Sodium hydride → 3-Tert-butyl-isoxazole-5-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl)-amide

HRID 570256Notes

Reaction equation

HRID 570256 reaction equation
[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[C:14]([C:18]1[CH:22]=[C:21]([C:23](O)=[O:24])[O:20][N:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:23]([C:21]2[O:20][N:19]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:22]=2)=[O:24])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 65578Oxalyl chlorideHCID 120977456-Bromo-3-nitro-2-pyridinamineHCID 216484973-Tert-butyl-1,2-oxazole-5-carboxylic acid

Product 1

HCID 866574273-Tert-butyl-isoxazole-5-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl)-amide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 6-bromo-3-nitro-pyridin-2-ylamine (500 mg, 2.29 mmol) in THF (10 mL) was treated with NaH (275 mg, 6.88 mmol) at room temperature for 1 h. Simultaneously a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (524 mg, 3.10 mmol, prepared as described in Example I) in DCM (10 mL) was treated with oxalyl chloride (270 μL, 3.10 mmol) and DMF (2 drops) at room temperature for 1 h. The acid chloride solution was concentrated to dryness in vacuo, taken up in THF (10 mL), and added to the sodium anilide solution. The resulting mixture was stirred at room temperature for 15 min, quenched with saturated aqueous NH4Cl (50 mL), and extracted twice with EtOAc (50 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system: Flow rate=25 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 1 min, then 1:99 to 3:17 v/v over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid (6-bromo-3-nitro-pyridin-2-yl)-amide as a solid. 1H-NMR (400 MHz, CDCl3) δ: 10.85 (br. s., 1H), 8.37 (d, J=8.6 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.03 (s, 1H), 1.39 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C13H13BrN4O4: 369.0 (M+H); Measured: 369.0.

Workup

  1. concentrationThe acid chloride solution was concentrated to dryness in vacuo
  2. additionadded to the sodium anilide solution
  3. customquenched with saturated aqueous NH4Cl (50 mL)
  4. extractionextracted twice with EtOAc (50 mL)
  5. dry with materialThe combined extracts were dried over MgSO4
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified on a 40-g SEPRA Si 50 SPE column (Isco system
  8. waitEluent=EtOAc/hexanes, 1:99 v/v for 1 min

Sources & evidence

ORD record
ord-de393fdadd46430d9d04bb9bbc836946
Source dataset
uspto-grants-2015_05
Patent number
US09023846B2

Reaction notes

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