Sodium borohydride → 4-[4-[4-(2-Fluoroethyl)-1-piperazinyl]-1-piperidinyl]-2-(methyloxy)aniline

HRID 1014269Notes

Reaction equation

HRID 1014269 reaction equation
[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[BH4-].[Na+]>O1CCCC1.CO.[Ni+2]>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:25][CH3:26])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1

Participants

6

Reactant 2

HCID 4311764Sodium borohydride2×HCID 598602761-(2-Fluoroethyl)-4-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine

Product 1

HCID 598602604-[4-[4-(2-Fluoroethyl)-1-piperazinyl]-1-piperidinyl]-2-(methyloxy)anilineYield 92.2%

Reagents, catalysts & solvents 3

HCID 934Nickel cationCatalyst2×HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of 1-(2-fluoroethyl)-4-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (15.94 g, 43.50 mmol) in tetrahydrofuran (200 mL) and methanol (300 mL) was cooled to 0° C. Nickel(II) chloridehexahydrate (5.18 g, 21.80 mmol) was added in one portion. The solution was stirred for 30 minutes followed by portion-wise addition of sodium borohydride (3.29 g, 87.00 mmol). Prior to warming the reaction to room temperature additional nickel (II) chloridehexahydrate (5.18 g, 21.80 mmol) and sodium borohydride (3.29 g, 87.00 mmol) were added to the reaction. The solvent was removed in vacuo and the residue was taken up in dichloromethane, filtered through celite, and washed with ethyl acetate. Purification by flash chromatography provided 4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)aniline (13.46 g, 40.10 mmol, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (qd, J=11.9, 3.6 Hz, 2 H) 1.76 (d, J=12.1 Hz, 2 H) 2.12-2.20 (m, 1 H) 2.35-2.45 (m, 10 H) 2.53 (dt, JHF=28.6 Hz, J=4.9 Hz, 2 H) 3.37 (d, J=12.1 Hz, 2 H) 3.68 (s, 3 H) 4.14 (br. s., 2 H) 4.47 (dt, JHF=47.9 Hz, J=4.94 Hz, 2 H) 6.24 (dd, J=8.2, 2.4 Hz, 1 H) 6.43 (d, J=2.4 Hz, 1 H) 6.45 (d, J=8.4 Hz, 1 H).

Workup

  1. temperaturePrior to warming
  2. additionwere added to the reaction
  3. customThe solvent was removed in vacuo
  4. filtrationfiltered through celite
  5. washwashed with ethyl acetate
  6. customPurification by flash chromatography

Sources & evidence

ORD record
ord-5c5d9c9241b64dc6827152b795320d18
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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