Acetic Acid → 3-(4-Benzylindol-3-yl)-2-nitro-5-oxahexanoic acid ethyl ester

HRID 1731749Notes

Reaction equation

HRID 1731749 reaction equation
[CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]([N+:27]([O-:29])=[O:28])[CH:22](O)[CH2:23][O:24][CH3:25])[CH3:18].C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:17]([O:19][C:20](=[O:30])[CH:21]([N+:27]([O-:29])=[O:28])[CH:22]([C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:12][CH:11]=1)[CH2:23][O:24][CH3:25])[CH3:18]

Participants

6

Reactant 3

HCID 176Acetic AcidHCID 131339864-Methoxy-3-hydroxy-2-nitrobutyric acid ethyl esterHCID 198001254-Benzyl-1H-indole

Product 1

HCID 541187213-(4-Benzylindol-3-yl)-2-nitro-5-oxahexanoic acid ethyl esterYield 87%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Under argon, 2.80 g (13.5 mmol) of 4-benzylindole is refluxed for 15 hours with 7.48 g (18 mmol) of a 50% strength solution of 4-methoxy-3-hydroxy-2-nitrobutyric acid ethyl ester in 84 ml of toluene with 8.3 ml of glacial acetic acid. After cooling, the reaction mixture is diluted with ethyl acetate and washed with water. The organic phase is dried, filtered, and concentrated, and the residue is chromatographed over silica gel with methylene chloride as the eluent, thus producing 4.7 g (87%) of 3-(4-benzylindol-3-yl)-2-nitro-5-oxahexanoic acid ethyl ester, which latter is hydrogenated in 50 ml of ethanol with 4.7 g of Raney nickel B 115-Z under normal pressure and at room temperature. After separation of the catalyst and evaporation, the product is chromatographed over silica gel with methylene chloride:ethanol=10:1, thus obtaining 1.16 g (24%) of 2-amino-3-(4-benzylindol-3-yl)-5-oxahexanoic acid ethyl ester; this product is combined with 349 mg of glyoxylic acid hydrate in 4 ml of ethyl acetate and 4 ml of water, adjusted to pH 4 with 10% potassium carbonate solution, and stirred overnight at room temperature. After the ethyl acetate has been removed by distillation, the product is diluted with water, extracted with methylene chloride, and the organic phase is dried, filtered, and concentrated, thus obtaining 1.7 g of a crude product which, without further purification, is refluxed in 40 ml of xylene for 5 hours. After concentration, the mixture is taken up in 40 ml of dimethyl sulfoxide, combined with 200 mg of sulfur, and heated for 75 minutes to 140° C. After the dimethyl sulfoxide has been removed by distillation, the mixture is chromatographed twice over silica gel, first with methylene chloride:ethanol=10:1 and then again with hexane:acetone=1:1, yielding 45 mg of 5-benzyl-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, mp 160°-168° C.

Workup

  1. temperatureAfter cooling
  2. washwashed with water
  3. customThe organic phase is dried
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customthe residue is chromatographed over silica gel with methylene chloride as the eluent

Sources & evidence

ORD record
ord-de698b5927d04154aac031e8001a6fa3
Source dataset
uspto-grants-1986_11
Patent number
US04623649

Reaction notes

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