Sulfuric Acid → 5-Bromo-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine

HRID 1844132Notes

Reaction equation

[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.S(=O)(=O)(O)O.[Br:23]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:23][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[C:7]([NH2:12])=[N:8][CH:9]=1

Participants

Conditions

Temperature: 0 °C

Procedure

32.6 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 4A; 138 mmol, 1 equivalent) were suspended in 552 ml of 10% strength sulphuric acid, and the mixture was cooled to 0° C. 8.5 ml of bromine (165 mmol, 1.2 equivalents) were dissolved in 85 ml of acetic acid and then, over a period of 90 min, added dropwise to the ice-cooled reaction solution. After the dropwise addition had ended, the mixture was stirred at 0° C. for 90 min and then diluted with 600 ml of ethyl acetate, and the aqueous phase was separated off. The aqueous phase was re-extracted with ethyl acetate and the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried and concentrated. The residue was dissolved in dichloromethane and chromatographed on silica gel (petroleum ether/ethyl acetate gradient as mobile phase). This gave 24 g (55% of theory) of the title compound. LC-MS (Method 1): Rt=0.96 min

Workup

temperaturecooled
customreaction solution
additionAfter the dropwise addition
customthe aqueous phase was separated off
extractionThe aqueous phase was re-extracted with ethyl acetate
washwashed with saturated aqueous sodium bicarbonate solution
customdried
concentrationconcentrated
dissolutionThe residue was dissolved in dichloromethane
customchromatographed on silica gel (petroleum ether/ethyl acetate gradient as mobile phase)

Sources & evidence

ORD record: ord-c997f530bc9e488e8042a28883f1fba4
Source dataset: uspto-grants-2015_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08946215B2

Reaction notes

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