反应详情

2,3-Dichloro-4-chloromethyl-pyridine (0.272 g, 1.39 mmol) was dissolved in 4 mL DMSO. Et3N (0.386 mL, 2.77 mmol) was added followed by the addition of 4-methyl-[1,4]diazepan-5-one hydrochloride (0.456 g, 2.77 mmol). The mixture was stirred for 16 h, then diluted with sat aq NaHCO3. The resulting precipitate was filtered and washed with water. Afforded a white solid—primarily desired contaminated with a small amount of the starting chloromethylpyridine. The filtrate was extracted 3× with EtOAc. The organic phases were washed 2× with sat aq NaCl, dried over Na2SO4, filtered, and concentrated to afford additional desired compound. Unpurified 1-(2-amino-3-chloro-pyridin-4-ylmethyl)-4-methyl-[1,4]diazepan-5-one (0.100 g, 0.347 mmol), NaOtBu (0.047 g, 0.49 mmol), BINAP (0.032 g, 0.050 mmol), and Pd2dba3 (0.016 g, 0.020 mmol) were stirred in 2 mL anhydrous toluene under N2. Benzophenone imine (0.070 mL, 0.42 mmol) was added and the reaction was heated to 80° C. After 3 h the reaction was cooled to RT and concentrated in vacuo. To the residue was added 1:1 THF/1M HCl. The mixture was stirred for 1 h, then adjusted to pH 10 with Na2CO3 (solid). The solution was extracted 3× with EtOAc and the combined organic extracts were dried over Na2SO4, filtered, concentrated. The residue was purified by flash column chromatography (DCM to 95:5 DCM/MeOH) to afford the pure titled compound. 1H NMR (CDCl3) δ7.96 (d, 1H, J=5.1 Hz), 6.82 (d, 1H, J=5.1 Hz), 4.95 (bs, 2H), 3.61 (s, 2H), 3.43 (m, 2H), 3.00 (s, 3H), 2.65 ( m, 6H).

1. filtrationThe resulting precipitate was filtered
2. washwashed with water
3. customAfforded a white solid—primarily
4. extractionThe filtrate was extracted 3× with EtOAc
5. washThe organic phases were washed 2× with sat aq NaCl
6. dry with materialdried over Na2SO4
7. filtrationfiltered
8. concentrationconcentrated