Preparation of 3,4,5-trimethoxybenzaldehyde5-bromovanillinA 2L 3-necked RB flask equipped with a mechanical stirrer, thermometer and 500mL dropping funnel was charged with 115.7g (0.722 mol, 37.4mL) of bromine. In the meantime, a solution of 100g (0.658 mol) of vanillin in 705g (470mL) of 48% hydrobromic acid was prepared in the dropping funnel. While the flask was immersed in an ice bath, the solution of vanillin was dropped into the bromine with stirring over a period of 1 h while keeping the temperature at about 5° C. The bromovanillin precipitated as light yellow crystals. The slurry was stirred for an additional hour in an ice bath, diluted with 950mL of water and kept at 0-5° C. The crystals were collected on a sintered glass funnel and washed thoroughly with 1000mL of water. The material was dried at room temperature to constant weight. Yield: 150.9g (99.4%); mp 163-164° C; VPC purity 98%.
5-hydroxyvanillin61.2g (1.53 mol) of NaOH were dissolved in 750mL of water in a 2L RB flask. To the still warm solution were added 50g (0.217 mol) of 5-bromovanillin and 0.5g of Cu powder. A white solid precipitated. The mixture was refluxed vigorously under nitrogen and with magnetic stirring. The colour changed gradually from yellow to green to dark green and, after ~6 h, all of the solid material had dissolved. After refluxing for 27 h, the mixture was acidified with 113mL of concentrated HCl (pH 2) and continuously extracted with toluene at 85° C for 47 h while being stirred magnetically. The toluene receiver contained 450mL of toluene. The total volume of toluene in the system was ~1300mL. The flask containing the hot toluene extract was disconnected while stil hot and the brown solution was transfered to a 1L beaker for crystallization in an ice bath. After cooling for 2 h, the product was filtered off, washed with ~100mL of ice-cold toluene and dried at 70° C to constant weight. Yield: 30.4g (83.3%) of light brown plates; mp 133-134° C.
3,4,5-trimethoxybenzaldehydeIn a 1L RB flask equipped with a magnetic stirrer and reflux condenser were placed 50g (0.298 mol) of 5-hydroxyvanillin, 500mL of acetone, 91g (0.716 mol) of dimethyl sulfate, 100g (0.806 mol) of finely ground sodium carbonate monohydrate and 10g of 10% KOH in MeOH. The heterogenous mixture was stirred under vigorous reflux for 24 h, after which the reflux condenser was replaced by a descending condenser. The solvent was distilled at ~100° C until the distillation ceased. To the solid residue were added 400mL of water and the heterogenous mixture was stired vigorously for 2 h at room temperature and then for 1 h at 0-5° C. The light brown crystals were filtered off under suction, washed three times with 150mL of ice-water and air dried to constant weight. Yield: 55.1g (94%); mp 73-74° C. After distillation at 130° C (0.5 mmHg), there was obtained a 90% yield of 3,4,5-trimethoxybenzaldehyde; mp 73.5-75° C; VPC purity 99.3%.
Reference: Patent GB1338890
