反应详情

温度

25 °C

A solution of 2-[(4-fluoro-benzylamino)-methyl]-2,5-dimethyl-hexanoic acid ethyl ester (93 mg, 0.30 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (100 mg, 0.30 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg, 0.315 mmol) in anhydrous N,N-dimethyformamide (4 mL) was treated with N-methyl morpholine (0.069 mL, 0.63 mmol). The reaction was stirred under a nitrogen environment at 25° C. for 1 h, quenched with a 1.0 M aqueous hydrochloric acid solution (50 mL), extracted with ethyl acetate (2×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was dissolved in ethanol (5 mL) and treated with a 60% oil dispersion of sodium hydride (48 mg, 2.0 mmol). The reaction was heated at 60° C. under a nitrogen environment for 1.5 h. The reaction mixture was allowed to cool to 25° C., quenched with a 0.5 M aqueous hydrochloric acid solution (50 mL), extracted with ethyl acetate (2×50 mL), washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated in vacuo. The crude resin was purified by flash column chromatography (ISCO RediSep column, 0 to 100% ethyl acetate in hexanes) to afford the desired product, N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}methanesulfonamide (67 mg, 38%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.81 (t, 6H, J=7.0 Hz), 0.87-1.04 (m, 3H), 1.14 (s, 3H), 1.23-1.56 (m, 4H), 3.06 (s, 3H), 3.15 (q, 2H, J=11.4 Hz), 4.62 (dd, 2H, J1=115.3 Hz, J2=14.7, Hz), 7.03-7.10 (m, 2H), 7.18-7.30 (m, 3H), 7.62-7.71 (m, 2H). LC-MS (ESI) calculated for C26H31FN4O6S2: 578.6, found 579.2 [M+H+].

1. customquenched with a 1.0 M aqueous hydrochloric acid solution (50 mL)
2. extractionextracted with ethyl acetate (2×50 mL)
3. dry with materialdried over sodium sulfate
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. dissolutionThe resulting oil was dissolved in ethanol (5 mL)
7. temperatureThe reaction was heated at 60° C. under a nitrogen environment for 1.5 h
8. temperatureto cool to 25° C.
9. customquenched with a 0.5 M aqueous hydrochloric acid solution (50 mL)
10. extractionextracted with ethyl acetate (2×50 mL)
11. washwashed with brine (50 mL)
12. dry with materialdried with sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customThe crude resin was purified by flash column chromatography (ISCO RediSep column, 0 to 100% ethyl acetate in hexanes)