反应详情

To a stirring solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (150 mg, 0.371 mmol) in dry DMF (7.4 mL) under nitrogen was added triethylamine (0.31 mL, 2.23 mmol) to give a white slurry. 4-Chlorobenzoyl chloride (0.106 mL, 0.835 mmol) was added dropwise to the slurry, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×20 mL), and the organic phase was back-extracted with 1 N HCl (15 mL). The organic layer was discarded, and all aqueous layers were combined and washed with ethyl acetate (2×15 mL). The aqueous layer was concentrated under reduced pressure to give the crude product which was purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column. 40 mL/min flow rate. Gradient: solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water; 5% to 50% A over 24 min, then 50% to 100% A over 1 min]. Product fractions were pooled and concentrated, and the residue was taken up in 0.5N HCl (3 mL)/acetonitrile (6 mL) and concentrated. The residue was once again treated with 0.5N HCl (3 mL)/acetonitrile (6 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-[1-(4-chlorobenzoyl)piperidin-4-yl]hexanoic acid hydrochloride (75 mg, 47%) as a faint yellow solid. 1H NMR (MeOH-d6, 400 MHz) δ 7.51 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 4.77 (m, 1H), 3.82 (m, 1H), 3.19 (m, 1H), 2.85 (m, 1H), 2.25 (m, 1H), 2.10-1.40 (m, 8H), 1.28 (m, 2H), 0.85 (bt, J=7.2 Hz, 2H). ESI+ MS found for C18H26BClN2O5 m/z 379.3 (M−18+H); ESI+ MS m/z 395.4 (M−H), 377.4 (M−18−H).

1. customto give a white slurry
2. extractionextracted with ethyl acetate (2×20 mL)
3. extractionthe organic phase was back-extracted with 1 N HCl (15 mL)
4. washwashed with ethyl acetate (2×15 mL)
5. concentrationThe aqueous layer was concentrated under reduced pressure
6. customto give the crude product which
7. customwas purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column
8. wait5% to 50% A over 24 min
9. wait50% to 100% A over 1 min]
10. concentrationconcentrated
11. concentrationconcentrated
12. additionThe residue was once again treated with 0.5N HCl (3 mL)/acetonitrile (6 mL)
13. concentrationconcentrated
14. customdried under high vacuum overnight