Lithium Hexamethyldisilazide → 2-(2-Fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-hydroxyethoxy)-amide

HRID 2387381Notes

Reaction equation

HRID 2387381 reaction equation
C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:17])[C:11]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[O:9])=C.COC(C1C=CC(=O)N(C)C=1NC1C=CC(C)=CC=1F)=O.C(OCCON)=C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH3:17])[C:11]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[O:9]

Participants

6

Reactant 4

HCID 2733832Lithium HexamethyldisilazideHCID 21867017O-(2-(Vinyloxy)ethyl)hydroxylamineHCID 598435712-(2-Fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl esterHCID 866723222-(2-Fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide

Product 1

HCID 112329322-(2-Fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-hydroxyethoxy)-amideYield 77%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Preparation of 2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide: To a solution of 2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.050 g, 0.17 mmol) in THF (1.5 mL) under N2 was added O-(2-vinyloxy-ethyl)-hydroxylamine (0.044 g, 0.43 mmol). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (0.86 mL, 0.86 mmol, 1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 40 minutes, the reaction mixture was quenched by the addition of NaHCO3 and partitioned between EtOAc and saturated NaCl. The layers were separated and the aqueous layer was reextracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/methanol, 20:1) gave 0.048 g (77%) pure desired product as an off-white foamy solid.

Workup

  1. temperatureThe reaction mixture was warmed to room temperature
  2. customthe reaction mixture was quenched by the addition of NaHCO3
  3. custompartitioned between EtOAc and saturated NaCl
  4. customThe layers were separated
  5. dry with materialThe combined organic extracts were dried (Na2SO4)
  6. concentrationconcentrated under reduced pressure
  7. customPurification by flash column chromatography (methylene chloride/methanol, 20:1)

Sources & evidence

ORD record
ord-88503ff270224862a2a4e0d30b8e7b50
Source dataset
uspto-grants-2012_09
Patent number
US08268852B2

Reaction notes

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