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

HRID 2275769Notes

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 1A; 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 extracted with ethyl acetate. 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.

Workup

temperaturecooled
customreaction solution
additionAfter the dropwise addition
customthe aqueous phase was separated off
extractionThe aqueous phase was 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-b433dee2556f4de39a8be48a67902273
Source dataset: uspto-grants-2015_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09126998B2

Reaction notes

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