Cilansetron, KC-9946, Calmactin
西兰司琼(10R)-10-[(2-甲基-1H-吡唑-1-基)甲基]-5,6,9,10-四氢-4H-吡啶[3,2,1-jk]碳铉-11(8H)-一盐酸水合物Chemical Name: (-)-(R)-10-(2-Methyl-1H-imidazol-1-ylmethyl)-4,5,6,8,9,10-hexahydro-11H-pyrido[3,2,1-jk]carbazol-11-one
CAS No. 120635-74-7, 120635-72-5 (monoHCl), 209859-87-0 (monoHCl monohydrate)
项目整合开发状态: Pre-Registered
项目研究机构: Solvay (Originator)
合成路线:The reaction of 1-indanone (I) with sodium azide in acetic acid/sulfuric acid gives the tetrahydroquinolone (II),which is reduced with LiAlH4 in THF,yielding the tetrahydroquinoline (III).The reaction of (III) with NaNO2 and sulfuric acid afords the N-nitroso derivative (IV),which is reduced wiith LiAlH4 in THF to the N-amino compound (V).The reaction of (V) with cyclohexane-1,3-dione (VI) gives the monohydrazone (VII),which is cyclized by means of HCl in refluxing acetic acid,yielding the tetracyclic compound (VIII).The reaction of (VIII) with dimethylamine and paraformaldehyde in hot acetic acid provides compound (IX),which is treated with 2-methylimidazole (X) in refluxing water to afford racemic cilansetron (XI).Finally,this racemate is submitted to optical resolution with di-p-toluyl-D-tartaric acid or D-pyroglutamic acid.
📌 参考资料/链接：
参考文献标题:New anellated indole derivs.
文献作者:Haeck,H.H.; Hamminga,D.; Van Wijngaarden,I.; Wouters,W.(Duphar International Research BV)
参考来源:AU 8818414; EP 0297651; JP 1989022870; US 4939136
📄 详细内容
合成路线:The reaction of 1-indanone (I) with sodium azide in acetic acid/sulfuric acid gives the tetrahydroquinolone (II),which is reduced with LiAlH4 in THF,yielding the tetrahydroquinoline (III).The reaction of (III) with NaNO2 and sulfuric acid afords the N-nitroso derivative (IV),which is reduced wiith LiAlH4 in THF to the N-amino compound (V).The reaction of (V) with cyclohexane-1,3-dione (VI) gives the monohydrazone (VII),which is cyclized by means of HCl in refluxing acetic acid,yielding the tetracyclic compound (VIII).The reaction of (VIII) with dimethylamine and paraformaldehyde in hot acetic acid provides compound (IX),which is treated with 2-methylimidazole (X) in refluxing water to afford racemic cilansetron (XI).Finally,this racemate is submitted to optical resolution with di-p-toluyl-D-tartaric acid or D-pyroglutamic acid.
参考文献标题:Process for the preparation of enantiomerically pure imidazolyl cpds.
文献作者:Verbeek,J.-M.; Van der Meij,P.F.C.(Duphar International Research BV)
参考来源:EP 0768309
合成路线:The reaction of 1-indanone (I) with sodium azide in acetic acid/sulfuric acid gives the tetrahydroquinolone (II),which is reduced with LiAlH4 in THF,yielding the tetrahydroquinoline (III).The reaction of (III) with NaNO2 and sulfuric acid afords the N-nitroso derivative (IV),which is reduced wiith LiAlH4 in THF to the N-amino compound (V).The reaction of (V) with cyclohexane-1,3-dione (VI) gives the monohydrazone (VII),which is cyclized by means of HCl in refluxing acetic acid,yielding the tetracyclic compound (VIII).The reaction of (VIII) with dimethylamine and paraformaldehyde in hot acetic acid provides compound (IX),which is treated with 2-methylimidazole (X) in refluxing water to afford racemic cilansetron (XI).Finally,this racemate is submitted to optical resolution with di-p-toluyl-D-tartaric acid or D-pyroglutamic acid.
参考文献标题:Development of high-affinity 5-HT3 receptor antagonists.Structure-affinity relationships of novel 1,7-annelated indole derivatives.1
文献作者:Van Wijngaarden,I.; Hamminga,D.; van Hes,R.; Standaar,P.J.; Tipker,J.; Tulp,M.T.M.; Mol,F.; Olivier,B.; de Jonge,A.
参考来源:J Med Chem 1993,36(23),3693
合成路线:The reaction of 1-indanone (I) with sodium azide in acetic acid/sulfuric acid gives the tetrahydroquinolone (II),which is reduced with LiAlH4 in THF,yielding the tetrahydroquinoline (III).The reaction of (III) with NaNO2 and sulfuric acid afords the N-nitroso derivative (IV),which is reduced wiith LiAlH4 in THF to the N-amino compound (V).The reaction of (V) with cyclohexane-1,3-dione (VI) gives the monohydrazone (VII),which is cyclized by means of HCl in refluxing acetic acid,yielding the tetracyclic compound (VIII).The reaction of (VIII) with dimethylamine and paraformaldehyde in hot acetic acid provides compound (IX),which is treated with 2-methylimidazole (X) in refluxing water to afford racemic cilansetron (XI).Finally,this racemate is submitted to optical resolution with di-p-toluyl-D-tartaric acid or D-pyroglutamic acid.
参考文献标题:Cilansetron
文献作者:Castar,J.; Rabasseda,X.; Silvestre,J.S.; Graul,A.
参考来源:Drugs Fut 1999,24(5),475