1,2-Dichloroethane → HCID 54414223, compound

HRID 1861309Notes

Reaction equation

HRID 1861309 reaction equation
[C:1]([O:5][C:6]([CH:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][N:9]1[C:15]([O:17]CC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].[CH2:27]([O:34][C:35]([NH:37][CH:38](C)[C:39](O)=O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)CCl.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>[Pd].CO>[C:1]([O:5][C:6]([CH:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][N:9]1[C:15](=[O:17])[CH:38]([NH:37][C:35]([O:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:36])[CH3:39])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

9

Reactant 6

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 95657N-(Benzyloxycarbonyl)-DL-alanineHCID 18623736HCID 18623736, compoundHCID 178418361HCID 178418361, compound

Product 1

HCID 54414223HCID 54414223, compoundYield 77%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid-1-benzyl ester-2-tert-butyl ester (113) (Karanewsky, et. al., J. Med. Chem. 33, pp. 1459-1469 (1990)) (0.42 g, 1.23 mmol) and 10% palladium on carbon (0.22 g) in methanol (6 mL) was stirred at 1 atm hydrogen pressure for 3 h. The mixture was filtered through Celite and evaporated. The residue was dissolved in CH2Cl2 (4 mL) and DMF (2 mL) and cooled to 0° C. 2-Benzyloxycarbonylamino-propionic acid (0.30 g, 1.35 mmol), EDC (0.30, 1.54 mmol), DIEA (0.65 mL) and HOBt (0.17 g, 1.23 mmol) was-added and the reaction was stirred 0.5 h at 0° C., then 16 h at room temperature under nitrogen. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate, then was washed with 10% sodium bisulfate, saturated sodium bicarbonate, water and brine, was dried over sodium sulfate and was evaporated. Purification by flash chromatography on silica, eluted with 25:75 ethyl acetate: hexanes provided 1-(2-benzyloxycarbonylamino-propionyl)-4,4-difluoro-pyrrolidine-2-carboxylic acid tert-butyl ester (0.39 g, 77% yield) as a colorless oil. 1H-NMR (500 MHz, CDCl3) δ 1.3-1.6 (m, 12H), 2.5 (m, 0.8H), 2.7 (m, 1.2H), 3.9 (m, 1H), 4.1 (m, 1H), 4.4 (m, 1H), 4.7 (m, 1H), 5.1 (m, 2H), 5.59 (br d, J=7.7 Hz, 0.8H), 5.7 (br d, J=7.7 Hz, 0.2H), 7.35 (m, 5H) ppm. Analytical HPLC (cyano column) 17.069 min. LC-MS (ES+): m/e=413 (M+H), 357 (M+H-tert-butyl), 313 [M+H-(CO2tert-butyl)].

Workup

  1. filtrationThe mixture was filtered through Celite
  2. customevaporated
  3. dissolutionThe residue was dissolved in CH2Cl2 (4 mL)
  4. custom16 h
  5. customat room temperature
  6. customThe solvent was removed in vacuo
  7. dissolutionthe residue was dissolved in ethyl acetate
  8. washwas washed with 10% sodium bisulfate, saturated sodium bicarbonate, water and brine
  9. dry with materialwas dried over sodium sulfate
  10. customwas evaporated
  11. customPurification by flash chromatography on silica
  12. washeluted with 25:75 ethyl acetate

Sources & evidence

ORD record
ord-ee51d87ba73c4623adbb3e84c0036c92
Source dataset
uspto-grants-2003_03
Patent number
US06531474B1

Reaction notes

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