Sutent, SU-011248, SU-11248
N-(2-二乙胺基乙基)-5-(5-氟-2-氧代-1,2-二氢吲哚-3-基亚甲基)-2,4-二甲基-1H-吡咯-3-甲酰胺 Chemical Name: (Z)-N-[2-(Diethylamino)ethyl]-5-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide
CAS No. 326914-13-0, 342641-94-5 (undefined isomer)
项目整合开发状态: Phase III
项目研究机构: Pfizer (Originator), Sugen (Originator)
合成路线:Nitrosation of tert-butyl acetoacetate (I) with NaNO2/AcOH produces the oximino ester (II).Reductive cyclization of (II) with ethyl acetoacetate (III) in the presence of Zn/AcOH leads to the pyrrole dicarboxylate (IV).Selective decarboxylation of the t-butyl ester of (IV) under acidic conditions,followed by Vilsmeier formylation of the intermediate ethyl 2,4-dimethylpyrrole-3-carboxylate furnishes the pyrrole aldehyde (V).Alternatively,this compound is directly obtained from (IV) upon treatment with trimethyl orthoformate and trifluoroacetic acid.Basic hydrolysis of the ethyl ester group of (V) yields the pyrrolecarboxylic acid (VI).This is coupled to 2-(diethylamino)ethylamine (VII) to afford the corresponding amide (VIII).
合成路线:5-Fluoroisatin (IX) is heated with neat hydrazine hydrate to produce 2-amino-5-fluorophenylacetic hydrazide (X),which,upon acidic treatment cyclizes to 5-fluorooxindole (XI).Subsequent condensation of oxindole (XI) with the formylpyrrole carboxamide (VIII) in the presence of piperidine in hot EtOH leads to the title compound.In an alternative procedure,oxindole (XI) is condensed with the formylpyrrole carboxylic acid (VI) giving (XII),which is further coupled with 2-(diethylamino)ethylamine (VII) in the presence of EDC/HOBt to yield the target carboxamide.
合成路线:Vilsmeier formylation of ethyl 2,4-dimethylindole-3-carboxylate (I) by means of POCl3 and DMF leads to aldehyde (II).Subsequent ester group hydrolysis in (II) under alkaline conditions furnishes acid (III),which is then coupled to N-(2-aminoethyl)pyrrolidine (IV) employing EDC/HOBt to afford the corresponding amide (V).Chemoselective reduction of the 3-carbonyl group of 5-fluoroisatin (VI) upon heating with hydrazine hydrate gives rise to 5-fluorooxindole (VII).Finally,condensation of (VII) with aldehyde (V) under Knoevenagel conditions provides the title compound
合成路线:In a related,scale-up procedure,5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (I) is condensed to 5-fluorooxindole (II) in the presence of pyrrolidine and AcOH to furnish adduct (III).This is then condensed with N-(2-aminoethyl)pyrrolidine (IV) in the presence of BOP to produce the target amide
📌 参考资料/链接：
参考文献标题:Pyrrole substd.2-indolinone protein kinase inhibitors
文献作者:Wei,C.C.; Miller,T.; Tang,P.C.; Nematalla,A.S.; Li,X.; Liang,C.; Shirazian,S.; Su,L.; Vojkovsky,T.(Sugen,Inc.)
参考来源:EP 1255752; US 2002156292; US 6573293; WO 0160814
📄 详细内容
合成路线:Nitrosation of tert-butyl acetoacetate (I) with NaNO2/AcOH produces the oximino ester (II).Reductive cyclization of (II) with ethyl acetoacetate (III) in the presence of Zn/AcOH leads to the pyrrole dicarboxylate (IV).Selective decarboxylation of the t-butyl ester of (IV) under acidic conditions,followed by Vilsmeier formylation of the intermediate ethyl 2,4-dimethylpyrrole-3-carboxylate furnishes the pyrrole aldehyde (V).Alternatively,this compound is directly obtained from (IV) upon treatment with trimethyl orthoformate and trifluoroacetic acid.Basic hydrolysis of the ethyl ester group of (V) yields the pyrrolecarboxylic acid (VI).This is coupled to 2-(diethylamino)ethylamine (VII) to afford the corresponding amide (VIII).
合成路线:5-Fluoroisatin (IX) is heated with neat hydrazine hydrate to produce 2-amino-5-fluorophenylacetic hydrazide (X),which,upon acidic treatment cyclizes to 5-fluorooxindole (XI).Subsequent condensation of oxindole (XI) with the formylpyrrole carboxamide (VIII) in the presence of piperidine in hot EtOH leads to the title compound.In an alternative procedure,oxindole (XI) is condensed with the formylpyrrole carboxylic acid (VI) giving (XII),which is further coupled with 2-(diethylamino)ethylamine (VII) in the presence of EDC/HOBt to yield the target carboxamide.
参考文献标题:Formulations for pharmaceutical agents ionizable as free acids or free bases
文献作者:Shenoy,N.; Sorasuchart,W.(Sugen,Inc.)
参考来源:JP 2003514851; WO 0137820
合成路线:Nitrosation of tert-butyl acetoacetate (I) with NaNO2/AcOH produces the oximino ester (II).Reductive cyclization of (II) with ethyl acetoacetate (III) in the presence of Zn/AcOH leads to the pyrrole dicarboxylate (IV).Selective decarboxylation of the t-butyl ester of (IV) under acidic conditions,followed by Vilsmeier formylation of the intermediate ethyl 2,4-dimethylpyrrole-3-carboxylate furnishes the pyrrole aldehyde (V).Alternatively,this compound is directly obtained from (IV) upon treatment with trimethyl orthoformate and trifluoroacetic acid.Basic hydrolysis of the ethyl ester group of (V) yields the pyrrolecarboxylic acid (VI).This is coupled to 2-(diethylamino)ethylamine (VII) to afford the corresponding amide (VIII).
合成路线:5-Fluoroisatin (IX) is heated with neat hydrazine hydrate to produce 2-amino-5-fluorophenylacetic hydrazide (X),which,upon acidic treatment cyclizes to 5-fluorooxindole (XI).Subsequent condensation of oxindole (XI) with the formylpyrrole carboxamide (VIII) in the presence of piperidine in hot EtOH leads to the title compound.In an alternative procedure,oxindole (XI) is condensed with the formylpyrrole carboxylic acid (VI) giving (XII),which is further coupled with 2-(diethylamino)ethylamine (VII) in the presence of EDC/HOBt to yield the target carboxamide.
参考文献标题:Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide,a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine
文献作者:Sun,L.; Liang,C.; Shirazian,S.; Zhou,Y.; Miller,T.; Ciu,J.; Fukuda,J.Y.; Chu,J.-Y.; Nematalla,A.; Wang,X.; Chen,H.; Sistla,A.; Luu,T.C.; Tang,F.; Wei,J.; Tang,C.
参考来源:J Med Chem 2003,46(7),1116
产品链接: CAS No.342641-94-5››