Indole-3-carboxylic acid ethyl ester

Hydroxy-2-methyl-1 H-indole-3-carboxylic acid ethyl ester... 

ETHYL INDOLE-2-C ARBO XYLATE (Indole-2-carboxylic acid, ethyl ester)... 

Indole, 1-methyl-, 40, 68 Indole-3-carbonttrile, 43, 58 Indoie-3-carboxaldehyde, conversion to indole-3-carbonitrile, 43, 58 Indole-2-carboxylic acid, ethyl ester, 43, 40... 

C jH2,NOSi) see Indanorex (lS-cii)-2,3-dihydro-l//-indene-l,2-diol (G7H10O2 6752S-22-7) see Indinavir sulfate (laS)-la,6a-dihydro-6//-indenori,2-6]oxirene (CgHjO 67528-26-1) see Indinavir sulfate (2,3-dihydro-l//-inden-4-yl)carbamimidothioic acid methyl ester monohydriodide (C, H 1N2S 40507-77-5) see Indanazoline 23-dibydro-l//-indole-2-carboxylic acid ethyl ester (C iH, N02 50501-07-0) see Perindopril... 

To a stirred suspension of 4.6 g (13.8 mmoles) of the (S)-3-(2-hydroxyethyl)-5-(2-oxo-l,3-oxazolidin-4- ylmethyl)-lH-indol-2-carboxylic acid ethyl ester in 42 ml of dichloromethane were added 4.2 ml of pyridine, 3.9 g (20.7 mmoles) oftosyl chloride and 170 mg (1.38 mmoles) of dimethylaminopyridine and the stirring continued at room temperature for 20 hours. The reaction mixture was poured over 20 ml of 3 N, HCI precooled to 0°C and extracted twice with dichlormethane. The organic phases were washed with brine, dried on anhydrous sodium sulphate and the solvent evaporated to dryness. The evaporated solid was crystallised with isopropyl alcohol to give 6.4 g (95%) of the title compound as a white crystalline solid. Melting point 166.4°-168.2°C. 

A stirred suspension of 5 g of (S)-5-(2-oxo-l,3-oxazolidin-4-ylmethyl)-3-[(2-toluen-4-sulphoniloxy)ethyl]-lH-indol-2-carboxylic acid ethyl ester in 30 ml of a 2 N solution of dimethylamine in ethanol was stirred at 50°C for 20 hours in a closed reactor. The solvent was evaporated to dryness, the residue dissolved in 20 ml of 2 N HCI and washed three times with 15 ml of dichloromethane. The washed aqueous phase was cooled and adjusted to pH 12 with a 40% sodium hydroxide solution and extracted three times with 20 ml of dichloromethane. The combined organic phases were washed with brine and dried above anhydrous sodium sulphate. The solvent was evaporated to dryness and the residue recrystallised from ethyl acetate to give 3.4 g (91%) of the title dimethylamine as a yellow solid. Melting point 67°-70°C. 

To a solution of 1.4 g (24.9 mmoles) of KOH in 10 ml of ethanol was added 2.8 g (7.8 mmoles) of (S)-3-(2- dimethylaminoethyl)-5-[2-oxo-l,3-oxazolidin-4-ylmethyl]-lH-indol-2-carboxylic acid ethyl ester. The resulting solution was heated at reflux temperature for one hour. It was cooled and the solvent evaporated to dryness. The residue was dissolved in 6 ml of water and washed three times with 10 ml of dichloromethane. The aqueous solution was cooled to 5°C, adjusted to pH 6 with glacial acetic acid, stirred for 30 minutes at that temperature and the water evaporated to dryness. The residue was redissolved in 30 ml of water and 5 g of ionic exchange resin (Dowex50WX8-400) added. The mixture was left under stirring at room temperature for 24 hours. The resin was filtered and it was washed with water. For desorbtion the resin was suspended with 20 ml of a 10% aqueous solution of ammonia and stirred at room temperature for 5 hours. After that it was filtered and washed with water, water was evaporated to dryness under reduced pressure to give 7.75 g (94%) of the title acid as a yellow crystalline solid. Melting point 230°C. 

Substituted 7,12-dihydroindolo[3,2-c(][l]benzazepin-6(5/0ones 2a and 2b were first reported in 1958 by MacPhillamy et al. [33] as the last intermediate in an 11-step synthesis of 4-ethyl-5,6,7,12-tetrahydro-2-methylindolo[3,2-t/][l]benzazepine. In 1992, Kunick reported the preparation of six indolo[3,2-d][l]benzazepin-6(5/f)ones [34] in a three-step procedure. The crucial step was the decarboxylation reaction of 2,3-dihydro-5-hydroxy-2-oxo-l/7-benz[(t]azepin-4-carboxylic acid ethyl ester into 3,4-dihydro-lH-benz[ ]azepin-2,5-dione, which made possible the subsequent Fischer indole synthesis, with formation of the desired 7,12-dihydroindolo[3,2-fiT [l]benzazepin-6(5/f)ones. 

Almotriptan has also been synthesized via decarboxylation of the carboxylic acid intermediate 65, but a detailed preparation of 65 was not provided in the patent literature (Scheme 22)." The patent indicates that the carboxy indole 65 was prepared according to the method of Gonzalez.°° Thus, (2-oxo-tetrahydro-3-furanyl)-glyoxylic acid ethyl ester (62) was heated in aqueous H2SO4 to give 2-oxo-5-hydroxypentanoic acid in situ, which was treated with hydrazine 59 to produce hydrazone 63. Fischer cyclization of 63 using HCl gas in DMF gave the lactone 64, which was converted to carboxylic acid 65. Decarboxylation of 65 was catalyzed by cuprous oxide in quinoline at 190 °C to afford almotriptan (5)." ... 

To a solution of the S-(+)-4-acethoxy-9-[2-(5-ethyl-l,2,3,6-tetrahydro-pyridin-3yl)-l-(lH-indol-2-yl)-l-methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy-8-methoxy-6-methyl-3a,4,5,5a,6,ll,12,12b-octahydro-lH-6,12a-diaza-indeno[7,l-ca]fluorene-5-carboxylic acid methyl ester in dioxane and glacial acetic acid was added 37% aqueous formaldehyde and the mixture stirred at 35°C for 24 h. The solution was evaporated in vacuo and the residue suspended in chloroform and washed with cold aqueous 5% K2C03 solution. The chloroform layer was dried (MgS04), filtered, and evaporated. The residue was chromatographed eluting with EtOAc/MeOH, 10% NH4OH to give the product navelbine. 

This result is not surprising since it was shown earlier that trichloromethyl ketones react more rapidly with methanol (alcohols) than with water under alkaline conditions.29 The ethanolic cleavage of a trichloromethyl ketone has been used to prepare ethyl 3,3-diethoxypropanoate,30 and aryl trifluoromethyl ketones can be cleaved to give carboxylic acids or esters.31 A similar reaction of 3-trifluoroacetylindole (19) with lithium dialkylamides affords good yields of the corresponding indole-3-carboxamides (20).3... 

Indole carboxylic acid 187 was converted via a Barton ester to fused indole 194 (11 examples, 5-79% yield). Barton ester 189 was formed by treatment of indole 187 with S-(l-oxido-2-pyridinyl)-l,l,3,3-tetramethyl thiouronium hexafluorophosphate (188, Garner s HOTT reagent) in the absence of light. Upon refluxing in MeCN, the Barton ester 189 decomposes to give nucleophilic ethyl radical 190, which adds to the unsubstituted carbon of alkyne 191 furnishing vinyl radical 192.This species cyclizes onto the C2 position of the indole to provide 193, which aromatizes to dehver the final product 194. The sequence proceeds without the need for an initiator or metal catalyst (14JOC5903). 

Indole-2-carboxylic acid, 5-hydroxy-ethyl ester acylation, 4, 219... 

In 1897, Reissert reported the synthesis of a variety of substituted indoles from o-nitrotoluene derivatives. Condensation of o-nitrotoluene (5) with diethyl oxalate (2) in the presense of sodium ethoxide afforded ethyl o-nitrophenylpyruvate (6). After hydrolysis of the ester, the free acid, o-nitrophenylpyruvic acid (7), was reduced with zinc in acetic acid to the intermediate, o-aminophenylpyruvic acid (8), which underwent cyclization with loss of water under the conditions of reduction to furnish the indole-2-carboxylic acid (9). When the indole-2-carboxylic acid (9) was heated above its melting point, carbon dioxide was evolved with concomitant formation of the indole (10). 

Under basic conditions, the o-nitrotoluene (5) undergoes condensation with ethyl oxalate (2) to provide the a-ketoester 6. After hydrolysis of the ester functional group, the nitro moiety in 7 is then reduced to an amino function, which reacts with the carbonyl group to provide the cyclized intermediate 13. Aromatization of 13 by loss of water gives the indole-2-carboxylic acid (9). 

This concept has also been applied to the acid-base equilibria of indole-2-carboxylic acids (15) and of coumarilic acids (16) and to the rates of saponification of their ethyl esters. The data were excellently... 

Esters of 2-(2-azidophenyl)ethyl alcohol are photolyzed under a high-pressure mercury lamp to a reactive nitrene intermediate which, following insertion into the alkyl side-chain, undergoes elimination to give the free carboxylic acid (up to 32%) and producing indole. The photochemical release was somewhat improved (65-80%) when 5-azido-4-(hydroxy-methyl)-l-methoxy naphthalene was used (see Scheme 27). 

Indole-2-carboxylic acid, 3-(arylazo)-ethyl ester reduction, 4, 301... 

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