新药Dapagliflozin（达格列净）合成检索总结报告
一、Dapagliflozin（达格列净）简介
Dapagliflozin（达格列净）适应症为糖尿病。2020年1月，美国食品药品监督管理局（FDA）接受了补充新药申请，并批准了Dapagliflozin（达格列净）的优先审阅，以降低患有和不患有T2D的HFrEF成年人的心血管死亡或HF恶化的风险。
Dapagliflozin（达格列净）分子结构式如下:
CAS：461432-26-8英文名称：Dapagliflozin中文名称：达格列净
本文主要对Dapagliflozin（达格列净）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。
二、Dapagliflozin（达格列净）合成路线一
三、Dapagliflozin（达格列净）合成路线二
1四、Dapagliflozin（达格列净）合成路线一检索总结报告(一)Dapagliflozin（达格列净）中间体2的合成（线路一）
合成方法
操作方法一
操作方法二
操作方法三
实验步骤
Addaceticanhydride100Kginthereactionkettle,addglucose(1)36Kg,stiratroomtemperaturetodissolve,add15gofperchloricaciddropwise,continuestirringforabout45min,add45Kgofwatertothereactionsolution,letstandfor2h,Thenthesupernatantwasdecantedandrecovered.Thesolidwaswashedwithwater,centrifugedanddriedtogive73Kgoftotalacetylglucose2ina96%yield.The
concentrationofaceticacidintherecoveredliquidwasabout59%.
D-glucose1(6.00g,33.33mmol)andiodine(0.66g)weredissolvedinaceticanhydride(60mL,634.73mmol),stirringandkeepingthismixtureat25°Covernight.Thenethylacetate(EA,120mL)wasaddedintothemixture,the
organicphasewaswashedbyNa2SO3saturatedsolutionandNaHCO3saturatedsolutionthreetimesrespectively.TheorganicphasewasdriedbyMgSO4thencondensedtoobtain2(12.31g,95%).
Addglucosemonohydrate1(50g,253mmol)andsodiumacetate(40g,410mmol)in360mLofaceticanhydride,Thereactionsolutionwasheatedto90°Candstirredfor2.5hours.ThereactionwasmonitoredbyTLCforcompletion.Thereactionsolutionwaspouredinto2.7Loficewaterandstirredfor3hours,andawhitesolidprecipitated.Filtrationanddryinggavewhitecrystallinesolidcompound2(92.57g,yield94%).
10gofanhydroussodiumacetate,10gofD-glucose1,wasaddedtoa250mLsingle-neckedflask.About100mlof
2参考文献
CN106432373;(2017);(A)Chinese
ChineseChemical
Letters;vol.30;nb.3;(2019);p.587-591.
CN110041383;(2019);(A)
CN109384821;
操作方法四
操作方法五
操作方法六
操作方法
aceticanhydridewasusedasasolvent,andthereactionwasheatedunderrefluxfor2hours.Afterthereactionwascompleted,100mloficewaterwasadded,stirred,andextractedwithethylacetatethreetimes.TheorganicphaseswerecombinedandwashedsuccessivelywithsaturatedNaHCO3solutionandwater.Evaporatethesolventunderreducedpressure.Thecrudeproductwasrecrystallizedfrom95%ethanol.Theyieldwas88%.
Ethylacetate(1000ml)wasaddedtothereactionflask.D-glucose1(200g)wasadded,then98%sulfuricacid(6ml)inethylacetatewasaddedtothereactionmixture.Thesolutionwascooledto5~10°C.withicebath,aceticanhydride(620ml)wasdropwiselyadded.Aftertheaddition,thesolutionwasheatedto20-25°C.,thento50-55°C.,thesolutionturnclear.ThereactionextentischeckedbyTLC(DCM/MeOH=3/1)untilcompletion.10%NaOHaqueoussolution(300ml)wasaddedtoquenchthereactionandthetemperaturewascontrolledat15-20°C.duringtheaddition.7%brinesolution(200ml)wasaddedandstirredfor20min,thenstandfor20min.7%brinesolution(500ml)wasaddedtoorganiclayerandstirredfor20min,thenstandfor20minagain.Saturatedsodium
bicarbonatewasaddedtoorganiclayerndstirredfor20min,thenstandfor20min.TheorganiclayerwasdriedoverMgSO4,thenevaporatedundervacuum(15torr).WhitepowderofCrude2(429g)wasobtained
Toasolutionofglucose1(5g,27.7mmol),TEA(16.85g,166.6mmol),DMF(150mL)andcatalyticamountofDMAPwasaddedAc2O(16.99g,166.6mmol)dropwisemaintainingthetemperatureat0°Cfor5-6h.CompletionofreactionwasmonitoredbyTLC,thenaddedaqueoussolutionofsodiumhydrogensulphatedropwisetothereactionmixtureunderstirringtillitattainedpH~8.ThenreactionmixturewasextractedwithEtOAc(2×50mL)andcombinedorganiclayerwaswashedwithwater(2×50mL),driedoverNa2SO4andevaporatedtodrynessundervacuum.Likewisemaltosylperacetatewaspreparedusingtwicethequantityofreagents.
D-Glucopyranose1(1.0g,5.55mmol)wasdissolvedin5mLofaceticanhydrideand7niLofpyridineat0oC.Tothismixturewasadded4-dimethylaminopyridine(200mg,1.63mmol),andthereactionwasstirredwhilewarmingtoroomtemperature.TLC(40%ethylacetate-hexane)after18hshowedcompleteconsumptionofthestartingmaterialand
3(2019);(A)Chinese;
CN109678915;(2019);(A)Chinese
US2017/15695;(2017);(A1)English
NaturalProductResearch;vol.32;nb.2;(2018);p.154-161.
WO2006/124713;(2006);(A2)
七
formationofahigherrunningspot.Thereactionwaspouredinto50mLofwaterandextractedintodichloromethane(3×50mL).Theorganiclayerswerecombine,washedwith1Nhydrochloricacid(3×20mL),driedoversodiumsulfate,filtered,concentratedandpurifiedbycolumn
chromatography(50gsilicagel,40%ethylacetate-hexane)toafford1,2,3,4,6-penta-O-acetyl-α-D-glucopyranose2(2.10g,5.37mmol).
English(二)Dapagliflozin（达格列净）中间体3的合成（线路一）
合成方法
操作方法一
操作方法二
操作方法三
实验步骤
33%Hydrogenbromideinaceticacid(250mL,1.02mol)wasaddeddropwisetoneatβ-D-glucosepentaacetate(2)(98.4g,0.25mol)powderina2-Lflaskover10minatroomtemperaturetoaffordayellowsolution.Themixturewasstirredfor1hatroomtemperature.Thesolventwasremovedbyazeotropicdistillationinvacuowithtoluene(3×100mL)followedbyhighvacuumtoafford2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide(3)(quantitative)asapaleyellowwaxysolid;Rf=0.49(1:1ethylacetate-hexane);NMRpurity>99A%.
Dissolvepentaacetyl-β-D-glucose2indrydichloromethaneandaddHBr-AcOH(33%WW)solution,thefinalmixturewasstirredat0°Cfor30min,allowedtostiratroom
temperatureovernight,andthereactionmixturewaspouredintoicewater.Afterextraction,theorganiclayerwas
extractedwithaqueousNaHCO3solutionandbrine,dried,andconcentratedtogivecompound3inayieldof98.6%.Toa500mlflaskwasadded50gofglucosepentaacetate2and80mlofmethylenechloride.Themixturewasstirredatice-waterbathfor20minHBrinHOAc(33%,50ml)wasaddedtothereactionmixture.Afterstirringfor2.5hr
another5mlofHBrwasaddedtothemixture.Afteranother30min,themixturewasadded600mlofmethylene
chloride.Theorganicmixturewaswashedwithcoldwater(200ml×2),SaturatedNaHCO3(200ml×2),water(200ml)andbrine(200ml×2).Theorganiclayerwasdriedover
4参考文献
US2008/287663;(2008);(A1)English
CN107973828;(2018);(A)Chinese
US2011/105418;(2011);(A1)English
新药Dapagliflozin(达格列净)合成检索总结报告
