4-Bromo-2-fluoroaniline → 2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

HRID 15938

Reaction equation

HRID 15938 reaction equation
C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=1[F:21])=[O:4].BrC1C=CC(N)=C(F)C=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC(C1C=CC(=O)N(C)C=1Cl)=O>C1COCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:6]2[N:7]([CH3:12])[C:8](=[O:11])[CH:9]=[CH:10][C:5]=2[C:3]([OH:4])=[O:2])=[C:15]([F:21])[CH:16]=1

Participants

6

Reactant 4

HCID 1230504-Bromo-2-fluoroanilineHCID 2733832Lithium HexamethyldisilazideHCID 57442171Methyl 2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylateHCID 66673525Methyl 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Product 1

HCID 576369362-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acidYield 65%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

Preparation of 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester: To a solution of 4-bromo-2-fluorophenylamine (0.192 g, 1.01 mmol) in THF (5 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (1.50 mL, 1.50 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. 2-Chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.202 g, 1.00 mmol) was then added dropwise as a solution in THF (5 mL) and the reaction mixture was stirred for one hour at −78° C. The reaction mixture was quenched by the addition of H2O and the pH was adjusted to pH 7 with saturated NH4Cl and then diluted with EtOAc. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave 0.232 g (65%) pure desired product as a white crystalline solid.

Workup

  1. stirringthe reaction mixture was stirred for one hour at −78° C
  2. customThe reaction mixture was quenched by the addition of H2O
  3. additiondiluted with EtOAc
  4. customThe organic layer was separated
  5. washwashed with saturated NaCl
  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-a7bb07a7451d4d20b7ec436a7e36c3c0
Source dataset
uspto-grants-2010_06
Patent number
US07732616B2

Linked notes

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