Lithium Hexamethyldisilazide → 4-Fluoro-2-(2-fluoro-4-methylsulfanyl-phenylamino)-3-formyl-benzoic acid

HRID 79026Notes

Reaction equation

HRID 79026 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C[O:22][CH:23](OC)[C:24]1[C:25](F)=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27]([OH:29])=[O:28]>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:10][C:3]2[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=2[F:1])[C:24]=1[CH:23]=[O:22]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 220256172-Fluoro-4-(methylsulfanyl)anilineHCID 583744063-Dimethoxymethyl-2,4-difluoro-benzoic acid

Product 1

HCID 866562374-Fluoro-2-(2-fluoro-4-methylsulfanyl-phenylamino)-3-formyl-benzoic acidYield 10.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a cold (−78° C.) solution of 2-fluoro-4-methylsulfanyl-phenyl amine (1.55 g, 9.9 mmol) in THF (15 mL) was added LHMDS (9.9 mL, 1.0 M solution in hexanes 9.9 mmol) dropwise so as to maintain the temperature below −65° C. After stirring for 30 minutes a solution of 3-dimethoxymethyl-2,4-difluoro-benzoic acid (700 mg, 3.0 mmol) in THF (15 mL) was added dropwise, the resultant mixture stirred cold for 3 hours then allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched by the addition of aqueous ammonium chloride and the products partitioned between ethyl acetate and water. The aqueous layer was separated and acidified to pH 1 (concentrated HCl) and then extracted twice with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated with diethyl ether to give the title compound as a yellow solid (105 mg, 10% yield). 1H NMR (CDCl3, 400 MHz) 10.26-10.23 (2 H, m), 8.04 (1 H, dd, J=8.76, 6.31 Hz), 7.03-6.96 (2H, m), 6.91 (1 H, d, J=1.96 Hz), 6.65 (1 H, dd, J=10.02, 8.77 Hz), 2.42 (3 H, s).

Workup

  1. temperatureto maintain the temperature below −65° C
  2. additionwas added dropwise
  3. customThe reaction was quenched by the addition of aqueous ammonium chloride
  4. customthe products partitioned between ethyl acetate and water
  5. customThe aqueous layer was separated
  6. extractionextracted twice with ethyl acetate
  7. dry with materialThe combined organic extracts were dried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe resultant residue was triturated with diethyl ether

Sources & evidence

ORD record
ord-15e95f4431e04b0aa2e3f89a56359bb9
Source dataset
uspto-grants-2014_09
Patent number
US08841462B2

Reaction notes

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