Dimethylformamide → HCID 59568695, compound

HRID 1474247Notes

Reaction equation

HRID 1474247 reaction equation
[C:1]([O:7][CH3:8])(=O)CC([O-])=O.[H-].[Na+].[H][H].[Cl:13][C:14]1[C:15](F)=[C:16]([CH:19]=[CH:20][C:21]=1F)[C:17]#[N:18].CN([CH:27]=[O:28])C>CCOCC>[Cl:13][C:14]1[C:15]([O:28][CH3:27])=[C:16]([C:17]#[N:18])[CH:19]=[CH:20][C:21]=1[CH:1]1[O:7][CH2:8]1

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 3801157Monomethyl malonateHCID 193739123-Chloro-2,4-difluorobenzonitrileHCID 178418361HCID 178418361, compound

Product 1

HCID 59568695HCID 59568695, compound

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

t-Butyl, methyl malonate (7.5 g, 43 mmol) in DMF (50 mL) was cooled in an ice bath before NaH (60% in mineral oil, 1.0 g, 42 mmol) was added portionwise over 5 minutes with hydrogen evolution. The suspension was allowed to warm to RT for 30 minutes at which time everything was in solution. 3-Chloro-2,4-difluorobenzonitrile (5.0 g, 28.8 mmol) was added as a solid and the reaction was heated to 90° C. for 4 hours and then at RT for 12 hours. TLC (15% ethyl acetate/hexanes) indicated still some starting material but mostly product at a slightly lower Rf. The reaction was diluted with ether and quenched into water containing 2N HCl. The mixture was extracted twice with ether and the ether layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was taken up in 1:1 methanol:dichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted to re-esterify any acid. The excess diazomethane was quenched with acetic acid and the mixture was reconcentrated. The product mixture was separated by flash chromatogrphy (5-10% ethyl acetate/hexanes, then 10-20%) to afford first some recovered starting material, then a mixture of product and isomeric t-butyl, methyl (R,S)-2-(2-chloro-6-cyano-3-fluorophenyl)malonate by NMR (900 mg), followed by clean title product isomer.

Workup

  1. temperaturethe reaction was heated to 90° C. for 4 hours
  2. customquenched into water containing 2N HCl
  3. extractionThe mixture was extracted twice with ether
  4. washthe ether layers were washed with brine
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated in vacuo
  7. additiondichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color
  8. customThe excess diazomethane was quenched with acetic acid
  9. customThe product mixture was separated by flash chromatogrphy (5-10% ethyl acetate/hexanes
  10. custom10-20%) to afford first some recovered

Sources & evidence

ORD record
ord-f2e768bce4624fdb84b6bebc694154d5
Source dataset
uspto-grants-2015_04
Patent number
US09018211B2

Reaction notes

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