Sulfuric Acid → 4-Bromo-3-fluoro-6-nitro-2-(tetrahydrofuran-2-yl)aniline

HRID 2274365Notes

Reaction equation

HRID 2274365 reaction equation
[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11]C(=O)C(F)(F)F)=[C:4]([CH:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[C:3]=1[F:23].O1CCOCC1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([CH:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[C:3]=1[F:23]

Participants

6

Reactant 4

HCID 1118Sulfuric AcidHCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 86667936N-(4-bromo-3-fluoro-6-nitro-2-tetrahydrofuran-2-yl-phenyl)-2,2,2-trifluoro-acetamide

Product 1

HCID 866679354-Bromo-3-fluoro-6-nitro-2-(tetrahydrofuran-2-yl)anilineYield 98.6%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

A reaction flask was charged with N-(4-bromo-3-fluoro-6-nitro-2-tetrahydrofuran-2-yl-phenyl)-2,2,2-trifluoro-acetamide (18) (242.3 g, 604.1 mmol), 1,4-dioxane (1.212 L), aqueous 2 M sulfuric acid (362.4 mL, 724.9 mmol), and stirred at reflux for 5 days (HPLC showed 98% conversion). Allowed to cool, diluted with EtOAc, neutralized with saturated aqueous NaHCO3, separated the layers, and re-extracted the aqueous phase with EtOAc (2×). The combined organic phase was washed with brine (2×), dried over MgSO4, filtered and concentrated in vacuo giving 19 as a greenish brown solid (181.7 g, 94% yield; 95% HPLC purity). The product was carried to the next step without further purification. LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 305.20 (3.63 min). 1H NMR (300 MHz, CDCl3) δ 8.35 (d, J=7.3 Hz, 1H), 7.45 (s, 2H), 5.23-5.16 (m, 1H), 4.23-4.14 (m, 1H), 3.93-3.84 (m, 1H), 2.31-1.96 (m, 4H) ppm.

Workup

  1. temperatureat reflux for 5 days (HPLC showed 98% conversion)
  2. temperatureAllowed to cool
  3. customseparated the layers
  4. extractionre-extracted the aqueous phase with EtOAc (2×)
  5. washThe combined organic phase was washed with brine (2×)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-8c992b76574e4d1ba024313fe4dd2067
Source dataset
uspto-grants-2015_09
Patent number
US09125922B2

Reaction notes

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