Acetic Acid → 1,1-Dimethylethyl 4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinecarboxylate

HRID 419422Notes

Reaction equation

HRID 419422 reaction equation
O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:20][CH2:19]1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 516892Sodium BicarbonateHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5049666Sodium triacetoxyborohydride2×HCID 210826721-(2-Fluoroethyl)piperazine

Product 1

HCID 594526881,1-Dimethylethyl 4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinecarboxylateYield 82.9%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (15.7 g, 78.7 mmol) and 1-(2-fluoroethyl)piperazine (5.2 g, 39 mmol) were dissolved in 150 mL 1,2-DCE. HOAc (3.4 mL, 59 mmol) and TEA (5.5 mL, 39 mmol) were added followed by sodium triacetoxyborohydride (12.5 g, 59.0 mmol). The reaction was stirred for 3 h. TLC revealed the presence of starting material and so an additional 1.5 eq (12.5 g, 59.0 mmol) of sodium triacetoxyborohydride were added. Reaction was allowed to stir overnight. Saturated aqueous NaHCO3 solution was added carefully until the reaction stopped bubbling. Aqueous layer was then extracted with EtOAc (3×). Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was adsorbed onto silica gel and purified by flash chromatography to give title compound of step C (10.2 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39-4.57 (m, 2H), 3.90 (d, J=12.46 Hz, 2H), 2.61-2.73 (m, 2H), 2.47-2.61 (m, 2H), 2.36-2.47 (m, 8H), 2.24-2.35 (m, 1H), 1.69 (d, J=12.46 Hz, 2H), 1.37 (s, 9H), 1.14-1.26 (m, 2H).

Workup

  1. customReaction
  2. stirringto stir overnight
  3. customstopped bubbling
  4. extractionAqueous layer was then extracted with EtOAc (3×)
  5. dry with materialCombined organic layers were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. custompurified by flash chromatography

Sources & evidence

ORD record
ord-16a5459f51674f809ef0b69f6ef212b9
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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