Dimethylformamide → tert-Butyl 2-[(3R*,4S*)-1-{[2-chloro-6-(difluoromethyl)phenyl]methyl}-3-[(1-hexylpiperidin-4-yl)carbamoyl]-4-methylpyrrolidin-3-yl]acetate

HRID 446031Notes

Reaction equation

HRID 446031 reaction equation
CN(C)C=O.Br[CH2:7][C:8]1[C:13]([CH:14]([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37]([C@:39]2([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:43]([CH3:44])[CH2:42][NH:41][CH2:40]2)=[O:38])[CH2:32][CH2:31]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O.C(OCC)(=O)C>[Cl:17][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH:14]([F:16])[F:15])[C:8]=1[CH2:7][N:41]1[CH2:42][C@@H:43]([CH3:44])[C@@:39]([CH2:45][C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])([C:37](=[O:38])[NH:36][CH:33]2[CH2:32][CH2:31][N:30]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:35][CH2:34]2)[CH2:40]1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 71293828tert-Butyl 2-[(3R*,4S*)-3-[(1-hexylpiperidin-4-yl)carbamoyl]-4-methylpyrrolidin-3-yl]acetateHCID 866782492-(Bromomethyl)-1-chloro-3-(difluoromethyl)benzene

Product 1

HCID 71293848tert-Butyl 2-[(3R*,4S*)-1-{[2-chloro-6-(difluoromethyl)phenyl]methyl}-3-[(1-hexylpiperidin-4-yl)carbamoyl]-4-methylpyrrolidin-3-yl]acetateYield 50.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

N,N-Dimethylformamide (400 μl), 2-(bromomethyl)-1-chloro-3-(difluoromethyl)benzene obtained in Example 10f (24.9 mg, 0.0976 mmol) and potassium carbonate (20.2 mg, 0.146 mmol) were added to tert-butyl 2-[(3R*,4S*)-3-[(1-hexylpiperidin-4-yl)carbamoyl]-4-methylpyrrolidin-3-yl]acetate obtained in Example 10i (20 mg, 0.0488 mmol), followed by stirring at room temperature overnight. Ethyl acetate and water were added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. This was concentrated, and the resulting crude product was purified by column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=98/2->80/20) to give the title compound (14.4 mg, yield 50.2%).

Workup

  1. extractionwas extracted with ethyl acetate
  2. washThe organic layer was washed with brine
  3. dry with materialdried over magnesium sulfate
  4. concentrationThis was concentrated
  5. customthe resulting crude product was purified by column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=98/2->80/20)

Sources & evidence

ORD record
ord-ff26438a96dc41d5930fc8996e85f857
Source dataset
uspto-grants-2013_07
Patent number
US08476301B2

Reaction notes

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