新产品编号:293179
Chemical Name: 1-[4-[3-(3,5-Difluorophenyl)-2-propynyloxy]-1,2,5-thiadiazol-3-yl]-4-azatricyclo[2.2.1.0(2,6)]heptane oxalate
CAS No. 198143-43-0, 198143-42-9 (free base), 198143-54-3 (HCl)
项目整合开发状态: Preclinical
项目研究机构: Novo Nordisk (Originator), Lilly (Codevelopment)
合成路线:Reduction of cyanoazatricycloheptane (I) with diisobutylaluminum hydride produced aldehyde (II),which was treated with KCN and ammonia yielding aminonitrile (III).Cyclization of (III) with sulfur monochloride in DMF gave the 3-chloro-1,2,5-thiadiazole (IV).Displacement of the halogen atom of (IV) with sodium hydrogen sulfide,followed by alkylation with propyl bromide afforded the propyl thioether (V),which was oxidized to sulfone (VI) using oxone(R).The arylpropynol intermediate (IX) was prepared by coupling of 1-bromo-3,5-difluorobenzene (VII) with propargyl alcohol (VIII) in the presence of PdCl2(PPh3)2 and CuI.Reaction of sulfone (VI) with arylpropynol (IX) in the presence of NaH in THF provided the target ether (X).Finally,treatment of (X) with oxalic acid in acetone furnished the corresponding oxalate salt.
📌 参考资料/链接：
参考文献标题:Heterocyclic cpds.and their preparation and use
文献作者:Jeppesen,L.; Olesen,P.H.; Sauerberg,P.(Novo Nordisk A/S)
参考来源:EP 0891363; JP 1999509864; US 5914338; WO 9736906
📄 详细内容
合成路线:Reduction of cyanoazatricycloheptane (I) with diisobutylaluminum hydride produced aldehyde (II),which was treated with KCN and ammonia yielding aminonitrile (III).Cyclization of (III) with sulfur monochloride in DMF gave the 3-chloro-1,2,5-thiadiazole (IV).Displacement of the halogen atom of (IV) with sodium hydrogen sulfide,followed by alkylation with propyl bromide afforded the propyl thioether (V),which was oxidized to sulfone (VI) using oxone(R).The arylpropynol intermediate (IX) was prepared by coupling of 1-bromo-3,5-difluorobenzene (VII) with propargyl alcohol (VIII) in the presence of PdCl2(PPh3)2 and CuI.Reaction of sulfone (VI) with arylpropynol (IX) in the presence of NaH in THF provided the target ether (X).Finally,treatment of (X) with oxalic acid in acetone furnished the corresponding oxalate salt.
参考文献标题:1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M1 agonists: Structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives
文献作者:Hansen,L.; Olesen,P.H.; Jeppesen,L.; Sheardown,M.J.; Thomsen,C.; Rasmussen,T.; Jensen,A.F.; Christensen,M.S.; Rimvall,K.; Ward,J.S.; Whitesitt,C.; Calligaro,D.O.; Bymaster,F.P.; Delapp,N.W.; Felder,C.C.; Shannon,H.E.; Sauerberg,P.
参考来源:J Med Chem 1999,42(11),1999