Potassium Iodide → N-{3-[(1R,2S,7R,8S)-3-(2-cyclopentyl-ethyl)-6-hydroxy-4-oxo-3-aza-tricyclo [6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1lambda6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide

Participants

Reaction Conditions

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 (0.15 g, 0.36 mmol, prepared as described in WO08124450A1) was dissolved in N,N-dimethylformamide (4 mL). Toluene-4-sulfonic acid 2-cyclopentyl-ethyl ester (0.193 g, 0.72 mmol) was added followed by triethylamine (0.109 g, 1.08 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; 0.127 g, 0.36 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.104 g, 0.54 mmol. The mixture was shaken at 25° C. for 16 h. Triethylamine (0.145 g, 1.44 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 (4 mL) and 1.0 M aqueous hydrochloric acid solution (6 mL). The organic phase was further washed with 1.0 M aqueous hydrochloric acid solution (2 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)-3-(2-cyclopentyl-ethyl)-6-hydroxy-4-oxo-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 (0.015 g, 0.026 mmol, 7.2%) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.11-1.18 (1H, m), 1.18-1.27 (1H, m), 1.27-1.34 (1H, m), 1.42-1.66 (10H, m), 1.67-1.81 (4H, m), 2.50-2.54 (1H, m), 2.61-2.63 (1H, m), 2.96-3.11 (5H, m), 3.58-3.68 (2H, m), 4.24 (2H, d, J=6.2 Hz), 7.28 (1H, s), 7.66 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C24H32N4O6S3 568.1. found 569.3 [M+H+].

Provenance & Evidence