ethyl 4,6-dichloro-3-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indole-2-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】32870

【品名】ethyl 4,6-dichloro-3-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indole-2-carboxylate

【CA登记号】

【分子式】C₁₈H₂₃Cl₂NO₄Si

【分子量】416.37586

【元素组成】C 51.92% H 5.57% Cl 17.03% N 3.36% O 15.37% Si 6.75%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

To prepare GV196771, the starting synthetic plan, shown in Scheme 22578901a, was to build the exocyclic double bond present at the position C-3 of the indole nucleus by way of an aldol condensation-elimination starting from a known indole aldehyde (I). The first issue to solve was the choice of the protecting group of the indole nitrogen and 2-(trimethylsilyl)ethoxymethyl (SEM) group was selected based on its high stability in basic conditions. The lithium enolate of N-phenylpyrrolidone (III), prepared by treatment of (III) with a stoichiometric amount of t-BuLi -78 C was reacted with (II) in THF allowing to increase the temperature from -78 C to 20 C. A single polar reaction product was detected by HPLC analysis. After treatment with TMSCHN2 in CH2Cl2/MeOH 4:1 as solvent and purification by flash chromatography, the methyl ester derivative (V) was isolated in 56% overall yield from (II). The removal of the SEM protecting group under strong acidic conditions (HCl 6N, EtOH), followed by basic hydrolysis of the ester (LiOH) and acidification of the solution, gave the target compound GV196771 in high yield, which was then transformed into the corresponding sodium salt.

参考文献中间体

合成目标

【1】 Di Fabio, R.; et al.; Substituted indole-2-carboxylates as in vivo potent antagonists acting at the strychnine-insensitive glycine binding site. J Med Chem 1997, 40, 6, 841-850.
【2】 Giacobbe, S.A.; Baraldi, D.; Di Fabio, R.; Unusual synthesis of new glycine antagonists via sequential aldol condensation-lactonization-elimination reaction. Bioorg Med Chem Lett 1998, 8, 13, 1689-92.
【3】 Di Fabio, R.; Corsi, M.; Ugolini, A.R.; Gaviraghi, G.; Giacobbe, S.; Gastaldi, P.; Pentassuglia, G.; Quartaroli, M.; Conti, N.; Donati, D.; Trist, D.G.; Ratti, E.; GV196771. Drugs Fut 2000, 25, 2, 137.

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)	32144	ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate		C₁₂H₉Cl₂NO₃	详情	详情
(II)	32870	ethyl 4,6-dichloro-3-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indole-2-carboxylate		C₁₈H₂₃Cl₂NO₄Si	详情	详情
(III)	32871	1-phenyl-2-pyrrolidinone	4641-57-0	C₁₀H₁₁NO	详情	详情
(IV)	32872	4,6-dichloro-3-[(2-oxo-1-phenyl-3-pyrrolidinylidene)methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indole-2-carboxylic acid		C₂₆H₂₈Cl₂N₂O₄Si	详情	详情
(V)	32873	methyl 4,6-dichloro-3-[(2-oxo-1-phenyl-3-pyrrolidinylidene)methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indole-2-carboxylate		C₂₇H₃₀Cl₂N₂O₄Si	详情	详情
(VI)	32874	methyl 4,6-dichloro-3-[(2-oxo-1-phenyl-3-pyrrolidinylidene)methyl]-1H-indole-2-carboxylate		C₂₁H₁₆Cl₂N₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The formation of the free carboxyl group derivative (IV), as shown in Scheme 22578901b, was suggested to occur through formation of the diasteromeric lactone intermediates (VIIIa, b). Although there is no evidence to support the following mechanism, it has been hypothesized that only the syn-lactone can eliminate in the presence of one equivalent of LiOEt to give the free carboxyl derivative which is then transformed into the final compound (IV). Conversely, as far as the anti-lactone derivative is concerned, it seems that, for steric reasons, this intermediate is unable to reach the necessary antiperiplanar conformation to evolve towards the Z-elimination product. In the latter case, LiOEt, acting this time as a nucleophile, could afford lithium aldolate (VII). The final retroaldolic reaction could regenerate the starting materials (II) and (III), repeating the aldol-elimination-lactonization process.

参考文献中间体

合成目标

【1】 Di Fabio, R.; et al.; Substituted indole-2-carboxylates as in vivo potent antagonists acting at the strychnine-insensitive glycine binding site. J Med Chem 1997, 40, 6, 841-850.
【2】 Di Fabio, R.; Corsi, M.; Ugolini, A.R.; Gaviraghi, G.; Giacobbe, S.; Gastaldi, P.; Pentassuglia, G.; Quartaroli, M.; Conti, N.; Donati, D.; Trist, D.G.; Ratti, E.; GV196771. Drugs Fut 2000, 25, 2, 137.
【3】 Giacobbe, S.A.; Baraldi, D.; Di Fabio, R.; Unusual synthesis of new glycine antagonists via sequential aldol condensation-lactonization-elimination reaction. Bioorg Med Chem Lett 1998, 8, 13, 1689-92.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIIa)	32902	ethyl 4,6-dichloro-3-[(S)-hydroxy[(3R)-2-oxo-1-phenylpyrrolidinyl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indole-2-carboxylate	C₂₈H₃₄Cl₂N₂O₅Si	详情	详情
(VIIb)	32903	ethyl 4,6-dichloro-3-[(S)-hydroxy[(3S)-2-oxo-1-phenylpyrrolidinyl]methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indole-2-carboxylate	C₂₈H₃₄Cl₂N₂O₅Si	详情	详情
(VIIIa)	32904	(1R)-6,8-dichloro-1-[(3S)-2-oxo-1-phenylpyrrolidinyl]-4-[[2-(trimethylsilyl)ethoxy]methyl]-1,4-dihydro-3H-furo[3,4-b]indol-3-one	C₂₆H₂₈Cl₂N₂O₄Si	详情	详情
(VIIIb)	32905	(1R)-6,8-dichloro-1-[(3R)-2-oxo-1-phenylpyrrolidinyl]-4-[[2-(trimethylsilyl)ethoxy]methyl]-1,4-dihydro-3H-furo[3,4-b]indol-3-one	C₂₆H₂₈Cl₂N₂O₄Si	详情	详情
(II)	32870	ethyl 4,6-dichloro-3-formyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indole-2-carboxylate	C₁₈H₂₃Cl₂NO₄Si	详情	详情
(III)	32901	lithium 1-phenyl-4,5-dihydro-1H-pyrrol-2-olate	C₁₀H₁₀LiNO	详情	详情
(IV)	32872	4,6-dichloro-3-[(2-oxo-1-phenyl-3-pyrrolidinylidene)methyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indole-2-carboxylic acid	C₂₆H₂₈Cl₂N₂O₄Si	详情	详情

Extended Information