Acetic Acid → rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile

HRID 909014Notes

Reaction equation

HRID 909014 reaction equation
[Cl:1][C:2]1[C:3]([F:20])=[C:4](/[CH:8]=[C:9](/[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])\[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[CH3:21][C:22]([CH3:32])([CH3:31])[CH2:23]/[CH:24]=[N:25]/[CH2:26][Si](C)(C)C.C(O)(=O)C.O>CN(C)P(N(C)C)(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:8]2[CH2:26][NH:25][CH:24]([CH2:23][C:22]([CH3:32])([CH3:31])[CH3:21])[C:9]2([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[F:19])[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 962Water2×HCID 58222849(E)-3,3-dimethyl-N-(trimethylsilylmethyl)butan-1-imineHCID 59249629(Z)-3-(3-Chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile

Product 1

HCID 67095302rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrileYield 24.4%

Reagents, catalysts & solvents 1

HCID 12679HexamethylphosphoramideSolvent

Procedure

To a solution of (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.2 g, 3.87 mmol) in hexamethylphosphoramide (20 mL) was added [3,3-dimethyl-but-(E)-ylidene]-trimethylsilanylmethyl-amine (1.1 g, 5.9 mmol), acetic acid (60 mg, 1 mmol) and H2O (0.1 g, 5.6 mmol) sequentially. The reaction mixture was stirred at room temperature for 18 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:4, 1;3) to give rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile as a white foam (0.4 g, 24%).

Workup

  1. extractionThe mixture was extracted with ethyl acetate
  2. customThe organic layer was separated
  3. extractionaqueous layer was extracted with ethyl acetate
  4. washwashed with water twice
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated
  7. customThe residue was purified by chromatography (EtOAc:hexanes=1:4, 1;3)

Sources & evidence

ORD record
ord-513cc70eb8514c9f8b113bad69f8c7a6
Source dataset
uspto-grants-2011_09
Patent number
US08017607B2

Reaction notes

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