ethyl 3-[(E)-3-(4-[[(aminocarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】35553

【品名】ethyl 3-[(E)-3-(4-[[(aminocarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate

【CA登记号】

【分子式】C₂₂H₂₀Cl₂N₄O₄

【分子量】475.33076

【元素组成】C 55.59% H 4.24% Cl 14.92% N 11.79% O 13.46%

与该中间体有关的原料药合成路线共 4 条

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

该中间体在本合成路线中的序号：(X)

The known indole-2-carboxylate intermediate (I) was protected as the N-benzenesulfonyl derivative (II) using benzenesulfonyl chloride and NaH, and the tert-butyl ester group of (II) was subsequently cleaved by means of formic acid. The resulting carboxylic acid (III) was activated as the 2-pyridyl thioester (IV) upon treatment with 2,2'-dipyridyl disulfide and triphenylphosphine. Selective protection of 4-aminobenzyl amine (V) with Boc2O produced the amino carbamate (VI). This was coupled with pyridyl thioester (IV) in refluxing THF to yield amide (VII). Subsequent removal of the N-Boc group of (VII) with trifluoroacetic acid afforded the free amino derivative (VIII), which was converted to the required urea (IX) upon treatment with trimethylsilyl isocyanate. Further hydrolysis of the benzenesulfonyl group of (IX) with ethanolic NaOH furnished the deprotected indole (X).

参考文献中间体

合成目标

【1】 Conti, N.; Di Fabio, R.; De Magistris, E.; Feriani, A. (Glaxo Wellcome plc); Indole derivs. as EAA antagonists. EP 0813524; JP 1999501041; US 5919811; WO 9627588 .

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)	32148	ethyl 3-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate		C₁₈H₁₉Cl₂NO₄	详情	详情
(II)	35545	ethyl 3-[(E)-3-(tert-butoxy)-3-oxo-1-propenyl]-4,6-dichloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate		C₂₄H₂₃Cl₂NO₆S	详情	详情
(III)	35546	(E)-3-[4,6-dichloro-2-(ethoxycarbonyl)-1-(phenylsulfonyl)-1H-indol-3-yl]-2-propenoic acid		C₂₀H₁₅Cl₂NO₆S	详情	详情
(IV)	35547	ethyl 4,6-dichloro-3-[(E)-3-oxo-3-(2-pyridinylsulfanyl)-1-propenyl]-1-(phenylsulfonyl)-1H-indole-2-carboxylate		C₂₅H₁₈Cl₂N₂O₅S₂	详情	详情
(V)	35548	4-(aminomethyl)aniline; 4-aminobenzylamine	4403-71-8	C₇H₁₀N₂	详情	详情
(VI)	35549	tert-butyl 4-aminobenzylcarbamate		C₁₂H₁₈N₂O₂	详情	详情
(VII)	35550	ethyl 3-[(E)-3-(4-[[(tert-butoxycarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate		C₃₂H₃₁Cl₂N₃O₇S	详情	详情
(VIII)	35551	ethyl 3-[(E)-3-[4-(aminomethyl)anilino]-3-oxo-1-propenyl]-4,6-dichloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate		C₂₇H₂₃Cl₂N₃O₅S	详情	详情
(IX)	35552	ethyl 3-[(E)-3-(4-[[(aminocarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate		C₂₈H₂₄Cl₂N₄O₆S	详情	详情
(X)	35553	ethyl 3-[(E)-3-(4-[[(aminocarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate		C₂₂H₂₀Cl₂N₄O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The precursor ethyl ester (X) was also prepared from the unprotected indole carboxylic acid (XII). Conversion into amide (XIV) was carried out using activation of the carboxyl group via formation of the corresponding 2-pyridyl thioester (XIII) and then coupling with aniline (VI). Trifluoroacetic acid-promoted cleavage of the N-Boc group of (XIV) provided amine (XV). This was converted to urea (X) by means of trimethylsilyl isocyanate.

参考文献中间体

合成目标

【1】 Provera, S.; Rovatti, L.; Sabbatini, F.M.; Reggiani, A.; Di Fabio, R.; De Magistris, M.; Conti, N.; Barnaby, R.J.; Feriani, A.; Substituted analogues of GV150526 as potent glycine binding site antagonists in animal models of cerebral ischemia. J Med Chem 1999, 42, 18, 3486.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	35549	tert-butyl 4-aminobenzylcarbamate	C₁₂H₁₈N₂O₂	详情	详情
(X)	35553	ethyl 3-[(E)-3-(4-[[(aminocarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate	C₂₂H₂₀Cl₂N₄O₄	详情	详情
(XII)	32149	(E)-3-[4,6-dichloro-2-(ethoxycarbonyl)-1H-indol-3-yl]-2-propenoic acid	C₁₄H₁₁Cl₂NO₄	详情	详情
(XIII)	32150	ethyl 4,6-dichloro-3-[(E)-3-oxo-3-(2-pyridinylsulfanyl)-1-propenyl]-1H-indole-2-carboxylate	C₁₉H₁₄Cl₂N₂O₃S	详情	详情
(XIV)	35554	ethyl 3-[(E)-3-(4-[[(tert-butoxycarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate	C₂₆H₂₇Cl₂N₃O₅	详情	详情
(XV)	35555	ethyl 3-[(E)-3-[4-(aminomethyl)anilino]-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate	C₂₁H₁₉Cl₂N₃O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(X)

In a more direct route, 4-aminobenzyl amine (V) was treated with trimethylsilyl isocyanate to yield amino urea (XVI). This was subsequently coupled with pyridyl thioester (XIII) to furnish the previously described intermediate (X).

参考文献中间体

合成目标

【1】 Conti, N.; Di Fabio, R.; De Magistris, E.; Feriani, A. (Glaxo Wellcome plc); Indole derivs. as EAA antagonists. EP 0813524; JP 1999501041; US 5919811; WO 9627588 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	35548	4-(aminomethyl)aniline; 4-aminobenzylamine	4403-71-8	C₇H₁₀N₂	详情	详情
(X)	35553	ethyl 3-[(E)-3-(4-[[(aminocarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate		C₂₂H₂₀Cl₂N₄O₄	详情	详情
(XIII)	32150	ethyl 4,6-dichloro-3-[(E)-3-oxo-3-(2-pyridinylsulfanyl)-1-propenyl]-1H-indole-2-carboxylate		C₁₉H₁₄Cl₂N₂O₃S	详情	详情
(XVI)	35556	N-(4-aminobenzyl)urea		C₈H₁₁N₃O	详情	详情

合成路线4

该中间体在本合成路线中的序号：(X)

Hydrolysis of the ethyl ester function of (X) by means of LiOH, followed by acidic workup, gave rise to carboxylic acid (XI), which was finally isolated as the title sodium salt by treatment with aqueous NaOH and subsequent freeze drying. Alternatively, hydrolysis of ethyl ester (X) with NaOH in isopropanol-water provided directly the target sodium salt.

参考文献中间体

合成目标

【1】 Conti, N.; Di Fabio, R.; De Magistris, E.; Feriani, A. (Glaxo Wellcome plc); Indole derivs. as EAA antagonists. EP 0813524; JP 1999501041; US 5919811; WO 9627588 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	35553	ethyl 3-[(E)-3-(4-[[(aminocarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate		C₂₂H₂₀Cl₂N₄O₄	详情	详情
(XI)	35557	3-[(E)-3-(4-[[(aminocarbonyl)amino]methyl]anilino)-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylic acid		C₂₀H₁₆Cl₂N₄O₄	详情	详情

Extended Information