反应详情

温度

25 °C

A solution of [1-(4-fluoro-benzylamino)-cyclopentyl]-acetic acid methyl ester (109 mg, 0.41 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (150 mg, 0.45 mmol) in anhydrous N,N-dimethylformamide (4 mL) was treated sequentially with N-methylmorpholine (100 μL, 0.91 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol). The reaction mixture was stirred at 25° C. for 1 h, diluted with a 1.0 M aqueous hydrochloric acid solution (20 mL), and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ethanol (5 mL), treated with a 21 wt % solution of sodium ethoxide in ethanol (1.0 mL, 2.73 mmol). The reaction was stirred and heated at 60° C. for 1.5 h, allowed to cool to 25° C., and quenched with a 0.5 M aqueous hydrochloric acid solution (10 mL). The resulting mixture was extracted with ethyl acetate (3×40 mL) and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by prep-HPLC [Column Luna 5μ C18(2) 100 Å AXIA 150×21.2 mm, 5 micron, 30-100% in7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, N-{3-[6-(4-fluoro-benzyl)-9-hydroxy-7-oxo-6-aza-spiro[4.5]dec-8-en-8-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (50 mg, 22%), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.55-1.73 (m, 6H), 1.75-1.87 (m, 2H), 2.93 (s, 2H), 3.05 (s, 3H), 4.66 (s, 2H), 7.12 (t, J=8.8 Hz, 2H), 7.34 (dd, J1=8.8 Hz, J2=5.2 Hz, 2H), 7.48 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.52-7.58 (m, 2H), 10.16 (s, 1H), 13.68 (s, br, 1H). LC-MS (ESI) calculated for C24H25FN4O6S2: 548.6, found 549.3 [M+H+].

1. extractionextracted with ethyl acetate (3×40 mL)
2. washThe combined organic layers were washed with brine (20 mL)
3. dry with materialdried over magnesium sulfate
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. dissolutionThe residue was dissolved in ethanol (5 mL)
7. stirringThe reaction was stirred
8. temperatureheated at 60° C. for 1.5 h
9. temperatureto cool to 25° C.
10. customquenched with a 0.5 M aqueous hydrochloric acid solution (10 mL)
11. extractionThe resulting mixture was extracted with ethyl acetate (3×40 mL)
12. washthe combined organic layers were washed with brine (20 mL)
13. dry with materialdried over magnesium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customThe crude residue was purified by prep-HPLC [Column Luna 5μ C18(2) 100 Å AXIA 150×21.2 mm, 5 micron, 30-100% in7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water]