Lithium Hexamethyldisilazide → Methyl 5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylate

HRID 15981Notes

Reaction equation

HRID 15981 reaction equation
[F:1][C:2]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:22]1[N:23]([CH3:34])[C:24](=[O:33])[C:25]([F:32])=[CH:26][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>C1COCC1>[F:32][C:25]1[C:24](=[O:33])[N:23]([CH3:34])[C:22]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([S:9][CH3:10])=[CH:8][C:2]=2[F:1])=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 220256172-Fluoro-4-(methylsulfanyl)anilineHCID 66674383Methyl 2-chloro-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Product 1

HCID 66673936Methyl 5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylateYield 77%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of 2-fluoro-4-(methylthio)aniline (0.236 g, 1.50 mmol) in THF (10 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (3.42 ml, 3.42 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. after the addition was complete. Methyl 2-chloro-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.300 g, 1.37 mmol) was then added dropwise as a solution in THF (5 mL) and the reaction mixture was stirred for 30 minutes at −78° C. The reaction was quenched by the addition of 1 M HCl until the pH of the reaction mixture was 5, and then diluted with EtOAc and saturated NaCl. The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave pure desired product (0.359 g, 75%) as a white solid.

Workup

  1. additionafter the addition
  2. stirringthe reaction mixture was stirred for 30 minutes at −78° C
  3. customThe reaction was quenched by the addition of 1 M HCl until the pH of the reaction mixture
  4. additiondiluted with EtOAc and saturated NaCl
  5. customThe organic layer was separated
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated under reduced pressure
  8. customPurification by flash column chromatography (methylene chloride/EtOAc, 15:1)

Sources & evidence

ORD record
ord-0d7ae6f48617428a82fc6300cafd3ff8
Source dataset
uspto-grants-2010_06
Patent number
US07732616B2

Reaction notes

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