4-Methoxybenzyl alcohol → 5-Bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine

HRID 1050007Notes

Reaction equation

[Br:1][C:2]1[C:3]([O:9][CH2:10][CH3:11])=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.[Cl-].[Na+].O.COC(C)(C)C>[Br:1][C:2]1[C:3]([O:9][CH2:10][CH3:11])=[CH:4][C:5]([O:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[N:6][CH:7]=1

Participants

Conditions

Temperature: 120 °C

Procedure

To a mixture of 5-bromo-2-chloro-4-ethoxypyridine (75 g, 317.1 mmol) in toluene (500 mL) was added (4-methoxyphenyl)methanol (52.6 g, 380.6 mmol), KOH (35.6 g, 634.3 mmol) and 18-crown-6 (8.4 g, 31.2 mmol) at rt. The reaction mixture was stirred at 120° C. for 2 h. The mixture was portioned between 2-methoxy-2-methylpropane (500 mL) and brine (800 mL). The organic layer was concentrated. The residue was purified by column (PE/EA=10:1, Rf=0.5) to give 5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (72.2 g, 221 mmol, 70% yield): 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.33 (d, J=8.8 Hz, 2H), 6.90-6.84 (m, 2H), 6.38 (s, 1H), 5.20 (s, 2H), 4.16-4.05 (m, 2H), 3.77 (s, 3H), 1.43 (q, J=6.8 Hz, 3H); ES-LCMS m/z 338 (M+2H).

Workup

concentrationThe organic layer was concentrated
customThe residue was purified by column (PE/EA=10:1, Rf=0.5)

Sources & evidence

ORD record: ord-4dfb848452644b269411bd1a570285f4
Source dataset: uspto-grants-2016_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09382238B2

Reaction notes

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