Side Reactions in Peptide Synthesis 多肽合成副反應

《Side Reactions in Peptide Synthesis 多肽合成副反應》是2015年清華大學出版社出版的圖書，作者是[中]Yi YANG。

基本介紹

• 書名：Side Reactions in Peptide Synthesis 多肽合成副反應
• 作者：[中]Yi YANG
• ISBN：9787302423157
• 定價：198
• 出版社：清華大學出版社
• 出版時間：2015.12.01

圖書簡介

本書是作者在十多年多肽合成第一手經驗的基礎之上，結合大量相關文獻完成的。全書系統地介紹了多肽合成中最常見的副反應，其產生的機理，以及相應的解決方案。其中很多副反應的產生是在GMP生產條件下被發現並加以研究的，其形成機理與生產工藝的開發緊密相關。多肽雜質的形成對於多肽類API的GMP生產具有非常關鍵的影響，因此檢測和分析多肽雜質對成功的API工業生產至關重要。而掌握多肽副反應產生的機理、分析手段及相應的最佳化方案，則是整個多肽API工藝開發和生產環節中的核心要素。本書可供學術界與工業界相關人員參考使用。

前言

Thankstotheirsuperiorpropertiesintermsofhighselectivity,enhancedefficacy,

andappreciablesafety,peptide/peptidomimeticAPIsareplayingincreasingly

importantrolesinthedomainsofpharmaceuticalsandbiotechindustries

bymeansofhormones,neurotransmitters,growthfactors,ion-channelligands,

anti-infectives,andsoforth.Simulatedbytheever-improvingperformancesof

diversepeptidetherapeutics,moreandmoreintentionsarethereforelegitimate

tobeemphasizedonthepeptidedesignandsynthesis,endeavoredjointlyby

academicandindustrialefforts.

Someinherentlyspecificpropertiesofpeptidesynthesisrelativetothoseof

conventionalsmallmoleculescouldcauserathercomplicatedimpurityprofiles.

Moreover,challengesoriginatedfromtheimpurityformationcouldbeintensified

bythefactthatcertain,ifnotall,peptideproductionslacktheintermediary

purifyingeffectsintheupstreamprocesspriortochromatographicpurification

treatment.Needlesstomention,theimpactsofscalingeffectsonpeptideimpurity

formationaresometimestrickytobeelucidated.Alltheseintrinsicchallenges

legitimatethenecessitytopayconsiderableattentiontothesidereactions

thatoccurinpeptidesynthesis.

Asafirststep,theimpurityprofileofthesubjectpeptideAPIissupposedto

bethoroughlyscrutinized,particularlyinpeptidecGMPproductiontoidentify

thecriticalitiesofeachsingleimpurityagainstthepredefinedspecifications.

Theimpurities,whicharepotentiallycriticaltoqualityorbusinessshouldbe

emphasizedandpaidwithpeculiarattentions.Itissubsequentlypertinentto

correlatetheformationofthesecriticalimpuritieswiththecorrespondingside

reactionsandmakeeffortstoelucidatethemechanismoftheidentifiedsidereactions.

Solutionstotackletherelevantsidereactionscouldbedesignedbased

onthesolidin-depthunderstandingoftheoriginsandattributesofthesesidereactions.

Differentreactionstrategiesand/orprocessparametersaresupposedto

beinvestigatedinordertofitthedesignedmodelstothepurposeoftheimpurity

suppression.Bythismeans,thecriticalimpuritiesencounteredinpeptideproduction

couldbediminishedoreliminatedattheupstreamprocessandalleviate

thestressonthepurificationsteps.Hence,thequalityofthefinalpeptideAPIis

assuredandtheprocessperformancecouldbeenhancedaccordingly.

Itisimpliedfromtheaforementionedprocessoptimizationprocedurethat

aninsightintothepeptidesidereactionsisofcrucialimportancetothesuccess

ofpeptideAPImanufacturing.Ihavewrittenthisbooktoaddressthemost

frequentsidereactionsinpeptidesynthesisonthebasisofaplethoraofside

reactionsencounteredinmy10yearsofcommitmenttopeptidesynthesisresearch

andpeptideAPIproduction(whichissimultaneouslyunfortunateand

fortunate).Thesidereactionsareclassifiedinaccordancewiththeirextrinsic

properties.Understandably,thesecategorizationsarenotabsolutelyorthogonal

andindeedsomeindependenceexists.Ineachchapterofthebook,thephenomenon

ofthesidereactionsiselucidated.Themechanismofeachsidereactionis

eitherdescribedortentativelyproposedforfurtherdiscussion.Finally,diverse

possiblesolutionsaresuggestedinordertotacklethereferredsidereactions.

Abundantliteraturereferencesarelistedforextensivereading.

Thesystematicallyorganizedknowledgebehindaplethoraofpeptide-related

sidereactionscouldbesortofhelpforthecolleagueswhoworkinthisarea,no

matterwhethertheyareacademicorproductionoriented.Itisespeciallymeaningful

forthecGMPproductioninwhichasingleout-of-specificationimpurity

couldruinthewholeproduction.Detectionandanalysisoftheimpuritiesin

peptidesynthesis,aswellastheircorrespondingsolutionisthereforehighlyaccentuated.

Howtofindoutthecluesfromacomplicatedimpurityprofilecould

understandablydecidetheoutcomesofthepeptideproduction.Hopefullythis

bookcouldbeofsomehelptotreattheproblemsraisedbypeptideimpurities,

particularlyintherealmofpeptideAPIproductionandcouldultimatelyassist

ustofightrelevantdiseases.

IwishtoexpressmythankstoBielefeldUniversity,LonzaAG,Ferring

Pharmaceuticals,andGenScriptInc.,theformerthreeinparticular,thatprovided

metheoutstandingplatformstoexplorethewonderlandofpeptide.Iam

gratefultoProf.Dr.NorbertSewaldandProf.FernandoAlbericio.Theformer

introducedmetothepeptiderealmasamentorandthelattergavemealot

ofinstructionsinmycareer.IalsoappreciatetheeffortsmadebyMalikLeila

andJ.rgenSj.grenfortheirreviewsofthemanuscript.FabrizioBadalassi(my

boss)offeredmetremendoussupportduringthepreparationofthebook.Last

butnottheleast,IamobligedtomywifeDanLiu,sincehersupportbestows

meallthestrengthtopursuemydream.

目錄

1PeptideFragmentation/DeletionSideReactions

1.1AcidolysisofPeptidesContainingN-Ac-N-alkyl-XaaMotif1

1.2Des-Ser/ThrImpuritiesInducedbyO-acylIsodipeptideBoc-Ser/Thr(Fmoc-Xaa)-OHasBuildingBlockforPeptideSynthesis3

1.3Acidolysisof-N-acyl-N-alkyl-Aib-Xaa-Bond6

1.4Acidolysisof-Asp-Pro-Bond9

1.5AutodegradationofPeptideN-TerminalH-His-Pro-Xaa-Moiety10

1.6AcidolysisofthePeptideC-TerminalN-Me-Xaa11

1.7AcidolysisofPeptideswithN-TerminalFITCModification12

1.8AcidolysisofThioamidePeptide14

1.9DeguanidinationSideReactiononArg18

1.10DKP(2,5-Diketopiperazine)Formation22

References28

2EliminationSideReactions

2.1EliminationofCysSulfhydrylSideChain33

2.2EliminationofPhosphorylatedSer/Thr37

References41

3PeptideGlobalDeprotection/Scavenger-InducedSideReactions

3.1Tert-ButylationSideReactiononTrpDuringPeptideGlobalDeprotection44

3.2TrpAlkylationbyResinLinkerCationsDuringPeptideCleavage/GlobalDeprotection47

3.3FormationofTrp-EDTandTrp-EDT-TFAAdductinPeptideGlobalDeprotection53

3.4TrpDimerizationSideReactionDuringPeptideGlobalDeprotection55

3.5TrpReductionDuringPeptideGlobalDeprotection57

3.6CysAlkylationDuringPeptideGlobalDeprotection58

3.7FormationofCys-EDTAdductsinPeptideGlobalDeprotectionReaction59

3.8PeptideSulfonationinSideChainGlobalDeprotectionReaction63

3.9PrematureAcmCleavageOffCys(Acm)andAcmS→OMigrationDuringPeptideGlobalDeprotection67

3.10MethionineAlkylationDuringPeptideSideChainGlobalDeprotectionwithDODTasScavenger69

3.11Thioanisole-InducedSideReactionsinPeptideSideChainGlobalDeprotection71

References73

4PeptideRearrangementSideReactions

4.1AcidCatalyzedAcylN→OMigrationandtheSubsequentPeptideAcidolysis77

4.2BaseCatalyzedAcylO→NMigration80

4.3His-Nim-InducedAcylMigration86

References93

5SideReactionsUponAminoAcid/PeptideCarboxylActivation

5.1FormationofN-AcylureaUponPeptide/AminoAcid-CarboxylActivationbyDIC95

5.2Uronium/GuanidiniumSaltCouplingReagents-InducedAminoGroupGuanidinationSideReactions97

5.3-LactamFormationUponArgActivationReaction100

5.4NCAFormationUponBoc/Z-AminoAcidActivation102

5.5DehydrationofSideChain-UnprotectedAsn/GlnDuringCarboxyl-Activation103

5.6FormationofH--Ala-OSufromHOSu-CarbodiimideReactionDuringAminoAcidCarboxyl-Activation105

5.7BenzotriazinoneRingOpeningandPeptideChainTerminationDuringCarbodiimide/HOOBtMediatedCouplingReactions107

5.8PeptideChainTerminationThroughtheFormationofPeptideN-TerminalUreainCDI-MediatedCouplingReaction108

5.9GuanidinoorHydantoin-2-ImideFormationfromCarbodiimideandNGrouponAminoAcid/Peptide110

5.10SideReactions-InducedbyCurtiusRearrangementonPeptideAcylAzide110

5.11FormationofPyrrolidinamide-InducedbyPyrrolidineImpuritiesinPhosphoniumSalt115

References116

6IntramolecularCyclizationSideReactions

6.1AspartimideFormation119

6.1.1FactorsThatInfluenceAspartimideFormation121

6.1.2SolutionsforAspartimideFormation127

6.2Asn/GlnDeamidationandOtherRelevantSideReactions137

6.2.1MechanismofAsn/GlnDeamidation137

6.2.2FactorsImpactingonAsn/GlnDeamidation140

6.2.3InfluencesofAsn/GlnDeamidationonPeptideChemicalSynthesis142

6.3PyroglutamateFormation144

6.4HydantoinFormation147

6.5SideReactionsonN-TerminalCys(Cam)andN-BromoacetylatedPeptide153References156

7SideReactionsonAminoGroupsinPeptideSynthesis

7.1N-AcetylationSideReactions163

7.2TrifluoroacetylationSideReactions166

7.3FormylationSideReactions171

7.3.1Trp(For)-InducedPeptideFormylation172

7.3.2FormicAcid-InducedPeptideFormylation173

7.3.3DMF-InducedPeptideFormylation175

7.4PeptideN-AlkylationSideReactions179

7.4.1ChloromethylResinInducedPeptideN-AlkylationSideReactions179

7.4.2PeptideN-AlkylationDuringDeblockingofN-UrethaneProtectingGroup180

7.4.3PeptideN-AlkylationDuringGlobalDeprotection183

7.4.4N-AlkylationSideReactiononN-TerminalHisviaAcetone-MediatedEnamination195

7.5SideReactionsDuringAminoAcidN-Protection(Fmoc-OSuInducedFmoc--Ala-OHandFmoc--Ala-AA-OHDipeptideFormation)196

References198

8SideReactionsonHydroxylandCarboxylGroupsinPeptideSynthesis

8.1SideReactionsonAsp/GluSideChainandPeptideBackboneCarboxylate203

8.1.1Base-CatalyzedAsp/Glu(OBzl)TransesterificationSideReactionDuringtheLoadingofChloromethylResin203

8.1.2EsterificationSideReactionsonAsp/GluDuringPeptidylResinCleavageandProductPurification204

8.2SideReactionsonSer/ThrSideChainHydroxylGroups207

8.2.1AlkylationSideReactionsonSer/ThrSideChainHydroxylGroups207

8.2.2AcylationSideReactionsonSer/ThrSideChainHydroxylGroups208

8.2.3EliminationSideReactionsonSer/Thr210

8.2.4N-TerminalSer/Thr-InducedOxazolidoneFormationSideReactions212

8.2.5Ser/Thr-InducedRetroAldolCleavageSideReaction214References215

9PeptideOxidation/ReductionSideReactions

9.1OxidationSideReactionsonCys217

9.2OxidationSideReactionsonMet223

9.3OxidationSideReactionsonTrp227

9.4OxidationSideReactionsonOtherAminoAcidsandatNonsyntheticSteps228

9.5PeptideReductionSideReactions230

References231

10RedundantAminoAcidCouplingSideReactions

10.1DipeptideFormationDuringAminoAcidN-FmocDerivatization235

10.2RedundantAminoAcidCouplingviaPrematureFmocDeprotection238

10.2.1Lys-Nε-InducedFmocPrematureCleavage239

10.2.2N-Proline-InducedFmocPrematureCleavage242

10.2.3DMF/NMP-InducedFmocPrematureCleavage245

10.2.4ResidualPiperidine-InducedFmocPrematureCleavage246

10.2.5DMAP/DIEA-InducedFmocPrematureCleavage247

10.2.6Hydrogenation-InducedFmocPrematureCleavage248

10.2.7FmocDeblockingintheStartingMaterial248

10.3RedundantAminoAcidCouplingInducedbyNCAFormation249

10.4His-NimPromotedGlyRedundantIncorporation250

10.5RedundantCouplingInducedbytheUndesiredAminoAcid-CTCResinCleavage250

10.6RedundantAminoAcidCouplingInducedbyInsufficientResinRinsing252

10.7RedundantAminoAcidCouplingInducedbyOveracylationSideReaction253

References254

11PeptideRacemization

11.1PeptideRacemizationMechanism257

11.1.1PeptideRacemizationviaOxazol-5(4H)-oneFormation257

11.1.2PeptideRacemizationviaEnolateFormation258

11.1.3PeptideRacemizationviaDirectHAbstraction259

11.1.4PeptideRacemizationviaAspartimideFormation260

11.1.5Acid-CatalyzedPeptideRacemization260

11.2RacemizationinPeptideSynthesis261

11.2.1AminoAcidswithaHighTendencyofRacemizationinPeptideSynthesis261

11.2.2DMAP-InducedRacemization267

11.2.3MicrowaveIrradiation-InducedRacemization268

11.2.4RacemizationDuringPeptideSegmentCondensation268

11.3StrategiestoSuppressRacemizationinPeptideSynthesis269

11.3.1AminoAcidN-ProtectingGroup269

11.3.2AminoAcidSideChainProtectingGroup274

11.3.3CouplingReagent276

11.3.4CouplingTactics282

11.3.5Solvent285

11.3.6Base285

11.3.7AminoAcidActivationMode286

11.3.8Temperature287

11.3.9Cu(II)SaltAdditive287References288

12SideReactionsinPeptidePhosphorylation

12.1FormationofH-PhosphonateSideProduct293

12.2FormationofPyrophosphateSideProduct296References297

13CysDisulfide-RelatedSideReactionsinPeptideSynthesis

13.1DisulfideScramblingviaThiol-DisulfideExchange299

13.2DisulfideDegradationandConsequentTrisulfideandLanthionineFormation302

13.2.1DisulfideDegradationPattern302

13.2.2TrisulfideFormation303

13.2.3LanthionineFormation308

References309

14Solvent-InducedSideReactionsinPeptideSynthesis

14.1DCM-InducedSideReaction311

14.2DMF-InducedSideReaction312

14.2.1DMF-InducedN-FormylpiperidineFormation312

14.2.2DMF-InducedFormylationSideReactions313

14.2.3DMF-InducedAcidChlorideFormationSideReactions313

14.3Methanol/Ethanol-InducedSideReactions315

14.3.1Methanol-InducedEsterificationSideReactions315

14.3.2Methanol-InducedN-AlkylationSideReactionsinCatalyticHydrogenation315

14.4Acetonitrile-InducedSideReaction316

14.5Acetone-InducedSideReaction317

14.6MTBE-InducedSideReaction319

14.7TFE-InducedSideReaction319

References320

AppendixI

MolecularWeightDeviationofPeptide

Impurity323

AppendixIIListofAbbreviations347

SubjectIndex353