N-Piperidinoethanol → 4-Fluoro-2-nitro-5-(2-piperidin-1-ylethoxy)-phenylamine

HRID 2274386Notes

Reaction equation

HRID 2274386 reaction equation
[N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:12][C:13]1[C:18](F)=[CH:17][C:16]([NH2:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:12][C:13]1[C:18]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:17][C:16]([NH2:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=1

Participants

7

Reactant 4

HCID 18232N-PiperidinoethanolHCID 24758Sodium hydrideHCID 1571514,5-Difluoro-2-nitroanilineHCID 516892Sodium Bicarbonate

Product 1

HCID 688421034-Fluoro-2-nitro-5-(2-piperidin-1-ylethoxy)-phenylamineYield 54.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
22 °C

Procedure

A solution of 1.11 g of 2-piperidin-1-ylethanol in 20 mL of N,N-dimethylformamide (DMF) is cooled to 0° C. with an ice bath. 689 mg of sodium hydride (60% in suspension in oil) are added in small portions. The suspension obtained is added dropwise to a suspension containing 500 mg of 4,5-difluoro-2-nitrophenylamine and 724 mg of sodium bicarbonate in 15 mL of DMF. The reaction medium is stirred at ambient temperature (22° C.) for 2 hours and then heated at 90° C. for 1 hour. The solvent is concentrated to dryness, then the reaction crude is taken up in 30 mL of ethyl acetate and the organic phase is washed with 2×30 mL of distilled water and 1×30 mL of a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate and the solvent is evaporated off under vacuum in a rotary evaporator. The crude is triturated in ethyl ether and the solid is filtered through sintered glass and rinsed with ethyl ether. 443 mg of 4-fluoro-2-nitro-5-(2-piperidin-1-ylethoxy)-phenylamine in the form of a red solid are isolated. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.37 (m, 2H); 1.48 (m, 4H); 2.43 (m, 4H); 2.69 (t, J=6.5 Hz, 2H); 4.13 (t, J=6.5 Hz, 2H); 6.65 (d, J=8.0 Hz, 1H); 7.48 (broad s, 2H); 7.75 (d, J=12.0 Hz, 1H).

Workup

  1. customThe suspension obtained
  2. additionis added dropwise to a suspension
  3. temperatureheated at 90° C. for 1 hour
  4. concentrationThe solvent is concentrated to dryness
  5. customthe reaction crude
  6. washthe organic phase is washed with 2×30 mL of distilled water and 1×30 mL of a saturated aqueous solution of sodium chloride
  7. dry with materialThe organic phase is dried over magnesium sulfate
  8. customthe solvent is evaporated off under vacuum in a rotary evaporator
  9. customThe crude is triturated in ethyl ether
  10. filtrationthe solid is filtered through sintered glass
  11. washrinsed with ethyl ether

Sources & evidence

ORD record
ord-b76d0cb034b4469ea9dce16bdb7ee073
Source dataset
uspto-grants-2015_09
Patent number
US09126969B2

Reaction notes

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