Preparation of the methyl ester of 3,5-dimethoxy-4-hydroxybenzoic acid

A 5-l., 3-necked, round-bottomed flask equipped with a mechanical stirrer, condenser capped with a drying tube, and thermometer was charged with 1.37 l. of methanol followed by 137.0 g. of clean sodium in small pieces. When all the sodium hadreacted, the methanol was removed completely and 29.5 g. of cuprous chloride was added. 308.0 G. of the methyl ester of 3,5-dibromo-4-hydroxybenzoic acid in 1.0 l. of dimethylformamide was added; the mixture was stirred at 90.degree.-95.degree. overnight (20 hours), and then evaporated in vacuo at 60.degree.. 500 Ml. of methanol was added to the residue, the mixture was stirred at room temperature for 15 minutes, cooled to 5.degree., and treated with a solution of gaseous hydrogen chloride(160 g.) in 400 ml. of methanol during 30 minutes at a rate such that the temperature was kept below 15.degree.. The methanol was removed in vacuo at 45.degree., 2.0 l. of ethyl acetate was added to the residue, followed by 50 g. of celite. Theheterogeneous mixture was boiled under reflux with stirring for 10 minutes, and then filtered hot over 100 g. of celite (a 3-l. filter funnel with coarse porosity is recommended). The filter cake was washed with 1.0 l. of hot (65.degree.) ethyl acetate,and the washing combined with the filtrate. The combined filtrate and washing (light purple) was washed with three 1-l. portions, a total of 3.0 l. of 20% brine. The aqueous phase was re-extracted with 500 ml. of ethyl acetate, washed with two 500 ml. portions, a total of 1.0 l. of 20% brine, and combined with the first extract. The combined ethyl acetate extracts were dried over magnesium sulfate, filtered, and evaporated to give 189 g. of crude methyl ester of 3,5-dimethoxy-4-hydroxybenzoic acid asan off-white solid, mp 92.degree.-110.degree.

Preparation of 3,5-dimethoxy-4-hydroxybenzaldehyde

A 5-l., 3-necked, round-bottomed flask equipped with a mechanical stirrer, condenser capped with a drying tube, and a thermometer was charged with 1.2 l. of methanol. 109.5 G. of clean sodium was then added in small pieces and under nitrogen. When all the sodium had reacted, the methanol was removed in vacuo at 50.degree. and a mixture of 500 ml. of dimethylformamide and 250 ml. of methanol added to the residue. To the vigorously stirred solution was added 9.45 g. of cuprous chloridefollowed, after 5 minutes, by 264.4 g. of 3,5-dibromo-4-hydroxybenzaldehyde. An exotherm resulted in which the temperature rose from 23.degree. to 50.degree. over a period of 10 minutes. The mixture was stirred at 95.degree. for 3.25 hours, duringwhich time the color of the reaction changed from blue to greyish-green. The solvents were removed in vacuo at 45.degree. and to the residue was added 700 ml. of 15% brine. The mixture was stirred at 60.degree. for 30 minutes, cooled to 0.degree. and treated with 400 ml. of cold (0.degree.) concentrated hydrochloric acid at such a rate that the temperature was kept below 30.degree.. The mixture was stirred at room temperature for 30 minutes, then at 0.degree. for another 30 minutes, andfiltered over 100 g. of celite. The filter cake was washed with four 400 ml. portions, a total of 1.6 l. of cold (5.degree.) water, followed, after removing the aqueous washings, by four 500 ml. portions, a total of 2.0 l. of hot (60.degree.) ethylacetate. The ethyl acetate washings were added to a separatory funnel, excess water (about 20 ml.) was removed, and the ethyl acetate dried over magnesium sulfate and evaporated to give 153.3 g. (88%) of 3,5-dimethoxy-4-hydroxybenzaldehyde as a paleyellow solid, mp 105.degree.-108.degree.. Purity of 99.38%.