反应详情

温度

55 °C

Example 1, Alternative Step 9f: The aminoester 6 (9.76 g, 2.12 mmol) was dissolved in 2N HCl (80 mL), then heated to ˜55° C. under inert atmosphere. The reaction was stirred for 20 h, then cooled to room temperature. The reaction solution was washed twice with toluene (25 mL portions), neutralized to pH 6-7 by the addition of KOH pellets, then extracted eight times with methylene chloride (100 mL portions). The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to 50 mL total volume. The concentrated solution was then slowly added to methyl tert-butyl ether (300 mL) over 15 min in an addition funnel with vigorous stirring. The resulting white slurry was stirred at ambient temperature for Ih, then cooled to 0° C. and stirred for 1 h. The product was filtered, and washed twice with methyl tert-butyl ether (25 mL portions). Water from the wet cake was removed by azeotropic distillation with acetonitrile (300 mL). The product was dried under reduced pressure to provide (1R,2S,5R)-2-((3S)-3-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-(isopropyl-methyl-amino)-cyclohexanecarboxylic acid 7, (7.69 g, 84% yield) as a white foam. 1H-NMR: (400 MHz, 50° C., CDCl3) δ 7.44-7.32 (m, 5H), 6.10 (broad s, 1H), 5.19 (app s, 2H), 4.42 (dd, J=15.6, 7.8 Hz, 1H), 4.29-4.23 (m, 1H), 3.68-3.60 (m, 2H), 3.33-3.27 (m, 2H), 3.20 (broad s, 1H), 2.99 (broad s, 1H), 2.51 (s, 3H), 2.49-2.45 (m, 3H), 2.33-2.31 (m, 1H), 2.00 (ddd, J=9.0, 8.6, 3.9 1H), 1.95-1.78 (m, 2H), 1.36-1.21 (m, 6H). LCMS: m/z 432.20 [Calc: C23H34N3O5 432.25].

1. temperaturecooled to room temperature
2. washThe reaction solution was washed twice with toluene (25 mL portions)
3. additionneutralized to pH 6-7 by the addition of KOH pellets
4. extractionextracted eight times with methylene chloride (100 mL portions)
5. dry with materialThe combined extracts were dried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure to 50 mL total volume
8. additionThe concentrated solution was then slowly added to methyl tert-butyl ether (300 mL) over 15 min in an addition funnel with vigorous stirring
9. stirringThe resulting white slurry was stirred at ambient temperature for Ih
10. temperaturecooled to 0° C.
11. stirringstirred for 1 h
12. filtrationThe product was filtered
13. washwashed twice with methyl tert-butyl ether (25 mL portions)
14. customWater from the wet cake was removed by azeotropic distillation with acetonitrile (300 mL)
15. customThe product was dried under reduced pressure