Potassium Carbonate → 2-{5-[1-(3,4-Difluoro-phenyl)-piperidin-3-yl]-4'-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester

HRID 889743Notes

Reaction equation

HRID 889743 reaction equation
[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].[F:47][C:48]1[CH:53]=[CH:52][C:51](I)=[CH:50][C:49]=1[F:55]>CS(C)=O.[I].[Cu]>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:51]3[CH:52]=[CH:53][C:48]([F:47])=[C:49]([F:55])[CH:50]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 145742L-ProlineHCID 27244441,2-Difluoro-4-iodobenzeneHCID 576660204-Methyl-2-(5-piperidin-3-yl-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester

Product 1

HCID 576660332-{5-[1-(3,4-Difluoro-phenyl)-piperidin-3-yl]-4'-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl esterYield 37%

Reagents, catalysts & solvents 2

HCID 178505378HCID 178505378, compoundCatalystHCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (110 mg, 0.25 mmol) in dimethylsulfoxide (0.2 ml) was added L-proline (4.4 mg, 0.04 mmol), potassium carbonate (52.5 mg, 0.38 mmol), and copper iodine (3.6 mg, 0.02 mmol). The reaction was degassed under nitrogen and 1,2-difluoro-4-iodobenzene (45.4 mg, 0.19 mmol), was added, the reaction was again degassed and then heated to 90° C. The reaction was stirred over 48 hours. The reaction was partitioned between EtOAc/H2O, washed with H2O (3×) and brine (1×). Purification by silica gel chromatography (Isco) gave the desired product, (39 mg, 37%). Calcd for C32H34F5NO2 (M+H) 559.60, Found 560.4.

Workup

  1. customThe reaction was degassed under nitrogen
  2. customthe reaction was again degassed
  3. customThe reaction was partitioned between EtOAc/H2O
  4. washwashed with H2O (3×) and brine (1×)
  5. customPurification by silica gel chromatography (Isco)

Sources & evidence

ORD record
ord-8bcb4319f12f4858a66be302d7733675
Source dataset
uspto-grants-2012_08
Patent number
US08252935B2

Reaction notes

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