反应详情

A solution of compound III (1.47 g, 5.90 mmol) in warm 70% acetic acid (59 ml) was cooled to 25° C., treated with diethyl p-aminobenzoyl-L-glutamate (2.28 g, 7.08 mmol) and hydrogenated in the presence of Raney nickel (6.3 g, weighed wet) at 25° C. and atmospheric pressure for 17 hours. The mixture was filtered and the catalyst was washed with 70% acetic acid (25 ml). The combined filtrate and wash was evaporated to dryness under high vacuum, and a solution of the residue in ethanol was filtered into 2 N Na2CO3 (60 ml). The mixture was stirred to give a homogeneous powder which was collected, washed with water and dried. A solution of the resultant powder in boiling ethanol (415 ml) was filtered hot and evaporated to dryness in vacuo. The residue was triturated with CHCl3 (85 ml), collected by filtration and the solid was washed with additional CHCl3 (40 ml). A suspension of the solid in boiling ethanol (140 ml) was stirred for 20 minutes and refrigerated. The product was collected by filtration and dried in vacuo (P2O5): yield 945 mg (32%), mp 262° C. (Kofler Heizbank). Mass spectrum, m/e 496 (M+1)+ ; λmax nm (ε×10-3); 0.1 N HCl --218 (42.4), 280 sh (19.3), 300 (22.0); pH 7--218 (36.4), 249 (20.2), 280 sh (22.3), 297 (23.6), 355 sh (6.10); 0.1 N NaOH --249 (22.0), 280 (23.8), 297 sh (22.5), 345 (7.23); 1H-NMR(DMSO-d6, 6% w/v), δ 1.18 m (CH3), 2.05 m (CH2CH2CO), 2.43 t (CH2CO), 4.08 m (CH2O), 4.32 m (CH2N, CHN), 6.31 s, 7.51 s (NH2), 6.67 d, 7.69 d (C6H4), 6.71 s (CH2NH), 8.25 d (CONH), 8.41 d (5 --CH, J=2.0 Hz), 8.66 d (7-CH, J=2.0 Hz).

1. filtrationThe mixture was filtered
2. washthe catalyst was washed with 70% acetic acid (25 ml)
3. washThe combined filtrate and wash
4. customwas evaporated to dryness under high vacuum
5. filtrationa solution of the residue in ethanol was filtered into 2 N Na2CO3 (60 ml)
6. customto give a homogeneous powder which
7. customwas collected
8. washwashed with water
9. customdried
10. filtrationwas filtered hot
11. customevaporated to dryness in vacuo
12. customThe residue was triturated with CHCl3 (85 ml)
13. filtrationcollected by filtration
14. washthe solid was washed with additional CHCl3 (40 ml)
15. additionA suspension of the solid
16. stirringwas stirred for 20 minutes
17. filtrationThe product was collected by filtration
18. dry with materialdried in vacuo (P2O5)
19. wait1H-NMR(DMSO-d6, 6% w/v), δ 1.18 m (CH3), 2.05 m (CH2CH2CO), 2.43 t (CH2CO), 4.08 m (CH2O), 4.32 m (CH2N, CHN), 6.31 s, 7.51 s
20. custom(NH2), 6.67 d, 7.69 d (C6H4), 6.71 s (CH2NH), 8.25 d (CONH), 8.41 d (5 --CH, J=2.0 Hz), 8.66 d (7-CH, J=2.0 Hz)