反应详情

温度

25 °C

[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.095 g, 0.269 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.113 g, 0.297 mmol) and 4-methylmorpholine (0.059 mL, 0.537 mmol) were added sequentially to a solution of) rac-3-(4-fluoro-benzylamino)-4-methyl-pentanoic acid ethyl ester (0.072 g, 0.269 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 20 h, then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (5 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.349 mL, 1.08 mmol) was added and the reaction mixture was heated to 60° C. for 4 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-6-isopropyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.020 g, 0.036 mmol, 13%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.86 (3H, d, J=7.0 Hz), 0.94 (3H, d, J=7.2 Hz), 2.04-2.09 (1H, m), 2.56 (1H, d, J=17.3 Hz), 2.95 (3H, s), 3.04-3.10 (1H, m), 3.38-3.41 (1H, m), 4.14 (1H, d, J=15.4 Hz), 4.23 (2H, d, J=5.7 Hz), 5.15 (1H, d, J=14.7 Hz), 7.11-7.16 (2H, m), 7.22 (1H, s), 7.35-7.38 (2H, m), 7.63 (1H, t, J=5.8 Hz). LC-MS (ESI) calculated for C22H25FN4O6S3 556.09. found 557.2 [M+H+].

1. concentrationwas concentrated in vacuo
2. customThe residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL)
3. dry with materialThe organic layers were dried over sodium sulfate
4. concentrationwere concentrated in vacuo
5. dissolutionThe residue was dissolved in ethanol (5 mL) at 25° C
6. temperaturethe reaction mixture was heated to 60° C. for 4 h
7. temperatureAfter cooling to 25° C.
8. customthe reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL)
9. dry with materialThe organic layers were dried over sodium sulfate
10. concentrationwere concentrated in vacuo
11. customThe residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes)