Eletriptan, UK-116044-04(HBr salt), UK-116044, Relpax, -Drug Synthesis Database

【结构式】

【药物名称】Eletriptan, UK-116044-04(HBr salt), UK-116044, Relpax

【化学名称】5-[2-(Benzenesulfonyl)ethyl]-3-[1-methylpyrrolidin-2(R)-ylmethyl]-1H-indole

【CA登记号】143322-58-1, 143577-61-1 (hemisuccinate), 179041-30-6 (monofumarate), 177834-92-3 (monoHBr salt), 180637-87-0 (monosuccinate)

【分子式】C₂₂H₂₆N₂O₂S

【分子量】382.52872

【开发单位】Pfizer (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, 5-HT1B Agonists, 5-HT1D Agonists

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

参考文献中间体

【1】 Macor JE, Wythes MJ.1992.Preparation of 3-(heterocyclylmethyl) indoles as drugs W0 9206973

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)	13309	5-Bromo-1H-indole; 5-Bromoindole	10075-50-0	C₈H₆BrN	详情	详情
(II)	17006	benzyl (2R)-2-(chlorocarbonyl)tetrahydro-1H-pyrrole-1-carboxylate		C₁₃H₁₄ClNO₃	详情	详情
(III)	17008	benzyl (2R)-2-[(5-bromo-1H-indol-3-yl)carbonyl]tetrahydro-1H-pyrrole-1-carboxylate		C₂₁H₁₉BrN₂O₃	详情	详情
(IV)	17009	5-bromo-3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-1H-indole		C₁₄H₁₇BrN₂	详情	详情
(V)	17011	(E)-2-(3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-1H-indol-5-yl)ethenyl phenyl sulfone; 3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-5-[(E)-2-(phenylsulfonyl)ethenyl]-1H-indole	180637-89-2	C₂₂H₂₄N₂O₂S	详情	详情

合成路线2

参考文献中间体

【1】 Macor JE, Wythes MJ. 1997. Indole derivatives. US 5607951
【2】 Ogilvie RJ. 2002. New process for the preparation of the anti-migraine drug, eletriptan. W0 2002050063

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	17009	5-bromo-3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-1H-indole	C₁₄H₁₇BrN₂	详情	详情
(II)	66298	(R)-1-(5-bromo-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indol-1-yl)ethanone	C₁₆H₁₉BrN₂O	详情	详情
(III)	66299	(R,E)-1-(3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1H-indol-1-yl)ethanone	C₂₄H₂₆N₂O₃S	详情	详情
(IV)	66300	(R)-1-(3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)ethyl)-1H-indol-1-yl)ethanone	C₂₄H₂₈N₂O₃S	详情	详情

合成路线3

参考文献中间体

【1】 Furlong PJ,Kelly CJ,el d.2005. Preparation of α-polymotphic eletriptan hydrobromide.US 2005020663

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)	66299	(R,E)-1-(3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1H-indol-1-yl)ethanone		C₂₄H₂₆N₂O₃S	详情	详情
(II)	17011	(E)-2-(3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-1H-indol-5-yl)ethenyl phenyl sulfone; 3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-5-[(E)-2-(phenylsulfonyl)ethenyl]-1H-indole	180637-89-2	C₂₂H₂₄N₂O₂S	详情	详情

合成路线4

The reaction of N-(benzyloxycarbonyl)-D-proline (I) with oxalyl chloride in dichloromethane/DMF gives the corresponding acyl chloride (II), which is condensed with 5-bromoindole (III) by means of ethylmagnesium bromide in ether yielding 3-(N-benzyloxycarbonyl-D-prolyl)-5-bromoindole (IV). The reduction of the carbonyl group of (IV) with LiAlH4 in THF affords 5-bromo-3-[1-methylpyrrolidin-2(R)-ylmethyl]indole (V), which is condensed with phenyl(vinyl)sulfone (VI) by means of tri-p-tolylphosphine, palladium acetate and triethylamine in refluxing acetonitrile giving the substituted (E)-vinyl sulfone (VII). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol/HCl.

参考文献中间体

【1】 Ngo, J.; Rabasseda, X.; Castañer, J.; Eletriptan. Drugs Fut 1997, 22, 3, 221.
【2】 Harding, V.D.; Macrae, R.J.; Ogilvie, R.J. (Pfizer Inc.); Salts of an anti-migraine indole deriv. EP 0776323; JP 1997512283; US 6110940; WO 9606842 .
【3】 Macor, J.E.; Wythes, M.J. (Pfizer Inc.); Indole derivs. EP 0592438; JP 1993507288; JP 1997003063; US 5545644; WO 9206973 .
【4】 Perkins, J.F. (Pfizer Inc.); Process for the preparation of 3-acyl-indoles. EP 1088817 .

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)	17005	(2R)-1-[(benzyloxy)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid		C₁₃H₁₅NO₄	详情	详情
(II)	17006	benzyl (2R)-2-(chlorocarbonyl)tetrahydro-1H-pyrrole-1-carboxylate		C₁₃H₁₄ClNO₃	详情	详情
(III)	13309	5-Bromo-1H-indole; 5-Bromoindole	10075-50-0	C₈H₆BrN	详情	详情
(IV)	17008	benzyl (2R)-2-[(5-bromo-1H-indol-3-yl)carbonyl]tetrahydro-1H-pyrrole-1-carboxylate		C₂₁H₁₉BrN₂O₃	详情	详情
(V)	17009	5-bromo-3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-1H-indole		C₁₄H₁₇BrN₂	详情	详情
(VI)	17010	phenyl vinyl sulfone; dioxo(phenyl)vinyl-lambda(6)-sulfane; Benzene, (ethenylsulfonyl)-	5535-48-8	C₈H₈O₂S	详情	详情
(VII)	17011	(E)-2-(3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-1H-indol-5-yl)ethenyl phenyl sulfone; 3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-5-[(E)-2-(phenylsulfonyl)ethenyl]-1H-indole	180637-89-2	C₂₂H₂₄N₂O₂S	详情	详情

Extended Information