Compound preparation method
A compound and organic solvent technology, applied in the field of preparation of boric acid derivatives of pharmaceutical intermediates, can solve problems such as yield decline, difficulty in separation and purification of compound 3, consumption of raw materials by by-products, etc., and achieve the effect of mild reaction conditions
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Embodiment 1
[0034]
[0035] Add 2.0 g of p-bromobenzoic acid (compound 1) and 1.11 g of triethylamine into the reaction flask, add 16 mL of dioxane, add 1.25 g of methanesulfonyl chloride dropwise to the system, raise the temperature to 40 °C and stir for 2 h, Add 1.35 g 4-dimethylaminopyridine and 1.41 g o-aminopyridine to the system, add the system and react at 60 °C for 3 h, quench the reaction with 20 mL of water, extract twice with 20 mL of ethyl acetate, combine the organic phases, The solvent was spin-dried and purified by n-heptane / ethyl acetate column chromatography to obtain the product with a yield of 69%.
[0036] The NMR data of compound 3 are as follows:
[0037] 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.40 (dd, J = 4.8, 1.1 Hz, 1H),8.18 (d, J = 8.4 Hz, 1H), 8.03 – 7.93 (m, 2H), 7.91 – 7.81 (m, 1H), 7.77 –7.67 (m, 2H), 7.26 – 7.11 (m, 1H).
Embodiment 2
[0039]
[0040] Add 20.0 g of p-bromobenzoic acid (compound 1), 19.34 g of N,N-carbonyldiimidazole into the reaction flask, add 200 mL of toluene, and stir the system at 60 °C for 2 h. 14.04 g o-aminopyridine was added, and the system was reacted at 100 °C for 4 h after the addition was completed. Wash once with saturated sodium carbonate, twice with purified water, once with saturated brine, and concentrate the organic phase to 100 mL, cool to 0-5 °C and stir for 1 h, filter with suction, and dry to obtain the product as a white solid. Yield 84%.
Embodiment 3
[0042]
[0043] Add 10 mL of 2 mol / L tetrahydrofuran solution of isopropylmagnesium chloride into the reaction flask, add 20 mL of tetrahydrofuran, cool the system to -20~-30 °C, add dropwise 16.4 mL of 2.5 mol / L n-butyllithium n-hexane solution, stirred for 10 min. Control the internal temperature at -20~-30 °C, add 35 mL of compound 3 in tetrahydrofuran dropwise, and stir for 20 min. Control the internal temperature at -20~-30 °C, add 3.75 g of trimethyl borate dropwise, maintain the system at -20~-30 °C for 16 h, pour 50 mL of saturated ammonium chloride to quench, and extract with 100 mL of ethyl acetate Three times, the organic phases were combined, the solvent was spin-dried, and purified by dichloromethane / methanol column chromatography to obtain the product with a yield of 45.8%.
[0044] The NMR data of compound 4 are as follows:
[0045] 1 H NMR (400 MHz, DMSO) δ 10.75 (s, 1H), 8.52 – 8.36 (m, 1H), 8.35 – 8.17(m, 2H), 8.11 – 7.79 (m, 5H), 7.24 – 7.12 (m, 1H )....
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