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[doc] t-Butyl Esters

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[doc] t-Butyl Esters

    t-Butyl Esters

iren,

    ;MENGL-juanandWANGJian—wu’

    ;1.SchoolofChemistryandChemicalEngineering,ShandongUniversity,Mn250100,P.R.China;

    ;2.ThePharmaceuticalResearchInstituteofTianjin,Tianjin300193,P.R.China

    ;ReceivedOct.8,2005

    ;Racemic2-n.butylbutanedioicacid4-t.butylestersweresynthesizedfrommethylhexanoateandt-butyla-iedoac-

    ;cratevhtalkylationandsubsequentlyselectivehydrolyzation.e(R).and(S)-2一凡一butylbutanedioicacid4?tbutyl

    ;esterswereobtainedbytheresolutionoftheabove.mentionedracemiccompoundswith(S)()or(R)(+)

    ;methylbenzylamine.respectively.rhee.e.valuesofthetwoopticalactiveproductsweredeterminedtobeabove

    ;99%byHPLCaftertheformationoftwopairsofdiastereoisomerswith(R)

    (+).methylbenzylamineand(S)?

    ;phenylalaninemethylester.

    ;KeywordsMethylhexanoate:4-t.Butyl2-n.butylbutanedioicacid;Resoluti

on;e.e.Value

    ;ArticleID1005-9040(2006)5-5845

    ;Introduction

    ;2-Substitutedenantiomericallypuresuccinicacid ;derivativeshaveattractedaconsiderableinterestinre- ;centyears,mainlybecauseoftheirimportancefitschiral ;buildingblocksandpeptidomimeticsinthefieldof ;pharmaceuticaldesign[].Mostapproachestoward ;thesynthesisofchiral2-alkylsuccinatesrequiretheuse ;ofexpensivechiralauxiliaries[?orchiralcata

    ;lysts[‘.

    ;Asalargenumberofcompoundswerere

    ;quiredforthisstudy,therepoaedproceduresappear ;notverypractica1.Thelargenumberwilt8becauseof ;0

    ;/

    ;o

    ;0

    ;thefactthattherequiredauxiliariesorchiralcatalysts ;werequiteexpensiveandtediousmuhistepsequence ;wasrequiredafterasymmetrichydrogenation. ;Duringtheresearchanddevelopmentofpeptide

;deformylase(PDF)inhibitors,enantiomericallypure

    ;2-alkylsuccinicacidmonoesterwas ;ingmaterialinlargequantities. ;requiredasastart

    ;Inviewoftheabovementioneddrawbacksofthe ;procedures,apracticalresolutionprocedure

    ;wilt8developedforthesynthesisofthetide

    ;(Scheme1)inthispaper.

    ;2

    ;0

    ;0/

    ;OBu

    ;0

    ;(R)(+)3().-Methylbenzylanne(R)(+)3 ;4

    ;()3

    ;0

    ;0H

    ;0B

    ;Motherliquor._-f_).()-3R.(+)一口-Methylbenzylane墨一().()3

    ;S

;compounds

    ;Reagentsandcon~fiom:a.(1)LDA,THF,

    78?;(2)ICH2CO2Bu’;b.LiOH,MeOH/H20;c.L-()..a-methylbenzylamine;d?1moVL

    ;HC1;e.1moVLHC1;f.R(+)-a-methylbenzylamine;g.1moVLHC1. ;Scheme1Thesyntheticrouteandresolutionprocessoftheriflecompounds?

    ;}SupportedbytheNationalBasicResearchPriorityProgram(No.2003CCA

    027).

    ;}}Towhomcorrespondenceshouldbeaddressed.Email:jwwang@sdu.edu.cn

    ;

    ;No.5ZHANGDatongeta1.585

    ;Experimental

    ;Themeltingpointsweredeterminedbyusingan ;XT-4microscopicapparatuswhichwereuncorrected. ;TheHNMRspectrawererecordedonaBruker

    ;AvanceDPX3o0andDPX4o0spectrometerswith ;CDClasthesolventandTMSastheinternalstandard. ;TheIRspectraweremeasuredonaBrukerVectorFT

    ;IRspectrophotome~rwithKBrpelletsorfilm.The ;massspectrawereobtainedwithanAPI4O0ospectrom. ;eter.TheelementalanalyseswereperformedonaPer

    ;kinElmer2400analyzer.Theopticalrotationswere ;measuredbyusingaWZZ-2polarimeter.TheHPLC ;analyseswerecarriedoutonaShimadzuLC10Ahquid

    ;chromatographyinstrumentequippedwithanLC10Tvp

    ;detectorat254nmandanAlltimaamino..bondedco1.. ;umn(4.6lnl/l×250mm)v/aelutionwithamixtureof ;isopropanol/hexane(volumeratio:4:96)ataflowrate ;of1mL/min.AIItheanhydroussolventswerefleshly ;purifiedbystandardprocedures.

    ;12--ButylbutanedioicAcid1-Methyl4-t.butyl ;Ester(Compound2)

    ;Asolutionofbutyllithiuminhexane(52mL,150 ;mmo1)wasaddedtoastirredmixtureofdiisopropyl

    ;amine(14.4g,143mmo1)andanhydrousTHF(100 ;mE)underN2,andtheresultingmixturewagheldat ;0?foranadditional15min.Itwasthencooledto ;

    ;78?,towhichmethylhexanoate(16.4g,130 ;mmo1)wasaddeddropwiseandthestirringwascontin

    ;uedforanother30minat78oC.Subsequentlyt

    ;butylot?iodoacetate(34.6g,143mmo1)wasadded ;dropwisetothemixture.whichwaskeptat78?for

;1h.andthentIlemixturewaswarmedto0?and

    ;quenchedwith1mot/LHCl(50mL).Afterdiluting ;thwater(50mE),themixturethus.obtainedwasex

    ;tractedwithethylacetate(100mL×3).andthecom

    ;binedextractswerewashedwithwaterandbrineSUC

    ;cessivelyandthendriedoveranhydrousMgSO4fol

    ;lowedbyevaporation.Thecrudeproductwasdistilled ;underthereducedpressuretoresultingincompound2 ;intheformofacolorlessoil(19g,60%),whichboils ;at103105?/400Pa.

    ;IR(film),cm:2957,2933,2863,1733,

    ;1367,1151,849.HNMR(CDC13,4OOMHz),: ;3.69(s,3H),2.76-2.80(m,1H),2.62(dd,J: ;16.2,9.3Hz,1H),2.35(dd,J:16.2,5.2Hz, ;1H),1.601.65(m,1H),1.441.51(m,1H),

    ;1.43(s,9H),1.251.32(m,4H),0.89(t,3H).

    ;MS(ESI),m/z(%):245(M+H),267(M+

    ;Na);Elementalana1.,calc.(%)f0rC13H2404:C ;63.91,H9.90;found(%):C64.11,H9.71. ;22-n-ButylbutanedioicAcid4-t-ButylEster ;[(?)-Compound3]

    ;Compound2(12.4g,50.8mmo1)andLiOH?

    ;H2O(2.49g,53.3mmo1)werestirredin100mLof ;5:1(volumeratio)methanol/wateratloomtempera

    ;turefor8h.Thereactionmixturewasconcentratedto ;removemethano1.andtheresiduewasdilutedt}1wa

    ;ter(20mL).rI1lemixturewasthenextractedt}I ;CH2C12(10mL×3),andtheaqueousphasewasacid

    ;ifiedtopH=2withconcentratedHC1.rI1leacidic ;aqueoussolutionwasthenextractedwithethylacetate ;(30mL×3),andthecombinedextractsweredried ;overanhydrousMgSO4andevaporatedtoaffordaresi

    ;due,whichwaspurifiedbycolumnchromatographyon ;silicagel(200--300mesh,petroleumether/ethylace

    ;latewiavolumeratioof3/1)toyield(?)com

    ;pound3intheformofacolorlessoil(7.6g,65%). ;IR(film),cm:2960,2933,2874,1733,

    ;1708,1368,1154,949,851.HNMR(CDC1,4OO ;MHz),:2.78-2.82(m,1H),2.62(dd;J=

    ;16.4,9.3Hz,1H),2.38(dd,J=16.4,5.2Hz, ;1H),1.521.67(m,2H),1.43(s,9H),1.31

    ;1.34(m,4H),0.89(t,3H).MS(ESI),m/z(%): ;231(M+H),253(M+Na);Elementalana1., ;calc.(%)f0rC12H2204:C62.58,H9.63;found

;(%):C62.36,H9.91.

    ;3(R)-2-n-ButylbutanedioicAcid44-ButylEster ;[(+)-Compound3]

    ;(?)Compound3(11.5g,50mmo1)wasdis

    ;solvedindiethylether(120mL),towhich(S)ot

    ;methylbenzylamine(3.63g,30mmo1)wasadded. ;Thesolutionwaskeptat4?ovemight.andthewhite

    ;solidwascollectedbyfiltration(6.58g).Recrystalli

    ;zationofthesohdfromethylacetatewasdonetwice, ;whichresultedintheformationofasalt,compound4. ;intheformofwhiteneedles(4.82g,54.9%). ;[ot]2D5:3.0.(c=1.5,CHC13).rI1leisolatedcrys

    ;tailineneedleswerethendissolvedinchloroform(100 ;mL)andwashedwithlmol/LHCI(30mL×2)and ;brine(20mL).rI1lechloroformphasewasdriedand ;concentratedtogive(R)(+)compound3(2.99g,

    ;95%),[ot]2D5=+15.5.(C=1,CHC13),e.e.> ;99%.

    ;4(S)-2-Jl-ButylbutanedioicAcid44-ButylEster ;[()-Compound3]

    ;rI1lemotherliquor.obtainedaftertheisolationof ;compound4,wasconcentratedtodrynessandtheresi

;duewasdissolvedinchloroform(100mL).rI1leresul

    ;tingsolutionwaswashedt}I1mol/LHC1f30mL× ;2).rI1leorganicphasewasdriedoveranhydrous ;

    ;586CHEM.RES.CHINESEU.V01.22

    ;MgSO4andevaporatedtoaffordaresidue,whichwaLs ;dissolvedindiethylether,towhich(R)-otmethyl-

    ;benzylamine(1equivalent)waLsadded.Thesolution ;waskeptat4oCovernight.andthewhitesolidwas ;collectedbyfihration.whichwaLsrecrystallizedfrom ;ethylacetatetwicetoprovidethedesiredproductinthe ;formofwhiteneedles(4.7g,53.6%).[a]: ;+2.67.(c=1.5,CHC13).Theisolatedcrystalline ;needlesweredissolvedinchloroform(100mL)and ;washedwith1mol/LHC1(30mL×2)andbrine(20 ;mL),successively.Theorganicphasewasdriedover ;anhydrousMgSO4andthenconcentratedtogive(S)

    ;().compound3(2.92g,95%),[ot]2D5:16.0.

    ;(c=1,CHC13),e.e.>99%.

    ;5?-[(R)廿Methylbenzy1]-(2R)-2-tert-butoxy- ;carbonylmethylhexamide[(R,R)-Compound6] ;Toasti~edsolutionof4,6-dimethoxy-2chloro-1,

;3,5triazine(CDMT)(86mg,0.49mmo1)and(R)

    ;2-nbutylbutanedioicacid4-tertbutylester(115mg,

    ;0.5mmo1)indryCH2C12(10mL)N-methylmorpho- ;line(NMM,50.5mg,0.5retoo1)wasaddeddropwise ;at0oCandwascontinuouslystirredat0oCfor4h.To ;thecrudesolution(R)-methylbenzylamine(59mg, ;0.49mmo1)inCH2C12(2mL)wasaddedat0oC. ;Stirringwascontinuedfor2handthenthemixturewas ;leftovernightatroomtemperature.Thesolventwas ;evaporatedandtheresiduewasdilutedwithCH2C12. ;ThesuspensionwaswashedsuccessivelywithH2O, ;0.5mol/LHC1,saturatedNaHCO3,andbrine.The ;organicphasewasdriedandevaporatedtogiveawhite ;solid.Thecrudeproductwaspurifiedbycolumnchro

    ;matographyonsilicagel(20o30omesh,petroleum

    ;ether/ethylacetatewithavolumeratioof5:1toyield ;(R,R)compound6intheformofcolorlesscrystals ;(122mg,75%),m.P.64.5-_65.5?.

    ;IR(KBr),cm:3287,3064,2954,2929,

    ;2870,1727,1647,1550,1160,699.HNMR

    ;(CDC13,300MHz),:7.197.30(m,5H),6.03

    ;(d,1H),5.11(m,1H),2.45_2.62(m,2H),

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