Tetrahydrofuran → (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N'-(tetrahydro-2H-pyran-2-yloxy)propanediamide

HRID 1519703Notes

Reaction equation

HRID 1519703 reaction equation
I[C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([CH3:25])[C@:9]([CH3:24])([C:14]([NH:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[O:15])[C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)#[CH:29].C1COCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(OCC)(=O)C>[CH:34]([C:33]1[CH:36]=[CH:37][C:30]([C:28]#[C:29][C:2]2[CH:27]=[CH:26][C:5]([C:6]([N:8]([CH3:25])[C@:9]([CH3:24])([C:14]([NH:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[O:15])[C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=2)=[CH:31][CH:32]=1)=[O:35]

Participants

7

Reactant 3

HCID 8028TetrahydrofuranHCID 27716454-EthynylbenzaldehydeHCID 86679252HCID 86679252, compound2×

Product 1

HCID 86679270(2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N'-(tetrahydro-2H-pyran-2-yloxy)propanediamideYield 76%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8857Ethyl AcetateSolvent

Procedure

TEA (10 mL) was added dropwise to a mixture of (2S)-2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 15, 12 g), 4-ethynylbenzaldehyde (4.1 g), PdCl2(PPh3)2 (0.85 g), CuI (0.46 g), and THF (60 mL) at room temperature in a nitrogen atmosphere, and the mixture was stirred for 2 hours and 15 minutes at room temperature. Ethyl acetate (0.20 L), OH type silica gel (12 g), cellpure (5.9 g) and activated carbon (0.60 g) were added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (ethyl acetate/hexane=50/50, followed by gradient elution with chloroform/acetone=100/0→80/20). Then, ethyl acetate and IPE were added to the resulting solid, and the solid was filtered off and washed with IPE to obtain (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow brown solid) (9.0 g, 76%).

Workup

  1. filtrationthe insolubles were filtered out
  2. concentrationthe filtrate was concentrated under reduced pressure
  3. customThe resulting residue was purified by OH type silica gel column chromatography (ethyl acetate/hexane=50/50, followed by gradient elution with chloroform/acetone=100/0→80/20)
  4. additionThen, ethyl acetate and IPE were added to the resulting solid
  5. filtrationthe solid was filtered off
  6. washwashed with IPE

Sources & evidence

ORD record
ord-5ecd9a05351f4316887588155e505ae7
Source dataset
uspto-grants-2015_07
Patent number
US09073821B2

Reaction notes

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