Formamidine acetate → 7-(4-Bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid methyl ester

HRID 500568Notes

Reaction equation

[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10](=O)[CH3:11])[C:7](F)=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23].C(O)(=O)C.[CH:29]([NH2:31])=[NH:30]>CC(N(C)C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23])[N:31]=[CH:29][N:30]=[C:10]2[CH3:11])=[O:24]

Participants

Conditions

Temperature: 95 °C

Procedure

A mixture of 5-acetyl-2-(4-bromo-2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (288 mg, 0.688 mmol) and formamidine acetate (77 mg, 0.74 mmol) in DMA (7 mL) was heated for 4 hours at 95° C. Additional 10 mg (0.096 mmol) of formamidine acetate was added and the reaction mixture was heated for additional 4 hours at 95° C. The reaction mixture was diluted with EtOAc, and washed with water (3×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2) to afford the desired product (140 mg, 48%).

Workup

temperaturethe reaction mixture was heated for additional 4 hours at 95° C
washwashed with water (3×)
dry with materialThe organic layer was dried over MgSO4
filtrationfiltered
concentrationconcentrated in vacuo
customto give the crude material which
customwas purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2)

Sources & evidence

ORD record: ord-fe89cb2bb1414f1d98464ecb239bf389
Source dataset: uspto-grants-2010_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07772234B2

Reaction notes

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