Background and overview[1][2]
3-Bromo-4-aldehyde benzoic acid is a white solid and an important pharmaceutical intermediate. The synthesis method reported in the literature is to use NBS to tetrabrominate two methyl groups from 2,5-dimethylbromobenzene as raw material, hydrolyze it into 2-bromoterephthalaldehyde, and disproportionate it to generate 3-bromo-4-( Hydroxymethyl) benzoic acid, after oxidation, the target product 3-bromo-4-aldehyde benzoic acid is obtained. This synthesis method requires tetrabromosubstitution and a photoreaction. The entire reaction requires special equipment, and the reaction time is long and difficult to purify; and diazomethane is used in the reaction process. This substance is highly toxic and explosive. In experiments On-site preparation is required in the room, which poses great safety risks.
3-Bromo-4-aldehyde benzoic acid
Preparation[2]
Add 250g of 3-bromo-4-methylbenzoic acid and 475g of NBS into a 3L three-necked flask, add 2.5L of carbon tetrachloride and 11g of benzoyl peroxide, raise the temperature to 80 degrees and reflux for 2 days, cool to room temperature, and filter. The filter cake was washed three times with 2L carbon tetrachloride, and the combined filtrate was spin-dried to obtain about 220g of crude 3-bromo-4-(dibromomethyl)benzoic acid, which was directly put into the next reaction step.
Add 220g of the crude 3-bromo-4-(dibromomethyl)benzoic acid prepared above into a 3L three-necked flask, add 1.5L of ethanol to dissolve it, raise the temperature to 50 degrees, add dropwise 200g of 300ml of silver nitrate aqueous solution, and finish adding Then keep the reaction at 55 degrees for 1 hour, cool to room temperature, filter, wash the cake three times with 1L ethanol, combine the filtrate and spin dry to get about 130g of crude product, beat the crude product with 500mL petroleum ether, filter to get about 110g of product 3-bromo-4 -Aldehyde benzoic acid, go directly to the next step.
Add 110g of the crude 3-bromo-4-aldehyde benzoic acid prepared above into a 2L three-necked flask, add 1.2 LDMF to dissolve, add 80g potassium carbonate and 200ml methyl iodide, react at room temperature for 2 hours, and pour the reaction solution into 2L water. , extracted with ethyl acetate, 500ml × 3, combined the organic phases, washed with saturated brine 500ml × 3, dried, and spin-dried to obtain about 160g of crude brown oil (containing DMF) 3-bromo-4-aldehyde benzoic acid methyl ester, crude product Go directly to the next step.
Add 160g of the crude 3-bromo-4-aldehyde methyl benzoate prepared above into a 2L three-necked flask, add 1.3L methanol to dissolve, add an ice bath and cool to 0 degrees, control the temperature to less than 5 degrees, and add in batches About 20g sodium borohydride, after adding, slowly raise to 20 degrees and react for 1 hour. Slowly add 100ml of water, spin off the methanol under reduced pressure, then add 1L of water, extract with ethyl acetate, 500ml × 3, combine the organic phases, and wash with saturated brine. 500ml×1, dried, and spin-dried to obtain about 120g of crude brown oil (containing DMF). After column purification of the crude product, about 84g of 3-bromo-4-(hydroxymethyl)benzoic acid was obtained, and then the hydroxyl group was further oxidized to obtain the final product. 3-Bromo-4-aldehyde benzoic acid.
Main reference materials
[1] Lin Murong, & Liao Lian’an. (1999). Synthesis of 4-bromo-3,5-dimethoxybenzaldehyde. Journal of Xiamen University (Nature Edition) (s1), 388-388.
[2] Yu Yankun, Wang Chao, Liu Aixia, & Ji Yafei. (2011). Synthesis study of nilotinib. Chemical Reagents, 33(3), 266-268.
[3] Wang Xi, Liu Wenbing, & Xu Daiwang.. A synthesis method of 3-bromo-4-(hydroxymethyl)benzoic acid methyl ester.
