Ethyl Acetate → tert-Butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate

HRID 446019Notes

Reaction equation

HRID 446019 reaction equation
[C:1]([O:5][C:6](=[O:39])[CH2:7][C@@:8]1([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[O:24])[C@H:12]([CH3:13])[CH2:11][N:10](CC2C(Cl)=CC=CC=2Cl)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:41][C:42]1[C:47]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:45]=[CH:44][C:43]=1[Cl:52].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.CN(C)C=O.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:39])[CH2:7][C@@:8]1([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[O:24])[C@H:12]([CH3:13])[CH2:11][N:10]([CH2:41][C:42]2[C:47]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:45]=[CH:44][C:43]=2[Cl:52])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium Carbonate2×HCID 177506812-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene2×HCID 71293846tert-Butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate

Product 1

HCID 71293630tert-Butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-4-methylpyrrolidin-3-amido]piperidine-1-carboxylateYield 32.4%

Reagents, catalysts & solvents 3

HCID 9942167Palladium hydroxideCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

20% palladium hydroxide (75.8 mg) was added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 5b (a chiral form corresponding to the peak with a shorter retention time) (758 mg, 1.29 mmol) in methanol (20 ml), followed by stirring at 40° C. for three hours under a hydrogen atmosphere. The reaction liquid was filtered, and the filtrate was concentrated to give a crude product (501 mg). 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (145 mg, 0.532 mmol) and potassium carbonate (53.2 mg) were added to a solution of this crude product (174 mg) in N,N-dimethylformamide (dehydrated) (6 mL), followed by stirring overnight. 2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (145 mg, 0.532 mmol) and potassium carbonate (106 mg) were further added, followed by stirring for four hours. Ethyl acetate was added to the reaction liquid, which was washed with a 1N aqueous sodium hydroxide solution and brine. This was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to give the title compound (82 mg, yield: 32.4%).

Workup

  1. customThe reaction liquid
  2. filtrationwas filtered
  3. concentrationthe filtrate was concentrated
  4. customto give a crude product (501 mg)
  5. stirringby stirring overnight
  6. stirringby stirring for four hours
  7. washwas washed with a 1N aqueous sodium hydroxide solution and brine
  8. dry with materialThis was dried over anhydrous magnesium sulfate
  9. concentrationconcentrated
  10. customThe residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate)

Sources & evidence

ORD record
ord-27fab51bd452467aa38de51a3a22c9c8
Source dataset
uspto-grants-2013_07
Patent number
US08476301B2

Reaction notes

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