反应详情

温度

45 °C

(R)-2-(4-Chloro-N-(2-fluoro-4-(N′-hydroxycarbamimidoyl)benzyl)-phenylsulfonamido)-5,5,5-trifluoropentanamide (246 g) was charged to a reactor followed by dry acetonitrile (509 mL), triethyl orthoformate (120 mL), and trifluoroacetic acid (7 mL). The solution was heated to 40-50° C. until the reaction was complete by HPLC (<0.15 relative AP starting material). Methanol (1.48 L) was charged in one portion, followed by water (1.034 L), keeping the batch at 45-50° C. The batch was then cooled to 15-20° C. and filtered. The cake was washed with 2:6:5 MeCN:MeOH:water and tray dried under vacuum at 50-60° C., giving the title compound as a white solid (228 g, 90% yield). 1H NMR, (CDCl3, 300 MHz) δ: 1.40-1.58 (m, 1 H) 1.75-1.90 (m, 1 H) 1.92-2.07 (m, 1 H) 2.10 -2.26 (m, 1 H) 4.37 (dd, J=8.67, 6.22 Hz, 1 H) 4.48 (d, J=15.64 Hz, 1 H) 4.64 (d, J=15.82 Hz, 1 H) 5.54 (s, 1 H) 6.33 (s, 1 H) 7.44-7.54 (m, 2 H) 7.62 (t, J=7.72 Hz, 1 H) 7.68-7.76 (m, 3 H) 7.85 (dd, J=7.91, 1.51 Hz, 1H) 8.76 (s, 1 H). 13C NMR, (DMSO-d6, 75 MHz) δ: 170.34, 167.75, 165.80, 159.64 (d, J=244.5 Hz, 1C), 138.19, 137.64, 131.25 (d, J=3.75 Hz, 1C), 129.31, 129.23, 129.05 (d, J=14.25 Hz, 1C), 126.74 (q, J=274.5 Hz, 1C), 126.91, 126.80, 123.12 (d, J=3.75 Hz, 1C), 113.7 (d, J=24.0 Hz, 1 C), 57.92, 41.38 (d, J=4.5 Hz, 1 C), 30.04 (d, J=30.0 Hz, 1C), 22.90. 19F NMR, (CDCl3, 282 MHz) δ: −116.3, −66.5. IR (KBr): 3454, 334, 3286, 2952, 1705, 1432, 1325, 1260, 1167, 1084, 828 cm−1.

1. customat 45-50° C
2. temperatureThe batch was then cooled to 15-20° C.
3. filtrationfiltered
4. washThe cake was washed with 2:6:5 MeCN
5. dry with materialMeOH:water and tray dried under vacuum at 50-60° C.