Hydrochloric Acid → (4-Chloro-8-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone

HRID 1801952Notes

Reaction equation

[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][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.Cl.[Na+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][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 solution of ethyl 4-chloro-8-fluoroquinazoline-2-carboxylate (360 mg, 1.42 mmol) in THF (20 mL) at −40° C. was added 1M 4-fluorophenylmagnesium bromide/THF (1.7 mL, 1.7 mmol) and the mixture was stirred at −40° C. for 3 h. After this time, and additional portion of 1M 4-fluorophenylmagnesium bromide/THF (0.3 mL, 0.3 mmol) was added and the mixture was stirred at −40° C. for 2 h. To the mixture was added 0.5N HCl to give pH ˜2, and then saturated aq NaCl (50 mL) was added, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (4-chloro-8-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone (0.4 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 7.04-7.25 (m, 1 H), 7.31-7.58 (m, 2 H), 7.70-8.36 (m, 4 H); LC-MS (ESI) m/z 305 (M+H)+, 327 (M+Na)+.

Workup

stirringthe mixture was stirred at −40° C. for 2 h
customto give pH ˜2
extractionthe mixture was extracted with EtOAc (3×50 mL)
washThe combined organic layers were washed with brine (80 mL)
dry with materialdried over Na2SO4
filtrationfiltered
concentrationconcentrated under reduced pressure

Sources & evidence

ORD record: ord-0c4da06001a4433fb554a6b55efffcfc
Source dataset: uspto-grants-2013_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08349851B2

Reaction notes

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