反应详情

温度

100 °C

(4aR,7aS)-1-(4-Fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (prepared as described in Example 39c, 301 mg, 0.53 mmol), α-toluenesulfonamide (272 mg, 1.59 mmol) copper(I) iodide (50.4 mg, 0.265 mmol) potassium phosphate (338 mg, 1.59 mmol), and sarcosine (N-methyl glycine) (37.4 mg, 0.42 mmol) were suspended in N,N-dimethylformamide (8 mL). The mixture was degassed and backfilled with nitrogen (3×). The resulting mixture was stirred at 100° C. for 20.5 h. The mixture was filtered through a plug of Celite. The Celite was washed with 10% methanol in dichloromethane and the combined filtrates were concentrated in vacuo to afford the crude product which was further purified by prep-HPLC [Column ODS-A 5μ 100 Å, 150×21.2 mm, 5 micron, 30%-100% in 13.5 min @ 22 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (4aR,7aS)-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-C-phenyl-methanesulfonamide 120.4 mg, 0.197 mmol, 37.2%, as a light purple solid. The estimated e.e. is 97% based on the chiral amino acid starting material used. 1H NMR (DMSO-d6, 400 MHz): δ 1.44-1.62 (m, 3H), 1.94-2.11 (m, 3H), 2.77 (t, 1H, J=7.4 Hz), 3.01 (t, 1H, J=7.4 Hz), 4.40-4.52 (m, 1H), 4.54 (s, 2H), 4.90 (d, 1H, J=15.6 Hz), 7.15 (t, 2H, J=8.8 Hz), 7.24-7.26 (m, 2H), 7.29-7.32 (m, 4H), 7.36-7.46 (m, 3H), 7.50-7.58 (m, 3H), 10.27-10.29 (m, 1H). LC-MS (ESI) calcd for C29H27FN4O6S2 610.14, found 611.5 [M+H+]. Anal. calcd for C29H27FN4O6S2H2O: C, 55.40; H, 4.65; N, 8.91; found: C, 55.41; H, 4.38; N, 9.11.

1. customThe mixture was degassed
2. filtrationThe mixture was filtered through a plug of Celite
3. washThe Celite was washed with 10% methanol in dichloromethane
4. concentrationthe combined filtrates were concentrated in vacuo
5. customto afford the crude product which
6. customwas further purified by prep-HPLC [Column ODS-A 5μ 100 Å, 150×21.2 mm, 5 micron, 30%-100% in 13.5 min @ 22 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water]