“Dutch”拆分研究进展

:20071,:20075*e-mail:[e-mail]/Dutch0拆分研究进展孙凤霞*付德才于奕峰郭军永张丽丽(河北科技大学化学与制药工程学院石家庄050018)本文综述了第一代Dutch拆分第二代Dutch拆分及反义Dutch拆分的拆分机理和研究进展,并展望了Dutch拆分的应用前景Dutch拆分能以高收率和近于100%ee值与所有的实验消旋体迅速形成非对映体的结晶第一代Dutch拆分中family拆分试剂形成非对映体晶体过程是典型的固溶体行为在第二代Dutch拆分中,成核抑制剂改变了非对映异构体的亚稳区宽度,溶解度较大的非对映体盐比溶解度较小的非对映体盐的结晶温度下降得更多,使溶解度较小的非对映体盐更容易析出Dutch拆分手性反义拆分第一代Dutch拆分第二代Dutch拆分:O62113+4;O656:A:1005-281X(2007)11-1746-08DutchResolutionSunFengxia*FuDecaiYuYifengGuoJunyongZhangLili(CollegeofChemicalandPharmaceuticalEngineering,HebeiUniversityofScienceandTechnology,Shijiazhuang050018,China)AbstractDevelopmentsandmechanismofthefirstgenerationDutchresolution,thesecondgenerationDutchresolutionandreverseDutchresolutionarereviewed.Diastereomericcrystallizationcanbeformedeasilyandrapidlywithhighyieldandnearly100%eeinDutchresolution.MembersofthefamilyresolvingagentsshowthesolidsolutionbehaviorinthefirstgenerationDutchresolution.InthesecondgenerationDutchresolution,nucleationinhibitorwidensthemetastablezoneofdiastereoisomers,andthenucleationtemperatureofthemoresolublediastereomericsaltdropsmorethanthatofthelesssolublediastereomericsalt.Sothelesssolublediastereomericsaltcancrystallizeeasily.TheapplicationandoutlookofDutchresolutionarepresentedintheendofthispaper.KeywordsDutchresolution;chirality;reverseresolution;firstgenerationDutchresolution;secondgenerationDutchresolution,[1)8],60%[1)8],,,FDA(FoodandDrugAdministration)SFDA(StateFoodandDrugAdministration)[9],,3(1):,,(2):,,1911200711化学进展PROGRESSINCHEMISTRYVol.19No.11Nov.,2007,[6](3):,,65%[6],,,[6]11848,LouisPaster,,,(),,,,:(1);(2);(3)[6],Dutch,2Dutch,1998,Vries[10],,100%ee,Vries[10]/familyapproach02000Vries/familyapproach0/Dutchresolution0,Dutch[11,12]Dutch,DutchDutchDutchKellogg[10]Dutch:(strongstructuralsimilarity)(stereochemicallyhomogeneous:homochiraliltyamongfamilymembersandenantiomericpurityofthecomponents)1VriesKelloggfamily1[9]Fig.1Familyresolvingagents[9]211Dutch)))FamilyApproach1998,VriesKellogg,)))familyapproach,Vries,11,3,3,,100%ee[10],1HNMRHPLCGC,#1747#11/Dutch02-,51B317,1B311,,(10),1B120,2--1-,20,31B14B55[10]2000,Vries[11]familyapproachDutch,Dutch[12,13]Dutchfamily1B1B1,;,3,[10][14]familyapproach(2S,3S)-(O-)-Collet[15]family(solidsolution),,,,,,,,,pn[15]Dutchee2000Vries(DL-D-Phg)(+)-CSA,X[11]Vries(DL-Hpg)(DL-Hpg)(+)-((+)-CSA)(5%ee),(DL-Phg)(+)-((+)-CSA)(+)-CSAX,HpgPhgPhg-(+)-CSA,Phg-(+)-CSAPhgHpg[11]Kitaigorodsky[16]:/AB(geometricalsimilarityofthemolecule)018,AB(packing),AB0Gervais[17]DutchVriesKellogg[10]Dutch100,3,VriesKellogg[10],,,,Dutch,TADDOL(para-substitutedbis(hydroxydiphenylmethyl)dioxalanes)A-[10][18,19][20]L-(2)family10B-,ee99%70%,(a+b+d)ee,Vries[21](2R,3R)-(-)-DMTA(d),Dutch2L-[20]Fig.2EsterderivativesofL-tartaricacid[20]Dutch,#1748#化学进展19,Dutch,Markovits[22],Dutch,,,,Markovits,family:iS=mSPcS:mSDutch;cS,VriesDutch100%ee,,;Vries,[10],Dutch[2],,1:DutchPE-Ó,,,,,[13,23],Dutch,[10],Mereyala[24]3-O--(3-O-hydrogenphthalateglucofuranose)(3),1-Dutch3121-,()1-,1-31-,,,33-O--1-[24]Fig.3Resolutionof1-arylalkylamineswith3-O-hydrogenphthalateglucofuranosederivatives[24]Dutch,,Vries,ee,[10];,212Dutch)))DutchResolutionNieuwenhuijzenfamilyapproachDutch[12,25]Nieuwenhuijzenfamilyapproach,Vries10,,;310%,Nieuwenhuijzen:#1749#11/Dutch0,3(1-)Dutch1-(4)(5)[12]E,,,Dutch,family-10-,,Dutch5cNieuwenhuijzen1,3--3--(6),DutchDutch1,3--3--[25]4[12]Fig.4Derivativesof1-phenylethanesulphonicacidsandderivativesofbenzylcamphorsulphonates[12]5[12]Fig.5Derivativesofchiralsulphonicacids[12]61,3--3--[12]Fig.6Derivativesof1,3-dipheny-l3-oxo-propanesulph-onates[12]Nieuwenhuijzen,/(parentresolvingagent)0;,/(additiveagent)0,,Dutch,,,[23]Dutch,100%ee,DutchNieuwenhuijzen(nucleationinhibitor)[25],,Dutch,,,Dutch100%ee[25],Nieuwenhuijzen2005,DalmolenDutch(7)A-2-N-chlocyphos(),A-Dutch,DalmolenA-,A-[26,27]7[26,27]Fig.7Derivativesofphenylglycineamideandarybutylamines[26,27]Dalmolen[26,27](R)-A-((R)-A-phenylethylamine,(R)-PEA),A-(A-phenylbutylamine,A-PBA),(A-A-N--DL-)89(R)-A-#1750#化学进展19(mandelicacid),(S)-#(R)-PEA(R)-A-189,18,(R)-PBA(0)6%),(7e2815e),8%,11e1(S)-#(R)-PEAPBA[27]Table1Nulceationanddissolutiontemperatureofthemoresoluble(S)-mandelicacid#(R)-PEAwithPBAadded[27]entryadditiveamountofadditivenucleationtemp.(e)dissolutiontemp.(e)widthmetastablezone(e)1))411849117132(R)-PBA4%2512481523133(R)-PBA6%1917481228154(R)-PBA8%3416451611105(?)-PBA6%2215471825136(S)-PBA6%3418471813108(S)-#(R)-PEA(R)-PBA[27]Fig.8Theturbidityexperimentofthemoresoluble(S)-mandelicacid#(R)-PEA[27]6%(R)-PBA,PBA,2815e2513e,9;(S)-PBA,13e10(R)-#(R)-PEAPBA2109(S)-#(R)-PEAPBA[27]Fig.9Theturbidityexperimentofthemoresoluble(S)-mandelicacid#(R)-PEA[27]210,PBA(R)-PBA(S)-PBA10(R)-#(R)-PEAPBA[27]Fig.10Theturbidityexperimentofthelesssoluble(R)-mandelicacid#(R)-PEA[27]2(R)-#(R)-PEAPBA[27]Table2Nulceationanddissolutiontemperatureofthelesssoluble(R)-mandelicacid#(R)-PEAwithPBAadded[27]entryadditiveamountofadditivenucleationtemp.(e)dissolutiontemp.(e)widthmetastablezone(e)1))651469133192(R)-PBA6%611468147103(?)-PBA6%621168105194(S)-PBA6%62116912711PBA,,(S)-#(R)-