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

HRID 1191201Notes

Reaction equation

HRID 1191201 reaction equation
[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH2:12])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[N:4]=1.[H-].[Na+].[C:25]([C:29]1[CH:33]=[C:32]([C:34](O)=[O:35])[O:31][N:30]=1)([CH3:28])([CH3:27])[CH3:26].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH:12][C:34]([C:32]2[O:31][N:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:33]=2)=[O:35])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[N:4]=1

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 65578Oxalyl chlorideHCID 216484973-Tert-butyl-1,2-oxazole-5-carboxylic acidHCID 674098312-Methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine

Product 1

HCID 674099163-Tert-butyl-isoxazole-5-carboxylic acid [2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine (163 mg, 0.519 mmol, prepared as described in STEP B above) in THF (10 mL) was treated with NaH (62.2 mg, 1.56 mmol, 60% dispersion in oil), and the mixture was allowed to stir at room temperature for 1 h. Simultaneously, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (114 mg, 0.674 mmol, prepared as described in Example I above) in anhydrous DCM (10 mL) was treated with oxalyl chloride (58.8 μL, 0.674 mmol) and DMF (2 drops), and the 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 [2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 10.62 (s, 1H), 8.39 (s, 1H), 7.82 (d, J=7.3 Hz, 1H), 7.63-7.69 (m, 1H), 7.58-7.63 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 4.09 (s, 3H), 1.38 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H19N4O5F3: 465.1 (M+H); Measured: 465.1.

Workup

  1. stirringthe 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-83d0bdfcc796498bb955854543763638
Source dataset
uspto-grants-2014_03
Patent number
US08680098B2

Reaction notes

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