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 (0.106 g, 0.279 mmol) and 4-methylmorpholine (0.055 mL, 0.500 mmol) were added sequentially to a solution of 3-cyclopropyl-3-(4-fluoro-benzylamino)-propionic acid ethyl ester (0.067 g, 0.252 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 17 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 (25 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.327 mL, 1.01 mmol) was added and the reaction mixture was heated to 60° C. for 3 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; 40-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[6-cyclopropyl-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 (0.045 g, 0.081 mmol, 32%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: −0.03-0.01 (1H, m), 0.25-0.39 (2H, m), 0.67-0.74 (1H, m), 0.93-0.96 (1H, m), 0.98-1.06 (1H, m), 2.48 (1H, d, J=17.0 Hz), 2.76-2.79 (1H, m), 2.81 (3H, s), 3.02 (1H, dd, J1=6.9 Hz, J2=17.0 Hz), 4.10 (2H, d, J=6.1 Hz), 4.21 (1H, d, J=15.5 Hz), 4.94 (1H, d, J=15.8 Hz), 6.96-7.12 (2H, m), 7.12 (1H, s), 7.19-7.22 (2H, m), 7.51 (1H, t, J=6.3 Hz). LC-MS (ESI) calculated for C22H23FN4O6S3 554.08. found 555.1 [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 (25 mL) at 25° C
6. temperaturethe reaction mixture was heated to 60° C. for 3 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; 40-100% ethyl acetate in hexanes)