Report background and overview of two preparation methods of 3-formylphenylboronic acid
3-Formyl phenylboronic acid is a light yellow solid and is an aldehyde phenylboronic acid. In recent years, the use of Suzuki coupling reaction for the synthesis of key drug intermediates has become increasingly common. For example, p-aldehyde phenylboronic acid is used in the synthesis of the powerful protease inhibitor atazanavir, a new drug on the market. o-, m-, p-formylphenylboronic acid is a basic structure used in many aspects of organic synthesis and an important intermediate in the synthesis of active substances in the agrochemical and pharmaceutical industries, but above all as an important and efficient Compounds that are enzyme stabilizers, enzyme inhibitors and fungicides.
Two preparation methods of 3-formylphenylboronic acid reported
Two preparation methods of 3-formylphenylboronic acid reported one,
Synthesis of m-bromophenylboronic acid trimer (formula II, X=m-Br):
In a 1L three-necked flask equipped with a reflux water separation device, add m-bromobenzoic acid (201 grams, 1.0 mol) and 600 ml of toluene, and heat to reflux and water separation. When the system separates about 17.5-18.5 grams of water , and stop the reaction when there is no more water in the system to continue to separate. After cooling, the heptane is distilled until no liquid flows, and the crude m-bromobenzene boric acid trimer is obtained, which at this time contains about 5-10% toluene. You can go directly to the next step of the reaction.
Synthesis of 3-formylbenzeneboronic acid:
Under nitrogen protection, add 600 ml of anhydrous tetrahydrofuran to the m-bromophenolboronic acid trimer obtained above and dissolve it evenly, then transfer it to a 2L three-necked bottle, and then add dimethylformamide (80.4 g, 1.1 mol) . Then the system was cooled to below -70°C, and 440 ml (1.1 mol) of 2.5M n-butyllithium hexane solution began to be slowly added dropwise. During the addition process, the maximum temperature was controlled not to exceed -60°C. After the addition was completed, stirring was continued while maintaining this temperature. React for 1-3 hours, then naturally rise to room temperature and stir for 3-5 hours. After the TLC detection reaction is completed, benzylpyridine cools the system to 0°C, adds 10% hydrochloric acid aqueous solution to quench the reaction, adjusts the pH to 1-2 and continues stirring at room temperature for 2-3 hours to ensure complete hydrolysis of the trimer. The reaction solution was distilled. After the organic solvent was distilled, a solid separated out and was filtered. After toluene recrystallization, 106.5 grams of light yellow solid 3-formylphenylboronic acid was obtained. HPLC: 99.5%. The total yield of the two steps was 71%.
Two preparation methods of 3-formylphenylboronic acid report 2,
Prepare 3.52g lithium chips and 180g THF at -50°C. 53.7g of 3-chlorobenzaldehyde-N,N&p barium carbonate-dimethylethylene diacetalamine (255mmol) was added dropwise within 90 minutes. It was then stirred for 2 hours and then cooled to -50°C, and 31.2g of trimethyl borate dissolved in 60ml of THF was added dropwise at this temperature over 15min. Let the contents melt overnight. Add 290g of water at 0°C and adjust the pH to 3.9 with 36.9g of 37% HCl. Distill out the hygroscopic THF as completely as possible under slight vacuum (under normal pressure, to ensure complete cleavage of acetal). The resulting suspension was cooled to 10°C and suction filtered at 10°C. The product is carefully washed with a small amount of ice water and dried in a weak nitrogen flow at 40°C. The yield of pure 3-formylphenylboronic acid was 34.5 g (92.1%).
References
[1] [Chinese invention, Chinese invention authorization] CN201510321210.5 A method for preparing aldehyde phenylboronic acid
[2] [Chinese invention, Chinese invention authorization] CN01819243.2 Preparation method of formylphenylboronic acid
