Synthesis of Heterocycles in Contemporary Medicinal Chemistry PDF
Preview Synthesis of Heterocycles in Contemporary Medicinal Chemistry
Topics in Heterocyclic Chemistry 44 Series Editors: Bert Maes · Janine Cossy · Slovenko Polanc Zdenko Časar Editor Synthesis of Heterocycles in Contemporary Medicinal Chemistry 44 Topics in Heterocyclic Chemistry SeriesEditors: Bert Maes, Antwerp, Belgium Janine Cossy, Paris, France Slovenko Polanc, Ljubljana, Slovenia Editorial Board: D. Enders, Aachen, Germany S.V. Ley, Cambridge, UK G. Mehta, Bangalore, India R. Noyori, Hirosawa, Japan L.E. Overmann, Irvine, CA, USA A. Padwa, Atlanta, GA, USA Aims and Scope The series Topics in Heterocyclic Chemistry presents critical reviews on present andfuturetrendsintheresearchofheterocycliccompounds.Overallthescopeisto covertopicsdealingwithallareaswithinheterocyclicchemistry,bothexperimental andtheoretical,ofinteresttothegeneralheterocyclicchemistrycommunity. The series consists of topic related volumes edited by renowned editors with contributionsofexpertsinthefield. More information about this series at http://www.springer.com/series/7081 ˇ Zdenko Casar Editor Synthesis of Heterocycles in Contemporary Medicinal Chemistry With contributions by (cid:1) (cid:1) ˇ (cid:1) (cid:1) (cid:1) R. Barth A. Bauer Z. Casar F. Gallou S. Lemaire (cid:1) (cid:1) (cid:1) (cid:1) S. Nerdinger F. Richter C.A. Rose D. Schils O. Scho¨ne (cid:1) E. Schreiner (cid:1) Y.S. Tsantrizos Editor ZdenkoCˇasar SandozDevelopmentCenterSlovenia,LekPharmaceuticalsd.d. Ljubljana Slovenia GlobalPortfolioManagement,SandozGmbH Kundl Austria FacultyofPharmacy UniversityofLjubljana Ljubljana Slovenia ISSN1861-9282 ISSN1861-9290 (electronic) TopicsinHeterocyclicChemistry ISBN978-3-319-39915-7 ISBN978-3-319-39917-1 (eBook) DOI10.1007/978-3-319-39917-1 LibraryofCongressControlNumber:2016944466 ©SpringerInternationalPublishingSwitzerland2016 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilarmethodologynowknownorhereafterdeveloped. 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Printedonacid-freepaper ThisSpringerimprintispublishedbySpringerNature TheregisteredcompanyisSpringerInternationalPublishingAGSwitzerland Preface Heterocycliccompounds havehadacentral roleinmedicinal chemistry,andthey havemadenotablecontributionstothequalityoflifeforhumanity.Itisdifficultto imaginetheprogressinpublichealthandtheincreasedlifeexpectancythatwehave witnessed in the last 70 years without drugs such as b-lactam antibiotics, ACE inhibitors, calcium channel blockers, and others. Over the last decade, some particularcompounds,likethestatins,haveestablishedtheirpositionasimportant drugs,whilemanynewtherapeuticclassesofcompoundshaveemergedthathave provided important advances in the area of modern medicinal chemistry. Indeed, statins,andinparticulartheirheterocyclicderivativesthatarefrequentlycalledthe super-statins, have markedly improved the management of hypercholesterolemia, whichhasledtoreducedriskofatherosclerosisandcardiovasculardisease.Nowa- days, these drugs are facing a patent cliff, which will allow the market entry of genericversionsofthesedrugsandthusincreasetheiraccesstopatientsworldwide. Then,earlyinthisdecade,amajorbreakthroughwasachievedinthetreatmentof hepatitis C virus (HCV) infections. Several compound classes have emerged that cannowprovidesignificantlyimprovedratesofsustainedvirologicalresponseina fewmonthsoforaltherapy,thusavoidingtheuseoflessefficientandmoredifficult to tolerate ribavirin/pegylated interferon therapies. Among these compounds, sofosbuvir (NS5B HCV polymerase/protease inhibitor) and simeprevir (NS3/4A HCV protease inhibitors) and its analogs have a central role in the battle against hepatitisC.Thetreatmentoftype2diabeteshasalsomovedtoinhibitionofglucose reabsorptioninthekidney,whichleadstoreducedbloodsugarlevels.Thishasbeen achieved with a new class of compounds that inhibit sodium-glucose transport protein 2 (SGLT2), which are now referred to as the “gliflozin” drugs. Over the past 5 years, several gliflozin family members have been put on the market: canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and tofogliflozin. These arosefromthefascinatingnewarsenalofsyntheticchemistrythatwasconstructed fortheirefficientpreparation.HIVtreatmenthasalsowitnessednotableprogressin thelastdecade,andonerecentlyapproveddrugthatmightchangethelandscapeof anti-HIVtherapiesisthesecond-generationHIVintegrasestrandtransferinhibitor dolutegravir,withitsimpressiveefficacyandgoodpatienttolerability.Anticancer v vi Preface drugs have also made significant progress in the last decade. Among these, the so-called tinibs and the tyrosine kinase inhibitors have had a pivotal role. At the same time, astonishing results have been achieved in the area of natural product derivatives, where eribulin was introduced into clinical practice recently for the treatment of metastatic breast cancer and inoperable liposarcoma. Based on its complexpolyethermacrolidestructurewith19stereocenters,thetotalsynthesisfor eribulinproductionrequiresmorethan60steps.Thisisanoutstandingachievement in industrial synthesis, and it represents the longest commercial drug synthesis todate. Therefore,alloftheseachievementshaveprovidedimpetusfortheassemblyof thisvolumeofTopicsinHeterocyclicChemistry,entitledSynthesisofHeterocycles in Contemporary Medicinal Chemistry, which highlights in detail the abovementioned achievements. This volume is special in several aspects. First, it was composed by industrial medicinal and process chemists with decades of industrialexperience.Secondly,itisdedicatedtotheheterocyclicdrugcompounds thathaveparticularlymarkedtheareaofmedicinalchemistryoverthelastdecade. Asthisvolumecontainsagoodblendofsyntheticorganic,medicinal,andprocess chemistry, it should be appealing to a broad area of chemistry professionals and graduatestudents.Ihopethatitwillinspirecurrentandfutureprocessandmedici- nalchemiststodesignnewdrugsinefficientandsustainablemanners. Gallouprovidesachapteronthedevelopmentofamanufacturingprocessforthe formation of a hepatitis C drug candidate with immense tutorial value from the process chemistry perspective. Lemaire and Schils describe the synthetic and processchemistryaspectsofSGLT2inhibitorsforthetreatmentoftype2diabetes. Scho¨neetal.giveadetailedoverviewofsyntheticroutestosofosbuvir,oneofthe best selling drugs of this decade. Prof. Tsantrizos discusses the discovery, early syntheticchemistry,andprocesschemistryofmacrocyclicHCVNS3/NS4Aprote- aseinhibitorsforthecaseofciluprevir(BILN-2061),whichbroughtolefinmetath- esis to the industrial scale and paved the way for the assembly of the marketed analogssimeprevir,paritaprevir,andvaniprevir.ThechapterthatIhavecontributed reviews the recent progress in super-statin chemistry. Schreiner et al. provide an overview and detailed analysis of the synthetic routes to dolutegravir. Bauer summarizes the discovery and the initial synthetic routes toward eribulin and its analogsanddescribestherecentsyntheticadvancesinthearea. To finish, I would like to thank the series editor, Prof. Slovenko Polanc, for givingmeanoutstandingopportunitytocompilethisvolumeofTopicsinHetero- cyclic Chemistry. I am also grateful to Prof. Janez Kosˇmrlj for his support in this matter.Imustalsoexpressmygratitudetotheentireeditorialandsupportstaffat Springerfortheirpromptsupportandguidanceduringthepreparationofthiswork. Iwouldliketoexpressmyappreciationtoalloftheauthorsofthisvolume,fortheir hardworkandoutstandingcontributions.IextendmysinceregratitudetoSandoz/ Lekmanagementforprovidinganinspiringscientificenvironmentand,inparticu- lar, to Dr. Josef Egerbacher, Dr. Susanne Raehs, Mr. Matjazˇ Trsˇek, Dr. Bojan Mitrovic´, and Mr. Pavel Drnovsˇek, who have been supportive in all my scientific endeavors.IwouldalsoliketoacknowledgeProf.StanislavGobecforhissupport Preface vii inmyacademicwork.Finally,Iwouldliketothankmyfamilyandespeciallymy wife, Renata, andmydaughter,Nezˇa,fortheir patience andunderstandingduring the time I spent writing my own chapter for this book, as well as during the time neededforthecompilationofthewholevolume. Ljubljana,Slovenia ZdenkoCˇasar March2016 ThiSisaFMBlankPage Contents DevelopmentofaManufacturingProcessfortheFormation ofaNucleosideDrugCandidate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 FabriceGallou DevelopmentofEfficientRoutestoAccessC-Glycosides asSGLT-2InhibitorsfortheTreatmentofType2Diabetes. . . . . . . . . 29 Se´bastienLemaireandDidierSchils SyntheticRoutestoSofosbuvir. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 RolandBarth,ChristopherA.Rose,andOlgaScho¨ne SyntheticChallengesintheAssemblyofMacrocyclic HCVNS3/NS4AProteaseInhibitors:TheCaseofBILN2061 andItsAnalogs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 YoulaS.Tsantrizos RecentProgressintheSynthesisofSuper-Statins. . . . . . . . . . . . . . . . . 113 ZdenkoCˇasar DevelopmentofSyntheticRoutestoDolutegravir. . . . . . . . . . . . . . . . . 187 ErwinSchreiner,FrankRichter,andSvenNerdinger StoryofEribulinMesylate:DevelopmentoftheLongestDrug Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 ArminBauer Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 ix
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