反应详情

Reflux a mixture of (2R,4R)-4-amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (198 g, 0.92 mol), 5-bromo-fluoronitrobenzene (224 g, 0.98 mol), triethylamine (273 mL, 1.96 mol) in ethyl acetate (2 L) for 16 h under nitrogen with vigorous stirring. Cool to room temperature and wash with brine. Back-extract the brine layer with ethyl acetate (1 L), combine the organic layers, dry over sodium sulfate, filter and concentrate. Dissolve the resulting solid in warm ethyl acetate (2 L), concentrate to approximately 500 mL and allow crystals to start forming Treat the solution slowly with hexanes (2 L) and allow the mixture to stand at room temperature for 2 h. Collect the yellow solid by filtration, wash with hexanes and dry at 40° C./20 mm Hg to obtain 227 g of desired product. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (2:3:5 ethyl acetate/dichloromethane/heptane gradually increasing to 2:3 ethyl acetate/heptane) to obtain an additional 54 g of desired product. Overall yield: 281 g (70%). [α]D20−81 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.40 (s, 9H), 1.90 (m, 1H), 2.48 (br s, 1H), 3.14 (m, 1H), 3.45 (m, 1H), 3.63 (m, 1H), 3.81 (m, 2H), 4.29 (m, 1H), 5.12 (m, 1H), 7.08 (d, 1H), 7.65 (dd, 1H), 8.15 (d, 1H), 8.57 (br d, 1H, NH).

1. temperatureReflux
2. washwash with brine
3. extractionBack-extract the brine layer with ethyl acetate (1 L)
4. dry with materialdry over sodium sulfate
5. filtrationfilter
6. concentrationconcentrate
7. dissolutionDissolve the resulting solid in warm ethyl acetate (2 L)
8. concentrationconcentrate to approximately 500 mL
9. customto start forming
10. customCollect the yellow solid
11. filtrationby filtration
12. washwash with hexanes
13. customdry at 40° C./20 mm Hg