Acetic Acid → 7-Fluoro-4-hydroxyquinoline-3-carbonitrile

HRID 1837347Notes

Reaction equation

C([Li])CCC.[C:6](#[N:8])[CH3:7].CN(/[CH:12]=[N:13]/[C:14]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:15]=1[C:16]([O:18]CC)=O)C.C(O)(=O)C>O1CCCC1>[F:25][C:23]1[CH:24]=[C:14]2[C:15]([C:16]([OH:18])=[C:7]([C:6]#[N:8])[CH:12]=[N:13]2)=[CH:21][CH:22]=1

Participants

Conditions

Temperature: -78 °C

Procedure

To a solution of 2.5 M n-butyl lithium in tetrahydrofuran (53.6 mL, 134 mmol) in 54 mL of tetrahydrofuran at −78° C. is added dropwise a solution of acetonitrile (7.1 mL, 136 mmol) in 100 mL of tetrahydrofuran. After stirring at −78° C. for 10 min, a solution of ethyl 2-{[(1E)-(dimethylamino)methylidene]amino}-4-fluorobenzoate (14.5 g, 60.9 mmol) in 100 mL of tetrahydrofuran is added over a period of 1.5 h. After stirring at −78° C. for 2 h, the reaction temperature is slowly allowed to warm to −10° C. The mixture is then cooled to −78° C. and acetic acid (18.3 g, 305 mmol) is added dropwise. The reaction mixture is allowed to warm to room temperature and stirred for 3 days. The precipitate is collected by filtration washing with tetrahydrofuran, water, diethyl ether, ethyl acetate and then additional diethyl ether to give 7.95 g of 7-fluoro-4-hydroxyquinoline-3-carbonitrile as an off-white solid, mp>250° C.

Workup

stirringAfter stirring at −78° C. for 2 h
temperatureto warm to −10° C
temperatureThe mixture is then cooled to −78° C.
temperatureto warm to room temperature
stirringstirred for 3 days
filtrationThe precipitate is collected by filtration
washwashing with tetrahydrofuran, water, diethyl ether, ethyl acetate

Sources & evidence

ORD record: ord-f855b67d85934d4c8e8d8e9bd26f6474
Source dataset: uspto-grants-2004_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06780996B2

Reaction notes

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