synthesis makes important contributions throughout the drug design and discovery process - from the generation of novel drug structures to the improved efficiency of large scale synthesis.Avoiding excessively detailed descriptions of the underlying synthetic pathways, the book focuses on how synthesis can be used in a strategic way - how and why different synthetic approaches are adopted, and the pros and cons of each. With examples used extensively to illustrate the concepts presented, An Introduction to Drug Synthesis is the ideal resource for any pharmaceutical or medicinal chemistry student who needs a thorough understanding of how the concepts of organic synthesis are applied to the development of therapeutic drugs. Online Resource CentreAn Introduction to Drug Synthesis is supported by an Online Resource Centre featuring: For registered adopters:* Figures from the book in electronic format; For students:* A suite of multiple-choice questions to support the learning process;* Additional case studies* More detailed descriptions of key synthetic reactions, as a source of further reference.

Table of contents provided by Syndetics

• Abbreviations and acronyms (p. xv)
• Part A Concepts
• 1 The drag discovery process (p. 3)
• 1.1 Introduction (p. 3)
• 1.2 The pathfinder years (p. 3)
• 1.3 The development of rational drug design (p. 4)
• 1.4 Identification of a drug target (p. 6)
• 1.4.1 Receptors (p. 6)
• 1.4.2 Enzymes (p. 7)
• 1.4.3 Transport proteins (p. 8)
• 1.5 Drug testing and bioassays (p. 9)
• 1.5.1 In vitro tests (p. 9)
• 1.5.2 In vivo bioassays (p. 9)
• 1.5.3 Pharmacokinetics (p. 10)
• 1.6 Identification of lead compounds (p. 14)
• 1.7 Structure-activity relationships and pharmacophores (p. 14)
• 1.8 Drug design (p. 18)
• 1.9 Identifying a drug candidate and patenting (p. 18)
• 1.10 Chemical and process development (p. 18)
• 1.11 Preclinical trials (p. 19)
• 1.12 Formulation and stability tests (p. 19)
• 1.13 Clinical trials (p. 19)
• 1.14 Regulatory affairs and marketing (p. 19)
• 1.14.1 The regulatory process (p. 19)
• 1.14.2 Fast-tracking and orphan drugs (p. 20)
• 1.14.3 Good laboratory, manufacturing, and clinical practice (p. 20)
• 1.15 Conclusion (p. 20)
• 2 Drug synthesis (p. 22)
• 2.1 The role of organic synthesis in the drug design and development process (p. 22)
• 2.2 Structural features that affect the ease of synthesis (p. 22)
• 2.2.1 The molecular skeleton (p. 22)
• 2.2.2 Functional groups (p. 23)
• 2.2.3 Substituents (p. 24)
• 2.2.4 Chiraliry and asymmetric centres (p. 25)
• 2.2.5 Conclusions (p. 26)
• 2.2.6 Exceptions to the rule (p. 27)
• 2.3 Synthetic approaches to drugs (p. 27)
• 2.3.1 Introduction (p. 27)
• 2.3.2 Types of reaction (p. 28)
• 2.4 Coupling reactions involving the formation of N-C bonds (p. 30)
• 2.4.1 N-C coupling reactions resulting in an amide linkage (p. 30)
• 2.4.2 N-C coupling reactions resulting in an amine linkage (p. 30)
• 2.4.3 N-C coupling reactions resulting in an imine linkage (p. 32)
• 2.4.4 Syntheses involving consecutive N-C couplings (p. 32)
• 2.5 Coupling reactions involving the formation of O-C bonds (p. 33)
• 2.5.1 O-C coupling reactions resulting in an ester linkage (p. 34)
• 2.5.2 O-C coupling reactions resulting in an ether linkage (p. 35)
• 2.6 Coupling reactions involving the formation of C-C bonds (p. 35)
• 2.7 Other types of coupling reaction (p. 36)
• 2.8 Syntheses involving different consecutive coupling reactions (p. 37)
• 2.9 Syntheses involving two coupling reactions in one step (p. 39)
• 2.10 Functional group transformations (p. 41)
• 2.10.1 Introducing a functional group in the final product (p. 41)
• 2.10.2 Introducing a functional group for a further coupling reaction (p. 42)
• 2.10.3 Activating a functional group (p. 42)
• 2.11 Functionalization and functional group removal (p. 43)
• 2.11.1 Functionalization (p. 43)
• 2.11.2 Functional group removal (p. 45)
• 2.12 Protection and deprotection (p. 46)
• 2.13 The decision to protect or not (p. 48)
• 2.14 Case Study-Synthesis of dofetilide (p. 54)
• 2.15 Case Study-Synthesis of salbutamol (p. 56)
• 3 Retrosynthesis (p. 61)
• 3.1 Introduction (p. 61)
• 3.2 Disconnections of C-C bonds (p. 61)
• 3.3 Functional group interconversions (p. 63)
• 3.4 Umpolung (p. 65)
• 3.5 Disconnections of carbon-heteroatom bonds (p. 66)
• 3.6 Disconnections of carbon-carbon double bonds (p. 68)
• 3.7 Examples of synthons and corresponding reagents (p. 70)
• 3.8 Protecting groups and latent groups (p. 72)
• 3.9 Molecular signatures (p. 75)
• 3.10 The identification of building blocks (p. 76)
• 3.11 Useful strategies in retrosynthesis (p. 77)
• 3.12 Case Study-Retrosynthetic analysis of haloperidol (p. 80)
• 4 Cyclic system in drug synthesis (p. 85)
• 4.1 Introduction (p. 85)
• 4.2 Carbocycles versus heterocycles (p. 88)
• 4.3 Synthetic strategy (p. 90)
• 4.4 Examples of syntheses using preformed ring systems (p. 91)
• 4.5 Examples of syntheses involving intramolecular cyclizations (p. 92)
• 4.5.1 The Friedel-Crafts reaction (p. 92)
• 4.5.2 Nucleophilic substitution (p. 95)
• 4.5.3 Nucleophilic addition and elimination (p. 97)
• 4.5.4 Nucleophilic addition (p. 98)
• 4.5.5 Palladium-catalysed couplings (p. 98)
• 4.6 Examples of syntheses involving concerted intermolecular cyciizations (p. 98)
• 4.6.1 The Diels-Alder reaction (p. 98)
• 4.6.2 The hetero Diels-Alder reaction (p. 101)
• 4.7 Examples of syntheses involving intermolecular coupling and cyclization reactions (p. 103)
• 4.7.1 Cyclization reactions which insert a one-atom unit into the resulting heterocycle (p. 103)
• 4.7.2 Cyclization reactions involving four reaction centres (p. 106)
• 4.8 Synthesis of dihydropyridines (p. 111)
• 4.9 The Fischer indole synthesis (p. 113)
• 4.10 Enzyme-catalysed cyciizations (p. 115)
• 4.11 Baldwin's rules (p. 115)
• 5 The synthesis of chiral drugs (p. 120)
• 5.1 Introduction (p. 120)
• 5.2 Relevance of chirality to the pharmaceutical industry (p. 122)
• 5.3 Asymmetric synthesis-resolution of racemates (p. 126)
• 5.3.1 Preferential crystallization (p. 126)
• 5.3.2 Chromatography (p. 126)
• 5.3.3 Formation of diastereomeric derivatives (p. 127)
• 5.3.4 Kinetic resolution (p. 128)
• 5.3.5 Asymmetric synthesis of propranolol (p. 130)
• 5.4 Asymmetric syntheses from a chiral starting material (p. 131)
• 5.5 Asymmetric syntheses involving an asymmetric reaction-general principles and terminology (p. 135)
• 5.5.1 Introduction (p. 135)
• 5.5.2 Definition of the re and si faces of a planar prochiral molecule (p. 136)
• 5.5.3 Diastereoselective reactions (p. 137)
• 5.6 Asymmetric reactions using enzymes (p. 140)
• 5.6.1 Natural enzymes (p. 140)
• 5.6.2 Genetically modified enzymes (p. 141)
• 5.7 Asymmetric reactions with an asymmetric starting material (p. 146)
• 5.8 Asymmetric reactions using chiral reagents (p. 149)
• 5.8.1 Introduction (p. 149)
• 5.8.2 Asymmetric hydrogenations with rhodium catalysts (p. 150)
• 5.8.3 The Sharpless epoxidation (p. 153)
• 5.8.4 Other asymmetric reducing agents (p. 154)
• 5.8.5 The asymmetric Strecker synthesis (p. 157)
• 5.9 Examples of asymmetric syntheses (p. 158)
• 5.9.1 Synthesis of modafinil and armodafinil (p. 158)
• 5.9.2 Asymmetric synthesis of eslicarbazepine acetate (p. 160)
• 6 Combinatorial and parallel synthesis (p. 164)
• 6.1 Combinatorial and parallel synthesis in medicinal chemistry projects (p. 164)
• 6.2 Solid phase techniques (p. 165)
• 6.2.1 Introduction (p. 165)
• 6.2.2 The solid support (p. 165)
• 6.2.3 The anchor/linker (p. 166)
• 6.2.4 Examples of solid phase syntheses (p. 167)
• 6.2.5 Protecting groups and synthetic strategy (p. 170)
• 6.3 Testing for activity (p. 170)
• 6.3.1 High throughput screening (p. 170)
• 6.3.2 Screening 'on bead' or 'off bead' (p. 171)
• 6.4 Parallel synthesis (p. 171)
• 6.4.1 Introduction (p. 171)
• 6.4.2 Solid phase extraction (p. 172)
• 6.4.3 The use of resins in solution phase organic synthesis (SPOS) (p. 173)
• 6.4.4 Reagents attached to solid support-catch and release (p. 174)
• 6.4.5 Microwave technology (p. 175)
• 6.4.6 Microfluidics in parallel synthesis (p. 175)
• 6.5 Combinatorial synthesis (p. 178)
• 6.5.1 Introduction (p. 178)
• 6.5.2 The mix and split method in combinatorial synthesis (p. 179)
• 6.5.3 Mix and split in the production of positional scanning libraries (p. 180)
• 6.5.4 Isolating and identifying the active component in a mixture (p. 180)
• 6.5.5 Structure determination of the active compound(s) (p. 185)
• 6.5.6 Dynamic combinatorial synthesis (p. 187)
• 6.5.7 Compound libraries using biological processes (p. 190)
• 6.5.8 Diversity-orientated synthesis (p. 191)
• Case study 1 Peptide synthesis (p. 200)
• Case Study 2 Palladium-catalysed reactions in drug synthesis (p. 211)
• Case Study 3 Synthesis of (-)-huperzine A (p. 221)
• Part B Applications of drug synthesis in the drug development process
• 7 Synthesis of lead compounds (p. 227)
• 7.1 Introduction (p. 227)
• 7.2 Characteristics of a lead compound (p. 228)
• 7.3 Scaffolds (p. 230)
• 7.3.1 Introduction (p. 230)
• 7.3.2 Linear scaffolds (p. 231)
• 7.3.3 Cyclic scaffolds (p. 233)
• 7.3.4 Positioning of substituents on scaffolds (p. 233)
• 7.3.5 Examples of scaffolds (p. 234)
• 7.4 Designing 'drug-like' molecules (p. 236)
• 7.5 Computer-designed libraries (p. 236)
• 7.5.1 Introduction (p. 236)
• 7.5.2 Planning compound libraries (p. 237)
• 7.6 Synthesis (p. 238)
• 7.6.1 Introduction (p. 238)
• 7.6.2 An example of a combinatorial synthesis to create a chemical library (p. 239)
• 7.7 Diversity-orientated synthesis (p. 242)
• 7.8 Fragment-based lead discovery (p. 245)
• 7.9 Click chemistry in lead discovery (p. 247)
• 7.9.1 Click chemistry in the design of compound libraries (p. 247)
• 7.9.2 Click chemistry in fragment-based lead discovery (p. 250)
• 7.9.3 Click chemistry in synthesizing bidentate inhibitors (p. 251)
• 7.10 De novo drug design (p. 252)
• 8 Analogue synthesis in drug design (p. 256)
• 8.1 Introduction (p. 256)
• 8.2 Analogues for SAR studies and pharmacophore identification (p. 259)
• 8.2.1 Introduction (p. 259)
• 8.2.2 Binding roles played by functional groups (p. 259)
• 8.2.3 Relevant analogues for SAR studies (p. 262)
• 8.2.4 Identification of a pharmacophore (p. 264)
• 8.3 Simplification of the lead compound (p. 264)
• 8.4 Drug optimization (p. 268)
• 8.4.1 Improvement of pharmacodynamic properties (p. 268)
• 8.4.2 Improvement of pharmacokinetic properties (p. 269)
• 8.5 Synthesis of analogues from a lead compound (p. 272)
• 8.5.1 Introduction (p. 272)
• 8.5.2 Introduction of substituents involving N-C bond formation (p. 272)
• 8.5.3 Introduction of substituents involving C-O bond formation (p. 276)
• 8.5.4 Introduction of substituents involving C-C bond formation (p. 278)
• 8.5.5 Addition of substituents to aromatic rings (p. 281)
• 8.6 Synthesis of analogues using a full synthesis (p. 282)
• 8.6.1 Diversity steps (p. 282)
• 8.6.2 Linear versus convergent syntheses (p. 284)
• 8.6.3 Preferred types of reaction for diversity steps (p. 284)
• 8.6.4 Development of the anti-asthmatic agent salbutamol (p. 286)
• 8.6.5 Development of the ACE inhibitors enalaprilate and enalapril (p. 287)
• 8.6.6 Development of fentanyl analogues as analgesics (p. 287)
• 8.6.7 Development of the anticancer agent gefitimb (p. 290)
• 9 Synthesis of natural products and their analogues (p. 296)
• 9.1 Introduction (p. 296)
• 9.2 Extraction from a natural source (p. 297)
• 9.3 Semi-synthetic methods (p. 299)
• 9.4 Full synthesis (p. 302)
• 9.5 Cell cultures and genetic engineering (p. 304)
• 9.5.1 Modification of microbial cells (p. 304)
• 9.5.2 Modification of normal host cells (p. 307)
• 9.6 Analogues of natural products (p. 307)
• 9.6.1 Introduction (p. 307)
• 9.6.2 Analogues obtained by biosynthesis/ fermentation (p. 308)
• 9.6.3 Analogues synthesized from the natural product itself (p. 309)
• 9.6.4 Analogues synthesized by fragmenting the natural product (p. 311)
• 9.6.5 Analogues synthesized from biosynthetic intermediates (p. 314)
• 9.6.6 Analogues from related natural products (p. 315)
• 9.6.7 Analogues from genetically modified cells (p. 315)
• 9.6.8 Synthesis of analogues with the aid of genetically modified enzymes (p. 317)
• 10 Chemical and process development (p. 322)
• 10.1 Introduction (p. 322)
• 10.1.1 Chemical development (p. 322)
• 10.1.2 Process development (p. 325)
• 10.1.3 Choice of drug candidate (p. 326)
• 10.1.4 Natural products (p. 326)
• 10.1.5 Green chemistry (p. 326)
• 10.2 Temperature and pressure (p. 327)
• 10.3 Reaction times (p. 328)
• 10.4 Solvents (p. 328)
• 10.4.1 Safety aspects (p. 328)
• 10.4.2 Effect of solvents on impurities and yield (p. 328)
• 10.4.3 Solubility of starting materials and products (p. 329)
• 10.4.4 Solvents to control heating temperatures (p. 330)
• 10.4.5 Effect of polar and non-polar solvents on reactions (p. 330)
• 10.4.6 Effect of concentration (p. 330)
• 10.4.7 Recycling solvents and environmental impact (p. 330)
• 10.5 Reagents (p. 331)
• 10.5.1 Replacing toxic reagents (p. 331)
• 10.5.2 Replacing an expensive reagent (p. 331)
• 10.5.3 Replacing reagents that produce hazardous or 'inconvenient' side products (p. 332)
• 10.5.4 Replacing reagents that have handling difficulties (p. 333)
• 10.5.5 Variation of reagents to improve yield (p. 333)
• 10.5.6 Using a reagent in excess (p. 333)
• 10.5.7 Methods of adding reagents to a reaction (p. 336)
• 10.6 Catalysts and promoters (p. 336)
• 10.7 Methods of increasing the yield of an equilibrium reaction (p. 337)
• 10.8 Troublesome intermediates (p. 337)
• 10.9 Avoiding impurities (p. 339)
• 10.10 Experimental and operational procedures on the large scale (p. 340)
• 10.10.1 Experimental procedure (p. 340)
• 10.10.2 Physical parameters (p. 341)
• 10.10.3 The number of operations in a process (p. 341)
• 10.10.4 Clean technology (p. 341)
• 10.10.5 Minimizing costs (p. 341)
• 10.11 Crystallization (p. 341)
• 10.11.1 Introduction (p. 341)
• 10.11.2 Crystal polymorphism (p. 342)
• 10.11.3 Examples of crystal polymorphs (p. 342)
• 10.11.4 Co-crystals (p. 343)
• 10.12 Synthetic planning in chemical and process development (p. 343)
• 10.12.1 Introduction (p. 343)
• 10.12.2 Cutting down the number of reactions in a route (p. 344)
• 10.12.3 Changing a linear route to a convergent route (p. 348)
• 10.13 Altering a synthetic route for patent reasons (p. 348)
• 10.14 Minimizing the number of operations in a synthesis (p. 351)
• 10.14.1 Introduction (p. 351)
• 10.14.2 One-pot reactions (p. 351)
• 10.14.3 Streamlining operations in a synthetic process (p. 352)
• 10.15 Continuous flow reactors (p. 353)
• 10.16 Case Study-Development of a commercial synthesis of sildenafil (p. 354)
• 11 Synthesis of isotopically tabelled compounds (p. 361)
• 11.1 Introduction (p. 361)
• 11.2 Radioisotopes used in the labelling of compounds (p. 361)
• 11.2.1 Types of radioactive decay (p. 361)
• 11.2.2 Radioactive and biological half-life (p. 351)
• 11.2.3 Commonly used radioisotopes (p. 362)
• 11.2.4 Commonly used stable isotopes (p. 363)
• 11.3 The production of isotopes and labelled reagents (p. 364)
• 11.3.1 Synthesis of radioisotopes and labelled reagents (p. 364)
• 11.3.2 Generation of stable, heavy isotopes and labelled reagents (p. 364)
• 11.4 The synthesis and radiosynthesis of labelled compounds (p. 364)
• 11.4.1 Radiosynthesis (p. 364)
• 11.4.2 Practical issues in radiosynthesis (p. 365)
• 11.4.3 Chemical and radiochemical purity (p. 356)
• 11.4.4 Radiodilution analysis (p. 366)
• 11.4.5 Chemical and radiochemical purity of radiolabelled starting materials (p. 367)
• 11.4.6 Stability of radiolabelled compounds (p. 367)
• 11.4.7 Practical considerations when synthesizing products labelled with heavy isotopes (p. 367)
• 11.4.8 Isotope effects (p. 367)
• 11.5 The use of labelled drugs in drug metabolism studies (p. 367)
• 11.5.1 The importance of studying drug metabolism (p. 367)
• 11.5.2 Synthetic priorities for radiolabelling (p. 368)
• 11.5.3 Incorporation of tritium (p. 368)
• 11.5.4 Incorporation of carbon-14 (p. 370)
• 11.5.5 Incorporation of stable heavy isotopes (p. 370)
• 11.5.6 Case Study-Radiolabelled synthesis of a potential prodrug for ticarcillin (p. 370)
• 11.6 The use of labelled compounds in biosynthetic studies (p. 371)
• 11.6.1 Introduction (p. 371)
• 11.6.2 Double-labelling experiments (p. 372)
• 11.7 The use of radiolabeled compounds in pharmacological assays (p. 374)
• 11.7.1 Detection of receptor distribution in different tissues (p. 375)
• 11.7.2 Detecting whether a ligand binds to a protein target (p. 376)
• 11.7.3 Measurement of binding affinities with a receptor (p. 376)
• 11.7.4 Radioligand binding studies in the study of opioid receptors (p. 377)
• 11.7.5 Radiolabelling experiments to determine whether a receptor ligand acts as an agonist or an antagonist (p. 378)
• 11.8 Isotopically labelled drugs (p. 379)
• 11.8.1 Radioactive drugs (p. 379)
• 11.8.2 Drugs containing stable isotopes (p. 380)
• 11.9 Fragment-based lead discovery (p. 381)
• 11.10 The use of radiolabeled compounds in diagnostic tests (p. 382)
• 11.10.1 Medical imaging with positron emission tomography (PET) (p. 382)
• 11.10.2 Synthesis of radiopharmaceuticals incorporating 18F (p. 382)
• 11.10.3 Examples of lsF-labelled radiopharmaceuticals prepared by nucleophilic substitution (p. 383)
• 11.10.4 Synthetic approaches to 6-[ 18 F]FDOPA (p. 385)
• 11.10.5 Synthesis of radiopharmaceuticals incorporating 11 C (p. 386)
• 11.10.6 Medical imaging with single photon emission computed tomography (SPECT) (p. 388)
• 11.10.7 Synthesis of radiopharmaceuticals incorporating 123 I (p. 388)
• 11.11 Case Study-Synthesis of [2- 14 C]-mupirocin (p. 389)
• 11.11.1 Introduction (p. 389)
• 11.11.2 Retrosynthetic analysis (p. 390)
• 11.11.3 Synthesis of methyl 9-hydroxynonanoate (p. 390)
• 11.11.4 Synthesis of the complex ketone (p. 392)
• 11.11.5 Trial runs of the synthesis of mupirocin (p. 392)
• 11.11.6 Radiolabelled synthesis of mupirocin (p. 392)
• Case Study 4 Studies on gliotoxin biosynthesis (p. 397)
• Case Study 5 Fluorine in drug design and synthesis (p. 406)
• Part C Design and synthesis of selected antibacterial agents
• 13 Design and synthesis of tetracyclines (p. 415)
• 12.1 Naturally occurring tetracyclines (p. 415)
• 12.2 Structure activity relationships-early analogues of natural tetracyclines (p. 416)
• 12.3 Pharmacophore and mechanism of action (p. 420)
• 12.4 Synthesis of semi-synthetic tetracyclines (p. 421)
• 12.5 Full synthesis of tetracyclines (p. 425)
• 12.6 Conclusions (p. 433)
• 13 Erythromycin and macrolide antibacterial agents (p. 435)
• 13.1 Introduction (p. 435)
• 13.2 Synthesis of erythromycin (p. 435)
• 13.3 Erythromycin analogues obtained from semi-synthetic methods (p. 437)
• 13.4 Biosynthesis of erythromycin (p. 439)
• 13.5 Precursor-directed biosynthesis as a means of synthesizing macrocyclic analogues (p. 449)
• 13.6 Conclusions (p. 456)
• 14 Quinolones and fluoroquinolones (p. 458)
• 14.1 Introduction (p. 458)
• 14.2 Mechanism of action (p. 458)
• 14.2.1 Function of topoisomerases (p. 458)
• 14.2.2 Mechanism of inhibition by fluoroquinolones (p. 460)
• 14.3 Properties and SAR (p. 460)
• 14.4 Clinical aspects of quinolones and fluoroquinolones (p. 461)
• 14.5 Synthesis of quinolones and fluoroquinolones (p. 462)
• 14.5.1 Introduction (p. 462)
• 14.5.2 Syntheses involving a Friedel-Crafts acylation (p. 462)
• 14.5.3 Syntheses involving nucleophilic substitution of an aryl halide (p. 463)
• 14.5.4 Tricyclic ring systems incorporating a quinolone ring system (p. 467)
• 14.6 Quinolones as scaffolds for other targets (p. 470)
• Appendix 1 Functional group transformations (p. 473)
• Appendix 2 Functionalization (p. 487)
• Appendix 3 Removal of functional groups (p. 489)
• Appendix 4 Coupling reactions involving carbon-heteroatom bond formation (p. 491)
• Appendix 5 Coupling reactions involving carbon-carbon bond formation (p. 495)
• Appendix 6 Protecting groups (p. 512)
• Appendix 7 Structures of amino acids (p. 517)
• Glossary (p. 518)
• Index (p. 543)

Author notes provided by Syndetics