SM-130686
Chemical Name: (+)-3(S)-(2-Chlorophenyl)-1-[2-(diethylamino)ethyl]-3-hydroxy-2-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-indole-6-carboxamide hydrochloride
CAS No. 259666-71-2 (free base), 259667-25-9 (racemate), 259666-75-6 (racemic, free base)
项目整合开发状态: Preclinical
项目研究机构: Sumitomo Pharmaceuticals (Originator)
合成路线:Iodination of 3-(trifluoromethyl)nitrobenzene (I) was accomplished by using N-iodosuccinimide in concentrated sulfuric acid to provide (II),which was then reduced to aniline (III) with SnCl2 in refluxing EtOH.Treatment of aniline (III) with sulfuryl chloride,followed by addition of ethyl (methylthio)acetate and Et3N gave rise to a mixture of regioisomeric 3-(methylthio)oxindoles (IV) and (V).Oxidation of this mixture with CuCl2/CuO generated the respective isatins (VI) and (VII) (1).After N-alkylation with 2-(diethylamino)ethyl chloride and NaH,the desired regioisomer (VIII) could be separated by column chromatography.Addition to (VIII) of the Grignard reagent (IX) provided the racemic 3-aryl-3-hydroxy oxindole (X).The enantiomers of (X) were separated using chiral,preparative HPLC,and the desired (S)-enantiomer (XI) was then converted to nitrile (XII) by iodide displacement with zinc cyanide in the presence of palladium catalyst.Finally,partial hydrolysis of nitrile (XII) with KOH in tert-butanol furnished the title amide
📌 参考资料/链接：
参考文献标题:Oxindole derivs.as growth hormone releasers
文献作者:Okazaki,K.; Kumagai,K.; Tokunaga,T.; Ueki,Y.; Nagata,R.; Umezome,T.; Hume,W.E.(Sumitomo Pharmaceuticals Co.,Ltd.)
参考来源:EP 1105376; JP 2002523400; WO 0010975
📄 详细内容
合成路线:Iodination of 3-(trifluoromethyl)nitrobenzene (I) was accomplished by using N-iodosuccinimide in concentrated sulfuric acid to provide (II),which was then reduced to aniline (III) with SnCl2 in refluxing EtOH.Treatment of aniline (III) with sulfuryl chloride,followed by addition of ethyl (methylthio)acetate and Et3N gave rise to a mixture of regioisomeric 3-(methylthio)oxindoles (IV) and (V).Oxidation of this mixture with CuCl2/CuO generated the respective isatins (VI) and (VII) (1).After N-alkylation with 2-(diethylamino)ethyl chloride and NaH,the desired regioisomer (VIII) could be separated by column chromatography.Addition to (VIII) of the Grignard reagent (IX) provided the racemic 3-aryl-3-hydroxy oxindole (X).The enantiomers of (X) were separated using chiral,preparative HPLC,and the desired (S)-enantiomer (XI) was then converted to nitrile (XII) by iodide displacement with zinc cyanide in the presence of palladium catalyst.Finally,partial hydrolysis of nitrile (XII) with KOH in tert-butanol furnished the title amide
参考文献标题:Oxindole derivatives as orally active potent growth hormone secretagogues
文献作者:Tokunaga,T.; Hume,W.E.; Umezome,T.; Okazaki,K.; Ueki,Y.; Kumagai,K.; Hourai,S.; Nagamine,J.; Seki,H.; Taiji,M.; Noguchi,H.; Nagata,R.
参考来源:J Med Chem 2001,44(26),4641
产品链接: CAS No. 259666-71-2›› 产品链接: CAS No.259667-25-9››