反应详情

4-(Tertiarybutyloxycarbonylamino)butanoic acid (0.3 g, 1.5 molar equivalents), 2-methoxycarbonyl-5,7-dichloro-4-amino-1,2,3,4-tetrahydroquinoline hydrochloride (Example 9a) (0.3 g, 0.000963M), hydroxybenzotriazole (0.156 g, 1.2 molar equivalents) and triethylamine (0.4 ml, 3 molar equivalents) were dissolved in anhydrous tetrahydrofuran (40 ml) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.22 g, 1.2 molar equivalents). After stirring at room temperature for 14 h the solvents were evaporated, the residue was dissolved in ethyl acetate (100 ml) and washed with 0.5M citric acid solution (2×50 ml), saturated sodium hydrogen carbonate solution (2×50 ml) and brine (1×50 ml). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to leave a residue which was dissolved in 50% aqueous methanol and treated with sodium hydroxide (0.5 g). After stirring the solution for 36 h at room temperature the methanol was removed under vacuum and the residual aqueous solution was treated with 1M HCl until a pH of 1 was attained. The precipitated solid was extracted into ethyl acetate (2×20 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue obtained was treated with 5 molar HCl in ethyl acetate (30 ml) and stirred at room temperature for 60 h. The solvents were evaporated and the residue recrystallised from methanol/diethyl ether/ethyl acetate to give the title compound as a white crystalline solid, m.p. 238°-240° C.; δ (360 MHz, DMSO) 1.63 (1H, ddd, J=13.0, 12.4 and 3.9 Hz, CHACHBHCCHD), 1.80 (2H, m, NHCOCH2CH2CH2NH3+), 2.13-2.21 (3H, m, CHACHBHCCHD and NHCOCH2CH2CH2NH3+), 2.77 (2H, t, J=7.6 Hz, NHCOCH2CHsCH2NH3+), 3.84 (1H, dd, J=12.4 and 2.7 Hz, CHACHBHCCHD), 5.02 (1H, m, CHACHBHCCHD), 6.65 (1H, d, J=1.9 Hz, 6-H or 8-H), 6.83 (1H, s, br, ArNH), 6.88 (1H, d, J=1.9 Hz, 6-H or 8-H), 7.97 (3H, s, br, NH3+), 8.31 (1H, d, J=7.3 Hz, CHDNHCO); Found C, 44.50; H, 4.95; N, 10.12. C14H17N3O3Cl2.HCl.0.25EtoAc requires C, 44.52; H, 4.98; N, 10.38%.

1. customwere evaporated
2. dissolutionthe residue was dissolved in ethyl acetate (100 ml)
3. washwashed with 0.5M citric acid solution (2×50 ml), saturated sodium hydrogen carbonate solution (2×50 ml) and brine (1×50 ml)
4. dry with materialThe organic layer was dried (Na2SO4)
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customto leave a residue which
8. customwas removed under vacuum
9. additionthe residual aqueous solution was treated with 1M HCl until a pH of 1
10. extractionThe precipitated solid was extracted into ethyl acetate (2×20 ml)
11. dry with materialthe combined organic layers were dried (Na2SO4)
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. customThe residue obtained
15. stirringstirred at room temperature for 60 h
16. customThe solvents were evaporated
17. customthe residue recrystallised from methanol/diethyl ether/ethyl acetate