Lithium Hexamethyldisilazide → 4-(2-Fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide

HRID 1510567Notes

Reaction equation

HRID 1510567 reaction equation
[CH:1]1([CH2:4][O:5][NH2:6])[CH2:3][CH2:2]1.C([O:9][C:10]([C:12]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[F:26])=[C:16]([CH3:27])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=1[CH3:30])=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:1]1([CH2:4][O:5][NH:6][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[F:26])=[C:16]([CH3:27])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=2[CH3:30])=[O:9])[CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 11182605O-(cyclopropylmethyl)hydroxylamineHCID 666746314-(2-Fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester

Product 1

HCID 576369104-(2-Fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amideYield 40.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

O-cyclopropylmethyl-hydroxylamine (0.046 g, 0.527 mmol) was added to a solution of 4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.070 g, 0.211 mmol) in THF (2 mL). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (1.05 mL, 1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 1 hour, the reaction was quenched by addition of a saturated aqueous solution of NaHCO3 and partitioned between EtOAc and brine. The aqueous layer was reextracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated. Purification by flash column chromatography (30:1 methylene chloride/MeOH) gave 0.032 g (40%) desired product as a yellow solid; MS ESI (+) m/z 374 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ 6.91 (d, 1H), 6.83 (d, 1H), 6.63 (t, 1H), 3.59 (s, 3H), 3.47 (d, 2H), 2.41 (s, 3H), 2.27 (s, 3H), 1.86 (s, 3H) 0.99 (m, 1H) 0.48 (m, 2H) 0.18 (m, 2H). 19F (376 MHz, CD3OD)-132.1 (s, 1F).

Workup

  1. temperatureThe reaction mixture was warmed to room temperature
  2. customthe reaction was quenched by addition of a saturated aqueous solution of NaHCO3
  3. custompartitioned between EtOAc and brine
  4. dry with materialThe combined organic extracts were dried (Na2SO4)
  5. concentrationconcentrated
  6. customPurification by flash column chromatography (30:1 methylene chloride/MeOH)

Sources & evidence

ORD record
ord-7c71b1ae329143039727d901e1c5d992
Source dataset
uspto-grants-2012_07
Patent number
US08211921B2

Reaction notes

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