Overview of 5-bromopyridine-3-carbaldehyde and synthesis method
5-Bromopyridine-3-carbaldehyde is also known as 5-bromonicotinic acid in Chinese, and it can be used as a pharmaceutical and chemical synthesis intermediate. In the existing technology, the synthesis method of 5-bromopyridine-3-carbaldehyde is to use 3,5-dibromopyridine as the raw material and exchange it with butyllithium bromide under ultra-low temperature (-78℃) conditions. Prepare 5-bromopyridine-3-carbaldehyde, or use 3,5-dibromopyridine as raw material, and combine butyllithium and n-butylmagnesium chloride at -15℃ to synthesize 5-bromopyridine Pyridine-3-carboxaldehyde; the above two synthesis methods can only be carried out under ultra-low temperature conditions, and the reaction conditions are harsh and difficult to industrialize; there are also literature reports using 5-bromo-3-methylpyridine as raw material and selenium dioxide oxidation to synthesize 5- Bromopyridine-3-carboxaldehyde; however, a large amount of selenic acid derivatives are attached to the inner wall of the reactor during the reaction, making post-processing very difficult.
Overview and synthesis method of 5-bromopyridine-3-carboxaldehyde [1]
A synthesis method of 5-bromopyridine-3-carboxaldehyde, including the following steps:
S1. Mix 3,5-dibromopyridine, tetrahydrofuran (THF), and tetramethylethylenediamine evenly, and cool it to 10-15°C in an ice-water bath; the 3,5 -The volume ratio of dibromopyridine to tetrahydrofuran is 1:3-6, the mass ratio of the 3,5-dibromopyridine to tetramethylethylenediamine is 1:0.5-1; the 3,5-dibromopyridine The molar ratio of pyridine, Grignard reagent and DMF is 1:1.2-1.5:1.5-2.
S2. Take the format reagent and drop it into the reaction solution prepared in step 1. Keep the reaction temperature below 15℃;
S3, the reaction solution obtained in step 2 is maintained at 20-25°C for fluorophenylboronic acid reaction for 1-2 hours, and the reaction solution is cooled to 5-10°C in an ice water bath;
S4. Take N,N-dimethylformamide (DMF) and dissolve it in THF. THF is used to dilute the concentration of DMF to prevent violent reactions during dropwise addition. Slowly add the DMF-THF mixture dropwise into step 3. In the obtained reaction liquid, after maintaining 10-15°C for 30 minutes, the reaction liquid is separated and purified to obtain crude 5-bromopyridine-3-carbaldehyde; the method for separation and purification of the obtained reaction liquid is: pour the reaction liquid into ice water, stir for 10 min., let stand, separate the liquids, wash, dry, and distill under reduced pressure the organic phase to obtain crude 5-bromopyridine-3-carbaldehyde; in order to increase the yield, the aqueous phase obtained by liquid separation can also be used Extract once with ethyl acetate, wash, dry and distill the organic phase under reduced pressure; more preferably, the volume of ice water is 1.5-4 times the volume of tetrahydrofuran in the reaction solution.
The purification method of the crude 5-bromopyridine meropenem sodium carbonate-3-carbaldehyde is: adding petroleum ether (PE): ethyl acetate (EA) = 6:1 (W:W) mixed solvent to the crude product, 20-25°C Beat for 1 hour, filter, wash and dry; more preferably, the amount of petroleum ether/ethyl acetate mixed solvent is: 5-bromopyridine-3-carbaldehyde per gram Add 1-2ml petroleum ether/ethyl acetate mixed solvent to the crude product.
