Dichloromethane → rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester

HRID 1806902Notes

Reaction equation

HRID 1806902 reaction equation
[C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH:14]1CC1)([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[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)=[C:31](C)[CH:30]=2)\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.Cl[CH2:46][Cl:47]>>[C: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:30]=[CH:31][C:46]([Cl:47])=[C:33]([CH3:32])[CH:34]=2)([C:27]#[N:28])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:17])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 4

HCID 6344DichloromethaneHCID 8471TriethylamineHCID 59249498(Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-3-methyl-phenyl)-acrylonitrileHCID 178451250HCID 178451250, compound2×

Product 1

HCID 67296884rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl esterYield 80%

Procedure

To a solution of [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (0.93 g, 7.3 mmol) and To a solution of [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 99a (1.6 g, 7.3 mmol) and (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.5 g, 4.9 mmol) prepared in Example 100a in dichloromethane (100 mL) were added triethylamine (1.7 g, 12 mmol) and AgF (0.9 g, 7.3 mmol), in one portion. The mixture was stirred at room temperature for 18 h. 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 tert-butanol (30 mL), and DBU (5 mL) was added. The mixture was heated at 100° C. for 18 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=1:10, 1:5) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-3-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2 g, 80%).

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 tert-butanol (30 mL), and DBU (5 mL)
  8. additionwas added
  9. temperatureThe mixture was heated at 100° C. for 18 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=1:10, 1:5)

Sources & evidence

ORD record
ord-184b04680e804b57b0b020cef0774a42
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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