新药Fisogatinib（非索替尼）合成检索总结报告一、Fisogatinib（非索替尼）简介Fisogatinib（非索替尼）是由Blueprint Medicines开发的一款在研的强效、高选择性成纤维细胞生长因子受体-4（FGFR4）抑制剂，用于治疗FGFR4驱动的晚期或转移性肝细胞癌HCC。
Fisogatinib（非索替尼）具有成为首个分子水平生物标记物驱动的HCC靶向药物的潜力。
Fisogatinib（非索替尼）分子结构式如下:英文名称：Fisogatinib中文名称：非索替尼本文主要对Fisogatinib（非索替尼）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、Fisogatinib（非索替尼）合成路线三、Fisogatinib （非索替尼）合成检索总结报告(一)Fisogatinib （非索替尼）中间体3的合成合成方法实验步骤参考文献操作方法一1(5.00g,20.5mmol)and 2(3.73g,20.5mmol)were dissolved in tetrahydrofuran (30ml),added with a solution of cesium carbonate (20.00g,61.5mmol)in water (30ml),and added with a catalytic amount of Pd(PPh 3)Cl 2.Theresulting mixture was heated to reflux for 4h under nitrogen atmosphere.The reaction solution was concentrated to dryness and extracted with ethyl acetate.The organic phase was washed once with saturated sodium chloride,dried over anhydrous sodium sulfate,and concentrated under reduced pressure.The resulting crude product was subjected tocolumn chromatography (200-300mesh silica gel,petroleum ether/ethyl acetate=10/1)to obtain intermediate 3(3.80g,yield of 62%)as a pale yellow solid.US2019/209564;(2019);(A1)English;CN110386921;(2019);(A).操作方法二A mixture of 6-bromo-2-chloroquinazoline (1)(5.0g,20.5mmol),3,5-dimethoxyphenylboronic acid (2)(3.7g,20.5mmol),Cs 2CO 3(20.0g,61.5mmol)and Pd(PPh 3)2Cl 2(1.4g,2.1mmol)in THF (50mL),dioxane (50mL)and water (10mL)was degassed with N 2three times,and stirred at 80°C for 3hours.An aliquot of the reaction mixture was analyzed by both TLC and LCMS,which indicated that the reaction had proceeded to completion.The mixture was cooled to room temperature,and extracted with EtOAc (3×200mL).The combined organic layers were washed with water and brine,dried over sodium sulfate,filtered and concentrated.The residue was purified by silica gel chromatography (petroleum ether/EtOAc =8:1)to obtain 2-chloro-6-(3,5-dimethoxyphenyl)quinazoline (3)as a light yellow solid (2.4g,38%).WO2014/11900;(2014);(A2)English;US2015/197519;(2015);(A1)English;US2017/9695165;(2017);(B2)English(二)Fisogatinib（非索替尼）中间体4的合成合成方法实验步骤参考文献操作方法一To a solution of2-chloro-6-(3,5-dimethoxyphenyl)quinazoline(3)(2.7g,8.9mmol)indry THF(80mL)wasadded dropwise sulfuryl chloride(3.0g,22.3mmol)at-20°C,and the reactionmixture was stirred for an additionalhour.An aliquot of the reaction mixture was analyzed byboth TLC and LCMS,which indicated that the reaction hadproceeded to completion.The reaction mixture wasquenched with water(1mL),and the solvents were removedunder reduced pressure.The precipitate was washed withCH3CN and dried to obtain2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline(4)(2.6g,79%)as a whitesolid.WO2014/11900;(2014);(A2)English;US2015/197519;(2015);(A1)English;US2017/9695165;(2017);(B2)English操作方法二3(3.80g,12.6mmol)was dissolved in tetrahydrofuran(100ml),under nitrogen cooled to-20~30o C,was addeddropwise sulfuryl chloride(5.11g,37.9mmol),the resultingmixture at the same temperature reaction for2hours.Thereaction mixture was slowly raised to ambient temperature,was added acetonitrile(100ml),stirred for10minutes,theresulting solid was collected by filtration.Drying,to giveintermediate4(2.80g,60%yield)as a pale yellow solid.US2019/209564;(2019);(A1)English;CN110386921;(2019);(A).(三)Fisogatinib（非索替尼）中间体6的合成合成方法实验步骤参考文献操作方法一(3R,4R)-3-(((S)-1-phenylethyl)amino)tetrahydro-2H-pyran-4-ol5(2.0g,9.04mmol)was taken up in methanol(10ml)followed by addition of Et3N(1.260ml,9.04mmol)andBOC-anhydride(2.308ml,9.94mmol).The reaction mixturewas stirred at room temperature overnight.The solvents werethen removed in vacuo and the residue was taken up in DCM(10ml)and hexane(20ml)and heated to80°C.until thesolvent level was reduced by half.The reaction mixture wasremoved from heat and cooled to room temperature whilestirring.5ml of ether was then added and the reaction wasstirred at room temperature for2hours.The reaction mixtureUS2015/119405;(2015);(A1)English。
