Tadalafil, GF-196960, IC-351, Cialis, -Drug Synthesis Database

【结构式】

【药物名称】Tadalafil, GF-196960, IC-351, Cialis

【化学名称】(6R,12aR)-6-(1,3-Benzodioxol-5-yl)-2-methyl-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione

【CA登记号】171596-29-5, 240822-07-5, 171488-03-2 (trans-isomer)

【分子式】C₂₂H₁₉N₃O₄

【分子量】389.41443

【开发单位】GlaxoSmithKline (Originator), Lilly Icos (Marketer), Lilly (Licensee), Lilly Icos (Licensee)

【药理作用】Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, RENAL-UROLOGIC DRUGS, Treatment of Diabetic Complications, Treatment of Erectile Dysfunction, Treatment of Female Sexual Dysfunction, Treatment of Male Sexual Dysfunction, Phosphodiesterase V (PDE5A) Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

参考文献中间体

【1】 Jiang WQ, Alford VC, Qiu YH. 2004. Synthesis and SAR of tetracyclic pyrroloquinolones as phosphodies-terase 5 inhibitors. Bioorg Med Chem, 12(6):1505～1515
【2】 Orme MW, Maninelli MJ, Doecke CW, et aL. 2004. Preparation of tetrahydro-β-carboline diastereomers by modified Pictet-Spengler reaction. W0 2004011463

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	10127	1,3-Benzodioxole-5-carbaldehyde; Heliotropine	120-57-0	C₈H₆O₃	详情	详情
(I)	66756	(R)-2-amino-3-(1H-indol-3-yl)propanoic acid		C₁₁H₁₂N₂O₂	详情	详情
(II)	66757	(R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride		C₁₂H₁₄N₂O₂.HCl	详情	详情
(IV)	66758	methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate hydrochloride		C₂₀H₁₈N₂O₄.HCl	详情	详情
(V)	43791	methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate		C₂₂H₁₉ClN₂O₅	详情	详情

合成路线2

参考文献中间体

【1】 Revell JD, Srinivasan N, Ganesan A. 2004. Two concise syntheses of Cialis via the N-acyliminium Pictet-Spengler reaction. Synlett, (8):1428～1430

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	66757	(R)-methyl 2-amino-3-(1H-indol-3-yl)propanoate hydrochloride		C₁₂H₁₄N₂O₂.HCl	详情	详情
(V)	66761	(1R,3R)-methyl 2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)acetyl)-1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate		C₃₈H₃₃N₃O₇	详情	详情
(II)	10127	1,3-Benzodioxole-5-carbaldehyde; Heliotropine	120-57-0	C₈H₆O₃	详情	详情
(III)	66759	(R,E)-methyl 2-((benzo[d][1,3]dioxol-5-ylmethylene)amino)-3-(1H-indol-3-yl)propanoate		C₂₀H₁₈N₂O₄	详情	详情
(IV)	66760	(9H-fluoren-9-yl)methyl (2-chloro-2-oxoethyl)(methyl)carbamate		C₁₈H₁₆ClNO₃	详情	详情

合成路线3

参考文献中间体

【1】 Revell JD, Srinivasan N, Ganesan A. 2004. Two concise syntheses of Cialis via the N-acyliminium Pictet-Spengler reaction. Synlett, (8):1428～1430

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	66759	(R,E)-methyl 2-((benzo[d][1,3]dioxol-5-ylmethylene)amino)-3-(1H-indol-3-yl)propanoate		C₂₀H₁₈N₂O₄	详情	详情
(II)	43791	methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate		C₂₂H₁₉ClN₂O₅	详情	详情

合成路线4

参考文献中间体

【1】 Sajja E, Vetukuri VR, Ningam SR, et aL. 2007. Process for producing tadalafiL. W0 2007100387

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	66758	methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate hydrochloride		C₂₀H₁₈N₂O₄.HCl	详情	详情
(I)	20416	methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate		C₁₂H₁₄N₂O₂	详情	详情
(II)	10127	1,3-Benzodioxole-5-carbaldehyde; Heliotropine	120-57-0	C₈H₆O₃	详情	详情
(IV)	32138	Sarcosine ethyl ester; Ethyl 2-(methylamino)acetate	52605-49-9	C₅H₁₁NO₂	详情	详情

合成路线5

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.

参考文献中间体

【1】 Daugan, A.; Grondin, P.; Ruault, C.; et al.; 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. J Med Chem 2003, 46, 21, 4533.
【2】 Martin, L.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; IC-351. Drugs Fut 2001, 26, 1, 15.
【3】 Daugan, A.C.-M. (Icos Corp.); Tetracyclic derivs., process of preparation and use. EP 0740668; JP 1997508113; US 5859006; US 6025494; US 6127542; WO 9519978 .
【4】 Daugan, A.C.-M. (Icos Corp.); Use of cGMP-phosphodiesterase inhibitors to treat impotence. JP 1999509221; US 6140329; WO 9703675 .
【5】 Gellibert, F.; Daugan, A.C.-M. (Icos Corp.); Tetracyclic cyclic GMP-specific phosphodiesterase inhibitors, process of preparation and use. US 6143746 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	20416	methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate		C₁₂H₁₄N₂O₂	详情	详情
(II)	10127	1,3-Benzodioxole-5-carbaldehyde; Heliotropine	120-57-0	C₈H₆O₃	详情	详情
(III)	43790	methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate		C₂₀H₁₈N₂O₄	详情	详情
(IV)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(V)	43791	methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate		C₂₂H₁₉ClN₂O₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)