反应详情

温度

25 °C

A solution of cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 154 mg, 0.580 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-acetic acid (175 mg, 0.527 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (117 mg, 0.609 mmol) in anhydrous N,N-dimethylformamide (6 mL) was treated with N-methylmorpholine (123 mg, 134 μL, 1.22 mmol). The reaction was stirred for 1 h at 25° C., diluted with 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was taken up in ethanol (6 mL) and treated with a 60% oil dispersion of sodium hydride (93 mg, 3.87 mmol). The reaction was heated at 70° C. for 1 h, allowed to cool to 25° C., and quenched with 1.0 M aqueous hydrochloric acid solution (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by prep-HPLC [Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 45-70% acetonitrile in water; 30 mL/min flow rate for 4 min run] to afford the desired product, cis-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[1,4]thiazin-7-yl}-methanesulfonamide (60 mg, 0.112 mmol, 21%), as a light yellow solid. 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, Acetone-d6) δ: 1.34-1.47 (m, 1H), 1.50-1.91 (m, 4H), 2.32-2.42 (m, 1H), 2.96-3.03 (m, 1H), 3.11 (s, 3H), 3.83-3.94 (m, 1H), 4.54-4.67 (m, 1H), 4.97-5.07 (m, 1H), 5.37-5.78 (m, 2H), 7.07-7.14 (m, 2H), 7.36-7.54 (m, 3H), 7.66-7.71 (m, 1H), 7.81-7.83 (m, 1H), 8.95 (bs, 1H). LC-MS calcd for C24H24FN3O6S2 533.6, found 534.3 [M+H+].

1. extractionextracted with ethyl acetate (3×50 mL)
2. dry with materialThe combined organic layers were dried over magnesium sulfate
3. filtrationfiltered
4. concentrationconcentrated in vacuo
5. temperatureThe reaction was heated at 70° C. for 1 h
6. temperatureto cool to 25° C.
7. customquenched with 1.0 M aqueous hydrochloric acid solution (50 mL)
8. extractionThe resulting mixture was extracted with ethyl acetate (3×50 mL)
9. dry with materialthe combined organic layers were dried over magnesium sulfate
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. customThe crude oil was purified by prep-HPLC [Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 45-70% acetonitrile in water; 30 mL/min flow rate for 4 min run]