Table5.PredictedpurgefactorsforthionylchlorideinBAY43-9006process

stagereactivity(R)solubility(S)volatility(V)processesphysical

(PP)comments

110010101SOClproposition.2isavery

vacuum.ThionylAnalytereactiveintermediate(R=100),andthehighyields(89%)supportahighreactione ciency

chloridehashighboilssolubilityat79°Cin(DMFV=10).(S=There10),isandnointermediatephysicalprocessing5isisolated,inthiswashedstage(PPand=dried1).under

21001013SOClAnalyte2will

though,hasreact

isdissolvedhighwithsolubilitymethylamine

inethylinTHFbase

acetate(Sand=and10).with

washed/extractedThereaqueousisnospecibrine

with c(useddryingto

aqueousstepextract

brine(V=isolatedintermediate)(R=100).

(PP1).=The3).isolatedintermediate(7),

31001013SOCl2willreactwithbases(K-tert-butoxide/K2CO3)andwithaqueousbrine(usedtoextractisolatedintermediate)(intermediateR=100).Analyte(7),though,hashighisdissolvedsolubilityininethylDMFacetate(S=10).andTherewashed/extractedisnospeci cwithdryingaqueousstep(brineV=1).(PPThe=3).isolated4110101Reactivitysolubilityisinpredicteddichloromethanetobelow,(asSthe=10).reactionAnyisresidualperformedthionylinachloride,nonaqueousthough,environmentislikelyto(Rbe=1).removedAnalyteonhasdrying.ahighScheme2.SynthesisofGSK183390A

a

aReactionsconditions:(a)NaOEt,0 80°C,yield99%;(b)CH3NHNH2,EtOH,90°C,yield22%(unwantedisomeryield45%);(c)NHCHroomtemperature,yield93%;ethyl(d)ammoniumbromoisobutyrate,formate,yieldPd/C69%;catalyst,(h)TFA,re ux,CHMeOH,yield50%;(e)aqHBr,yield97%;(f)2OH·HCl,NaOAc,EtOH,Boc2O,2Cl2,Et3N,yield96%;(g)K2COthen3,DMF,Et2Cl2,yield82%;(i)NaOH,roomtemperature,yield98%;(j)SOCl2,toluene,80°C,3N,10,roomtemperature,yield96%;(k)NaOH,80°C,yield73%.

Table6.TheoreticalpurgefactorsforGTIsinPPARα/γagonist(1)syntheticprocess

GTIstagereactivityM=10,HL==100,1solubilityM=3,FL==10,1volatilityM=3,HL==10,1totalpermultiplestagerationaleforpurgefactor

CH3NHNH221001033000bpdistillation/partialofCH3NHNH288drying 90°C,solventremovedby

31339productisolatedanddried

410103300likelyformedreaction(stepwithj);productSO2Clandisolatedalsowithandthedriedacylchloride

ALL8.1×106

SO2Cl4(j)100101010000highlyreactive,volatilebp79°C

4(k)100101010000reactsinstantaneouslyinaqueousenvironment

1.0×108

(2-pyridyl)]-N-methylcarboxamide)(9)in87%yield.This(1)Methylhydrazineisusedinstage2tocyclisetheintermediate(9)isthencoupledwithisocyanate(10)toyielddiketone(4)toproducethepyrazoleester(5).theAPI(3).(2)Thionylchlorideisusedtoactivatethepyrazole(10)viaThebasisbywhichpredictedvaluesareselectedandthetheformationofanacidchloridewhichisthenreactedassociatedrationalesaredescribedinTable5.withthebenzylamine(10)toformtheAPI.Theoverallpurgefactoris9×10.12Theextremelyhigh

reactivityofthionylchloridetohighpH/aqueousconditionsApurgefactorassessmenthasbeenappliedtothisroutetodominatesthepurgingfactorinthe rstthreestages.determinethelevelofriskfromagenotoxicimpurities

3.2.CaseStudy2:RetrospectiveEvaluationofaperspectiveaspartofanevaluationofthepotentialcontinuedPPARα/γAgonist(GSK183390A).Thesyntheticschemeuseoftheproceduredescribed(Table6).

(Scheme2)showstheoriginalmedicinalchemistryrouteusedEmpirically,theriskofcarryoverofGTIs/PGIsisoftentomanufactureaPPARα/γagonistindrugdevelopment.Fromassessedonthebasisofproximity(pointofintroductioninthesynthesis)tothe nalAPI.Thus,thionylchloridetheoreticallyaGRAperspectivetherearetwoknowngenotoxiccompoundsposesthehighestriskwithrespecttocarryoverintotheAPIasinvolvedinthesynthesis:itisintroducedintothe nalcouplingstage.Inpracticethisis