Ethanol → Rac-n-{3-[1-cyclobutyl-4-hydroxy-5-methyl-5-(3-methyl-butyl)-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; 0.266 g, 0.753 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.314 g, 0.826 mmol) and 4-methylmorpholine (0.165 mL, 1.50 mmol) were added sequentially to a solution of rac-2-cyclobutylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (0.192 g, 0.752 mmol) in N,N-dimethylformamide (8 mL) at 25° C. The reaction mixture was stirred at 25° C. for 22 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 (12 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (1.46 mL, 4.51 mmol) was added and the reaction mixture was heated to 70° C. for 24 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 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 rac-N-{3-[1-cyclobutyl-4-hydroxy-5-methyl-5-(3-methyl-butyl)-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 (0.095 g, 0.174 mmol, 23%) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ: 0.82-0.86 (6H, m), 0.94-0.99 (1H, m), 1.04 (3H, s), 1.07-1.23 (5H, m), 1.40-1.54 (2H, m), 1.65-1.70 (1H, m), 2.07 (1H, bs), 2.19-2.26 (1H, m), 2.95 (3H, s), 3.26-3.31 (1H, m), 3.46-3.51 (1H, m), 3.99-4.06 (1H, m), 4.23 (2H, d, J=6.1 Hz), 7.27 (1H, s), 7.65 (1H, t, J=6.3 Hz). LC-MS (ESI) calculated for C22H32N4O6S3 544.15. found 545.1 [M+H+].

Provenance & Evidence