Metesind glucuronate, AG-265(free base), AG-331
6-[N-甲基-N-[4-(吗啉基磺酰基)苄基]氨基苯[cd]吲吲-2(1H)-亚胺葡萄糖醛酸盐Chemical Name: 6-[N-Methyl-N-[4-(morpholinosulfonyl)benzyl]amino]benz[cd]indol-2(1H)-imine glucuronate
CAS No. 157182-23-5, 138384-68-6 (free base)
项目整合开发状态: Phase I
项目研究机构: Agouron (Originator)
合成路线:The reaction of 1,8-naphthoic anhydride (I) with hydroxylamine and NaOAc in water gives the N-hydroxynaphthalimide (II),which is condensed with 2,4-dinitrochlorobenzene (III) by means of Na2CO3 in hot water yielding the expected naphthalimide derivative (IV).The rearrangement of (IV) induced by NaOH in ethanol/water affords 8-amino-1-naphthoic acid (V),which is cyclized by means of sulfuric acid to the benz[cd]indolin-2-one (VI).The nitration of (VI) with HNO3 in acetic aid gives the expected 6-nitro derivative (VII),which is reduced with H2 over Pd/C in THF to the corresponding amino derivative (VIII).The condensation of (VIII) with the benzyl bromide (IX) by means of DIEA in hot DMF affords the secondary amine (X),which is methylated with methyl iodide and DIEA in hot DMF to provide the tertiary amine (XI).The reaction of the carbonyl group of (XI) with Lawesson's reagent gives the thione (XII),which is methylated with methyl iodide and NaOH to give the methylsulfanyl derivative (XIII).Finally,this compound is treated with ammonia in methanol.
📌 参考资料/链接：
参考文献标题:Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase
文献作者:Varney,M.D.; Marzoni,G.P.; Palmer,C.L.; Deal,J.G.; Webber,S.E.; Welsh,K.M.; Bacquet,R.J.; Bartlett,C.A.; Morse,C.A.; Booth,C.L.; et al.
参考来源:J Med Chem 1992,35(4),663
📄 详细内容
合成路线:The reaction of 1,8-naphthoic anhydride (I) with hydroxylamine and NaOAc in water gives the N-hydroxynaphthalimide (II),which is condensed with 2,4-dinitrochlorobenzene (III) by means of Na2CO3 in hot water yielding the expected naphthalimide derivative (IV).The rearrangement of (IV) induced by NaOH in ethanol/water affords 8-amino-1-naphthoic acid (V),which is cyclized by means of sulfuric acid to the benz[cd]indolin-2-one (VI).The nitration of (VI) with HNO3 in acetic aid gives the expected 6-nitro derivative (VII),which is reduced with H2 over Pd/C in THF to the corresponding amino derivative (VIII).The condensation of (VIII) with the benzyl bromide (IX) by means of DIEA in hot DMF affords the secondary amine (X),which is methylated with methyl iodide and DIEA in hot DMF to provide the tertiary amine (XI).The reaction of the carbonyl group of (XI) with Lawesson's reagent gives the thione (XII),which is methylated with methyl iodide and NaOH to give the methylsulfanyl derivative (XIII).Finally,this compound is treated with ammonia in methanol.
参考文献标题:An improved large-scale synthesis of benz[cd]indol-2(1H)-one and 5-methylbenz[cd]indol-2(1H)-one
文献作者:Marzoni,G.; et al.
参考来源:Org Process Res Dev 1997,1(1),81
产品链接: CAS No. 157182-23-5›› 产品链接: CAS No.138384-68-6››