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上市新药厄达替尼（Erdafitinib）合成检索总结报告
一、厄达替尼（Erdafitinib）简介
记忆英文
厄达替尼（Erdafitinib）是由杨森公司研发，并于2019年4月在美国上市抗肿瘤药物。厄达替尼（Erdafitinib）用于治疗携带特定成纤维细胞生长因子受体(FGFR)基因突变的局部晚期或转移性尿路上皮癌成人患者，具体指携带易感FGFR3或FGFR2基因突变和化疗期间或之后接受至少1种含铂化疗(包括新辅助或辅助含铂化疗12个月内)的局部晚期或转移性尿路上皮癌患者。
厄达替尼作用机制：FGFR激酶抑制剂，可与FGFRl、FGFR2、FGFR3和FGFR4结合并抑制FGFR磷酸化和信号传导，抑制肿瘤细胞的点突变、扩增和融合。
厄达替尼（Erdafitinib）分子结构式如下：
下载酷狗2008
CAS：1346242-81-6
英文名称：Erdafitinib
二、厄达替尼（Erdafitinib
）合成路线
婚礼三、厄达替尼（Erdafitinib ）合成检索总结报告(一)厄达替尼中间体2鱿鱼粥
的合成序号
实验步骤参考文献1
To a suspension of 1,2-diaminobenzene 1(1equiv.)in ethanol (1mol/L)was added ethyl 2-oxoacetate (1.1equiv.).The mixture was stirred at reflux for 1h,then at room temperature overnight.The precipitated solid was filtered and washed with ethanol,then dried to give quinoxalinone 2.Carrer,Amandine;Brion,Jean-Daniel;Messaoudi,Samir;Alami,Mouad;Organic Letters ;vol.15;nb.21;(2013);p.5606-56092To a suspension of o-arylenediamine 1(4.0mmol,1.0equiv)and potassium carbonate (2.0equiv.)in ethanol (1mol/L)was added ethyl 2-oxoacetate (1.1equiv).The reaction mixture was stirred and heated at reflux in an oil bath for 12h,then at room temperature for 12h.Upon completion,the suspension was washed with ethanol,then filtered and dried to give quinoxalinone 2.
Noikham,Medena;Kittikool,Tanakorn;Yotphan,Sirilata;Synthesis ;vol.50;nb.12;(2018);p.2337-2346Ethyl 2-oxoacetate (1.1equiv.)was added to a suspension of o -arylenediamine 1(4mmol,1equiv.)in ethanol (1mol/L).The reaction mixture was stirred and
Sumunnee,Ladawan;Pimpasri,Chaleena;Noikham,Medena;
3heated at reflux in an
oil bath for 1h,then at room temperature for 16h.Upon completion (as monitored by
擅长于用英语怎么说潮语TLC),the precipitate was filtered and washed with ethanol,then dried to give quinoxalinone 2.
Yotphan,Sirilata;Organic and Biomolecular Chemistry ;vol.16;nb.15;(2018);p.2697-27044To a stirred suspension of o-phenylenediamine (50g,462.9mmol)in ethanol(200ml),at rt was added a solution of ethyl glyoxalate in toluene (50;113ml_,555.48mmol)over a period of 45min.After heating to 45°C for 10h,the mixture was left at rt under stirring.The precipitate was filtered and the residue was washed with water and dried to give 1H-quinoxalin-2-one as an off-white powder (63g,93%).WO2011/26579;(2011);(A1)English
(二)厄达替尼中间体3的合成序号
实验步骤参考文献1
To a solution of quinoxalin-2(lH)-one 2(54.64g,374mmol,1.0eq.)in HOAc (1000mL)was added a solution of Br 2(19.18mL,374mmol,1.0eq.)in HOAc (200mL)dropwi.The resulting mixture was stirred at rt for 12h,then poured into ice-water.The precipitate was collected by filtration and dried to afford 7-bromoquinoxalin-2(lH)-one 3as an off-white solid (74g,88%).NEUPHARMA,INC.;QIAN,Xiangping;ZHU,Yong-liang;WO2013/40515;(2013);(A1)English.US2013/53384;(2013);(A1)English 2
Quinoxalone 2(250g,1.7mol)is dissolved in acetic acid (4500mL).A mixture of acetic acid (988mL)an
d bromine (108mL,2.1mol)is added dropwi,and the mixture stirred at room temperature for 12hours,then heated to 60°C for 12hours.After cooling to room temperature,the reaction is filtered and the solid washed with water.The wet cake (500g)is then dissolved in 1500mL of methanol and heated to 60°C,then filtered and dried at 60°C to give 3in 85%yield CLAVIUS PHARMACEUTICALS,LLC;SAWYER,J.,Scott;(109pag.);WO2019/5241;(2019);(A1)English 3To a cooled 0°C solution of quinoxalinone 2(50g,342.2mmol)in acetic acid (800ml)was added in a dropwi manner a solution of bromine (32ml)in acetic acid (200ml_)over a period of 30min.Solids formed within the reaction upon addition of bromine,and the reaction was allowed to stir slowly for a further 90min.
蛇瓜WO2016/97918;(2016);(A1)English
