Triethylamine → (2R,4R)-4-(4-Bromo-2-nitro-phenylamino)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 244351Notes

Reaction equation

HRID 244351 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH2:13])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 27363284-Bromo-1-fluoro-2-nitrobenzeneHCID 45072438tert-butyl (2R,4R)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate

Product 1

HCID 58564432(2R,4R)-4-(4-Bromo-2-nitro-phenylamino)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl esterYield 59.3%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-2d71fb7c95884cddb2631a588dfd8b88
Source dataset
uspto-grants-2014_02
Patent number
US08658638B2

Reaction notes

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