药物Binimetinib（比美替尼）合成检索总结报告一、Binimetinib（比美替尼）简介
Binimetinib（比美替尼）是由时arrayBiopharma公司研发，于2018年6月在美国上市，主要用于BRAF基因V600E位点或V600K位点突变的不可切除或转移性黑素瘤患者的治疗。Binimetinib（比美替尼）是一种BRAF激酶抑制剂，binimetinib是一种丝裂原活化细胞外信号调节激酶(MEK)抑制剂，而MEK是细胞外信号调节激酶(ERK)途径的上游调节剂，因此可以抑制RAS-RAF-MEK-ERK信号通路，并最终抑制肿瘤细胞的增殖、分化和转移。
Binimetinib（比美替尼）不良反应：疲劳，恶心，腹泻，呕吐和腹痛。
Binimetinib（比美替尼）分子结构式如下:
CAS:606143-89-9英文名称：Binimetinib中文名称：比美替尼
二、Binimetinib（比美替尼）合成路线
1三、Binimetinib（比美替尼）合成检索总结报告(一)Binimetinib（比美替尼）中间体2的合成
合成方法
合成方法一
实验步骤
Ammoniumhydroxidesolution(30%inwater)(35mL,271mmol)isaddedtoasolutionof2,3,4-trifluoro-5-nitro-benzoicacid1(15g,67.8mmol)in30mLwaterat0°C.withstirring.Uponcompletionofammoniumhydroxideadditionthereactionmixtureiswarmedtoroomtemperaturewithstirring.After2.5hours,thereactionmixtureiscooledto0°C.andconcentratedHCliscarefullyaddeduntilpHofreactionmixtureisnear0.Thereactionmixtureisdilutedwithwater(30mL)andextractedwithdiethylether(3×50mL).Thecombinedorganicextractsaredried(MgSO4)andconcentratedunderreducedpressuretogive14g(95%)ofpuredesiredproduct2.
Toamixtureof2,3,4-trifluoro-5-nitrobenzoicacid1(167.2g,0.756mol,1equiv.)in400mLofdistilledwaterwasaddedconcentratedammoniumhydroxide(28%NH3solution;340g,380mL,4.23mol,5.6equiv),ensuringthatinternaltemperaturewasbelow6.0°Cover2-2.5hours.The
2参考文献US2004/116710;(2004);(A1)English;
WO2007/76245;(2007);(A2)English;
US2003/232869;(2003);(A1)English;
WO2013/142182;(2013);(A2)English
合成方法二
合成方法三
mixturewasstirredfor50minutesandthenwarmedtoroomtemperaturefor3-4hours.Whenthereactionwas>90%completeasdeterminedbyHPLC,themixturewascooledinanice-waterbath,andconcentratedHCl(350mL)wasthenaddeddropwisetoadjustpH=2.Theslurrywasstirredfor1hourwithicebathcoolingandthenfiltered.Thecakewasrinsedwith1Lofdistilledwaterandthenwith350mLofMTBE.Thecakewasoven-driedat48oCovernighttogive134.9gofayellowsolid.HPLCwas83.6a%(220nm)and96.96a%(254nm).TheMTBEfiltratewasconcentratedonarotaryevaporatorandpumpedovernighttogive9.9gofasecondcropasayellowsolid:HPLCwas81.1a%(220nm)and95.40a%(254nm).Combinedyieldof4-amino-2,3-difluoro-5-nitrobenzoicacid2was144.8g(88%).
Solid5-nitro-2,3,4-trifluorobenzoicacid1(0.75g,0.00339mol)wasdissolvedinconcentratedammoniumhydroxide(25ml)togiveinstantlyayellowsolution.Aprecipitatebegantoformwithinfiveminutes,afterwhichtimethemixturewasacidifiedtopH0withconcentratedaqueoushydrochloricacid.Ayellowprecipitaterapidlyformed.Themixturewasheatedtoboilingandwasfilteredhot.Theyellowsolidswerewashedwith10%aqueoushydrochloricacidandweresuctiondriedtoafford0.47gofayellowpowder2;64%yield.
WO2007/2092;(2007);(A1)English
US7030119;(2006);(B1)English;US6469004;(2002);(B1)English
(二)Binimetinib（比美替尼）中间体3的合成
合成方法
合成方法一
合成方法
实验步骤
A2MsolutionofTMSdiazomethaneinhexanes(6.88mL,13.75mmol)isaddedtoasuspensionof4-amino-2,3-difluoro-5-nitro-benzoicacid2(2.00g,9.17mmol)in25mLof4:1THF:MeOHat0°C.undernitrogenatmosphere.Uponcompletionofaddition,reactionmixtureiswarmedtoroomtemperature.After0.5hours,excessTMSdiazomethaneisdestroyedbythecarefuladditionofaceticacid.Thereactionisthenconcentratedunderreducedpressureanddriedinvacuotogive1.95g(92%)ofpuredesiredproduct3.
Trimethylsilylateddiazomethane(1.26g,11.02mmol)wasslowlyaddeddropwisetoasolutionofcompound2(2.0g,9.17mmol)inmethanolat0°C,andthereactionwas
3参考文献US2004/116710;(2004);(A1)English;
US2003/232869;(2003);(A1);
WO2013/142182;(2013);(A2);WO2007/76245;(2007);(A2)CN109438362;(2019);(A)
药物Binimetinib(比美替尼)合成检索总结报告
