Ethyl 3-(trimethylsilyl)propynoate → 4-[1-[6-(2,4-Difluorophenyl)pyridin-2-yl]-2-oxo-4-(trimethylsilyl)but-3-yn-1-yl]-3,5-difluorobenzonitrile

HRID 1360694Notes

Reaction equation

HRID 1360694 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH2:15][C:16]2[C:23]([F:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[F:25])[CH:12]=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:36][Si:37]([CH3:46])([CH3:45])[C:38]#[C:39][C:40](OCC)=[O:41]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH:15]([C:16]2[C:23]([F:24])=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=2[F:25])[C:40](=[O:41])[C:39]#[C:38][Si:37]([CH3:46])([CH3:45])[CH3:36])[CH:12]=[CH:11][CH:10]=1

Participants

5

Reactant 3

HCID 568601Ethyl 3-(trimethylsilyl)propynoateHCID 2733832Lithium HexamethyldisilazideHCID 577003784-{[6-(2,4-Difluorophenyl)pyridin-2-yl]methyl}-3,5-difluorobenzonitrile

Product 1

HCID 577003654-[1-[6-(2,4-Difluorophenyl)pyridin-2-yl]-2-oxo-4-(trimethylsilyl)but-3-yn-1-yl]-3,5-difluorobenzonitrileYield 84.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 4-{[6-(2,4-difluorophenyl)pyridin-2-yl]methyl}-3,5-difluorobenzonitrile (from Step E above, 6.10 g, 17.83 mmol) in THF (200 mL) was added lithium bis(trimethylsilyl)amide (53.49 mL, 1.0 M in THF) at −78° C. After stirring 1¼ h at −78° C., ethyl 3-(trimethylsilyl)prop-2-ynoate (4.01 mL, 21.37 mmol) was added to the reaction mixture. The reaction continued to stir at −78° C. for 1 hr and was warmed to −20° C. until the reaction was complete via LMCS. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with 1N HCl (1×), water, brine, dried over MgSO4, and condensed. The crude material was purified via silica gel chromatography (hexanes/methylene chloride) to give the title compound (7.0 g).

Workup

  1. stirringto stir at −78° C. for 1 hr
  2. temperaturewas warmed to −20° C. until the reaction
  3. customThe reaction was quenched with aqueous NH4Cl
  4. extractionextracted with EtOAc (3×)
  5. washThe combined organic layers were washed with 1N HCl (1×), water, brine
  6. dry with materialdried over MgSO4, and condensed
  7. customThe crude material was purified via silica gel chromatography (hexanes/methylene chloride)

Sources & evidence

ORD record
ord-7f5634764edf4596ad4c61a66ac13a40
Source dataset
uspto-grants-2011_02
Patent number
US07879875B2

Reaction notes

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