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; 0.088 g, 0.249 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.104 g, 0.274 mmol) and 4-methylmorpholine (0.055 mL, 0.500 mmol) were added sequentially to a solution of rac-3-(4-fluoro-benzylamino)-5-methyl-hexanoic acid ethyl ester (0.070 g, 0.249 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 20 h, and 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 (0.322 mL, 0.994 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-isobutyl-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 (0.032 g, 0.056 mmol, 23%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.81 (3H, d, J=6.3 Hz), 0.87 (3H, d, J=6.2 Hz), 1.30-1.37 (1H, m), 1.50-1.60 (1H, m), 2.47 (1H, d, J=18.0 Hz), 2.96 (3H, s), 3.10 (1H, dd, J1=6.4 Hz, J2=16.3 Hz), 3.35-3.40 (1H, m), 3.51-3.55 (1H, m), 4.14 (1H, d, J=14.9 Hz), 4.24 (2H, d, J=5.5 Hz), 5.04 (1H, d, J=15.1 Hz), 7.13-7.18 (2H, m), 7.24 (1H, s), 7.36-7.39 (2H, m), 7.64 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C23H27FN4O6S3 570.11. found 571.3 [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)