2,3-Difluoro-4-hydroxybenzonitrile

2,3-Difluoro-4-cyanophenol can be used as a pharmaceutical synthesis intermediate. It can be prepared by reacting 2,3-difluorophenyl with N-formaldehyde piperidine to prepare intermediate 4-ethoxy-2,3-difluorobenzaldehyde, further reacting it with hydroxylamine-O-sulfonic acid to prepare intermediate 4-ethoxy-2,3-difluorobenzyl nitrile, and then reacting it with aluminum chloride to obtain the final product.

Colorless needles

a) 4-ethoxy-2,3-difluorobenzaldehyde

Add 125 ml, 0.2 mol of n-butyllithium hexane solution, 0.2 mol of 2,3-difluorophenyl, 0.2 mol of tetramethylethylenediamine to 400 ml of tetrahydrofuran solution at -78C, stir the mixture at 70C, keep it at -60C for 2 h. Add dropwise 0.2 mol of N-formylpiperidine and 20 ml of tetrahydrofuran mixture into this mixture, warmed to -20C and processed conventionally to obtain 4-ethoxy-2,3-difluorobenzaldehyde as a colorless solid, mp 70C.

b) 4-ethoxy-2,3-difluorobenzonitrile

A mixture of 0.12 mol hydroxylamine-O-sulfonic acid and 50 ml of water was added to a mixture of 0.1 mol 4-ethoxy-2,3-difluorobenzaldehyde and 100 ml of water at 30C and the mixture was stirred for 1 hour. After heating at 65C for 2 hours and conventional treatment, a colorless solid 4-ethoxy-2,3-difluorobenzonitrile was obtained, mp 45C.

c) 2,3-difluoro-4-cyanophenol

A mixture of 0.1 mole of 4-ethoxy-2,3-difluorobenzonitrile, 0.12 mole of aluminum chloride, and 150 ml of toluene was heated at the boiling point for 2 h. Conventional treatment yielded 2,3-difluoro-4-cyanophenol as a colorless solid, mp 145C.