4-Iodo-2-(phenylMethoxy)phenol synthesis

Yield:289471-92-7 62.9%

Reaction Conditions:

with sodium hypochlorite;sodium iodide;sodium hydroxide in methanol at -10 - 10; for 0.166667 h;

Steps:

6.1

Stej 1[0337] A solution of 2-(benzyloxy)phenol (63.7 ml, 364 mmol) in MeOH (1050 ml) was cooled to -10 °C and sodium iodide (54.5 g, 364 mmol) and sodium hydroxide (382 ml, 764 mmol) were added (NaOH over 5 mm, temp to 10 °C and dark solution with NaOH addition). Cooled back to <5 °C and added sodium hypochlorite (247 ml, 400 mmol) dropwise, keeping the temperature at < 5 °C.After 10 mm, removed 500 mL MeOH by rotary evaporation, then added MTBE (730 mL) and 2 N HCI (909 ml, 1818 mmol), washed with 1 N Na2S2O3 (130 mL x 3; lighter each time) and brine (64 mL), dried (Na2SO4), conc, and flushed with cyclohexane (100 mL) to a crude yellow solid. Added cyclohexane (130 mL), heated to 55 °C (yellow solution), then cooled slowly, seeding at 45 °C ( 50 mg-15 solution) and 40 °C ( 50 mg, slurry developed). Continued cooling to roomtemperature (‘‘20-252C) and stirred vigorously overnight. Filtered, washing with cyclohexane (64 mL), giving crop 1 material (69.93 g, 59%, very pure by 1 H NMR, slightly off-white solid). Concentrated the mother liquors to 70 mL, seeded, aged 1 h, and sticky dark material was precipitating with product. Added MTBE (7 mL),sonicated (good for color dissolution), stirred 20 mm, and filtered. Washed with10% MTBE/cyclohexane (32 mL), giving crop 2 material (4.65 g, some small impurities by 1 H NMR). Overall, isolated 2-(benzyloxy)-4-iodophenol (74.6 g, 229 mmol, 62.9 % yield). 1H NMR (501 MHz, DMSO-d6) 6 9.33 (5, 1 H), 7.49 -7.42 (m, 2H), 7.42 - 7.35 (m, 2H), 7.35 - 7.29 (m, 1 H), 7.24 (d, J = 2.0 Hz, 1 H), 7.09(dd, J = 8.3, 2.1 Hz, 1 H), 6.64 (d, J = 8.3 Hz, 1 H), 5.09 (5, 2H).

References:

WO2016/65019,2016,A1 Location in patent:Paragraph 0336; 0337