新药基因毒性杂质风险分析Risk assessment of genoto(4)

Scheme3.SynthesisofAZD9056

19Scheme4.Synthesisofstartingmaterial

(III)

API.Thetheoreticalpurgefactoris1.0×108,whichsupportsthecontentionthattherewillbenorequirementtotestforthionylchlorideinAPI.Similarly,methylhydrazine(theoreticalpurge8.1×108)willbee cientlypurgedfromthereaction.3.3.CaseStudy3:AZD9056.Thisexamplerelatestothe

synthesisofadevelopmentaldrugAZD9056.Withinthelaterstagesofthesynthesisthreepotentiallygenotoxicimpuritieswereidenti edasbeingofconcern(seeScheme3).ThethreepotentialGTIswerethefollowing:

(1)AZD9056aldehyde:anintermediatewithinthesynthesisofAZD9056;(2)isopropylchloride:formedduringtheisolationstagethroughthereactionbetweenisopropylchlorideandhydrochloricacid(HCl),(3)AZD9056chloride:formedthroughreactionbetweentheAPI(analcohol)andHCl.

Ariskassessmentwasconductedforeachoftheseinturn,andtheoverallresultsaredisplayedinTable7.notthecaseforthefollowingreasons.Thionylchlorideis3.3.1.AZD9056Aldehyde.Onthebasisofapurgefactor

highlyreactive,bothwiththeintendedreactant(11)andwithpredictionof10,000,thiswouldindicatethatthelikelywater°(stepk,Table6);this,combinedwithitscarryoverofthiscompoundintothe nalAPIislikelytobe<100ppm.Givenitscloseproximityto nalAPI,thepuri edanC)e andcientitspurgemiscibilityofanyintolueneunreacted(reactionmaterialsolvent),volatilityandensuresfacilitates(bp79thatAPIwasinvestigatedanalyticallyto ndtheactuallevelstherewillbenocarryoverintothe nalAPIand,importantly,parisonofpredictedandmeasuredpurgefactorsforAZD9056process

identityofpotentiallyimpuritygenotoxicstagereactivitysolubilityvolatilityfactor/stagepurgeoverallpurgefactormeasuredfactorpurge

AZD9056aldehydecrudenonisolated(freebase)10(moderate)a1b1involatile10

AZD9056aldehydecrudeisolated1unreactive101involatile10

AZD9056aldehydepure1unreactive101involatile10

AZD9056aldehyde10×10×10=112000AZD9056chlorideccrudenonisolated(freebase)N/AN/AN/AN/A

AZD9056chloridecrudeisolated1unreactive11involatile1

AZD9056chloridepure1unreactive3d1involatile3

AZD9056chloride1×3=10

isopropylchloridecrudenonisolated(freebase)N/AN/AN/AN/A

isopropylchloridecrudeisolated11010100

isopropylchloridepure11010100

isopropylchloride100×100=1000038500a

toAlthoughconversionessentiallygoesto

d100).bAlthoughhighlysoluble,thealdehydecompletion,isnotthepurgedreactionbecauseisonlythemoderatelycrudeisnotfast;isolated.hence,acChlorideconservativeimpurity gureisofgenerated10wasappliedinthe(ascrudeopposedstage.Solubility,althoughlow,isgreaterthanthatofAZD9056HClsalt.