Sodium hydride → 3-Tert-butyl-isoxazole-5-carboxylic acid [3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide

HRID 1191209Notes

Reaction equation

HRID 1191209 reaction equation
[N+:1]([C:4]1[C:5]([NH2:24])=[N:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])([O-:3])=[O:2].[H-].[Na+].[C:27]([C:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[O:33][N:32]=1)([CH3:30])([CH3:29])[CH3:28].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[C:5]([NH:24][C:36]([C:34]2[O:33][N:32]=[C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:35]=2)=[O:37])=[N:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:21])[F:22])=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])([O-:3])=[O:2]

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 65578Oxalyl chlorideHCID 216484973-Tert-butyl-1,2-oxazole-5-carboxylic acidHCID 866574103-Nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine

Product 1

HCID 866574113-Tert-butyl-isoxazole-5-carboxylic acid [3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (64.0 mg, 0.182 mmol, prepared as described in STEP D above) in THF (10 mL) was treated with NaH (21.9 mg, 0.547 mmol, 60% dispersion in oil), and the resulting mixture was allowed to stir at room temperature for 1 h. Simultaneously, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (40.1 mg, 0.237 mmol, prepared as described in Example I above) in anhydrous DCM (10 mL) was treated with oxalyl chloride (20.7 μL, 0.237 mmol) and DMF (2 drops), and the resulting mixture was stirred at room temperature for 1 h. Volatile components were removed in vacuo, and the residue was taken up in anhydrous THF (6 mL). The above-prepared acid chloride solution was added to the sodium anilide solution above, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted twice with EtOAc (25 mL). The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid [3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as an off-white solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C21H16N4O4F6: 503.1 (M+H); Measured: 503.2.

Workup

  1. stirringthe resulting mixture was stirred at room temperature for 1 h
  2. customVolatile components were removed in vacuo
  3. additionThe above-prepared acid chloride solution was added to the sodium anilide solution above, and the mixture
  4. stirringwas stirred at room temperature for 1 h
  5. customThe mixture was quenched with saturated aqueous NH4Cl (20 mL)
  6. extractionextracted twice with EtOAc (25 mL)
  7. customThe residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=15 mL/min
  8. waitEluent=EtOAc-hexanes, 1:99 for 10 min

Sources & evidence

ORD record
ord-ff324a6c5f84459b8a9de6f1c2afdca8
Source dataset
uspto-grants-2014_03
Patent number
US08680098B2

Reaction notes

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