贝曲西班（Betrixaban）合成检索总结报告
一、贝曲西班（Betrixaban）简介
贝曲西班（Betrixaban）于2017年6月在美国上市，主要用于预防急性高危成年患者因住院卧床时间过长或运动受限导致的静脉栓塞。贝曲西班（Betrixaban）分子结构式如下:
英文名称：Betrixaban中文名称：贝曲西班
英文名称：Betrixabanmaleate中文名称：贝曲西班马来酸盐
本文主要对贝曲西班（Betrixaban）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、贝曲西班（Betrixaban）合成路线
1贝曲西班（Betrixaban）关键中间体9的其他合成路线如下：
三、贝曲西班（Betrixaban）合成检索总结报告(一)贝曲西班（Betrixaban）中间体2的合成
合成方法
操作方法一
操作方法二
操作方法三
操作方法四
实验步骤
Toasolutionof5-methoxy-2-nitrobenzoicacid1(1.0g,5.07mmol)inMeOH(15mL)wasadded5%Pd/C(20mg).Thereactionwashydrogenated(15psi)for15hthenfiltered.Thefiltratewasconcentratedanddriedtogive
2-amino-5-methoxybenzoicacid2(840mg,100%yield)asalightyellowsolid.LCMS:MH168andTR=0.410min.Usedwithoutfurtherpurification.
Toasolutionof2-nitro-5-methyoxybenzoicacid1(500mg,2.54mmol)inEtOH(5.50mL)wasadded10%palladiumoncharcoal(8%w/w).Thereactionmixturewassequentiallyevacuatedandpurgedwithhydrogenthreetimesthenstirredunderhydrogenatapproximatelyatmosphericpressureandroomtemperature.ThereactionwasmonitoredbyTLCanduponcompletionthecatalystwasfilteredoffthroughapadofCeliteTM.Thesolventwasremovedinvacuotogive2-amino-5-methyoxybenzamide2(424mg,2.54mmol,quant.);mp:144-146°C.
5-Methoxy-2-nitrobenzoicacid1(30.0g,152.2mmol)washydrogenatedoverPd/C(10%,300mg)inTHF(250mL)atroomtemperatureunderH2balloon.Themixturewasstirredfor18h.Afterthereactionwascompleted,thecatalystwasremovedbyfiltrationoverCeliteandthefiltratewas
concentratedtoafford25.0gof2-amino-5-methoxybenzoicacid2asabrownsolid(98%).
Amixtureof5-methoxy-2-nitrobenzoicacid1(80.8mg,0.410mmol),Pd/C(10%,8.9mg)andmethanol(5mL)wasstirredatroomtemperatureunderanatmosphereof
hydrogenfor3h.ThemixturewasfilteredthroughCeliteandconcentratedinvacuotogivethetitlecompound2asabrownsolid(66.5mg,97%).
2参考文献WO2016/23826;(2016);(A1)English
Synthesis;vol.49;nb.1;(2017);p.135-144
US2015/307477;(2015);(A1)English;
Synlett;vol.27;nb.8;(2016);p.1237–1240.
操作方法五
操作方法六
Asolutionof2-nitro-5-methoxybenzoicacid1(60.3g,306mmol)inEtOAc(1.5L)wasdegassedunderreduced
pressureandrefilledwithargon(repeated3times).Palladium(10%w/woncarbon,3.9g,1.2mol%)wasaddedtotheabovesolution.ThereactionflaskwasevacuatedunderreducedpressureandrefilledwithH2fromaballoon(repeated3-4timestomakesurethatthesolutionwas
saturatedwithH2).Thereactionmixturewasstirredfor6h.Afterthecompletionofthereaction(TLC,silicagel),thesolutionwasfilteredoverabedofcelitetoremovethePd.Thesolidswerewashedwithethylacetate.Thesolventwasremovedunderreducedpressuretoyieldacid2asayellowsolidin97%(49.7g)yield:M.p147-149°C.
5-Methoxy-2-nitrobenzoicacid(1)(30.00g,152.17mmol),palladiumcarbon(10wt%,5.0g),andtetrahydrofuran(200mL)wereputinanautoclave.H2gas(15atm)was
introducedintotheautoclave,andthereactionmixturewasstirredfor6hat55°C.Theproductwasobtainedby
filtrationofpalladiumcarbon,andsolventevaporationgaveapaleyellowsolid2;yield96%(24.47g);m.p.148.4-149.4°C.
EuropeanJournalofMedicinal
Chemistry;vol.126;(2017);p.550–560.
JournalofChemical
Research;vol.39;nb.9;(2015);p.524-526
(二)贝曲西班（Betrixaban）中间体4的合成方法一
合成方法
操作方法一
实验步骤
2-Amino-5-methoxybenzoicacid(2)(27.73g,165.88mmol)wasdissolvedinTHF(550mL).Thesolutionwasstirredat-5-0°Cfor20minandEt3N(17.92g,177.09mmol)wasaddedtothesolution.Then,4-cyanobenzoylchloride3(27.46g,165.88mmol)inTHF(50mL)wasaddeddropwisetotheabovemixtureat-5-0°C.Subsequently,themixturewasstirredatroomtemperaturefor1h(monitoredbyTLC).Thenthemixturewasevaporatedtoyieldawhitesolid4;yield94%(46.13g);m.p.222.5-223.5°C.
参考文献JournalofChemical
Research;vol.39;nb.9;(2015);p.524–526.
(三)贝曲西班（Betrixaban）中间体4的合成方法二（此合成方法比较繁杂，不建议使用）
①贝曲西班（Betrixaban）中间体5的合成
3
贝曲西班(Betrixaban)合成检索总结报告
