Yield:1404115-37-2 59%

Reaction Conditions:

with potassium hydroxide in water;acetonitrile at -25 - 20; for 1.25 h;

Steps:

33.1 Step 1: 2-Bromo-6-(difluoromethoxy)benzaldehyde

Step 1: 2-Bromo-6-(difluoromethoxy)benzaldehyde A solution of 2-bromo-6-hydroxybenzaldehyde (5.0 g, 25 mmol) in MeCN (120 mL) and a solution of potassium hydroxide (27.9 g, 497 mmol) in H₂0 (124 mL) was cooled to below -25 °C. Diethyl (bromodifiuoromethyi)phosphonate (7.1 mL, 40 mmol) was added dropwise at a rate to maintain the reaction temperature below about -20 °C. After about 15 min at or below about -20 ° , the bath was allowed to warm to rt. After about i h, the reaction was extracted with EtOAc (2 x 100 mL), The combined organic layers were washed with sat. aq. NaCl (100 mL), dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue was purified on silica gel using 10% EtOAc in heptanes to give the title product (3.70 g, 59 %); NMR (400 MHz, CDC1₃) δ 10.34 (s, 1H), 7.57 (dd, J = 8.1, 1.0 Hz, IH), 7.41 ( J= 8.2 Hz, IH), 7.28 - 7.22. (m, IH), 6.60 (t, J= 73.5 Hz, 1H).

References:

WO2016/168633,2016,A1 Location in patent:Page/Page column 184