Dapivirine, TMC-120, R-147681
达匹韦林Chemical Name: 4-[4-(2,4,6-Trimethylphenylamino)pyrimidin-2-ylamino]benzonitrile
CAS No. 244767-67-7, 244773-75-9 (HBr), 244768-47-6 (HCl)
项目整合开发状态: Phase II
项目研究机构: Janssen (Originator), Tibotec-Virco (Originator), IPM (Licensee)
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.
📌 参考资料/链接：
参考文献标题:HIV inhibiting pyrimidine derivs.
文献作者:Heeres,J.; Kukla,M.J.; Andries,K.J.L.M.; Janssen,P.A.J.; Ho,C.Y.; Janssen,M.A.C.; Ludovici,D.W.; de Corte,B.; de Jonge,M.R.; Koymans,L.M.H.; van Aken,K.J.A.(Janssen Pharmaceutica NV)
参考来源:EP 0945442; EP 0945443; US 6197779; US 6440986; WO 9950250
📄 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. 244767-67-7›› 产品链接: CAS No.244768-47-6››