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Active Pharmaceutical Ingredients in Synthesis: Catalytic Processes in Research and Development, First Edition. Anthony J. Burke.© 2018 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2018 by Wiley-VCH Verlag GmbH & Co. KGaA.

aabacavir 393–394abiraterone acetate 202ABT‐239 226ABT‐450 272–273ABT‐493 272–273ABT‐546 158–1592‐acetamido‐5‐bromopyridine 189active pharmaceutical ingredients

(APIs)1,2‐addition reactions 1471,4‐addition reactions 291asymmetric hydrogenation

reaction 14asymmetric synthetic methods 11bicyclic β‐lactams 12biotransformation 20carbonic anhydrase inhibitor 20carbonyl groups 13catalytic synthesis 20CBS reduction 15cycloaddition reactions 291cyclopropanation reaction 11homogeneous catalytic

hydrogenation 12Jacobsen–Katsuki epoxidation 15Merck’s synthesis 12Mizoroki–Heck reaction 18multi‐functional groups and

stereocenters 11Ru catalyst 13Ru‐I‐SegPhos catalyst 13Sharpless–Katsuki epoxidation 16Sharpless–Katsuki system 17

sulphide asymmetric oxidation 18acyclovir 3941,2‐addition reactions

acetalization 154asymmetric catalytic aldol

reaction 154AZD5423 synthesis 156C–C bond formation 148Cu‐catalyzed asymmetric

addition 148(+)‐discodermolide 150enantioenriched alcohols 149FR901512 synthesis 150halichondrins 150HIV‐1 protease inhibitors 152NHK reactions 150(+)‐preussin 156(R)‐salmeterol 154(R)‐tembamide 155saturated alcohols/dienes 149

1,4‐addition reactionsABT‐546 158arylboron species 160conjugate addition/dehydrative

cyclization reaction 161continuous flow processes 162dinoprost and tafluprost 159(–)‐epibatidine 170erogorgiaene 168HVC drug development 167(–)‐paroxetine 163prostaglandins 165(R)‐ and (S)‐rolipram 164telcagepant 169

Index

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Index416

1,4‐addition reactions (contd.)warfarin 162Zn‐catalyzed diastereoselective

Michael reaction 164adrenaline 85ALB 109780 218–219alcohol dehydrogenases (ADHs) 394aliskiren 23, 79–80, 275–277alkenes, enamides 77allylic substitution reactions 234almorexant (ACT‐078573A) 93α‐amino acids 393(S)‐α‐aminoindane synthesis 392α‐arylenol acetates 82α‐chiral aldehyde 408α‐chloro ketone 397(–)‐α‐conidendrin 355–356α,β‐unsaturated carboxylic acids 409α‐diazoketone derivative 333α‐diazo‐β‐keto sulfones 337(+)‐ambruticin 302–303(+)‐ambruticin S 331, 333–334AMG 925 219–220amino acid dehydrogenases

(AADH) 4107‐aminocephalosporinic acid (7‐

APA) 400anacetrapib 239–240anastrozole 362, 363angiotensin II receptor blockers

(ARBs) 240aperidine 348aprepitant 82–83, 91, 94, 395AR‐A2 211–212Armidex® 362aryl bromide 1914‐aryl‐n‐butyraldehyde 1823‐aryloxy‐2‐propanolamines 389AstraZeneca 188asymmetric Michael reaction 158atorvastatin 393, 397–398ATSP-7041 279, 281avitriptan 62–63axitinib 57–59, 190–191aza‐diketopiperazines (aza‐DKPs) 102AZD1480 64–65AZD3409 188–189

AZD5423 156–157AZD8926 139, 140, 248–249azomethine ylides 302–304

bbaclofen 162, 347–348, 398–399balanol 283–284bendamustine hydrochloride 106benzoxazole 2454‐benzyloxy‐propiophenone 368benzyne dienes 296berberine bridge enzyme (BBE) 404β2‐adrenergic receptor agonists 91β‐aminoacrylate analogs 78β‐blockers 389β‐keto ester 237β‐lactams 400bicyclic β‐lactams 12BI-201302 272–273BILN‐2061 55, 272, 376bimatoprost 160, 293biocatalysis

attributes of 387C–X bond formation

α‐chiral aldehyde 408α,β‐unsaturated carboxylic

acids 409DERA catalyses 403enantioselective cyanohydrin

synthesis 405ephedrine and pseudo‐ephedrine

synthesis 404glasdegib 407halohydrin dehalogenase

(HHD) 410levomilnacipran synthesis 404niraparib 407ω‐transaminases 406vernakalant via reductive

amination 409zanamavir synthesis 402

hydrolysis and reverse hydrolysis(S)‐α‐aminoindane 392β‐blockers (S)‐propanolol

synthesis 389Candida antarctica lipase B

(CAL‐B) 388

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Index 417

cephalexin 390γ‐amino acids 393glutaryl acylase 391naproxen synthesis 389(S)‐1‐phenylethylamine 391ramipril 390valaciclovir via transesterification

synthesis 394industrial application 387oxidation 399reduction 394

Biotage 33bis‐tetrahydrofuranyl (bis‐THF)

moiety 152BMS-180048 62BMS‐247243 195BMS‐986097 167–168boceprevir 399–400boomerang catalysts 35Bosch, Carl 3BRL 55834 116–1172‐bromo‐6‐methoxynaphthalene 176bromonaphthalene

derivative 2141‐(4‐bromophenyl)‐2,2,2‐

trifluoroethanone 2033‐bromoquinoline 194Bruton’s tyrosine kinase (BTK)

inhibitor 206Buchwald–Hartwig reaction

ALB 109780 synthesis 218(R)‐3‐aminopentanenitrile 210AstraZeneca’s synthesis 211bromonaphthalene

substrate 212CCK 1R receptor agonist 213cholecystokinin (CCK) 1R receptor

agonist 212copper catalysts 210Cu‐Catalyzed C–N coupling

reaction 2158‐hydroxyquinoline 220macrocyclic integrase

inhibitor 223–224Pd‐Catalyzed amination

reaction 214buphenine 269, 368

ccandesartan cilexetil 240–241Candida antarctica lipase B

(CAL‐B) 25, 388cannabinoid‐1 receptor (CB1R) 216carbonyl groups 84carbonyls 133carbonyl ylides 307catalysis and prerequisites

API synthesis developments 2asymmetric

cis‐dihydroxylation 16asymmetric hydrogenation

reaction 14asymmetric synthetic methods 11bicyclic β‐lactams 12biotransformation 20carbonic anhydrase inhibitor 20carbonyl groups 13CBS reduction 15C–C coupling reactions 19commercial applications 15cyclopropanation reaction 11Haber–Bosch (H–B) process 3heterogeneous catalytic processes 3hydroformylation 6Jacobsen–Katsuki epoxidation 15Mizoroki–Heck reaction 9, 18multi‐functional groups and

stereocenters 11Negishi‐coupling reaction 19nickel carbonyl catalyst 6organocatalysis 9, 10Pd‐catalyzed coupling reaction 9physico‐chemical behaviour, of

oxygen and hydrogen 4RhCl(PPh3)3 catalyst 7Ru catalysts 13Sharpless–Katsuki

epoxidation 16, 17Suzuki–Miyaura coupling

reaction 19TiCl3 catalyst 7Wacker reaction 5

cleaner reaction conditions 1catalyst immobilization 25catalyst recycling 45

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Index418

catalytic cross‐coupling reactionsallylic substitution reactions 234antimitotic agent 227aryl bromide and propargyl

alcohol 228aryl chloride intermediate and

tert‐butylacetylene 2263‐bromo‐4‐methylbenzoic

acid 232Buchwald–Hartwig reaction 210C–H activation processes 239diastereoselective synthesis 230drug candidate 228eniluracil synthesis 225–226farnesyl transferase inhibitor 226fingolimod synthesis 224–225Heck–Mizoroki reaction 176imidazole 479754 229oxidative C–C bond formation 248pyrrolquinolone

PHA‐529311 229–230Suzuki–Miyaura coupling

reactions 195, 224terbinafin synthesis 224–225TRPV1 antagonist 226–227Wyeth’s synthesis of

GRN‐529 230–231catalytic cyclopropanation reactions

metal catalyzed processes α‐diazo‐β‐keto sulfones 337(+)‐ambruticin S 331CPA 333Cu‐catalyzed intramolecular arene

cyclopropanation reaction 333Cu‐catalyzed intramolecular

diastereoselective reaction 323cyclopropyl carboxylic acid

derivative 324(–)‐desoxyeseroline 331(+)‐digitoxigenin 338LY2140023 synthesis 328serotonin reuptake inhibitor 324tandem continuous flow

procedure 324TRPV1 antagonists 333

synthetic methods 322catalytic process design

API manufacture, catalytic reactionsbatch operations 49continuous flow operations 63

heterogeneous and homogeneous catalysts

adsorption/desorption mechanism 33

boomerang catalysts 35encapsulated/immobilized Pd

catalysts 33hydrogenation reactions 33immobilized and encapsulated

catalysts 35metathesis reactions 35

product safety and regulatory requirements 36–37

residual metals, control of catalyst recycling 45design of experiment

(DoE) 43–44extraction and scavenging

38–40filtration and adsorption 38organic solvent nanofiltration

(OSN) 41–42scalability, safety and

environmental aspects 46–48catalytic reductions

nitro units 104, 106–107organocatalysts 103

cathepsin K inhibitor 203cathepsin S inhibitor 78CEP‐33779 222–223cephalexin 390, 391cephalosporin C 400–401cethromycin 194(+)‐cetiedil 354C–H bond insertion reaction

aperidine synthesis 348(+)‐cetiedil synthesis 354(–)‐decursivine 345dictyodendrins synthesis 343D‐threo‐methylphenidate

synthesis 355(–)‐ephedradine A 343(–)‐epi‐conocarpan and

(+)‐conocarpan 344

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Index 419

γ‐aminobutyric acid (GABA) 347(–)‐hamigeran B 353(+)‐imperanene 355(–)‐incarviatone A 350mechanism 342(+)‐methoxyphenylkainic acid and

(+)‐phenylkainic acid 345methylphenidate 355pradimicinone 349(+)‐przewalskin B 349(+)‐przewalskin synthesis 350(R)‐(–)‐rolipram 342Ru and Cu complexes 342(–)‐serotobenine synthesis 345–346tetronic acid derivatives 348transition‐metal‐carbenoid

intermediate 342(–)‐virginiamycin M2 synthesis 351

chiral (1R,2S)‐1‐amino‐2‐vinylcyclopropanecarboxylic acid (ACCA) moiety 376

chiral diaminophosphine oxide ligand (DIAPHOX) 238

(–)‐chloramphenicol 126, 127chlorodeazapurine 203cholecystokinin (CCK) 1R receptor

agonist 212chronic hepatitis C virus (HVC)

infection 167CI‐1034 197cilastatin 11–12ciluprevir 39, 41, 55–57, 272, 376cinacalcet 98, 177–178CJ‐15161 215–216clofazimine 107clopidogrel 405colchicine 307–308(+)‐conocarpan 344Corey, EJ 291CP‐724 714, 186, 188Crestor® 19crizotinib 53, 86, 200Cu(II) catalyst 307cyclizidine 11[2+2] cycloaddition reaction 312

lobucavir 312orlistat 312

[2+2+2] cycloaddition reaction 313–315[3+2] cycloaddition reaction

azomethine ylides 302carbonyl ylides 307Click reactions 308HCV inhibitor 305RG7388 synthesis 306

[5+2] cycloaddition reaction 315–316cycloaddition reactions

CuAAC reaction 308Diels–Alder reaction 291, 292

cyclopropylamine intermediate (1R,2S)‐2‐(3,4‐difluorophenyl)cyclopropylamine (CPA) 333

ddanoprevir 272–273Daxas® 368dapoxetine 94–95(–)‐decursivine 345dehydrative cyclization 161deoxyribose phosphate aldolase (DERA)

catalyses 403design of experiment (DoE) 43, 67(–)‐desoxyeseroline 331Dess–Martin periodinane oxidant 248dextromethorphan 87–88DG‐041 186, 1881,2‐diaminopropane (1,2‐DAP) 191diazepam 23Diels–Alder (DA) reaction 291

carbogens, synthesis of 292commercial prostaglandin APIs 294disadvantages 293ifetroban sodium 2966‐membered ring formation 291MK‐1256 297oseltamivir phosphate synthesis 295paclitaxel 298prostaglandins 293taxadienone 2981,2,3‐triazole intermediate 295Woodward–Hoffmann symmetry

rules 292(+)‐digitoxigenin 338diketoreductase (DKR) 397diltiazem 119–120

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Index420

dinoprost 159–160, 293dinoprostone 2931,4‐dioxane 206(+)‐discodermolide 150discodermolide 151–153, 196donezepil 360, 361dorzolamide 14–15, 20, 90dronedarone 366–367D‐threo‐methylphenidate 355dual catalysis 24(S)‐duloxetine 96dynamic kinetic asymmetric

transformations (DYKAT) 24

eEDP-420 365efavirenz 22, 374Efivar® 374elbasvir 270eletriptan 178–179emicerfont 215, 217ene reductases (ERED) 398eniluracil 225–226(–)‐ephedradine A 343ephedrine 160, 404(–)‐epibatidine 170(–)‐epi‐conocarpan 344epoprostenol 293eribulin 150–151(–)‐erinacine B 338erogorgiaene 168Ertl, Gerhard 3esomeprazole 17, 18, 127, 131–132, 402estrone 299, 314–315ethyl acrylate 192, 194ethylene 176, 189

fFanapt® 361farnesyl transferase inhibitor 188, 226febuxostat 200, 247fendiline 104fesoterodine 54–55filibuvir 230–231fingolimod 224–225, 377–378fingolimod (FTY720) 377–378firategrast 274

Fischer–Tropsch reaction 6(R)‐fluazifop 4104‐fluorostyrene 189(R)‐flurbiprofen 398fluoxetine 96FR901512 150Friedel–Crafts acylation 23FTY720 377–378

ggabapentin 162, 347gandotinib 244garenoxacin 201γ‐aminobutyric acid (GABA) 241, 347γ‐butyrolactone 240GDC‐0084 208–209, 364GDC‐0994 134glasdegib 407glecaprevir 272–273glutaryl acylase 391glycogen synthase kinase‐3β (GSK3β)

inhibitor 248grazoprevir 269–271, 376GRN‐529 230–231Grignard reagents 148Grignard, Victor 7GSK1360707 209GSK966587 antimicrobial agent 115GSK966587 114–115, 192GW 0430 92

hHaber–Bosch (H–B) process 3Haber, Fritz 3halichondrins 150haloalkane dehalogenase 405halohydrin dehalogenase 410haloperoxidases 401(–)‐hamigeran B 353healthcare services 1Heck–Mizoroki reaction

2‐acetamido‐5‐bromopyridine and ethylene 189

αvβ3 antagonist 192antibiotic ABT-773 194axitinib 190AZD3409 synthesis 189

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Index 421

benzazepine compound SB‐273005 synthesis 186

2‐bromo‐6‐methoxynaphthalene and ethylene 176

3‐bromoquinoline and ethyl acrylate 194

chiral N‐benzylated‐3‐acylindole 184cinacalcet 177DG‐041 synthesis 188double zwitterion BMS‐247243 195eletriptan 178ester hydrolysis 193glycine antagonist 182H1–H3 antagonist 183iodo‐indole derivative and allylic

alcohol 193ketolide antibiotic ABT‐773 194leukotriene synthesis 177methyl 2‐acetamidoacrylate 184methyl 2‐chloro‐5‐nitrobenzoate and

4‐fluorostyrene 189nebivolol 181optically active diol 189–190paclitaxel synthesis 180Pd‐catalyzed coupling reactions 176Pd(OAc)2 and P(o‐Tol)3 188pemetrexed disodium synthesis 182peroxisome proliferator‐activated

receptor (PPARγ) inhibitor 183phosphine‐free Heck–Mizoroki

reaction 185resveratrol 179rilpivirine 180second‐generation Heck–Mizoroki

route 186tricyclic indole‐2‐carboxylic

acids 193trimercaptotriazine (TMT) 183unnatural amino acid 6‐

dimethyltyrosine 2, 184Henry reaction 10hepatitis C virus (HCV) inhibitor 304hetero‐Diels–Alder (hDA) reaction

(+)‐ambruticin 302–303imidodiphosphorimidate Brønsted

acid catalysts 302Jacobsen catalyst 302

6‐membered nitrogen‐containing heterocycles 299

nomenclature of 300rifamycin S 299SDZ SER‐082 300UK‐156406 300vabicaserin 301

homogenous catalytic hydrogenation 7horse liver alcohol dehydrogenase

(HLADH) 394HS‐10168 203–204human immunodeficiency virus 1

(HIV‐1) protease inhibitors 152

hydroformylation reactionbicyclic lactam and

application 101cinacalcet 98Roche aldehyde synthesis 100

hydrogenationalkenes

α,β‐unsaturated carboxylic acids, esters, itaconates 79

enamides 77asymmetric catalytic hydrogenation

processes 77carbonyl groups 84of imines 87transfer hydrogenation

of ketones 88on imines 92

hydrolytic kinetic resolution (HKR) 117

8‐hydroxyquinoline 220

iibuprofen 13, 23idasanutlin 305ifenprodil 368, 369ifetroban sodium 296–297iloperidone 361–362ilepratil 98–99iloprost 293imatinib 22imidazotriazine 191, 241imines 87(+)‐imperanene 355, 356

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Index422

(–)‐incarviatone A 350(+)‐indacrinone 359, 370(+)‐indatraline 354indinavir 16, 401International Council of Harmonization

(ICH) 36International Conference on

Harmonization (ICH) guidelines 311

5‐iodouracil substrate 225irbesartan 241–242HS-10168 203–204isoproterenol 155

jJacobsen–Katsuki epoxidation 15, 116Janus‐associated kinase 2 (JAK2) 203Januvia® 19, 59

kKagan–Modena method 127(S)‐ketoprofen 394–395ketoreductases (KREDs) 394, 395Kulinkovich reaction 322

lL‐679,336 125L‐699,392 18, 177L‐733,060 125–126L‐784,512 122–123lansoprazole (LPS) 130, 131(R)‐lansoprazole 130lapatinib 202latanoprost 293L‐azatyrosine 78L‐carnitine 397L‐DOPA 13, 76letermovir 375–376levcromakalim 120–121levofloxacin 13–14, 85levomilnacipran 329–330, 404lidocaine hydrochloride 23Lipitor® 19lobucavir 312, 314lofexidine 405(S)‐lofexidine 406losartan 19, 199–200, 241–242

lowest unoccupied molecular orbital (LUMO) 292

L‐Valine methyl ester 394LY2140023 328–329LY235959 293–294LY2497282 78LY2623091 205–206LY2801653 65Lyrica® 375

m(S)‐MA20565 90macrocyclic integrase inhibitor 223(–)‐malyngolide 337Mannich reaction 10maraviroc 135–136matrix metalloprotease (MMP‐3)

inhibitor 80mavatrep 207–208(–)‐menthol 76merestinib 65–67methyl 2‐chloro‐5‐nitrobenzoate 189methyl 2‐iodobenzoate 177(+)‐methoxyphenylkainic acid 345methylphenidate 355metolachlor 76Michael addition 10(S)‐miconazole 155mineralocorticoid receptor (MR)

antagonist 205Miyaura borylation reaction 205–206Mizoroki–Heck (M–H)

reactions 9, 18MK-0417 14–15MK-0822 378MK-1256 296, 298MK‐3207 378–380MK-5172 269MK-6325 272MK-7009 267MK‐8742 205, 270MK‐8825 380MK-8831 271–272(R)‐modafinil 131modithromycin 235, 365monoamine oxidase (MAO) 399montelukast 86, 176–177, 395–396

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Index 423

Multaq® 366multiwalled carbon nanotubes

(MWNT) 156

nnaproxen 13–14, 18, 176–177, 389(S)‐naproxen 82, 389nebivolol 181Negishi coupling reaction 18nemonapride 380, 381neuropeptide Y (NPY)‐5 receptor

antagonist 196nevirapine 198niraparib 220, 407, 408N‐methyl‐d‐aspartate (NMDA) 2B

receptor 85N‐methyl‐N‐nitrosourea 337Non‐asymmetric dihydroxylation

reactions 125noremopamil 114(S)‐noremopamil 114, 115Nozaki–Hiyama–Kishi (NHK)

reaction 149NPS 53574 140NPS R‐568 103N‐sulfonated diamine‐η6‐arene

ruthenium catalyst 89nucleophilic addition reaction 147nucleophilic methods 119N‐vinylphthalimide 192Nylidrin® 368

oodanacatib 203–204, 378, 379olefin aminohydroxylation 125olefin dihydroxylation 121olefin epoxidation

Jacobsen–Katsuki asymmetric epoxidation 116

nucleophilic methods 119organocatalytic methods 119Sharpless–Katsuki asymmetric

epoxidation 113olmesartan medoxomil 241–242olopatadine hydrochloride 232Olysio® 267omapatrilat 98–99

ombitasvir 272omeprazole 17, 127, 130, 131(S)‐omeprazole 130one variable a time (OVAT)

approach 43OPC‐29030 127–128organic solvent nanofiltration (OSN) 41organocatalysts 103organocatalytic methods 119orlistat 87, 312, 314oseltamivir phosphate 295–296Ostwald, Wilhelm 2OSU 6162 196oxazaborolidine reductions 94oxidation

asymmetric catalytic oxidation 113carbonyls 133olefin aminohydroxylation 125olefin dihydroxylation 121olefin epoxidation

Jacobsen–Katsuki asymmetric epoxidation 116

nucleophilic methods 119organocatalytic methods 119Sharpless–Katsuki asymmetric

epoxidation 113oxidative dehydrogenations

(OD) 139sulfur oxidation 127

oxidative dehydrogenations (OD) 139

ppaclitaxel 125, 180, 298pacritinib 273–274palbociclib 194paritaprevir 272–273(–)‐paroxetine 163–164pemetrexed disodium 182perindopril 409phase transfer catalysis (PTC)

achiral PTCsanastrozole synthesis 3624‐benzyloxy‐propiophenone

synthesis 369donepezil 360dronedarone synthesis 366–367GDC‐0084 synthesis 364

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Index424

phase transfer catalysis (PTC) (contd.)iloperidone synthesis 361modithromycin synthesis 365pharmaceutical

manufacturing 360ranolazine synthesis 363roflumilast synthesis 368tenofovir disoproxil

synthesis 366viloxacine synthesis 361

asymmetric PTCs ACCA synthesis 377alkylation and nitro‐Mannich

reactions 372chiral guanidinium and

pentanidium 372cinchonidine and cinchonine

selection 370efavirenz synthesis 374fingolimod (FTY720)

synthesis 377letermovir synthesis 376MK‐3207 synthesis 378MK‐8825 synthesis 380nemonapride synthesis 380novel chiral spiro ammonium and

phosphonium catalysts 371odanacatib synthesis 379(S)‐pregabalin synthesis 375

(+)‐indacrinone synthesis 359, 370organic/aqueous liquid‐liquid

mixture 359solid–liquid conditions 359

phenpyramine 96–97phenylephrine 85(S)‐1‐phenylethylamine 391(+)‐phenylkainic acid 3451‐phenyl‐3‐oxabicyclo[3.1.0]hexan‐2‐

one 329phosphites 98phosphonites 98polymerase chain reaction (PCR) 10potassium 6‐trimethylbenzenesulfonate

(TMBSK) 2, 4, 240–241pradimicinone 349(±)‐preclamol 246–247(S)‐pregabalin 375, 399

pregabalin 81, 82, 162, 398(+)‐preussin 156process analytical technology

(PAT) 66, 68(R)‐1,2‐propanediol 85(2S)‐propranolol 14, 122, 123prostaglandins 165, 293(+)‐przewalskin B 349pseudo‐ephedrine 404(1R,2R)‐ pseudo‐ephedrine 403Pseudomonas fluorescens esterase I

(PFEI) 393pyridazinone 214pyrrolquinolone

PHA‐529311 229–230

qquality assurance (QA) 64quality by design (QbD) 49, 64, 68quinoline 44, 52, 140, 141(+)-Quebrachamine 283

rrac‐tolterodine 97–98rac‐modafinil 132ramipril 390Ranexa® 363ranolazine 363rasagiline 392Rasilez® 275rebeccamycin analog 249(S,S)‐reboxetine succinate 114, 115Relacatib 264–267Reppe, Walter 6resveratrol 179RG7388 305–307Rh‐catalyzed addition reaction 149rifamycin S 299rilpivirine 180–181ring‐opening‐metathesis

polymerization (ROMP) 7ritodrine 269, 368ritonavir 272rivastigmine 85–86, 94,

103–105, 406Ro 67‐8867 67roflumilast 368

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Index 425

rolapitant 277–278(R)‐(–)‐rolipram 164, 342–343(R)‐rolipram 164(S)‐rolipram 164–165rolipram 162rosuvastatin (Crestor) 137, 138, 403ruxolitinib 203RWJ‐53308 82, 84

sSabatier, Paul 3(R)‐salmeterol 154saxagliptin 410SB-1317 274SB-1518 273–274SB-273005 80–81, 185–186SB-462795 264SB-683699 274SCH-619734 277SDZ NKT 78 343SDZ SER‐082 300–301selective serotonin reuptake inhibitor

(SSRI) 163serine palmitoyl transferase (SPT)

inhibitor 243–244(–)‐serotobenine 345–346sertraline 88, 94–95(4S)-sertraline 88cis‐(1S,4S)‐sertraline 88–89serotonin‐norepinephrine reuptake

inhibitor (SNRI) 329Sharpless–Katsuki system 17Sharpless–Katsuki Ti‐catalyzed

epoxidation 14sibenadet hydrochloride 133simeprevir 267–268, 376Simmons–Smith reaction 321Singulair® 18, 19, 86, 176, 395–396sitagliptin 59–62, 78–79, 407solithromyin 309–313(S)‐sotalol 155statine 84sulfur oxidation

titanium, molybdenum catalysts 127–128, 130

tungsten catalysts 132vanadium catalysts 127–128, 130

sulindac 127–128Sustiva® 374suvorexant 92–93Suzuki–Miyaura reaction 9, 18, 22, 66

2‐amino‐5‐phenylpyrazine 196API lapatinib 202approach 51borylation reactions 205bromosulfone and pyridyl borane

substrate 196Bruton’s tyrosine kinase (BTK)

inhibitor 206chloropyrimidine and arylboronic

ester 208crizotinib synthesis 200double borylation 205ethyl 3‐[4‐(1,1‐dimethylethyl)

phenyl]‐1H‐indole‐2‐carboxylate 197

febuxostat synthesis 200garenoxacin synthesis 201GlaxoSmithKline’s synthesis 209losartan synthesis 199nevirapine analog 198Ni catalysts 195P(o‐Tol)3 198ruxolitinib 2031,3,4‐trifluorophenyl‐6‐boronic

acid 197trithiocyanuric acid 197vemurafenib and abiraterone

acetate 202

ttafamidis 247tafluprost 159–160, 293(–)‐tangutorine 238taranabant 79, 80, 216–217tasimelteon 117–118, 123, 124Taube, Henry 7taxadienone 298–299Taxol® 125, 298TCM 20 185Technivie® 272Tekturna® 275telaprevir 399–400telcagepant 149, 169–170

bindex.indd 425 7/9/2018 2:22:50 PM

Index426

telmisartan 22–23TEMPO/NaClO2 oxidation

procedure 138tenofovir disoproxil 366terbinafine 149, 224–225tert‐butylhydroperoxide

(TBHP) 114texaline 248(+)‐thiamphenicol 126, 127thienamycin 12(R)‐tiagabine 107ticagrelor 333, 336–337TIQ‐A 65–66TMC-435 267tofacitinib 107torcetrapib 210transfer hydrogenation

on imines 92of ketones 88

transient receptor potential vanilloid‐1 (TRPV1) antagonists 207

travoprost 160, 293tricyclic indole‐2‐carboxylic

acids 1931,3,4‐trifluorophenyl‐6‐boronic

acid 1972,4,6‐trimercaptotriazine (TMT) 40trithiocyanuric acid 197Tsuji, Jiro 8Tsuji–Trost Allylation 235tungsten catalysts 132

uUK‐370,106 81UK‐156406 300, 302Umbelliferone 282ustiloxin D 237

vvabicaserin 301valaciclovir 394valsartan 50, 51, 52, 200, 241–242valsartan 49–53vanadium catalyst 131Vanihep® 267vaniprevir 267–270, 376Vanihep® 277Varubi® 277vemurafenib 201, 202venlafaxine 354vernakalant 409Vicilan® 361(+)‐vigulariol 352Viekira Pak® 272viloxacine 361Viread® 366(–)‐virginiamycin M2 351vismodegib 107Vivalan® 361

wwarfarin 162Woodward–Hoffmann symmetry

rules 292

yYM-09151 380Yutopar® 368

zzanamavir 402ZD2249 128Zepatier™ 269Ziegler, Karl 7zolpidem 250

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