1
(51)InternationalPatentClassification:
C07D498/22(2006.01)(21)InternationalApplicationNumber:
PCT/IN2019/050369
(22)InternationalFilingDate:
09May2019(09.05.2019)
(25)FilingLanguage:(26)PublicationLanguage:(30)PriorityData:
201821017401
09May2018(09.05.2018)
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EnglishEnglish
IN
(72)Inventor;and
(71)Applicant:ALAPARTHI,LakshmiPrasad[IN/IN];
BhavikPatel,InfinventIP,A/9,AmnitaSociety,Nizampu-ra,Vadodara-390002,Gujarat(IN).(72)Inventor:RAO,GinjupalliSadasiva;HouseNo.D/No.
3-106,Pedamaddur(post)Amaravathi(Mandal),Guntur522020,AndhraPradesh(IN).(74)Agent:INFINVENTIP;BhavikPatel,InfinventIP,A/9,
AmrutaSociety,Nizampura,Vadodara-390002,Gujarat(IN).(81)DesignatedStates(unlessotherwiseindicated,forevery
kindofnationalprotectionavailable):AE,AG,AL,AM,AO,AT,AU,AZ,BA,BB,BG,BH,BN,BR,BW,BY,BZ,CA,CH,CL,CN,CO,CR,CU,CZ,DE,DJ,DK,DM,DO,DZ,EC,EE,EG,ES,FI,GB,GD,GE,GH,GM,GT,HN,HR,HU,ID,IL,IN,IR,IS,JO,JP,KE,KG,KH,KN,KP,KR,KW,KZ,LA,LC,LK,LR,LS,LU,LY,MA,MD,ME,MG,MK,MN,MW,MX,MY,MZ,NA,NG,NI,NO,NZ,OM,PA,PE,PG,PH,PL,PT,QA,RO,RS,RU,RW,SA,SC,SD,SE,SG,SK,SL,SM,ST,SV,SY,TH,TJ,TM,TN,TR,TT,TZ,UA,UG,US,UZ,VC,VN,ZA,ZM,ZW.(84)DesignatedStates(unlessotherwiseindicated,forevery
kindofregionalprotectionavailable):ARIPO(BW,GH,GM,KE,LR,LS,MW,MZ,NA,RW,SD,SL,ST,SZ,TZ,UG,ZM,ZW),Eurasian(AM,AZ,BY,KG,KZ,RU,TJ,TM),European(AL,AT,BE,BG,CH,CY,CZ,DE,DK,EE,ES,FI,FR,GB,GR,HR,HU,IE,IS,IT,LT,LU,LV,MC,MK,MT,NL,NO,PL,PT,RO,RS,SE,SI,SK,SM,TR),OAPI(BF,BJ,CF,CG,Cl,CM,GA,GN,GQ,GW,KM,ML,MR,NE,SN,TD,TG).
(54)Title:ANIMPROVEDPROCESSFORPREPARATIONOFMIDOSTAURIN
(57)Abstract:TheinventionrelatestoaprocessforpreparationofMidostaurin.MorepreferablytheinventionrelatestoprocessforthepreparationofMidostaurincomprisingreactingthestaurosporinewithbenzoicacidinpresencesofcondensingagent.Inoneaspectoftheinvention,toanewprocessforpurifyingMidostaurin.
TITLE:ANIMPROVEDPROCESSFORPREPARATIONOF
MIDOSTAURIN
FIELDOFTHEINVENTION
ThepresentinventionrelatestoanovelprocessforpreparationofMidostaurinof
formulaI.
BACKGROUNDOFTHEINVENTIONMidostaurin
is
N-[(9S,l0R,llR,l3R)-2,3,l0,ll,l2,l3-hexahydro-l0-methoxy-9-'-lm]pyrrolo[3,4-j][l,7]
methyl-l-oxo-9,l3-epoxy-lH,9H-diindolo[l,2,3-gh:3',2',l
benzodiazonin-ll-yl]-N-methylbenzamideofthefollowingformula:
ThedrugMidostaurinisusedasananti-tumouragent.Ingeneral,thepreparationofMidostaurinisdisclosedinU.S.PatentNo.5,093,330.However,efficient,andindustriallyviableprocessofpreparationtheMidostauriniscertainimportant.Therefore,thereisacontinuingneedfornewprocessofpreparationofMidostaurin.Staurosporine,thebasicelementofthederivativesaccordingtothepresentinventionwasisolatedalreadyintheyear1977fromculturesofStreptomycesstaurosporeusAWAYA,TAKAHASHIandOMURA,sp.nov.AM2282,cf.S.Omuraetal.,J.Antibiot.30,275-281(1977).Hitherto,onlytherelative,butnottheabsoluteconfigurationofstaurosporinwasknown.TheabsoluteconfigurationwaspublishedonlyrecentlybyN.Funatoetal.,TetrahedronLetters35:8,1251-1254(1994)andcorrespondstothemirrorimageofthestructure,useduptonowinthe
literaturetodenotetherelativeconfigurationofstaurosporine.Accordingly,intheTetrahedronLetterspublicationitisliterallyrecommended\"thatthestereochemicalnotationforstaurosporinewhichhasbeenincommonusehithertoshouldberevised\".Althoughtheabsoluteconfigurationwasnotknownhitherto,itwasunequivocallyfixed(defined)bythedesignationas\"staurosporinederivatives\".Therefore,inordertoavoiderrorsuponcomparisonwiththepriorityapplications,theoriginalformulaearestillusedinthepresentapplication.
U.S.PatentNo.5,093,330disclosesN-benzoyl-staurosporine.Theinventionrelates
especiallytoaparticularN-benzoyl-staurosporinederivativeofthecompound.TheU.S.PatentNo.5,093,330disclosesinExample18processforthepreparationofN-
benzoyl-staurosporinederivative(Midostaurin)byreactingstaurosporinewithbenzoylchlorideatroomtemperatureinpresencesofN,N-diisopropylethylamineandchloroform.Thisprocessrequiresanhydrousconditionsasbenzoylchloridegetsconvertedtobenzoicacidandthereactiondoesn’tproceedtocompletion.Moreoveritisobservedthatmoreimpuritiesareformedinthisreaction.
EuropeanPatentNo.EP2272850B1disclosesprocessforthepreparationofcrystallineformIIofN-benzoyl-staurosporine.TheinventionrelatesespeciallytoaparticularcrystallineformIIofN-benzoyl-staurosporineofthecompound.TheEuropeanPatentNo.EP2272850B1disclosesprocessforthepreparationofN-benzoyl-staurosporinebyreactingpurifiedstaurosporineinanalcoholsolventwithbenzoicanhydride.Thisprocessrequireslongerreactiontimestoproceedforreactioncompletion.
ThepresentinventionisdirectedtoprovidenovelprocessforthepreparationofMidostaurinofformulaIwhichisefficient,industriallyviablewhereinreactionconditionsaremildandsimpleforoperation,lessexpensivecosteffectiveprocess.
SUMMARYOFTHEINVENTION
Inaccordancewithoneaspect,ofthepresentinventionistoprovideanimproved
processforthepreparationofN-[(9S,l0R,llR,l3R)-2,3,l0,ll,l2,l3-hexahydro-l0-methoxy-9-methyl-1-oxo-9,l3-epoxy-lH,9H-diindolo[1,2,3-gh:3',2',1'-
lm]pyrrolo[3,4-j][l,7]benzodiazonin-ll-yl]-N-methylbenzamide(Midostaurin)offormulaIandpharmaceuticallyacceptablesaltsthereof.
Inaccordancewithyetanotheraspect,ofthepresentinventionistoprovide
improvedprocessforthepreparationofMidostaurinbyreactingstaurosporinewithbenzoicacid.
Inaccordancewithyetanotheraspect,ofthepresentinventionistoprovideimprovedprocessforthepurifyingofMidostaurinbytreatingwithsolventandanti-solventprecipitationprocess.
DETAILEDDESCRIPTIONOFTHEINVENTION
Unlessdefinedotherwise,alltechnicalandscientifictermsusedhereinhavethesamemeaningascommonlyunderstoodbyoneofordinaryskillinthearttowhich
thisinventionbelongs.Althoughanymethodsandmaterialssimilarorequivalentto
thosedescribedhereincanbeusedinthepracticeortestingofthepresentinvention,thepreferredmethodsandmaterialsaredescribed.
Forthepurposesofthepresentinvention,thefollowingtermsaredefinedbelow.Thesingularforms\"a,\"\"an,\"and\"the\"mayrefertopluralarticlesunlessspecificallystatedotherwise.
Theterm\"about,\"asusedherein,isintendedtoqualifythenumericalvalueswhichitmodifies,denotingsuchavalueasvariablewithinamarginoferror.Whennoparticularmarginoferror,suchasastandarddeviationtoameanvaluegiveninachartortableofdata,isrecited,theterm\"about\"shouldbeunderstoodtomeanthatrangewhichwouldencompasstherecitedvalueandtherangewhichwouldbeincludedbyroundingupordowntothatfigureaswell,takingintoaccountsignificantfigures.
Asusedherein,theterm“pharmaceuticallyacceptablesalt”referstothosesalts
whicharesuitableforpharmaceuticaluse,preferablyforuseinthetissuesofhumansandloweranimalswithoutundueirritation,allergicresponseandthelike.
Pharmaceuticallyacceptablesaltsofamines,carboxylicacids,andothertypesofcompounds,arewellknownintheart.Forexample,S.M.Berge,etal.,describepharmaceuticallyacceptablesaltsindetailinJPharmaceuticalSciences,66:1-19(1977),incorporatedhereinbyreference.Thesaltscanbepreparedinsituduringthefinalisolationandpurificationofthecompoundsoftheinvention,orseparatelybyreactingafreebaseorfreeacidfunctionwithasuitablereagent,asdescribedgenerallybelow.Forexample,afreebasefunctioncanbereactedwithasuitableacid.Furthermore,wherethecompoundsoftheinventioncarryanacidicmoiety,suitablepharmaceuticallyacceptablesaltsthereofmay,includemetalsaltssuchasalkalimetalsalts,e.g.sodiumorpotassiumsalts;andalkalineearthmetalsalts,e.g.calciumormagnesiumsalts.Examplesofpharmaceuticallyacceptable,nontoxicacidadditionsaltsaresaltsofanaminogroupformedwithinorganicacidssuchashydrochloricacid,hydrobromicacid,phosphoricacid,sulfuricacidandperchloricacidorwithorganicacidssuchasaceticacid,oxalicacid,maleicacid,tartaricacid,citricacid,succinicacidormalonicacidorbyusingothermethodsusedintheartsuchasionexchange.Otherpharmaceuticallyacceptablesaltsincludeadipate,alginate,ascorbate,aspartate,benzoate,bisulfate,borate,butyrate,camphorate,camphorsulfonate,heptanoate,nicotinate,
citrate,cyclopentanepropionate,
hydroiodide,
oxalate,
digluconate,dodecylsulfate,
gluconate,hernisulfate,
lactobionate,persulfate,
formate,fumarate,glucoheptonate,
hexanoate,nitrate,
glycerophosphate,
2-hydroxy-ethanesulfonate,palmitate,
pectinate,
lactate,laurate,laurylsulfate,malate,maleate,malonate,methanesulfonate,
oleate,
3-
phenylpropionate,phosphate,picrate,pivalate,propionate,stearate,succinate,sulfate,tartrate,thiocyanate,p-toluenesulfonate,undecanoate,valeratesalts,andthelike.Representativealkalioralkalineearthmetalsaltsincludesodium,lithium,potassium,calcium,magnesium,andthelike.Furtherpharmaceuticallyacceptablesaltsinclude,whenappropriate,nontoxicammonium,quaternaryammonium,and
aminecationsformedbydirectreactionwiththedrugcarboxylicacidorbyusing
counterionssuchashalide,hydroxide,carboxylate,sulfate,phosphate,nitrate,sulfonateandarylsulfonate.
Theterm\"purified\"referstoacompoundthathasbeenprocessedtoremoveimpurities.Impuritiescanincludesolvents,reagentsusedtopreparethecompound,startingmaterials,andbyproductsofareactiongivingrisetothecompound.Insome
embodiments,apurifiedcompoundissubstantiallyfreeofotherspecies.
Theterm\"crudecompound\"referstoamixturecontainingadesiredcompound(suchasacompoundofFormulaIasdescribedherein)andatleastoneotherspeciesselectedfromasolvent,areagentsuchasabase,astartingmaterial,andabyproductofareactiongivingrisetothedesiredcompound.
\"Anti-solvent\"isasolventwhichwhenaddedtoanexistingsolutionofasubstancereducedthesolubilityofthesubstance.
Whenreferringtoachemicalreaction,theterms\"treating\\"contacting\"and\"reacting\"areusedinterchangeablyhereinandrefertoaddingormixingtwoor
morereagentsunderappropriateconditionstoproducetheindicatedand/ordesiredproduct.Itshouldbeappreciatedthatthereactionwhichproducestheindicatedand/ordesiredproductmaynotnecessarilyresultdirectlyfromthecombinationoftworeagentswhichwereinitiallyadded,i.e.,theremaybeoneormoreintermediateswhichareproducedinthemixturewhichultimatelyleadstotheformationoftheindicatedand/ordesiredproduct.
Inthefirstembodimentthepresentinventionprovidesprocessforpreparationof
MidostaurincompoundofformulaIwhichcomprising:
(i)reactingthestaurosporinewithbenzoicacidinpresenceofcondensingagentandsolvent;
isolatingtheproductwhichisMidostaurin.
(ii)
Theaboveprocessisrepresentedstepwiseasshownbelow:SchemeI
Incertainembodiments,saidcondensingagentisselectedfromthegroupconsisting
of2-(1H-benzotriazol-1-y1)-1,1,3,3-tetramethyluroniumhexafluorophosphate
(HBTU)/N-Hydroxybenzotriazole(HOBt)/Diisopropylethylamine(DIPEA)Incertainembodiments,productMidostaurinmaybefurtherpurifiedorwashed
withthesolventmultipletimestoproduceMidostaurinessentiallyfreeofimpurites.Invariousembodiments,thesolventisselectedfrombutnotlimitedtopolaraproticsolvents
are
N-Methyl-2-pyrrolidone(NMP),Dichloromethane(DCM),
Tetrahydrofuran(THF),Ethylacetate(EtOAc),Acetone,Dimethylformamide(DMF),Acetonitrile(MeCN),Dimethylsulfoxide(DMSO),Dimethylacetamide;Ν,Ν-Diisopropylethylamine,dioxane,tetrahydrofuran,acetone,hexane,benzene,
toluene,l,4-dioxane,chloroform,diethylether,n-butanol,isopropanol,n-propanol,ethanol,methanol,water,water,alcohols,ketones,diols,triols,esters,amides,
ethers,hydrocarbons,sulfolanemethanol,ethanol,propanol,butanol,methylenechloride,monochlorobenzene,andEDCandethylenechloride,toluene,xylene,heptane,cyclohexaneandhexane,andcombinationsthereof.
Incertainembodiments,productMidostaurinmaybefurtherpurifiedorwashedcomprising:
i.treatingMidostaurincrudewithfirstsolvent;
ii.addingasecondsolventtothecrudeMidostaurin-firstsolventmixture,
whereinthesecondsolventisananti-solvent;;
iii.precipitatingMidostaurinfromthesolvents;
iv.collectingthecrystalsofMidostaurin;and
v.optionallywashinganddryingMidostaurin.
whereintheMidostaurinobtainisessentiallyfreeofimpurities.
Thesolvent,asmentioned,canbeanyliquidinwhichtheMidostaurincrudedissolveswhereinthesolventcanbeamixtureofco-solventstheimportantpointbeingthatthesolutionofMidostaurincrudetobetreatedwithanothersolventoramixtureofco-solventsasanti-solvent.Solventsusefulintheinventionincludematerialsthatareliquidatroomtemperature,dissolvethematerial.
Preferably,inthisembodiment,thecrudeMidostaurinisdissolvedinanamountoffirstsolventsufficienttodissolvetheMidostaurin.OptionallytheresultingMidostaurinsolutionisheatedtoabouttheboilingpointofthefirstsolvent.Preferably,inthisembodiment,theadditionofthesecondsolvent,oranti-solvent,takesplace,withtheadditionofthesecondsolventoranti-solventbeingaddedinanamount
sufficient
to
precipitating
Midostaurin
from
the
solvents.
PreferablytheprecipitationstepcomprisescoolingtheMidostaurinsolutiontoroomtemperaturesufficienttobringaboutMidostaurin.MostpreferablythetemperaturesufficientforprecipitationofMidostaurinisabout25°C.
Preferably,inthisembodiment,firstsolvent:secondsolventoranti-solventsystemcombinationisIPA:water.
EXAMPLES
Example-1:ProcessforpreparationofMidostaurin
Preparedasolutionofbenzoicacid(315mg;2.6mmo)andHBTU(1076mg;2.8mmol)inDMFcoolthesolutionatlO°CandaddΝ,Ν-Diisopropylethyalmine(1.37mL;7.7mmol).Stirredthereactionmixturefor90minutesat25°C.Tothereaction
mixturechargedstaurosporine(600mg;1.3mmol).Stirredthereactionmixturefor4hours.Thereactionmassisdilutedwithwaterfollowedbyextractionwithethylacetate.Theorganiclayerisdriedoversodiumsulphateanddistilledundervacuumtogetresidue.Trituratedtheresiduewithether.Thesolidobtainedisfilteredand
driedtogetMidostaurin.(Yield:61%;puritybyHPLC:water.(PuritybyHPLC:97%)
88%).Midostaurinas
obtainedispurifiedbysolvent-anti-solventprecipitationprocedureusingIPAand
Example-2:ProcessforpreparationofMidostaurin
Preparedasolutionofbenzoicacid(50mg;0.4mmol)andHBTU(170mg;0.45mmol)inDMF.AddedΝ,Ν-Diisopropylethyalmine(220mL;1.3mmol).Stirred
themixturefor90minutesat25°C,chargedstaurosporine(600mg;1.3mmo)tothereactionmixture.Stirredthereactionmixturefor4hours.Thereactionmassis
dilutedwithwaterfollowedbyextractionwithethylacetate.Theorganiclayerisdriedoversodiumsulphateanddistilledundervacuumtogetresidue.Trituratedtheresiduewithether.ThesolidobtainedisfilteredanddriedtogetMidostaurin.(Yield:70%;puritybyHPLC:88%).Theobtainedsolidiselutedwithethylacetate
anddichloromethanesystemtogetMidostaurinwithpurity>97%byHPLC.
WeClaim,
[CLAIM1],[CLAIM2\\.[CLAIM3].[CLAIM4].
[CLAIM5].AprocessforthepreparationofMidostaurincompoundofformula
Iwhichcomprising:
(i)
reactingthestaurosporinewithbenzoicacidinpresencesofcondensingagentandsolvent;(ii)
purifyingMidostaurin;(iii)
isolatingMidostaurin.
Theprocessaccordingtoclaim1,whereincondensingagent
selectedfromthegroupconsistingof2-(lH-benzotriazol-l-yl)
-
1,1,3,3-tetramethyluroniumhexafluorophosphate
(HBTU),N-
Hydroxybenzotriazole(HOBt),Diisopropylethylamine(DIPEA).
Theprocessaccordingtoclaim1,whereinsolventselectedfrom
thegroupconsistingpolaraproticsolvents.
Theprocessaccordingtoclaim1,whereinpolaraproticsolventsareN-Methyl-2-pyrrolidone(NMP),Dichloromethane(DCM),
Tetrahydrofuran(THF),Ethylacetate(EtOAc),Acetone,
Dimethylformamide(DMF),Acetonitrile(MeCN),Dimethyl
sulfoxide(DMSO),Dimethylacetamideandcombinationsthereof.
Theprocessaccordingtoclaim1,whereinpurificationof
Midostaurincomprises,
(i)
treatingMidostaurincrudewithfirstsolvent;
[CLAIM6].[CLAIM7].(ii)addingasecondsolventtothecrudeMidostaurin-firstsolventmixture,whereinthesecondsolventisananti-solvent;
(iii)precipitatingMidostaurinfromthesolvents;(iv)
collectingthecrystalsofMidostaurin;and(v)
optionallywashinganddryingMidostaurin.
Theprocessaccordingtoclaim5,whereinsolventisIPA.Theprocessaccordingtoclaim5,whereinantisolventiswater.
FormPCT/ISA/210(secondsheet)(July2019)
INTERNATIONALSEARCHREPORTInformationonpatentfaintlymembers
InternationalapplicationNo
PCT/IN2019/050369
Citation
US8198435B2
Pub.Date
12-06-2012
Family
EP1812448B1US8710216B2
O2006048296A1MX9205726AHU201329BGR3019064T3
Pub.Date
23-29-11-01-28-31-05-04-05-04-10-05-201220142006199319901996
WO
1993007153A1EP0296110A215-04-199321-12-1988
ForPCT/ISA/210(patentfamilyannex)(July2019)
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