Cyclopropylboronic acid, as an important coupling agent in the Suzuki coupling reaction, has been increasingly involved in drug research since the Suzuki coupling reaction won the Nobel Prize in Chemistry in 2010. Due to the special structure of cyclopropyl, it has become an indispensable raw material in drug synthesis and is difficult to be replaced by other raw materials.
Existing Synthesis Methods of Cyclopropylboronic Acid
The existing synthesis methods basically use cyclopropyl bromide as the raw material, first prepare it into a Grignard reagent or a lithium reagent, and then react it with trimethyl borate. After acidification treatment, cyclopropylboronic acid is obtained. There are also patent reports that cyclopropyl Grignard reagent reacts with alkoxyboronic acid pinacol ester to first obtain cyclopropylboronic acid pinacol ester, and then acidify it under the catalysis of sodium periodate to obtain cyclopropylboronic acid. The problems existing in the above methods are that when preparing the Grignard reagent from cyclopropyl bromide, due to the existence of coupling, the yield of the Grignard reagent is low, and when the concentration exceeds 1M, the Grignard reagent precipitates in tetrahydrofuran solvent. Cyclopropyl lithium has a half-life problem in different solvents, and it is difficult to ensure reproducibility when scaled up.
In addition, cyclopropylboronic acid can also be prepared from commercially available and inexpensive cyclopropyl formic acid. Starting from cyclopropyl formic acid, a large steric hindrance base/tert-butyl lithium solution is added at ultra-low temperature, followed by the addition of triisopropyl borate to obtain 1-carboxycyclopropylboronic acid. Then, heating for decarboxylation/dehydration to form a trimer, and acidification to obtain cyclopropylboronic acid. This method requires a large amount of base, and carbon dioxide gas is produced during decarboxylation. If the addition is too fast, the reaction is prone to overflow.
Invention Content
To overcome the above deficiencies, the present invention discloses a synthesis method of cyclopropylboronic acid. Starting from aldehyde boronic acid, it reacts with a strong electron-withdrawing sulfonyl hydrazide to form a hydrazone, and then reacts with ethylene under the catalysis of iron porphyrin to obtain cyclopropylboronic acid. This method is simple to operate, uses a metal-catalyzed cyclopropanation reaction, and avoids the use of cyclopropyl bromide in traditional processes, providing a new synthetic route for the synthesis of cyclopropylboronic acid.
The method for preparing cyclopropylboronic acid provided in the present invention comprises the following steps: starting from aldehyde boronic acid, reacting with a strong electron-withdrawing sulfonyl hydrazine to form a hydrazone, then dehydrating to form a trimer, and then reacting with ethylene under the catalysis of iron porphyrin, and finally hydrolyzing to obtain cyclopropylboronic acid.
Advantages of the present invention
The present invention discloses a method for preparing cyclopropylboronic acid by starting from aldehyde boronic acid, reacting with NH2NHNs to form a hydrazone, and then reacting with ethylene under the catalysis of FeCl(TPP) to obtain cyclopropylboronic acid. This method is simple to operate, uses a metal-catalyzed cyclopropanation reaction, and avoids the use of cyclopropyl bromide in traditional process methods, providing a new synthetic route for the synthesis of cyclopropylboronic acid.
