反应详情

H-Val-Ala-OH 11 (1.0 g, 5.313 mmol, 1.0 eq.) and Na2CO3 (1.42 g, 13.282 mmol, 2.5 eq.) were solubilised in distilled H2O (40 mL) and the mixture was cooled to 0° C. before dioxane (40 mL) was added. Partial precipitation of the amino acid salt occurred. A solution of Fmoc-Cl (1.44 g, 5.579 mmol, 1.05 eq.) dissolved in dioxane (40 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0° C. for 2 hours before the ice bath was removed and the stirring maintained for 16 hours. The solvent was evaporated under reduced pressure and the solid remaining dissolved in water (450 mL). The pH was adjusted to 2 with 1N HCl (25 mL) and the aqueous layer was subsequently extracted with EtOAc (3×250 mL). The combined organics were washed with brine (100 mL), dried over MgSO4, filtered and the volatiles removed under reduced pressure to afford pure HO-Ala-Val-Fmoc 12 as a white solid (2.06 g, 94%). LC/MS (2.758 min (ES+)), m/z: 411.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (br s, 1H), 8.20 (d, 1H, J=6.7 Hz), 7.89 (d, 2H, J=7.5 Hz), 7.75 (t, 2H, J=6.8 Hz), 7.43-7.38 (m, 3H), 7.34-7.30 (m, 2H), 4.31-4.16 (m, 4H), 3.88 (dd, 1H, J=8.8, 7.2 Hz), 1.98 (m, 1H), 1.26 (d, 3H, J=7.3 Hz), 0.89 (d, 3H, J=6.8 Hz), 0.86 (d, 3H, J=6.8 Hz).

1. additionwas added
2. customPartial precipitation of the amino acid salt
3. additionwas added dropwise
4. customwas removed
5. temperaturethe stirring maintained for 16 hours
6. customThe solvent was evaporated under reduced pressure
7. dissolutionthe solid remaining dissolved in water (450 mL)
8. extractionthe aqueous layer was subsequently extracted with EtOAc (3×250 mL)
9. washThe combined organics were washed with brine (100 mL)
10. dry with materialdried over MgSO4
11. filtrationfiltered
12. customthe volatiles removed under reduced pressure