Preparation background and overview of 2-pyridineboronic acid
2-Pyridineboronic acid is used as an advanced pharmaceutical intermediate. For example, after coupling and reduction, it is used as a piperidinyl structural unit to synthesize Ceritinib, a marketed drug for the treatment of ALK-positive metastatic non-small cell lung cancer. ). The existing synthesis methods of 2-pyridineboronic acid mainly include two categories: 1) As early as 1965, pyridine bromide was exchanged with butyllithium, then reacted with trimethyl borate, acetic acid was added to reflux to quench the reaction, and the isolation yield 20%. The low yield of potassium trifluoroborate is mainly due to the certain hydrophilicity of 2-pyridineboric acid itself, which makes separation and purification difficult; at the same time, under different pH conditions, the degree of amphotericity of 2-pyridineboronic acid is different. For example, under the condition of pH=4, 2-pyridineboronic acid mainly exists in the form of pyridine with hydrogen protons.
2-pyridineboronic acid
Preparation of 2-pyridineboronic acid
In the reaction bottle, control the temperature from -10°C to -5°C, add 2-bromopyridine hydrochloride (23.9g, 0.1mol) and 80mL of diethoxymethane, and add dropwise 30% sodium hydroxide aqueous solution (approximately 1.5-1.6eq), the system gradually stratifies under stirring. After HPLC detects that the water layer is completely free, let it stand for stratification. Add solid sodium hydroxide to the lithium diethoxycarbonate methane layer to dry it, and then extract the supernatant liquid and set aside for use. The external standard calibrated 2-bromopyridine content was 96.8%.
The diethoxymethane layer is cooled to -20°C to -10°C, and Bu3MgLi (0.042mol) generated by mixing 2.5MBuLi and 2MBuMgCl Grignard reagent according to a 2:1 molar ratio is added dropwise. After the dropwise addition is completed, continue Stir the reaction for 1-2 hours, add D2O to the sample and send it for HNMR detection (the ratio of deuterated pyridine to pyridine is 97:3), and the exchange is completed. Begin to add dropwise a mixed solution of BrB(NMe2)2 (23.6g, 95% content, 0.126mol) and 40mL diethoxymethane. After the addition is completed, keep stirring overnight. After an interval of 1 hour, the reaction was stopped after sampling twice. The sample was added to pinacol and refluxed. After derivatization, GC detected the product. After conversion, the external standard content of the product was 84.4%.
The reaction solution was filtered through diatomaceous earth, and after distillation under reduced pressure, sulfolane solvent was added, and butyl (bisdimethylamino) boron impurities were removed by rectification to obtain 14.3 grams of pyridine-2-(bisdimethylamino) boron ( GC: 99.2%), after adding 80 mL of methanol, reflux the reaction. When the reaction is completed and dimethylamine no longer overflows, the excess methanol is evaporated and brought to room temperature. After adding 4 times the amount of water, continue stirring and the solid will precipitate. Filter and dry to obtain 9.85 g of powdery off-white solid 2-pyridineboronic acid, HPLC: 99.4%, yield 80%. HNMR(MHz,CD3OD):8.27(d,2H),7.59(d,2H).
