Ethanol → Rac-n-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1lambda6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide

Participants

Reaction Conditions

Reaction Steps

[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; 0.109 g, 0.308 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.129 g, 0.339 mmol) and 4-methylmorpholine (0.068 mL, 0.618 mmol) were added sequentially to a solution of rac-3-(4-fluoro-benzylamino)-2-methyl-propionic acid ethyl ester (0.074 g, 0.309 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 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 (4 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.400 mL, 1.23 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; 60-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-methyl-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 (0.040 g, 0.076 mmol, 25%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.08 (3H, d, J=7.3 Hz), 2.84-2.86 (1H, m), 2.96 (3H, s), 3.17 (1H, dd, J1=13.0 Hz, J2=7.2 Hz), 3.55 (1H, dd, J1=5.7 Hz, J2=12.7 Hz), 4.24 (2H, d, J=5.4 Hz), 4.54 (1H, d, J=14.9 Hz), 4.69 (1H, d, J=14.8 Hz), 7.14-7.18 (2H, m), 7.26 (1H, s), 7.37 (2H, d, J=14.0 Hz), 7.65 (1H, t, J=6.3 Hz). LC-MS (ESI) calculated for C20H21FN4O6S3 528.06. found 529.2 [M+H+].

Provenance & Evidence