Ethyl Acetate → N1-(cyanomethyl)-N2-{(S)-(4-fluorophenyl)[4'-(methylsulfonyl)-1,1'-biphenyl-4-yl]methyl}-L-leucinamide

HRID 1880536Notes

Reaction equation

HRID 1880536 reaction equation
[C:1]([CH2:3][NH:4][C:5](=[O:27])[C@@H:6]([NH:11][C@@H:12]([C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([CH2:3][NH:4][C:5](=[O:27])[C@H:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:11][C@H:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][C:23]([C:35]2[CH:36]=[CH:37][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=2)=[CH:22][CH:21]=1)#[N:2]

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 27595302-(4-Methanesulfonylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 86590549(2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino)-4-methylpentanoic acid cyanomethylamide

Product 1

HCID 59715505N1-(cyanomethyl)-N2-{(S)-(4-fluorophenyl)[4'-(methylsulfonyl)-1,1'-biphenyl-4-yl]methyl}-L-leucinamide

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
82.5 °C

Procedure

A mixture of (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentanoic acid cyanomethylamide (0.27 g, 0.636 mmol), 2-(4-methanesulfonylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.177 g, 0.626 mmol) and potassium carbonate (0.703 mL of a 2.0 M solution) in DMF (5 mL) was degassed. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (27 mg, 0.038 mmol) was added. The reaction mixture was heated in a sealed tube at 80-85° C. for 3 hours and cooled to room temperature. Ethyl acetate (15 mL) was added. The reaction mixture was washed with brine (10 mL), saturated aqueous NaHCO3 (10 mL), brine (10 mL), filtered through a plug of MgSO4/DARCO activated charcoal/silica gel, concentrated in vacuo, and purified by preparative TLC (Chromatotron® using 5% ethyl acetate/dichloromethane to elute to give N1-(cyanomethyl)-N2-{(S)-(4-fluorophenyl)[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]methyl}-L-leucinamide.

Workup

  1. customwas degassed
  2. temperaturecooled to room temperature
  3. washThe reaction mixture was washed with brine (10 mL), saturated aqueous NaHCO3 (10 mL), brine (10 mL)
  4. filtrationfiltered through a plug of MgSO4/DARCO
  5. concentrationconcentrated in vacuo
  6. custompurified by preparative TLC (Chromatotron®
  7. washto elute

Sources & evidence

ORD record
ord-9e694589b4b14751bfd347acd31f82be
Source dataset
uspto-grants-2012_11
Patent number
US08318748B2

Reaction notes

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