Methyl cyanoacetate → Dimethyl 2-cyano-3-(2,4,5-trifluorophenyl)pentanedioate

HRID 1362892Notes

Reaction equation

HRID 1362892 reaction equation
C[O-].[Na+].[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[N:5].[F:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[CH:20]=[CH:21][C:22]([O:24][CH2:25]C)=[O:23]>CO>[C:4]([CH:6]([CH:20]([C:13]1[CH:14]=[C:15]([F:19])[C:16]([F:18])=[CH:17][C:12]=1[F:11])[CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:7]([O:9][CH3:10])=[O:8])#[N:5]

Participants

5

Reactant 3

HCID 7747Methyl cyanoacetateHCID 10942334Sodium MethoxideHCID 66790812HCID 66790812, compound

Product 1

HCID 57447907Dimethyl 2-cyano-3-(2,4,5-trifluorophenyl)pentanedioate

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Procedure

To a solution of 15 mL (64 mmol, 25% in methanol) of sodium methoxide in 200 mL of methanol was added 5.5 mL (62 mmol) of methyl cyanoacetate and the mixture was stirred at ambient temperature for 30 min. To this solution was added 14 g (62 mmol) of the product of Step A in 50 mL of methanol and the resulting yellow mixture was heated to reflux for 6 h. The mixture was then quenched carefully at ambient temperature with 1N aqueous hydrochloric acid (100 mL) and concentrated to remove methanol. The resulting mixture was extracted with three 300-mL portions of ethyl acetate, and the organic phases combined and washed sequentially with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous brine (100 mL each). The organic phase was then dried over magnesium sulfate, filtered, and evaporated in vacuo to yield a viscous oil. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 25% ethyl acetate/hexanes gradient) to give the title compound as a mixture of stereoisomers. 1H NMR (500 MHz, CDCl3): δ 7.33-6.96 (m, 2H), 4.23-3.93 (series of m, 2H), 3.81-3.67 (series of s, 6H), 3.05-2.84 (m, 2H).

Workup

  1. temperaturethe resulting yellow mixture was heated
  2. temperatureto reflux for 6 h
  3. customThe mixture was then quenched carefully at ambient temperature with 1N aqueous hydrochloric acid (100 mL)
  4. concentrationconcentrated
  5. customto remove methanol
  6. extractionThe resulting mixture was extracted with three 300-mL portions of ethyl acetate
  7. washwashed sequentially with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous brine (100 mL each)
  8. dry with materialThe organic phase was then dried over magnesium sulfate
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customto yield a viscous oil
  12. customThe crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 25% ethyl acetate/hexanes gradient)

Sources & evidence

ORD record
ord-7588552d195c4bd3906fae9671a77046
Source dataset
uspto-grants-2011_02
Patent number
US07884104B2

Reaction notes

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