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; 0.103 g, 0.291 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.122 g, 0.321 mmol) and 4-methylmorpholine (0.064 mL, 0.582 mmol) were added sequentially to a solution of rac-3-(4-fluoro-benzylamino)-hexanoic acid ethyl ester (0.078 g, 0.292 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 (0.378 mL, 1.17 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; 40-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-6-propyl-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 (0.027 g, 0.049 mmol, 17%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.85 (3H, t, J=7.2 Hz), 1.15-1.38 (2H, m), 1.54-1.60 (2H, m), 2.51 (1H, d, J=15.1 Hz), 2.96 (3H, s), 3.12 (1H, dd, J1=6.5 Hz, J2=16.8 Hz), 3.54-3.58 (1H, m), 4.19 (1H, d, J=15.2 Hz), 4.24 (2H, d, J=6.1 Hz), 5.04 (1H, d, J=15.5 Hz), 7.13-7.17 (2H, m), 7.25 (1H, s), 7.36-7.39 (2H, m), 7.64 (1H, t, J=6.3 Hz). LC-MS (ESI) calculated for C22H25FN4O6S3 556.09. found 557.3 [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 (25 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; 40-100% ethyl acetate in hexanes)