Triethylamine → rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid methyl ester

HRID 1806896Notes

Reaction equation

HRID 1806896 reaction equation
[C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH:14]1[CH2:16][CH2:15]1)([CH3:13])[CH3:12])(C)(C)C.[Cl:18][C:19]1[C:20]([F:37])=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=2[F:37])[C:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[CH:9]([CH2:10][C:11]([CH:14]2[CH2:16][CH2:15]2)([CH3:13])[CH3:12])[NH:8]1)=[O:17]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 59249629(Z)-3-(3-Chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrileHCID 178451250HCID 178451250, compound

Product 1

HCID 67297219rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid methyl esterYield 50%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 99a (0.9 g, 3.76 mmol) and (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.16 g, 3.76 mmol) prepared in Example 52a in dichloromethane (100 mL) were added triethylamine (0.76 g, 7.5 mmol) and AgF (0.47 g, 3.76 mmol), in one portion. The mixture was stirred at room temperature for overnight. The mixture was then quenched with sat. NH4Cl and extracted with CH2Cl2. The organic phase was separated, filtered through celite and dried over Na2SO4, and concentrated. The residue was dissolved into methanol (40 mL), and DBU (3 mL) was added. The mixture was heated at 100° C. for 5 h, then cooled to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer were separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:5, 1:3) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid methyl ester as a white foam (0.95 g, 50%).

Workup

  1. customThe mixture was then quenched with sat. NH4Cl
  2. extractionextracted with CH2Cl2
  3. customThe organic phase was separated
  4. filtrationfiltered through celite
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved into methanol (40 mL), and DBU (3 mL)
  8. additionwas added
  9. temperatureThe mixture was heated at 100° C. for 5 h
  10. temperaturecooled to room temperature
  11. concentrationconcentrated
  12. customThe residue was partitioned between ethyl acetate and water
  13. customThe organic layer were separated
  14. dry with materialdried over MgSO4
  15. concentrationconcentrated
  16. customThe residue was purified by chromatography (EtOAc:hexanes=1:5, 1:3)

Sources & evidence

ORD record
ord-9b55212a74394d049aac42af90e79341
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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