2,2'-(3-Methoxy-1,2-phenylene)diethanol synthesis

Yield:847199-04-6 89%

Reaction Conditions:

Stage #1: 1,4-dihydro-5-methoxynaphthalenewith ozone in ethanol;dichloromethane at -65; for 30 h;
Stage #2: with sodium tetrahydroborate in ethanol;dichloromethane at -65 - 20; for 0.5 h;

Steps:

Preparation 1

2,3-Bis-(2-hydroxyethviyi-methoxybenzene: ; Charge a four-neck 5 L flask equipped with an over-head mechanical stirrer, reflux condenser, thermocouple, and gas dispersion apparatus with 5-methoxy-l,4-dihydronaphthalene (264.54 g, 89.5% potency based on ¹H-NMR, 1.478 mol) in DCM (1.3 L) and 2B-3 ethanol (1 L). Add sudan III (10 mg) to give a faint red color. Cool the solution to -65°C or lower, then pass O₃ through the solution until the solution turns a light yellow color and the TLC (10:1 hexane/EtOAc, KMnO₄ stain) shows the absence of the starting material (about 30 h). Transfer the solution via cannula into a slurry of NaBH₄ (97.8 g, 2.59 mol) in 2B-3 ethanol (500 niL) cooled in ice/water. It is important that the temperature be maintained at or above O⁰C, as for example between O⁰C and 10⁰C, throughout the transfer to ensure the ozonide is completely reduced to the diol. After the transfer is complete, warm the solution to ambient temperature and stir for about 30 min. Cool the slurry to 0⁰C with ice/water then slowly add acetone (540 mL, 7.4 mol) to remove excess NaBH₄. After all the solids dissolve, remove the solvent in vacuo. Dissolve the yellow solid in DCM (1 L) and water (1 L), separate the layers and extract the aqueous layer with DCM (750 mL). Wash the combined organic layers with brine (1.5 L), add toluene (750 mL) and remove the solvent in vacuo. Dissolve the solid in DCM (500 mL) with heating, then add toluene (750 mL) and concentrate the solution in vacuo to give the desired intermediate as a light yellow solid (283.7 g, 89% potency corrected, mp 82-83°C) (contains l,2,3,4-tetrahydro~5- methoxynaphthalene as an impurity (8.6%)). Further purify the product by vacuum drying overnight at 75°C, 5 Torr, to remove all but trace amount of the l,2,3,4-tetrahydro-5- methoxynaphthalene impurity. ¹H NMR (300 MHz, CDCl₃), δ 7.16 (dd, IH, / = 8.2,7.6), 6.83 (s, IH, J= 7.0), 6.76 (s, IH, J= 8.2), 3.85-3.77 (m, 7H), 3.01-2.91 (m, 4H), 2.35 (s, 2H); ¹³C NMR (300 MHz, DMSO-^₆), δ 157.5, 138.9, 126.5, 125.2, 122.0, 108.4, 62.1, 60.5, 55.3, 36.1, 29.6; IR (KBr): 3006, 2960, 2886, 2829, 1583, 1461, 1440, 1264, 1091, 1041 cm⁴; MS (ES+) m/z 178 (M+H)⁺; Anal. Calc'd for C₁₁H₁₆O₃: C, 67.32; H, 8.22; N, 0. Found: C, 67.26, H, 8.10, N, 0.21; R_f = 0.23 eluting with 95:5

References:

WO2007/28131,2007,A1 Location in patent:Page/Page column 36-42