1,2-Dichloroethane → Benzyl (S)-1-((S)-2-((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-ylcarbamoyl)-pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate

HRID 2215969Notes

Reaction equation

HRID 2215969 reaction equation
C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:24])[NH:14][C:15]1[CH:16]([O:21][CH2:22][CH3:23])[O:17][C:18](=[O:20])[CH:19]=1)=[O:7])(C)(C)C.N1C(C)=CC=CC=1C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(=O)(O)[O-].[Na+].[CH2:50]([O:57][C:58]([NH:60][CH:61]([C:65]([CH3:68])([CH3:67])[CH3:66])C(O)=O)=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>ClCCl.C(OCC)(=O)C>[CH2:50]([O:57][C:58](=[O:59])[NH:60][CH:61]([C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:24])[NH:14][CH:15]1[CH2:19][C:18](=[O:20])[O:17][CH:16]1[O:21][CH2:22][CH3:23])=[O:7])[C:65]([CH3:67])([CH3:66])[CH3:68])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1

Participants

10

Reactant 7

HCID 111,2-DichloroethaneHCID 79372,6-LutidineHCID 65367Trimethylsilyl triflateHCID 757711-HydroxybenzotriazoleHCID 516892Sodium BicarbonateHCID 34012063,3-dimethyl-2-(phenylmethoxycarbonylamino)butanoic acidHCID 68576080(R)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 59730815Benzyl (S)-1-((S)-2-((2R,3S)-2-ethoxy-5-oxotetrahydrofuran-3-ylcarbamoyl)-pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamateYield 59.8%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (R)-2-(2-ethoxy-5-oxo-2,5-dihydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (X, R1=Et) (0.14 g, 0.41 mmol) (1H-NMR shows ˜8:2 syn:anti epimers) and lutidine (0.48 mL, 4.1 mmol) in dichloromethane (5 mL) at room temperature under nitrogen was dropwise added trimethylsilyltrifluoromethane-sulfonate (0.48 mL, 2.46 mmol). The reaction was stirred for 0.5 h, then was treated with saturated sodium bicarbonate, was extracted with three portions of dichloromethane, was dried (sodium sulfate), and was evaporated. To the crude intermediate was added 2-benzyloxycarbonylamino-3,3-dimethylbutyric acid (0.12 g, 0.45 mmol) in dichloromethane (5 mL), EDC (0.10 g, 0.51 mmol) and HOBT (0.07 g, 0.51 mmol). The resulting mixture was stirred at room temperature under nitrogen for 3 days. The reaction was diluted with ethyl acetate, was washed with 10% potassium bisulfate, saturated sodium bicarbonate and brine, was dried (sodium sulfate) and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate hexanes provided {1-[2-(2-ethoxy-5-oxo-tetrahydrofuran-3-yl carbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethylpropyl}carbamic acid benzyl ester (0.12 g, 59% yield) as a white foam. 1H-NMR (500 MHz, CDCl3) δ 7.43 (br d, J=7.7 Hz, 1H), 7.28 (s, 5H), 5.40 (m, 2H), 5.02 (AB q, J=12.1, 31.0 Hz, 2H), 4.55 (m, 2H), 4.29 (d, J=9.6 Hz, 1H), 4.23 (m, 0.2H), 3.85 (m, 0.8H), 3.73 (m, 1H), 3.58 (m, 2H), 2.90 (m, 0.2H), 2.74 (dd, J=17.0, 8.4 Hz, 0.8H), 2.30 (m, 2H), 2.05 (m, 1H), 1.90 (m, 1H), 1.80 (m, 1H), 1.20 (t, J=7.0 Hz, 2.4H), 1.15 (t, J=7.0 Hz, 0.6H), 0.93 (s, 9H) ppm.

Workup

  1. customat room temperature
  2. extractionwas extracted with three portions of dichloromethane
  3. dry with materialwas dried (sodium sulfate)
  4. customwas evaporated
  5. stirringThe resulting mixture was stirred at room temperature under nitrogen for 3 days
  6. washwas washed with 10% potassium bisulfate, saturated sodium bicarbonate and brine
  7. dry with materialwas dried (sodium sulfate)
  8. customwas evaporated
  9. customPurification by flash chromatography (SiO2)
  10. washeluted with 1:1 ethyl acetate hexanes

Sources & evidence

ORD record
ord-55a4fdfe3c1f458ebfa0a46280739aa3
Source dataset
uspto-grants-2006_09
Patent number
US07109357B2

Reaction notes

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