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

HRID 419360Notes

Reaction equation

HRID 419360 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+]>C1COCC1.CO.O.O.O.O.O.O.[Ni](Cl)Cl>[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 11791229Dichloronickel;hexahydrateCatalyst2×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 THF (200 mL) and MeOH (300 mL) was cooled to 0° C. Nickel(II) chloride hexahydrate (5.18 g, 21.80 mmol) was added in one portion. The solution was stirred for 30 min followed by portion-wise addition of NaBH4 (3.29 g, 87.00 mmol). Prior to warming the reaction to rt additional nickel(II) chloride hexahydrate (5.18 g, 21.80 mmol) and NaBH4 (3.29 g, 87.00 mmol) was added to the reaction. The solvent was removed in vacuo and the residue was taken up in DCM, filtered through Celite®, and washed with EtOAc. Purification by flash chromatography provided the title compound of step E (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, 2H), 1.76 (d, J=12.1 Hz, 2H), 2.12-2.20 (m, 1H), 2.35-2.45 (m, 10H), 2.53 (dt, JHF=28.6 Hz, J=4.9 Hz, 2H), 3.37 (d, J=12.1 Hz, 2H), 3.68 (s, 3H), 4.14 (br. s., 2H), 4.47 (dt, JHF=47.9 Hz, J=4.94 Hz, 2H), 6.24 (dd, J=8.2, 2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 6.45 (d, J=8.4 Hz, 1H).

Workup

  1. temperaturePrior to warming
  2. additionwas added to the reaction
  3. customThe solvent was removed in vacuo
  4. filtrationfiltered through Celite®
  5. washwashed with EtOAc
  6. customPurification by flash chromatography

Sources & evidence

ORD record
ord-f22ec1773dc142c0a00cb789f91904fd
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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