反应详情

温度

120 °C

(1R,2S,7R,8S)-3-(4-Fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.5 g, 0.84 mmol) and copper(I) cyanide (0.151 g, 1.7 mmol) were suspended in anhydrous N,N-dimethylformamide (4 mL). The mixture was stirred at 120° C., under nitrogen for 24 h. Upon cooling, the mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous ammonium chloride solution (3×15 mL). The organic phase was passed through a short plug of Celite followed by a short plug of silica gel (Merck silica gel 60, 40-63 μm), eluting with ethyl acetate. The filtrate was concentrated in vacuo to afford a yellow solid. Purification by flash column chromatography (Teledyne Isco RediSep column; 25-100% ethyl acetate in hexanes) followed by concentration in vacuo afforded the desired product, (1R,2S,7R,8S)-3-[3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazine-7-carbonitrile (0.398 g, 0.808 mmol, 96%), as a white, brittle foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.15-1.15 (1H, m), 1.34-1.61 (5H, m), 2.48-2.48 (1H, m), 2.60 (1H, d, J=3.3 Hz), 2.90 (1H, d, J=9.4 Hz), 3.48 (1H, d, J=9.4 Hz), 4.38 (1H, d, J=15.6 Hz), 4.96 (1H, d, J=15.4 Hz), 7.11-7.16 (2H, m), 7.31 (2H, dd, J1=8.6 Hz, J2=5.4 Hz), 7.60 (1H, d, J=8.6 Hz), 8.02 (1H, dd, J1=8.6 Hz, J2=2.5 Hz), 8.37 (1H, s). LC-MS (ESI) calculated for C25H21FN4O4S 492.13. found 493.1 [M+H+].

1. temperatureUpon cooling
2. washwashed with saturated aqueous ammonium chloride solution (3×15 mL)
3. washeluting with ethyl acetate
4. concentrationThe filtrate was concentrated in vacuo
5. customto afford a yellow solid
6. customPurification by flash column chromatography (Teledyne Isco RediSep column; 25-100% ethyl acetate in hexanes)
7. concentrationfollowed by concentration in vacuo