Reaction Steps
(1R,2R,3S,4S)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl)-methanesulfonate (0.3 g, 0.72 mmol, prepared as described in WO08124450A1) was dissolved in N,N-dimethylformamide (4 mL). Toluene-4-sulfonic acid 1-trifluoromethyl-cyclopropylmethyl ester (0.424 g, 1.44 mmol) was added followed by triethylamine (0.218 g, 2.16 mmol) and potassium iodide (approximately 0.05 g, 0.03 mmol). The mixture was shaken for 40 h at 75° C. Upon cooling, [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; 0.254 g, 0.72 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.208 g, 1.08 mmol. The mixture was shaken at 25° C. for 16 h. Triethylamine (0.290 g, 2.88 mmol) was added and the mixture was shaken for at 75° C. for 24 h. Upon cooling to 25° C., the mixture was concentrated in vacuo to afford a thick oil. The oil was partitioned between dichloromethane (6 mL) and 1.0 M aqueous hydrochloric acid solution (10 mL). The organic phase was further washed with 1.0 M aqueous hydrochloric acid solution (5 mL). The organic phase was directly purified by flash column chromatography (Teledyne Isco RediSep column; 5-100% ethyl acetate in hexanes). The resulting solid was triturated with diethyl ether, filtered and dried in vacuo to afford N-{3-[(1R,2S,7R,8S)-6-hydroxy-4-oxo-3-(1-trifluoromethyl-cyclopropylmethyl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.006 g, 0.01 mmol, 1.4%) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.79-0.92 (3H, m), 1.00-1.21 (3H, m), 1.37-1.60 (4H, m), 2.49-2.56 (2H, m), 2.88 (3H, s), 2.97 (1H, d, J=9.6 Hz), 3.03 (1H, d, J=15.3 Hz), 3.67 (1H, d, J=9.3 Hz), 4.17 (2H, d, J=6.2 Hz), 4.53 (1H, d, J=15.6 Hz), 7.21 (1H, s), 7.59 (1H, t, J=6.3 Hz). LC-MS (ESI—negative mode) calculated for C22H25F3N4O6S3 594.09. found 593.25 [M−H].
