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

HRID 2068934Notes

Reaction equation

HRID 2068934 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-e5f9232f6a0347b695c22bbe856cb2b3
Source dataset
uspto-grants-2012_10
Patent number
US08299076B2

Reaction notes

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