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; 0.089 g, 0.252 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-cyclopentyl-3-(4-fluoro-benzylamino)-propionic acid methyl ester (0.070 g, 0.250 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 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 (0.324 mL, 1.00 mmol) was added and the reaction mixture was heated to 60° C. for 6 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 diethyl ether) rac-N-{3-[6-cyclopentyl-1-(4-fluoro-benzyl)-4-hydroxy-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 (0.018 g, 0.031 mmol, 12%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.07-1.17 (1H, m), 1.35-1.43 (1H, m), 1.45-1.68 (3H, m), 1.70-1.76 (1H, m), 2.20-2.26 (1H, m), 2.47 (1H, d, J=14.1 Hz), 2.95 (3H, s), 3.06-3.12 (1H, m), 3.43-3.47 (1H, m), 4.09 (1H, d, J=15.8 Hz), 4.23 (2H, d, J=6.3 Hz), 5.21 (1H, d, J=14.9 Hz), 7.11-7.15 (2H, m), 7.21 (1H, s), 7.34-7.38 (2H, m), 7.62 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C24H27FN4O6S3 582.11. found 583.1 [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 6 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)