反应详情

(S)-2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-N-[(R)-1-(3-phenyl-propylcarbamoyl)-ethyl]-propionamide (J. Med. Chem. 1994, 37, 888) (449 mg, 1.0 mmol) and 3,5-dimethylpyrazole-1-carboxamidine (240 mg, 1.2 mmol) were heated in ethanol at 60° C. After 24 hours, triethylamine (167 μl, 1.2 mmol) was added. The reaction was heated for a further 24 hours. The solvent was evaporated and the crude material was redissolved in dichloromethane containing 2% methanol. The resulting solution was washed with a solution of citric acid followed by sodium bicarbonate solution. The organic phase was washed with brine then dried over MgSO4. The organics were filtered and evaporated leaving a small amount of a crude gum. The gum was purified using an ISCO chromatography system on a 12 g silica column using gradient elution from 95:5:0.5 to 80:20:5 DCM:MeOH:NH3 to afford the title compound as a solid in 5% yield, 20 mg. 1H NMR (400 MHz, MeOH-d4) δ : 1.18 (d, 3H), 1.75-1.82 (m, 2H), 2.21 (s, 1H), 2.49 (s, 1H), 2.58-2.63 (m, 2H), 2.95-3.02 (m, 1H), 3.10-3.24 (m, 3H), 3.28-3.32 (m, 1H), 4.18-4.22 (m, 1H), 4.35-4.40 (m, 1H), 6.51 (s, 2H), 7.08-7.28 (m, 5H). LRMS m/z 440 [M+H]+.

1. temperatureThe reaction was heated for a further 24 hours
2. customThe solvent was evaporated
3. dissolutionthe crude material was redissolved in dichloromethane containing 2% methanol
4. washThe resulting solution was washed with a solution of citric acid
5. washThe organic phase was washed with brine
6. dry with materialthen dried over MgSO4
7. filtrationThe organics were filtered
8. customevaporated
9. customleaving a small amount of a crude gum
10. customThe gum was purified
11. washelution from 95:5:0.5 to 80:20:5 DCM