1-{[4-(4-Bromobenzenesulfonyloxy)-1-(2-tert-butoxycarbonylamino-3,3-dimethylbutyryl)-pyrrolidine-2-carbonyl]amino}-2-ethylcyclopropanecarboxylic acid methyl ester → 1-{[1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-(4-bromobenzenesulfonyloxy)pyrrolidine-2-carbonyl]amino}-2-ethyl-cyclopropanecarboxylic acid methyl ester

HRID 2405848Notes

Reaction equation

HRID 2405848 reaction equation
[CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][N:14]2[C:29](=[O:43])[CH:30]([NH:35][C:36]([O:38][C:39]([CH3:42])(C)[CH3:40])=[O:37])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].O=C1CCC(=O)N1OC(=O)OC1C[CH:58]2[CH:56]([CH2:57]2)C1>Cl.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][N:14]2[C:29](=[O:43])[CH:30]([NH:35][C:36]([O:38][CH:39]2[CH2:40][CH:58]3[CH:56]([CH2:57]3)[CH2:42]2)=[O:37])[C:31]([CH3:33])([CH3:32])[CH3:34])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4]

Participants

5

Reactant 2

HCID 766049171-{[4-(4-Bromobenzenesulfonyloxy)-1-(2-tert-butoxycarbonylamino-3,3-dimethylbutyryl)-pyrrolidine-2-carbonyl]amino}-2-ethylcyclopropanecarboxylic acid methyl esterHCID 76604972Carbonic acid bicyclo[3.1.0]hex-3-yl ester 2,5-dioxo-pyrrolidin-1-yl ester

Product 1

HCID 766050501-{[1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-(4-bromobenzenesulfonyloxy)pyrrolidine-2-carbonyl]amino}-2-ethyl-cyclopropanecarboxylic acid methyl esterYield 92%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 312751,4-DioxaneSolvent

Procedure

1-{[4-(4-Bromobenzenesulfonyloxy)-1-(2-tert-butoxycarbonylamino-3,3-dimethylbutyryl)-pyrrolidine-2-carbonyl]amino}-2-ethylcyclopropanecarboxylic acid methyl ester was dissolved in 4N HCl in dioxane (300 mL) at room temperature and stirred for 2 h. It was then concentrated under vacuum, and co-evaporated with dichloromethane (2×200 mL) to dryness. The residue was dissolved in EtOAc (600 mL) and sat'd aq. NaHCO3 (1 L). It was stirred vigorously. After 10 min, carbonic acid bicyclo[3.1.0]hex-3-yl ester 2,5-dioxo-pyrrolidin-1-yl ester (41.4 g, 173.1 mmol) was added in one portion. After the resulting mixture was stirred for another 30 min, the organic layer was collect and washed with brine (500 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel with ethyl acetate/hexane to afford 94.4 g (92% yield) of 1-{[1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-(4-bromobenzenesulfonyloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethylcyclopropanecarboxylic acid methyl ester.

Workup

  1. concentrationIt was then concentrated under vacuum
  2. dissolutionThe residue was dissolved in EtOAc (600 mL)
  3. stirringIt was stirred vigorously
  4. waitAfter 10 min
  5. stirringAfter the resulting mixture was stirred for another 30 min
  6. customthe organic layer was collect
  7. washwashed with brine (500 mL)
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified by flash chromatography on silica gel with ethyl acetate/hexane

Sources & evidence

ORD record
ord-073c5c025f1d45f58abb3f6ff190ea92
Source dataset
uspto-grants-2014_08
Patent number
US08809267B2

Reaction notes

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