反应详情

A stirring solution of (1R,2S,5R)-tert-butyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate (108 g, 0.236 mol) in THF (1 L) was charged with lithium hydroxide monohydrate (21.74 g, 0.519 mol). Water (0.3 L) was added slowly, such that the temperature did not exceed 20° C. The reaction was stirred at room temperature overnight and the volatiles were removed in vacuo. The pH was adjusted to ˜4 through the addition of 1N HCl (450 mL) and NaH2PO4. The resultant white precipitates were collected by filtration and washed with water (2×1 L). The solid was dissolved in dichloromethane (1.5 L) and water (˜1 L). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in EtOAc (0.7 L) and the resultant solution was heated at reflux for 1 h. Solids separated after cooling to RT, and were collected via filtration. These solids were purified by recrystallization in isopropanol to afford the desired (1R,2S,5R)-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid as a white solid (104.5 g, 93% yield). LC/MS for primary peak: [M-tBu+H]+=420.2; [M-Boc+H]+=376.2; [M+H]+=476.2. 1H-NMR (400 MHz, d4-MeOH): δ 7.35 (m, 5H), 5.11 (s, 2H), 4.35 (m, 2H), 3.71 (m, 1H), 3.45-3.6 (m, 2H), 2.99 (m, 1H), 2.41 (m, 1H), 2.15 (m, 1H), 2.0 (m, 2H), 1.6-1.9 (m, 4H), 1.46 (s, 9H).

1. customdid not exceed 20° C
2. customthe volatiles were removed in vacuo
3. additionThe pH was adjusted to ˜4 through the addition of 1N HCl (450 mL) and NaH2PO4
4. customThe resultant white precipitates
5. filtrationwere collected by filtration
6. washwashed with water (2×1 L)
7. dissolutionThe solid was dissolved in dichloromethane (1.5 L)
8. dry with materialThe organic layer was dried (Na2SO4)
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. dissolutionThe residue was dissolved in EtOAc (0.7 L)
12. temperaturethe resultant solution was heated
13. temperatureat reflux for 1 h
14. customSolids separated
15. temperatureafter cooling to RT
16. filtrationwere collected via filtration
17. customThese solids were purified by recrystallization in isopropanol