Sodium hydride → 7-Chloro-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-indole-3-carboxylic acid

HRID 2358453Notes

Reaction equation

[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]([OH:13])=[O:12].[H-].[Na+].[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18][CH2:17]1>CN(C)C=O>[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[C:7]([C:11]([OH:13])=[O:12])=[CH:8]2)[CH2:18][CH2:17]1

Participants

Conditions

Temperature: 50 °C

Procedure

To a solution of 7-chloro-1H-indole-3-carboxylic acid (7.5 g, 38.0 mmol) in dimethylformamide (100 ml) at 10° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 3.1 g, 76.0 mmol) portionwise over 10 mins, maintaining the temperature below 15° C. The cooling bath was removed and the suspension stirred for 90 mins. Toluene-4-sulfonic acid tetrahydropyran-4-ylmethylester (14.6 g, 53.0 mmol) was added. The mixture was heated at 50° C. with stirring for 6 h. Dimethylformamide was removed by evaporation and the residue was dissolved in water (500 ml). The emulsion was washed with dichloromethane (2×100 ml). The aqueous phase was acidified to pH 1 using 5 M hydrochloric acid and the precipitate filtered off, washed with water to neutrality and dried to afford 1-(tetrahydropyran-4-yl)methyl-7-chloro-1H-indole-3-carboxylic acid (15.0 g, 51.0 mmol) as a white solid.

Workup

temperaturemaintaining the temperature below 15° C
customThe cooling bath was removed
stirringwith stirring for 6 h
customDimethylformamide was removed by evaporation
dissolutionthe residue was dissolved in water (500 ml)
washThe emulsion was washed with dichloromethane (2×100 ml)
filtrationthe precipitate filtered off
washwashed with water to neutrality
customdried

Sources & evidence

ORD record: ord-40ca8b47188d4ee7ab20e2ccbf00f862
Source dataset: uspto-grants-2010_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07763732B2

Reaction notes

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