Acetic Acid → 3-(2-ethoxycarbonylethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid ethyl ester

HRID 1860898Notes

Reaction equation

[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]([C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=O)[CH3:2].Cl.NC(C(OCC)=O)C(OCC)=[O:26].C([O-])(=O)C.[Na+].C(O)(=O)C>C(OCC)(=O)C.O>[CH2:19]([O:18][C:17]([C:16]1[NH:15][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[C:7]=1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])=[O:26])[CH3:20]

Participants

Conditions

Temperature: 50 °C

Procedure

Crude 4-(2-morpholin-4-ylcyclohex-1-enyl)-4-oxo-butyric acid ethyl ester (454 g), 398 g of diethyl aminomalonate hydrochloride, 162 g of sodium acetate and 350 mL of glacial acetic acid were heated to 108° C. over 30 minutes. The mixture was held at 100-108° C. for 2 hours and then cooled to about 50° C. in a water bath. Water (2500 mL) and 700 mL of ethyl acetate were added. The ethyl acetate layer was separated and washed three times with brine, twice with saturated sodium bicarbonate solutiona and once with brine. The solution was dried over anhydrous sodium sulfate, and the ethyl acetate was removed using a rotary evaporator to give 494 g (105% yield) of crude 3-(2-ethoxycarbonylethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid ethyl ester as an oil. The crude mixture was chromatographed on a silica gel column using a 1:10 mixture of ethyl acetate:hexane as the eluent to give 122.1 g of pure 3-(2-ethoxycarbonylethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid ethyl ester as a low melting solid.

Workup

customThe ethyl acetate layer was separated
washwashed three times with brine
dry with materialThe solution was dried over anhydrous sodium sulfate
customthe ethyl acetate was removed
customa rotary evaporator

Sources & evidence

ORD record: ord-9ceda506f906411cb49f1d17fd4d5e52
Source dataset: uspto-grants-2003_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06531502B1

Reaction notes

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