A class of mercaptoamide boronic acid derivatives and their use as mbl and/or sbl inhibitors
A methyl compound technology, applied in the field of medicine, can solve the problems of MBL inhibitors that have not yet entered
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[0061] The following is the preparation of intermediate compounds:
[0062] 1. Intermediate compound A: 1-aminomethylboronic acid pinacol ester hydrochloride
[0063]
[0064] Step 1: Synthesis of bromomethylboronic acid pinacol ester (A-2)
[0065]Compound A-1 triisopropyl borate (10 g, 55 mmol) and dibromomethane (4.2 mL, 60 mmol) were dissolved in dry tetrahydrofuran solution, and pre-cooled at -78°C for 20 minutes. A 2.5M n-butyllithium solution in n-hexane (20 mL, 50 mmol) was slowly dropped into the reaction solution, and stirring was continued at -78°C for 2 hours. The reaction was warmed up to 0°C, methanesulfonic acid (3.2 mL, 50 mmol) was slowly added dropwise, then warmed up to room temperature and stirred for 1 hour. The reaction temperature was lowered to 0° C., pinacol (5.9 g, 50 mmol) was added, and then the temperature was raised to room temperature and stirred for 1 hour. Stop the reaction, spin to remove the solvent, and distill under reduced pressure (...
Embodiment 1
[0142] Example 1: (S)-1-(3'-mercapto-2'-methylpropionamido)methylboronic acid (1)
[0143]
[0144] Step 1: Synthesis of (S)-1-(3'-acetylmercapto-2'-methylpropionamido)methylboronic acid pinacol ester
[0145] Dissolve intermediate compound A (193mg, 1mmol), (S)-3-acetylmercapto-2-methylpropionic acid (162mg, 1mmol) in DMF (10mL), pre-cool at -10°C for 20 minutes, add TBTU (385mg, 1.5mmol) and DIPEA (387mg, 3mmol), the reaction was continued at -10°C for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, an appropriate amount of water was added, extracted several times with ethyl acetate, the combined organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent is CH 2 Cl 2 / MeOH=100:1) to obtain 212 mg of the product as a colorless oil, with a yield of 74%. 1 H-NMR (400MHz, CDCl 3 ):δ1.23(d,3H,J=6.8Hz),1.2...
Embodiment 2
[0148] Example 2: 1-(3'-mercaptopropionamido)methylboronic acid (2)
[0149]
[0150] Using the intermediate compound A as the starting material, the (S)-3-acetylmercapto-2-methylpropionic acid used in step 1 was replaced by 3-acetylmercaptopropionic acid by the synthetic method of compound 1, and the same Compound 2 can be obtained through the synthetic steps. Colorless oil. 1 H-NMR (400MHz, CDCl 3 ): δ0.84(t, 3H, J=7.2Hz), 1.54(m, 2H), 2.14(t, 2H, J=7.2Hz), 2.36(s, 2H). 13 C-NMR (100MHz, CDCl 3 ): δ13.65, 18.65, 36.82, 41.28, 176.80. MS(ESI+): 146.0[M+H-H 2 O].
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