美托洛尔的合成新工艺研究

:2009-05-31:(1984-),(),,;(1968-),(),,,,,Te:l(0571)86843247,Emai:[e-mail]:1005-0108(2010)01-0044-03宋光伟,姚国新,陈刚,朱锦桃*(,310018):,Darzen4,,IRMS1HNMR13CNMR,,:Darzen;;:R914:AAnovelsynthetictechnologyofmetoprololSONGGuangwe,iYAOGuoxin,CHENGang,ZHUJintao*(DepartmentofChemistry,ZhejiangSciTechUniversity,Hangzhou310018,China)Abstract:AimTosynthesizeanovelconcisesyntheticrouteformetoprolo.lMethodsStartingfrom4hydroxybenzaldehyde,4benzyloxyphenylacetaldehydewasobtainedviabenzylprotection,Darzencondensationandrearrangementreaction.Themetoprololwassynthesizedbyusingadditionreactionofsodiumbisulfiteand4benzyloxyphenylacetaldehyde,reductionbypotassiumborohydride,methylation,deprotection,etherification,andamination.ResultsandconclusionThestructureoftargetcompoundwasconfirmedbyIR,MS,1HNMRand13CNMR.Themethodisconvenientoperationwithoutcomplicatepurificationandsuitableforindustrializedproduction.Keywords:Darzencondensation;chemicalsynthesis;metoprolol(metoprolo,l1)13[(2)]2,,()[1-2],,,[3]3:,4(2)[4],1,,,;,Pd/CSharpless[5],OsO4,;,,,4(2)[6],,,(),2012010293ChineseJournalofMedicinalChemistryVol20No1p.44Feb2010Sum93,,:,4(2),2,4(3),3(4),2(4)(5),51,,,,,1Figure1Thenovelsyntheticrouteofmetoprolol1X-4,NicoletAvator370FT-IRNMRBruker-AV-400MHz,TMSVarianSaturn2200114(2)366g(03mol)538g(039mol)097g(3mmol)(TBAB)120mLDMF,417g(033mol),,653h,,,(20mL3),5%,(2)605g,951%,mp71~73([7]:997%,mp67~68)1HNMR(CDCl3):516(s,2H,OCH2Ph)708(d,2H,J=88Hz,ArH)736~745(m,5H,ArH)784(d,2H,J=88Hz,ArH)989(s,1H,CHO)IR(KBr):30653034293328291688160815771507142612531157864696cm-1124(4)212g(01mol)2100mL,147g(012mol),30%(216g,012mol),,3h50mL,30%(46g,0115mol),,,(10mL2),,(10mL2),,100mL,60,pH=25,,5h,,,(3)212g3,,,20mL,,(10mL2),(4)205g,665%,mp220~2241HNMR(CDCl3):274(dd,1H,J1=140Hz,J2=108Hz,CH2Ph)319(dd,1H,J1=144Hz,J2=28Hz,CH2Ph)446(dd,1H,J1=108Hz,J2=28Hz,CHOH)507(s,2H,OCH2Ph)694(d,2H,J=84Hz,ArH)719(d,2H,J=84Hz,ArH)731~742(m,5H,ArH)IR(KBr):3436303429261612151312491218117710501015695647cm-1451:132(4)(5)66g(20mmol)450mL95%086g(16mmol),05h,pH=6,(20mL3),(5)42g,921%,mp71~73([8]:mp68~70)1HNMR(CDCl3):282(,t2H,J=64Hz,CH2Ph)383(,t2H,J=64Hz,CH2OH)505(s,2H,OCH2Ph)693(d,2H,J=88Hz,ArH)715(d,2H,J=88Hz,ArH)737~744(m,5H,ArH)IR(KBr):32692936158115131453124911191011830767694cm-1142(4)(6)228g(01mol)5100mLTHF,50%(672g,014mol),05h164g(013mol)10mLTHF,,352h,200mL,(30mL3),(6)238g,984%,mp590~600([8]:mp58~60)1HNMR(CDCl3):283(,t2H,J=72Hz,CH2Ph)335(s,3H,OCH3)357(,t2H,J=72Hz,CH2OCH3)505(s,2H,OCH2Ph)691(d,2H,J=88Hz,ArH)714(d,2H,J=84Hz,ArH)732~744(m,5H,ArH)IR(KBr):302929852929286728291609151214511385124011781117830738695cm-1154(2)(7),242g(01mol)608g10%150mL,5MPa,60,,,,,,(7)122g,803%,mp410~420([4]:mp40~42)1HNMR(CDCl3):282(,t2H,J=72Hz,CH2Ph)337(s,3H,OCH3)359(,t2H,J=72Hz,CH2OCH3)547(s,1H,OH)673(d,2H,J=88Hz,ArH)707(d,2H,J=84Hz,ArH)IR(KBr):322730142990292928982866161515951515144913851236120511741092958836823548cm-1163[4(2)]1,2(8)152g(01mol)7278g(03mol)193g(014mol)08g(25mmol)TBAB,75~8015h,,,,94~97/533Pa,(8)179g,86%1HNMR(CDCl3):275(dd,1H,J1=52Hz,J2=28Hz,CHCH2O)282(,t2H,J=70Hz,CH2Ph)290(,t1H,J=46Hz,CHCH2O)333~335(m,4H,OCH3,CHOCH2)356(,t2H,J=72Hz,CH2OCH3)392(dd,1H,J1=112Hz,J2=56Hz,OCH2CH)419(dd,1H,J1=108Hz,J2=32Hz,OCH2CH)685(d,2H,J=84Hz,ArH)714(d,2H,J=88Hz,ArH)IR(film):2984292528702826161215821492145411141036915836cm-117(1)125g(60mmol)830mL,141g(024mol),5h,(1)155g,969%,mp410~420([9]:98%,mp390~400)MSm/z:267[M]+1HNMR(CDCl3):109[d,6H,J=64Hz,CH(CH3)2]226(brs,2H,OH,NH)269~290(m,5H,CHCH2NH,CH2Ph,NHCH)335(s,3H,OCH3)356(,t2H,J=70Hz,CH2OCH3)394~399(m,2H,OCH2CH)399~402(m,1H,CHOH)683(d,2H,J=88Hz,ArH)713(d,2H,J=84Hz,ArH)13CNMR(CDCl3):1571131312981144739705685492489353231230IR(KBr):3289296729242866161115831513145813831244117611141025969824cm-1:[1]NATHANSONJA.Stereospecificityofbetaadrenergicantagonists:Renantiomersshowincreasedselectivityforbeta2receptorsinciliaryprocess[J].JPharmacolExpTher,1988,245(1):94-101.(60)46204DPPH(scavengingactivity,SA)DPPH100!L,96,4,2min,28min490nm,95%,3:SA(%)=[A0-(A1-A2)]/A0100%,DPPH,A0DPPH;A1DPPH;A2,DPPH(%)(1),50%(SC50),SC50!∀Compd.2;#∀Compd.4;∃∀Compd.5;%∀positivecontrol(rosmarinciacid)Figure1ScavengingcapacityofDPPHbycompound2,4,5,androsmarinciacid,245,SC501349mg&L-1,30mg&L-1,DPPH7474%;245SC5097129134044!mol&L-1,SC50964!mol&L-1:[1].:[M]::,1985:42.[2],,.[J].,2003,34(8):12-14.[3],,,.[J].,2007,5(5):459-461.[4],,,.[J].,2002,37(10):740-742.[5]TAKAYUKIH,TOSHIHIKOH,HIROKAZUK.StructuralandfunctionalcharacterizationofpolyphenolsisolatedfromAcerola(MalpighiaemarginataDC.)fruit[J].BiosciBiotechnolBiochem,2005,69(2):280-286.[6],,,.(∋)[J].,2006,23(3):145-147.[7]ZHOULY,LIUHY,XIEBB,eta.lTwonewglycosidesfromSaniculalamelligera[J].ChemSc,i2006,61(5):607-610.[8],,,.[J].,2008,31(8):1172-1174.[9],,,.([J].,2006,36(11):732-734.(46)[2]YOUNGJW,BARBERICHTJ.Compositionandmethodcontainingopticallypure(S)metoprolo:lUS,5362757[P].1994-11-08.[3].(1995):[Z].:,1995:775.[4],.4(2)[J].,1993,24(10):470-471.[5]GURJARMK,JOSHISV,SASTRYBS,eta.lAnewroutetometoprolol[J].SynthCommun,1990,20(22):3489-3496.[6].(2):,1800128A[P].2006-0