Yaozh News Star Club Edu TOP100 Customer Service APP
Iphone Download Android Download
  • English
  • 简体中文
Login Register
Search
Current Location： Home > Feedback Help Print

【结 构 式】

【分子编号】32144

【品名】ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate

【CA登记号】

【 分 子 式 】C12H9Cl2NO3

【 分 子 量 】286.1138

【元素组成】C 50.38% H 3.17% Cl 24.78% N 4.9% O 16.78%
与该中间体有关的原料药合成路线共 5 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5

合成路线1

该中间体在本合成路线中的序号：(VI)

GW150526 was easily prepared starting from the known 3-unsubstituted indole derivative (IV) following the general synthetic route described in Scheme 20235901a. The known indole derivative (IV) was formylated at the C-3 position according to the well known Vilsmaier-Haack procedure obtaining the intermediate (VI) in high yield. The subsequent Wittig-type olefination reaction afforded the compound (VII) with high regio control in the formation of the olefinic moiety. The hydrolysis of the ethyl ester group afforded GV-150526 as sodium salt derivative.

参考文献 中间体
合成目标
【1】 Di Fabio, R.; Cugola, A.; Donati, D.; Ferinai, A.; Gaviraghi, G.; Ratti, E.; Trist, D.G.; Reggiani, A.; Identification and pharmacological characterization of GV150526, a novel glycine antagonist as potent neuroprotective agent. Drugs Fut 1998, 23, 1, 61.
【2】 Salituro, F.G.; et al.; 3-(2-Carboxyindol-3-yl)propionic acid derivatives: Antagonists of the strychnine-insensitive glycine receptor associated with the N-methyl-D-aspartate receptor complex. J Med Chem 1990, 33, 11, 2946-8.
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) 28066 1-(3,5-dichlorophenyl)hydrazine 39943-56-1 C6H6Cl2N2 详情 详情
(II) 17491 ethyl acetate 141-78-6 C4H8O2 详情 详情
(III) 32141 ethyl 2-[(E)-2-(3,5-dichlorophenyl)hydrazono]propanoate C11H12Cl2N2O2 详情 详情
(IV) 32142 ethyl 4,6-dichloro-1H-indole-2-carboxylate C11H9Cl2NO2 详情 详情
(V) 32143 N-methyl-N-phenylacetamide 579-10-2 C9H11NO 详情 详情
(VI) 32144 ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate C12H9Cl2NO3 详情 详情
(VII) 32145 N-phenyl-2-(triphenylphosphoranylidene)acetamide C26H22NOP 详情 详情
(VIII) 32147 ethyl 3-[(E)-3-anilino-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate C20H16Cl2N2O3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Alternatively, for the synthesis of analogues of GV-150526 substituted at the terminal phenyl ring belonging to the C-3 side chain as shown in Scheme 20235902a, compound (I) was transformed int the intermediate (III) in high yield. Following chemoselective deprotection of the tert-butyl ester group, the free carboxylic acid derivative (IV) was submitted to amidation reaction using different synthetic methods. In particular, the activation of the carboxy group through the formation of the corresponding 2-pyridyl thioester, generated in situ by the mild oxidation-reduction condensation reaction in the presence of 2,2'-dipyridyl disulfide and PPh3, was found to be highly efficient, also in the case of poor nucleophilic aromatic amines, affording the desired amide derivatives (VI) in high yield (either from the isolated 2-pyridyl thioester intermediate (V) or from the acid (IV) using a one pot procedure). Finally, target compounds were easily prepared by basic hydrolysis of the 2-carboxyethyl ester protecting group.

参考文献 中间体
合成目标
【1】 Struys, M.M.R.F.; et al.; Tetrahedron 1993, 49, 10, 2239.
【2】 Davison, S.C.; et al.; VCH Publichers: Stuttgart 1989, 147, 4, 972-6.
【3】 Di Fabio, R.; Cugola, A.; Donati, D.; Ferinai, A.; Gaviraghi, G.; Ratti, E.; Trist, D.G.; Reggiani, A.; Identification and pharmacological characterization of GV150526, a novel glycine antagonist as potent neuroprotective agent. Drugs Fut 1998, 23, 1, 61.
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) 28066 1-(3,5-dichlorophenyl)hydrazine 39943-56-1 C6H6Cl2N2 详情 详情
(II) 17491 ethyl acetate 141-78-6 C4H8O2 详情 详情
(III) 32141 ethyl 2-[(E)-2-(3,5-dichlorophenyl)hydrazono]propanoate C11H12Cl2N2O2 详情 详情
(IV) 32142 ethyl 4,6-dichloro-1H-indole-2-carboxylate C11H9Cl2NO2 详情 详情
(V) 32143 N-methyl-N-phenylacetamide 579-10-2 C9H11NO 详情 详情
(VI) 32144 ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate C12H9Cl2NO3 详情 详情
(VII) 32145 N-phenyl-2-(triphenylphosphoranylidene)acetamide C26H22NOP 详情 详情
(VIII) 32147 ethyl 3-[(E)-3-anilino-3-oxo-1-propenyl]-4,6-dichloro-1H-indole-2-carboxylate C20H16Cl2N2O3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(I)

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4

该中间体在本合成路线中的序号：(I)

GV217828 was prepared following the synthetic route shown in Scheme 22578902a. In this event, due to the lability of the cyclic imide in basic medium, indole aldehyde (I) was transformed into the corresponding tert-butyl ester derivative (XI). Wittig reaction with phosphorane (XII) gave the olefinic intermediate (XIII) as a single E regioisomer. The removal of the tert-butyl protecting group afforded the desired compound G-217828 in high yield.

参考文献 中间体
合成目标
【1】 Hedaya, E.; Theodoropulos, S.; Preparation and reactions of stable phosphorus ylides derived from malic anhydrides. Tetrahedron 1968, 24, 2241.
【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.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
21059 N-[di(tert-butoxy)methyl]-N,N-dimethylamine; di(tert-butoxy)-N,N-dimethylmethanamine 36805-97-7 C11H25NO2 详情 详情
(I) 32144 ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate C12H9Cl2NO3 详情 详情
(IX) 32906 4,6-dichloro-3-formyl-1H-indole-2-carboxylic acid C10H5Cl2NO3 详情 详情
(X) 32909 tert-butyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate C14H13Cl2NO3 详情 详情
(XI) 32910 di(tert-butyl) 4,6-dichloro-3-formyl-1H-indole-1,2-dicarboxylate C19H21Cl2NO5 详情 详情
(XII) 32907 5-oxo-1-phenyl-4-(triphenylphosphonio)-4,5-dihydro-1H-pyrrol-2-olate C28H22NO2P 详情 详情
(XIII) 32908 di(tert-butyl) 4,6-dichloro-3-[(2,5-dioxo-1-phenyl-3-pyrrolidinylidene)methyl]-1H-indole-1,2-dicarboxylate C29H28Cl2N2O6 详情 详情

合成路线5

该中间体在本合成路线中的序号：(V)

Diazotization of 3,5-dichloroaniline (I), followed by reduction of the resultant diazonium salt provides hydrazine (II). Subsequent reaction of 3,5-dichlorophenylhydrazine (II) with ethyl pyruvate (III) under Fischer reaction conditions gives rise to indole (IV). Vilsmeier formylation of (IV) using N-methylformanilide and phosphoryl chloride produces aldehyde (V). This is reductively aminated with methyl glycinate and NaBH(OAc)3 to afford aminoester (VI). Condensation of (VI) with phenyl isocyanate, followed by cyclization in the presence of Et3N leads to hydantoin (VII). Finally, ester (VII) is hydrolyzed employing LiOH to furnish the target indolecarboxylic acid.

参考文献 中间体
合成目标
【1】 Jansen, M.; Potschka, H.; Brandt, C.; Loscher, W.; Dannhardt, G.; Hydantoin-substituted 4,6-dichloroindole-2-carboxylic acids as ligands with high affinity for the glycine binding site of the NMDA receptor. J Med Chem 2003, 46, 1, 64.
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) 26542 3,5-dichloroaniline 626-43-7 C6H5Cl2N 详情 详情
(II) 28066 1-(3,5-dichlorophenyl)hydrazine 39943-56-1 C6H6Cl2N2 详情 详情
(III) 12135 ethyl 2-oxopropanoate; Ethyl pyruvate 617-35-6 C5H8O3 详情 详情
(IV) 32142 ethyl 4,6-dichloro-1H-indole-2-carboxylate C11H9Cl2NO2 详情 详情
(V) 32144 ethyl 4,6-dichloro-3-formyl-1H-indole-2-carboxylate C12H9Cl2NO3 详情 详情
(VI) 64389 ethyl 4,6-dichloro-3-({[2-(methyloxy)-2-oxoethyl]amino}methyl)-1H-indole-2-carboxylate C15H16Cl2N2O4 详情 详情
(VII) 64390 ethyl 4,6-dichloro-3-[(2,4-dioxo-3-phenyl-1-imidazolidinyl)methyl]-1H-indole-2-carboxylate C21H17Cl2N3O4 详情 详情
Extended Information