Etravirine, TMC-125, R-165335
依曲韦林Chemical Name: 4-[6-Amino-5-bromo-2-(4-cyanophenylamino)pyrimidin-4-yloxy]-3,5-dimethylbenzonitrile
CAS No. 269055-15-4
项目整合开发状态: Phase II
项目研究机构: Janssen (Originator), Tibotec-Virco (Originator)
合成路线:The reaction of 5-bromo-2,4,6-trichloropyrimidine (I) with 4-aminobenzonitrile (II) by means of DIEA in refluxing dioxane gives the diarylamine (III),which is condensed with 4-hydroxy-3,5-dimethylbenzonitrile (IV) by means of NaH in NMP to yield the corresponding adduct (V).Finally,this compound is treated with ammonia in dioxane at 150 C in a pressure vessel.
📌 参考资料/链接：
参考文献标题:HIV replication inhibiting pyrimidines
文献作者:Heeres,J.; De Corte,B.; Kukla,M.J.; Van Aken,K.J.A.; Janssen,P.A.J.; Ludovici,D.W.; De Jonge,M.R.; Kavash,R.W.; Ho,C.Y.; Koymans,L.M.H.(Janssen Pharmaceutica NV)
参考来源:EP 1002795; WO 0027825
📄 详细内容
合成路线:The synthesis can be performed by two related ways:1) The condensation of 2-(methylsulfanyl)pyrimidin-4-ol (I) with 4-aminobenzonitrile (II) in hot diglyme gives 4-(4-hydroxypyrimidin-2-ylamino)benzonitrile (III),which is treated with POCl3 to yield the corresponding chloro derivative (IV).Finally,this compound is condensed with 2,4,6-trimethylaniline (V) in dioxane to afford the target 4-aminobenzonitrile derivative.2) Condensation of 2,4,6-trimethylaniline (VI) with 2,4-dichloropyrimidine (VII) by means of DIEA in refluxing 1,4-dioxane,followed by chromatographic purification furnishes intermediate (VIII),which is finally converted into the desired compound by condensation with 4-aminobenzonitrile (II) in refluxing water by means of HCl in 2-propanol.
合成路线:The cyclization of 4-guanidinobenzonitrile (I) with diethyl malonate (II) by means of NaOEt in ethanol gives 4-(4,6-dihydroxypyrimidin-2-ylamino)benzonitrile (III),which is treated with POCl3 to yield the corresponding dichloro derivative (IV).The bromination of (IV) with Br2 and NaHCO3 in methanol/water affords 4-(5-bromo-4,6-dichloropyrimidin-2-ylamino)benzonitrile (V),which is condensed with sodium 4-cyano-2,6-dimethylphenolate (VI) and N-methylpyrrolidone in dioxane to provide the chloro precursor (VII).Finally,this compound is treated with ammonia in isopropanol to yield the target dinitrile derivative.
参考文献标题:Evolution of anti-HIV drug candidates.Part 3: Diarylpyrimidine (DAPY) analogues
文献作者:Ludovici,D.W.; De Corte,B.L.; Kukla,M.J.; Ye,H.; Ho,C.Y.; Lichtenstein,M.A.; Kavash,R.W.; Andries,K.; de Bethune,M.P.; Azijn,H.; Pauwels,R.; Lewi,P.J.; Heeres,J.; Koymans,L.M.; de Jonge,M.R.; Van Aken,K.J.; Daeyaert,F.F.; et al.
参考来源:Bioorg Med Chem Lett 2001,11(17),2235
产品链接: CAS No. 269055-15-4››