Hydrochloric Acid → 4-chloro-3-fluoro-2,N-dimethoxy-N-methylbenzamid

HRID 1945123Notes

Reaction equation

[Cl:1][C:2]1[C:3]([F:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:16][O:17][N:18]([CH3:25])[C:19](N(OC)C)=[O:20].Cl>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]([N:18]([O:17][CH3:16])[CH3:25])=[O:20])=[C:4]([O:8][CH3:9])[C:3]=1[F:10]

Participants

Conditions

Temperature: -70 °C

Procedure

1 g (6.2 mmol) 3-Chloro-2-fluoroanisole in 10 ml THF are cooled to −70° C. and 2.7 ml of a 2.5 M n-butyl lithium solution in hexane are added. After 1.5 hours at −70° 1 g (6.9 mmol) N,N′-dimethoxy-N,N′-dimethyl urea in 6 ml THF are added at −70° C. and the mixture is stirred another hour at −70° C. 7.5 ml of a 2 M aqueous HCl are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 30%) to yield 0.59 g 4-chloro-3-fluoro-2,N-dimethoxy-N-methylbenzamid. 1H-NMR (CDCl3); δ=3.35 (br, 3H), 3.49 (br, 3H), 3.98 (s, 3H), 6.99 (dd, 1H), 7.13 (dd, 1H).

Workup

temperaturethe reaction is warmed to ambient temperature over 18 hours
customThe reaction mixture is partitioned between diethyl ether and water
extractionThe aqueous phase is extracted with diethyl ether
washthe combined organic phases are washed with brine
dry with materialdried over sodium sulfate
customevaporated
customThe crude product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 30%)

Sources & evidence

ORD record: ord-2e81f5960b1e46b1a661942bc52e36eb
Source dataset: uspto-grants-2013_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08394958B2

Reaction notes

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