Background and overview of the preparation method of 2-fluorophenylboronic acid
2-Fluorophenylboronic acid belongs to fluorophenylboronic acid and its derivatives. Since the atomic radii of fluorine atoms and hydrogen atoms in 2-fluorophenylboronic acid are similar, when the hydrogen atoms in the molecule are replaced by fluorine atoms, it will not cause significant changes in the three-dimensional configuration of the molecule. However, because fluorine atoms have strong electron withdrawal, the electronic properties of the original molecules often change greatly, so that fluorine-containing phenylboronic acid has good stability and large dielectric anisotropy. In recent years, it has played a very important role in organic synthesis, biomedicine, pesticides and materials science, especially in liquid crystal display materials.
Deuterated tetrahydrofuran
Preparation method of 2-fluorophenylboronic acid
Preparation method report of 2-fluorophenylboronic acid 1.
Under nitrogen protection, add 14kg (22.9mol) of o-fluorobenzene and 20L of THF into a 50L reaction kettle in sequence, and cool down to -70°C. Control the temperature below -70°C and add 6.8kg of n-BuLi dropwise. After the dripping is completed, stir for 0.5 hours below -70°C. Control the temperature below -70°C and add 4.75kg of triisopropyl borate dropwise. After the dripping is completed, the temperature will return to normal overnight. Pour into 20L (1N) dilute hydrochloric acid, separate the liquids, and extract the water phase again with EA10L. The organic phases were combined, washed once with 10 L of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 22.4 kg of compound 2-fluorophenylboronic acid, with a yield of 85%.
Preparation method report 2 of 2-fluorophenylboronic acid
Dissolve 2-fluorophenylboronic acid (1 equivalent) in the first organic solvent (tetrahydrofuran, 8mL/g), and then add the basic ligand PMDTA (pentamethyldiethylenetriamine, CAS#:3030-47- 5, 1.1 equivalent) and mix well to prepare solution A. n-Butyllithium (22.5 wt% n-hexane solution, 1.6 equivalents) without any dilution was used as solution B. Isopropyl borate (2.0 equiv) was diluted with THF (2 mL/g) as solution C.
As shown in Figure 2, the continuous reaction equipment is installed and debugged. Solution A, solution B and solution C are connected to the first material pump 11, the second material pump 13 and the third material pump 41 in sequence, and through automatic feeding The system automatically controls the flow rate. The delivery pipeline of solution A has a first one-way valve 12, and the delivery pipeline of solution B has a second one-way valve 14 (to prevent backflow, solution C decides whether to install a one-way valve as needed).
According to the set flow rate, solution A is passed into the first precooling device 10, and solution B is passed into the second precooling device 20 for precooling (solution C determines whether to install a precooling device according to temperature requirements). Then, the cooled solution A and solution B are mixed through the online mixing device 30 to obtain a mixed liquid.
The above mixed liquid is transported to the continuous lithiation reaction device 40 (coil reactor) to perform the continuous lithiation reaction process to obtain the lithiation product. The residence time of the raw materials in the entire process is 30 minutes.
After the continuous lithiation reaction is completed, the above mixed liquid and solution C are transported to the continuous boration reaction device 50 (coil reactor) for continuous boration reaction. The residence time of the reaction raw materials is 30 minutes. The first precooling device 10, the second precooling device 20, the continuous lithiation reaction device 40 and the continuous boration reaction device 50 are all cooled down by a low-temperature refrigeration system, and the first precooling device 10, the second precooling device 20 and The external bath temperature of the continuous lithiation reaction device 40 is -90°C, and the external bath temperature of the continuous boration reaction device 50 is -85°C.
After the continuous boration reaction is completed, the reaction system is transported to the quenching device 60 (continuous stirred tank reactor), and a quenching agent (12wt% hydrochloric acid aqueous solution) is added to adjust the pH of the system to 2.5 for quenching. , temperature control below 30℃.
The system obtained after quenching is passed into the extraction device 80 (continuous extraction column) and continuously extracted with the second organic extractant (ethyl acetate, 4 mL/g). The target product is transferred to the organic phase, and then the above The organic phase is passed into the concentration device 70 (thin film evaporator) for concentration (temperature is 35°C, vacuum degree is 0.1MPa), and the concentration time is 30 minutes to remove the first organic solvent (tetrahydrofuran), and then the remaining aqueous phase is transported into in the first stage continuous crystallization reaction device 91.
At the same time, the anti-solvent (n-heptane, 5 mL/g) is continuously pumped into the first-stage continuous crystallization reaction device 91 to perform acidification and crystallization to obtain a crystallization system. The temperature of the system is controlled to be 0 to 30°C, and crystallization The time is 1h. Then, the above-mentioned crystallization system overflows into the second-stage continuous crystallization reaction device 92 for cooling and crystallization to obtain the required 2-fluorophenylboronic acid. The system temperature is controlled to -5 to 10°C, and the crystallization time is 4 hours. After separation, the product 2-fluorophenylboronic acid was dried under nitrogen protection at 30°C until the sodium bicarbonate reached a constant weight to obtain the target product, with an isolation yield of 86wt%.
References
[1][Chinese invention] CN201811205025. Continuous synthesis method of X2-fluorophenylboronic acid compounds
[2][China invention, China invention authorization] CN201610225503.8 Preparation method of benzochromene derivatives
