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MINIREVIEWSINMEDICINALCHEMISTRY,2004,4,20723320713895575/044500002004BENTHAMSCIENCEPUBLISHERSLTDSYNTHETICAPPROACHESTOTHE2002NEWDRUGSJINLIANDKEVINKCLIUPFIZERGLOBALRESEARCHANDDEVELOPMENT,PFIZERINC,GROTONCT06340,USAABSTRACTNEWDRUGSAREINTRODUCEDTOTHEMARKETEVERYYEARANDEACHINDIVIDUALDRUGREPRESENTSAPRIVILEGEDSTRUCTUREFORITSBIOLOGICALTARGETINADDITION,THESENEWCHEMICALENTITIESNCESNOTONLYPROVIDEINSIGHTSINTOMOLECULARRECOGNITION,BUTALSOSERVEASDRUGLIKELEADSFORDESIGNINGFUTURENEWDRUGSTHEREFORE,ITISIMPORTANTTOBEACQUAINTEDWITHTHESENEWSTRUCTURESASWELLASTHEIRSYNTHESESTOTHESEENDS,THISREVIEWCOVERSTHESYNTHESESOF28NCESMARKETEDIN2002KEYWORDSSYNTHESIS,NEWDRUG,NEWCHEMICALENTITIES,MEDICINE,THERAPEUTICAGENTSINTRODUCTIONDOZENSOFNEWDRUGSAREREGISTEREDANDLAUNCHEDEVERYYEARAROUNDTHEWORLDALTHOUGHTHOUSANDSOFDRUGSHAVEBEENMARKETEDHISTORICALLY,THESTRUCTURESIMILARITYAMONGSOMEDRUGSISOBVIOUSANDEVENMORESOFORDRUGSTARGETINGINTHESAMEGENEFAMILYFURTHERMORE,ITHASBEENDEMONSTRATEDTHATMOLECULESWHICHSHARETHESAMEORSIMILARCHEMICALTEMPLATECANBEFURTHERMODIFIEDFORDIFFERENTTHERAPEUTICINDICATIONSAGAINSTTHESIMILARGENEFAMILYTHEREFORE,MEDICINALCHEMISTS,BEINGAWAREOFTHESENEWDRUGSTRUCTURES,CANSTRIKEANDADOPTIDEASFORTHEIROWNINNOVATIONSINADDITION,PREPARATIONOFTHESEDRUGMOLECULESHASBEENSTUDIEDEXTENSIVELYTOMAKEITCONCISEDUETOTHECOSTOFGOODSCONSIDERATIONANDTOENSUREENVIRONMENTFRIENDLINESSHAVINGSUCHROBUSTANDRELIABLESYNTHETICMETHODSINHANDTOACCESSTHESECORESTRUCTURESWILLSTEERSYNTHETICEFFORTSMOREEFFECTIVELYTOWARDTHEMOSTPROMISINGCOMPOUNDSANDHELPFOCUSTHEOPTIMIZATIONTOWARDOTHERCHALLENGINGPROPERTIESSUCHASADMEIN2002ALONE,33NCESINCLUDINGBIOLOGICALDRUGS,ANDTWODIAGNOSTICAGENTSREACHEDTHEMARKET15THISREVIEWARTICLEWILLFOCUSONTHESYNTHESESOFTHE28NEWDRUGSMARKETEDLASTYEARFIGURE1,BUTEXCLUDESNEWINDICATIONSFORKNOWNDRUGS,NEWCOMBINATIONSANDNEWFORMULATIONSTHESYNTHESESOFTHESENEWDRUGSWEREPUBLISHEDSPORADICALLYINDIFFERENTJOURNALSANDPATENTSITISOURINTENTIONTOCOMPILETHESYNTHESESOFNEWDRUGSYEARLYINTOANANNUALREVIEWFORTHEREADERSADVANTAGETHESYNTHETICROUTESCITEDHEREREPRESENTTHEMOSTSCALABLEMETHODSACCORDINGTOTHEBESTOFTHEAUTHORSKNOWLEDGEANDAPPEARINALPHABETICALORDERBYGENERICNAMEADEFOVIRDIPIVOXILHEPSERATMADEFOVIRDIPIVOXIL1,DISCOVEREDBYGILEAD,BECAMETHEFIRSTNUCLEOSIDEANALOGUETOGAINFDAAPPROVALFORTHETREATMENTOFCHRONICHEPATITISBINFECTION6ADEFOVIRWORKSBYBLOCKINGVIRALREPLICATION6THESYNTHESIS7,8OFADEFOVIRDIPIVOXIL1INVOLVESAFOURSTEPPROCESS9,10ASDEPICTEDINSCHEME1ADENINE29WASCONDENSEDWITHETHYLENECARBONATE30INHOTDMFTOAFFORDINTERMEDIATE9ADDRESSCORRESPONDENCETOTHESEAUTHORSATTHEPFIZER,GROTON,CT06340,USATEMAILJIN_LIGROTONPFIZERCOMKEVIN_K_LIUGROTONPFIZERCOM2HYDROXYETHYLADENINE31IN8395YIELDALKYLATIONOF31WASCARRIEDOUTUSINGDIETHYLPTOLUENESULFONYLOXYMETHANEPHOSPHONATE32ANDSODIUMTBUTOXIDEINDMFPHOSPHONATEESTER33WASTHENCLEAVEDWITHBROMOTRIMETHYLSILANETOFURNISH34ANDESTERIFICATIONOFTHEPHOSPHORICACIDTOAPPENDTHEPIVALOYLOXYMETHYLGROUPPROVIDEDADEFOVIRDIPIVOXIL1AMRUBICINHYDROCHLORIDECALSEDTHISDRUGISTHEFIRSTANTHRACYCLINEANTICANCERANTIBIOTICPRODUCEDBYPURELYSYNTHETICMETHODSITWASDISCOVEREDBYSUMITOMOPHARMACEUTICALS,ANDISFORTHETREATMENTOFNONSMALLCELLLUNGCANCERANDSMALLCELLLUNGCANCER11TETRALONE35WASTREATEDWITHAMMONIUMCARBONATEANDPOTASSIUMCYANIDESTRECKERREACTIONTOGIVETHECORRESPONDINGAMINONITRILEINTERMEDIATE,WHICHWASHYDROLYZEDUNDERBASICCONDITIONSTOAFFORDAMINOACID36INEXCELLENTYIELD12THECARBOXYLICACIDIN36WASESTERIFIEDWITHHCLINMETHANOLTOTHECORRESPONDINGMETHYLESTER,WHICHWASTREATEDWITHDMANDELICACIDINTOLUENETOGIVEOPTICALLYPURELEVOROTATORYESTER37IN33YIELDSODIUMMETHYLSULFINYLMETHIDETREATMENTOF37FOLLOWEDBYREDUCTIONWITHZINCYIELDEDAMINOKETONE38,WHICHWASACYLATEDTOGIVEAMIDOKETONE39IN81YIELDFROM37COMPOUND39WASCONVERTEDTOTETRACYCLICAMIDOKETONE40INONESTEP90YIELDBYHEATINGWITHPHTHALICANHYDRIDEINTHEPRESENCEOFALCL3NACLAT170CKETONE40WASPROTECTEDASITSKETAL41INORDERTOPROVIDEFORSUBSEQUENTREGIOSPECIFICBROMINATIONTREATMENTOF41WITH1,3DIBROMO5,5DIMETHYLHYDANTOINDDHUNDERILLUMINATIONINREFLUXINGBENZENEFORMEDOXAZINE42IN89YIELDHYDROLYSISOFTHEOXAZINERINGANDDEKETALIZATIONWERESIMULTANEOUSLYAFFECTEDBYHEATING42WITH3NSULFURICACIDTOGIVECISAMINOALCOHOL43IN82YIELDMODIFIEDARCAMONECONDITIONSAGOSO2CF3INETHER/TETRAMETHYLUREA/DCMWEREEMPLOYEDFORTHESTEREOSELECTIVEGLYCOSIDATIONOF43WITH2DEOXY3,4DIOACETYLDERYTHROPENTOPYRANOSYLBROMIDE4413TOGIVETHEPROTECTEDGLYCOSIDEIN86YIELDBASICHYDROLYSISOFTHEPROTECTEDCOUPLINGPRODUCTFOLLOWEDBYHCLSALTFORMATIONGAVEAMRUBICINHYDROCHLORIDE2IN90YIELDARIPIPRAZOLEABILIFYTMTHISATYPICALANTIPSYCHOTICAGENTWASORIGINALLYDISCOVEREDBYOTSUKAANDWASCODEVELOPEDANDCOMARKETED208MINIREVIEWSINMEDICINALCHEMISTRY,2004,VOL4,NO2LIANDLIUNHOHOOHOSNHNHOOONAHONNCFCO2HCO2HOOOHOOSOOONSOOOOHOOOOHOOHOOSOOONSOHOOOSOOOOOOOHOHHOOOSOOONSOHOOOHOSOOONANANANANANANANANANAHOHOHHHSOFFFFFFNHCLNNOMEONONOOHFOHFNNNNNH2OPOOOOOOOOOOOOHHOOHOOHNH2HCLCLCLNNONHOOONHHCLNHONHFFFFFFHHHHONNSOOCLNHNH2HNO7FULVESTRANT12GEFITINIB13ADEFOVIRDIPIVOXIL1AMRUBICINHYDROCHLORIDE2ARIPIPRAZOLE3DEXMETHYLPHENIDATEHCL4DUTASTERIDE5ERTAPENEMSODIUM6ESCITALOPRAMOXALATE7ETORICOXIB8EZETIMIBE9FONDAPARINUXSODIUM10FROVATRIPTAN11SYNTHETICAPPROACHESTOTHE2002NEWDRUGSMINIREV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