氮杂胞苷的合成工艺研究

:2008-04-10:(30328030):(1976-),(),,;(1964-),(),,,,,Tel:[phone],E2mail:[e-mail]:1005-0108(2008)05-0377-02,,,,(,110016):,52,52,,1H2NMRMS,2616%:;;;:R914:AImprovedsynthesisofazacytidineGUOGang,YANGQian2jiao,ZHAOLi2hui,LIUDan,ZHAOLin2xiang(SchoolofPharmaceuticalEngineering,ShenyangPharmaceuticalUniversity,Shenyang110016,China)Abstract:Cyanoguanidineandacetylated2D2ribosewereusedasstartingmaterialstogivetargetcompoundviasaltformation,cyclization,silylation,couplingreactionanddeprotection.Thetargetcompoundwaschar2acterizedby1H2NMR,MSspectraandthetotalyieldwas2616%.Thesyntheticconditionswereoptimizedandthetotalyieldwasincreased.Keywords:processimprovement;chemicalsynthesis;azacytidine;cyanoguanidine(azacytidine,1)12(2D2)24221,3,5222(1H)2,SuperGenDNA2004,Vidaza,DNA,DNA,,,DNA,DNA,,DNA,152[1]52(5)3:1)DMF[2],;2)[3],3,3416%;3),[4-5],6010%3,(2)(3),,5,5613%,;5(HMDS)6,61,18520081085ChineseJournalofMedicinalChemistryVol118No15p.377Oct12008Sum852,3,522O222D2(7),,8,821,4810%7[1]1222,3,522O222D2[6]1222,3,522O222D2,[1],,3514%4810%,[6],,4810%5212%,,,[7];1,22,6SnCl4[8],[9],,,1H2NMRMS,2616%1Figure1Thesyntheticrouteofazacytidine21H2NMRBrukerARX-300,TMSX-42114221,3,5222(1H)2(5)1618g(1mol)21814g(2mol),,120,20min,,,10mL,,,(4)41cm,,145145min,51516g[5]5:530mL,,,,,pH=6,,,,51216g,5613%mp300([4]:mp300)1H2NMR(300MHz,DMSO2d6):7136(2H,s)8105(1H,s)11156(1H,s)ESI2MS:m/z11311[M+H]+22510[2M+H]+212N226221,3,52222(6)5g(40mmol)550mL012g,1308h,50,61113g(9816%)621312(2D2)24221,3,5222(1H)2(1)416g(1mol)6517g(1mol)730mL,215mL(112mol),30min30mL,1132molL-1(20mL3),,,,12(2,3,522O222D2)24221,3,5222(1H)2(8)8012molL-1,30min,,,1216g,211g,4810%(383)87318ContinuedTable1PositionCompd.11H2NMR13C2NMRHMBCsericicacid13C2NMR212911(t)2814(t)223317(t)3010(t)2311672319(q)7413,6512,4917,45122411(q)24318141106512(t)7413,4512,23197413,4512,23196516(t)2511051715(q)6512,3818,4917,4815,4219,17151714(q)2611061710(q)4212,4013,33181711(q)2711562418(q)2911,4013,4212,144192418(q)2818019(s)18110(s)2911172818(q)8112,2418,35172911(q)3011092418(q)8112,3517,2818,28142418(q):[1]HISASHIK,HARUOO.TriterpenoidsfromPrunellavulgaris[J].Phytochemistry,1986,25(3):729-733.[2]SHASHIBM,ASISHPK.13C2NMRspectraofpen2tacyclictriterpenoids2acompilationandsomesalientfeatures[J].Phytochemistry,1994,37(6):1517-1575.[3],,.[J].,2002,33(3):184-187.[4]HOSUPY,SHINYP,JINWOONGK.A2ringcon2tractedtriterpenoidfromRosamultiflora[J].Phyto2chemistry,1998,48(8):1399-1401.(378),2616%,2013%[5,8]mp234236([1]:mp235237)1H2NMR(300MHz,DMSO2d6):31533157(1H,d)31673171(1H,m)31843186(1H,s)4101(1H,s)4108(1H,s)5104(1H,s)5112(1H,s)5143(1H,s)51665167(1H,s)71517153(2H,d)8158(1H,s)ESI2MS:m/z24313[M-H]+27913[M+Cl]-48714[2M-H]+:[1]WINKLEYMW,ROBONSRK.Directglycosylationof1,3,52triazinones.Anewapproachtothesynthesisofthenucleosideantibiotic52azacytidine(42amino2122D2ribofuranosyl21,3,52triazin222one)andrelatedderivatives[J].JOrgChem,1970,35(2):491-495.[2]PISLALAA.Nucleicacidcomponentsandtheirana2logues.Cl.3Synthesisof52azacytosine(42amino21,22dihydro21,3,52triazin222one)anditsmethylderiva2tives[J].CollectionCzechoslovChemCommun,1967,32(11):3966-3976.[3]NIEDBALLAU,VORBRUGGENH.Ageneralsyn2thesisofN2glycoside.V.Synthesisof52azacytidines[J].JOrgChem,1974,39(25):3672-3674.[4]HARTENSTEINR,FRIDOVICHI.Amidinoureaformate,aprecursorof22amino242hydroxyl2s2triazine[J].JOrgChem,1967,32(5):1653-1654.[5],,,.52[J].,2003,49(4):454-456.[6]HANNANB,ZAJICEKJ,PISKALAA.62Methyl252azactidine2synthesis,conformationalpropertiesandbio2logicalactivity.Acomparisionofmolecularconforma2tionwith52azacytidine[J].NucleosidesNucleotides,1997,16(1/2):129-144.[7]LINKT,MOMPARLERRL,RIVARDG.High2performanceliquidchromatographicanalysisofchemi2calstabilityof52aza222deoxycytidine[J].JPharmSci,1981,70(11):1228-1232.[8]VORBRUGGENH,HOFLEG.Onthemechanismofnucleosidesynthesis[J].ChemBer,1981,114:1256-1268.[9]DUMITRUI,ANNA,PETEB.Synthesisof52azacy2tidine:US,7038038[P].2006-03-02.3835: