反应详情

To 2-(4-chloro-3-(dibutylcarbamoyl)-5-methyl-1H-pyrazol-1-yl)-5-(naphthalen-2-ylsulfonylcarbamoyl)benzoic acid (Intermediate 91F, 50 mg, 0.080 mmol) in CH2Cl2 (890 μL) was added 1-chloro-N,N-2-trimethylprop-1-en-1-amine (21 μL, 0.16 mmol). After stirring for 30 min at room temperature, (R)-methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (20 mg, 0.088 mmol) in THF (900 μL) was added followed by i-Pr2EtN (42 μL, 0.24 mmol). The resulting reaction mixture was stirred at room temperature for 1 h, then quenched with sat. aq. NH4Cl solution and extracted with EtOAc (1×). The organic layer was washed with 1N aq. HCl solution, and the combined aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (24 mg, 37%). 1H NMR (1:1 CD3OD:CDCl3, 1:1 mixture of amide rotamers) δ 8.62 (d, J=15.9 Hz, 1H), 8.20 (dd, J=13.9, 9.0 Hz, 1.5H), 8.13-7.85 (m, 5H), 7.63-7.52 (m, 1.5H), 7.47 (d, J=8.4 Hz, 1H), 7.24-7.06 (m, 3.5H), 6.93 (d, J=6.8 Hz, 0.5H), 5.17 (t, J=5.4 Hz, 0.5H), 5.02 (d, J=17.6 Hz, 0.5H), 4.75 (d, J=5.9 Hz, 1H), 4.49 (d, J=18.0 Hz, 1.5H), 3.64 (br s, 1.5H), 3.55-3.41 (m, 2.5H), 3.27-3.09 (m, 4H), 3.05-2.99 (m, 0.5H), 2.31 (s, 1.5H), 2.24 (s, 1.5H), 1.50-0.95 (m, 8H), 0.95-0.82 (m, 3H), 0.74 (t, J=7.5 Hz, 1.5H), 0.71-0.63 (m, 1.5H); MS(ESI+) m/z 798.3 (M+H)+.

1. customThe resulting reaction mixture
2. stirringwas stirred at room temperature for 1 h
3. customquenched with sat. aq. NH4Cl solution
4. extractionextracted with EtOAc (1×)
5. washThe organic layer was washed with 1N aq. HCl solution
6. extractionthe combined aqueous layer was extracted with EtOAc (2×)
7. dry with materialThe combined organic extracts were dried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. customThe residue was purified by preparative HPLC