Hydrochloric Acid → rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-amide

HRID 1807255Notes

Reaction equation

HRID 1807255 reaction equation
C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:21]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[F:40])([C:31]#[N:32])[CH:20]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH:19]2)=[O:17])=[CH:11][C:10]1=[O:46])(C)(C)C.Cl>C1COCC1>[OH:6][CH2:7][CH2:8][N:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:21]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=3[F:40])([C:31]#[N:32])[CH:20]([CH2:41][C:42]([CH3:44])([CH3:43])[CH3:45])[NH:19]2)=[O:17])=[CH:11][C:10]1=[O:46]

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 72243958rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl)-amide

Product 1

HCID 72243998rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-amideYield 41%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl)-amide (35 mg, 0.049 mmol) in THF (5 ml) was added an aqueous solution (1 N) of HCl (5 mL). The reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated and the residue was partitioned between aqueous saturated Na2SO4 and ethyl acetate. The organic layer was collected and washed with H2O (25 mL), brine (25 mL), dried over MgSO4 and concentrated. The residue was purified by flash chromatography (silica gel, 12 g, 20% to 100% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-amide as a white solid (12 mg, 41%).

Workup

  1. concentrationThe mixture was concentrated
  2. customthe residue was partitioned between aqueous saturated Na2SO4 and ethyl acetate
  3. customThe organic layer was collected
  4. washwashed with H2O (25 mL), brine (25 mL)
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated
  7. customThe residue was purified by flash chromatography (silica gel, 12 g, 20% to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-066233f1cd8d4a96975cd19e58e78da7
Source dataset
uspto-grants-2013_01
Patent number
US08354444B2

Reaction notes

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