【药物名称】Cilansetron, KC-9946, Calmactin
化学结构式(Chemical Structure):
参考文献No.9639
标题:New anellated indole derivs.
作者:Haeck, H.H.; Hamminga, D.; Van Wijngaarden, I.; Wouters, W. (Duphar International Research BV)
来源:AU 8818414; EP 0297651; JP 1989022870; US 4939136
合成路线图解说明:

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No.39397
标题:Process for the preparation of enantiomerically pure imidazolyl cpds.
作者:Verbeek, J.-M.; Van der Meij, P.F.C. (Duphar International Research BV)
来源:EP 0768309
合成路线图解说明:

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No.234729
标题:Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annelated indole derivatives. 1
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.
来源:J Med Chem 1993,36(23),3693
合成路线图解说明:

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No.489133
标题:Cilansetron
作者:Casta馿r, J.; Rabasseda, X.; Silvestre, J.S.; Graul, A.
来源:Drugs Fut 1999,24(5),475
合成路线图解说明:

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.

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