(1), preparation of 6-(10-acetoxy-1-oxodecyl)-2,3-dimethoxy-5-methylphenol
Install a mechanical stirrer and a thermometer in a dry and clean 5L reaction flask, and add 2000ml of 1,2-dichloroethane, 182g (about 1mol) of 3,4,5-trimethoxytoluene, and 10-acetoxydecanoyl chloride under stirring. 273g (about 1.5mol), then add 333g (about 2.5mol) of fresh anhydrous aluminum trichloride powder, start the reaction after cooling down to 5°C in an ice-water bath, control the temperature at 0-5°C, after 4 days of reaction, the reaction ends, pour Put into 5000ml of ice water, separate the organic layer, then add 2000ml of 1,2-dichloroethane to extract, combine the organic layers, wash with water three times, 1000ml each time; finally, dry with anhydrous sodium sulfate, decolorize with activated carbon, and evaporate the solvent , to obtain 310 g of a colorless oily substance, which is 6-(10-acetoxy-1-oxodecyl)-2,3-dimethoxy-5-methylphenol, and the calculated molar yield is 81.5% , HPLC measured content 99.2%.
(2), preparation of 6-(10-acetoxydecyl)-2,3-dimethoxy-5-methylphenol
In a 5L hydrogenation kettle, add 380g of 6-(10-acetoxy-1-oxodecyl)-2,3-dimethoxy-5-methylphenol (about 1.0 mol), DMF 3000ml, 19g of 5% Pd-C (mass is 6-(10-acetoxy-1-oxodecyl)-2,3-dimethoxy-5-methylphenol 5% ). Catalytic hydrogenation under normal temperature and pressure and stirring reaction until no hydrogen absorption, then add 206g (about 1mol) of dehydrating agent DCC, continue stirring reaction at normal temperature and pressure for 7h, continue catalytic hydrogenation under normal temperature and pressure for more than 10h until no hydrogen absorption. After the reaction, the catalyst was filtered off, and the filtrate was concentrated to obtain 353 g of a light-colored oily substance, which was 6-(10-acetoxydecyl)-2,3-dimethoxy-5-methylphenol;
Add 40 g (1 mol) of sodium hydroxide and 1200 ml of methanol to the above oil, cool down to 5°C, stir for 24 hours, distill off the solvent under reduced pressure, add 1500 ml of dichloromethane to dissolve, wash with water for 3 times, dry over anhydrous sodium sulfate and reduce Concentrate to dryness under pressure to obtain 311.5 g of colorless oily matter which is 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methylphenol, the calculated molar yield is 96.0%, and the HPLC content is 99.91 %, the maximum simple impurity is 0.06%).
(3) Preparation of Idebenone Tablet
Add 6-(10-acetoxydecyl)-2,3-dimethoxy-5-methylphenol 324.5g (about 1mol), DMF 3000ml, Cu(Salen) 10g (mass of 3% of the reaction substrate). Control the temperature at 35-40°C, pass pure oxygen to carry out the catalytic oxidation reaction, about 70 hours, TLC tracking until the raw material point disappears. After the reaction was completed, the catalyst was filtered off, concentrated to dryness under reduced pressure, then diluted with 2000ml of water, extracted 2 times with dichloromethane, 1000ml each time, the combined organic layers were washed 3 times with 1000ml each time, dried over anhydrous sodium sulfate, Distill to dryness under reduced pressure. Recrystallized with a mixed solvent of n-hexane-diethyl ether to obtain 254 g of orange needle-like product (0.75 mol, yield 75%, HPLC content 99.70%, maximum simplex 0.12%).