反应详情

To a solution of benzisothiazole-3-carboxylic acid (0.93 mmol) in tetrahydrofuran (10 mL) and N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (2.87 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride (0.99 mmol). The reaction mixture was maintained at room temperature for 30 min under nitrogen and then HATU (1.00 mmol) was added. After 18 h, the reaction mixture was partitioned between saturated aqueous potassium carbonate solution and 95/5 dichloromethane/methanol. The aqueous layer was extracted with 95/5 dichloromethane/methanol (2×), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using a mixture of [90/10/1 dichloromethane/methanol/ammonium hydroxide] as the eluent, thus providing the product in 20% yield. Alternatively, the residues were purified by preparative HPLC. 1H NMR (CD3OD) δ 8.79 (dd, J=8.3, 1.0, 1H), 8.10-8.06 (m, 1H), 7.63-7.49 (m, 2H), 4.39-4.32 (m, 0.5H), 4.17-4.15 (m, 0.5H), 3.33-3.27 (m, 2H), 2.35 (s, 1.5H), 2.34 (s, 1.5H), 2.31-1.75 (m, 8H); LC/MS (EI) tR 3.76 min, m/z 302 (M++1).

1. customthe reaction mixture was partitioned between saturated aqueous potassium carbonate solution and 95/5 dichloromethane/methanol
2. extractionThe aqueous layer was extracted with 95/5 dichloromethane/methanol (2×)
3. washthe combined organic layers were washed with brine
4. dry with materialdried over sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customThe residue was purified by silica gel flash column chromatography
8. additiona mixture of [90/10/1 dichloromethane/methanol/ammonium hydroxide] as the eluent
9. customthus providing the product in 20% yield
10. customAlternatively, the residues were purified by preparative HPLC