【药物名称】Tadalafil, GF-196960, IC-351, Cialis
化学结构式(Chemical Structure):
参考文献No.27672
标题:Tetracyclic derivs., process of preparation and use
作者:Daugan, A.C.-M. (Icos Corp.)
来源:EP 0740668; JP 1997508113; US 5859006; US 6025494; US 6127542; WO 9519978
合成路线图解说明:

Cyclization of D-tryptophan methyl ester (I) with piperonal (II) by means of TFA in dichloromethane gives, after separation of the undesired trans-isomer by flash chromatography, the (1R,3R-cis)-pyrido-indole derivative (III). The acylation of (III) with chloroacetyl chloride (IV) and NaHCO3 in chloroform yields the chloroacetyl derivative (V), which is finally cyclized with methylamine in methanol.

参考文献No.32434
标题:Use of cGMP-phosphodiesterase inhibitors to treat impotence
作者:Daugan, A.C.-M. (Icos Corp.)
来源:JP 1999509221; US 6140329; WO 9703675
合成路线图解说明:

Cyclization of D-tryptophan methyl ester (I) with piperonal (II) by means of TFA in dichloromethane gives, after separation of the undesired trans-isomer by flash chromatography, the (1R,3R-cis)-pyrido-indole derivative (III). The acylation of (III) with chloroacetyl chloride (IV) and NaHCO3 in chloroform yields the chloroacetyl derivative (V), which is finally cyclized with methylamine in methanol.

参考文献No.46213
标题:Tetracyclic cyclic GMP-specific phosphodiesterase inhibitors, process of preparation and use
作者:Gellibert, F.; Daugan, A.C.-M. (Icos Corp.)
来源:US 6143746
合成路线图解说明:

Cyclization of D-tryptophan methyl ester (I) with piperonal (II) by means of TFA in dichloromethane gives, after separation of the undesired trans-isomer by flash chromatography, the (1R,3R-cis)-pyrido-indole derivative (III). The acylation of (III) with chloroacetyl chloride (IV) and NaHCO3 in chloroform yields the chloroacetyl derivative (V), which is finally cyclized with methylamine in methanol.

参考文献No.606182
标题:IC-351
作者:Mart韓, L.; Sorbera, L.A.; Leeson, P.A.; Casta馿r, J.
来源:Drugs Fut 2001,26(1),15
合成路线图解说明:

Cyclization of D-tryptophan methyl ester (I) with piperonal (II) by means of TFA in dichloromethane gives, after separation of the undesired trans-isomer by flash chromatography, the (1R,3R-cis)-pyrido-indole derivative (III). The acylation of (III) with chloroacetyl chloride (IV) and NaHCO3 in chloroform yields the chloroacetyl derivative (V), which is finally cyclized with methylamine in methanol.

参考文献No.757016
标题:The discovery of tadalafil: A novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-Hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues
作者:Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville, A.C.; Coste, H.; Linget, J.M.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R.
来源:J Med Chem 2003,46(21),4533
合成路线图解说明:

Cyclization of D-tryptophan methyl ester (I) with piperonal (II) by means of TFA in dichloromethane gives, after separation of the undesired trans-isomer by flash chromatography, the (1R,3R-cis)-pyrido-indole derivative (III). The acylation of (III) with chloroacetyl chloride (IV) and NaHCO3 in chloroform yields the chloroacetyl derivative (V), which is finally cyclized with methylamine in methanol.

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