Ethyl 4-chloro-6-fluoroquinazoline-2-carboxylate → (4-Chloro-6-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone

HRID 1424458Notes

Reaction equation

[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]([O:15]CC)=O)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.C1COCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:15])[N:3]=1

Participants

Conditions

Temperature: -40 °C

Procedure

To a stirred solution of ethyl 4-chloro-6-fluoroquinazoline-2-carboxylate (1.06 g, 4.5 mmol) in THF (15 mL) at −40° C., was added dropwise 1 M 4-fluorophenylmagnesium bromide/THF (5.85 mL, 5.85 mmol). The mixture was stirred at −40° C. for 2 h. The reaction was quenched by adding 0.5 N HCl at 0° C. and then the mixture was extracted with EtOAc (2×20 mL). The solid that precipitated from the combined organic layers was removed by filtration and the filtrate was washed with brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford (4-chloro-6-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone as a solid (950 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ 8.32-8.36 (m, 1H), 8.13-8.21 (m, 4H), 7.43 (t, J=8.2 Hz, 2H); LC-MS (ESI) m/z 305 (M+H)+.

Workup

customThe reaction was quenched
additionby adding 0.5 N HCl at 0° C.
extractionthe mixture was extracted with EtOAc (2×20 mL)
customThe solid that precipitated from the combined organic layers
customwas removed by filtration
washthe filtrate was washed with brine
dry with materialThe organic phase was dried over MgSO4
filtrationfiltered
concentrationconcentrated under reduced pressure
customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record: ord-63b26ed183654625a273ce45459a97a2
Source dataset: uspto-grants-2015_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08927711B2

Reaction notes

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