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

HRID 419363Notes

Reaction equation

HRID 419363 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.Cl.Cl.[F:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([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)[CH2:22][CH2:21]1

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 516892Sodium BicarbonateHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5049666Sodium triacetoxyborohydrideHCID 665456881-(2-Fluoroethyl)piperazine dihydrochloride

Product 1

HCID 594526881,1-Dimethylethyl 4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinecarboxylateYield 94.6%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (38.9 g, 195 mmol) and 1-(2-fluoroethyl)piperazine dihydrochloride (20 g, 97 mmol) were dissolved in 485 mL 1,2-DCE. TEA (81.5 mL, 585 mmol) was added and the reaction was stirred for 30 min. HOAc (8.4 mL, 146 mmol) was added and the reaction was stirred for an additional 30 min followed by the addition of sodium triacetoxyborohydride (49.6 g, 234 mmol). The reaction was stirred overnight. Saturated aqueous NaHCO3 solution was added carefully until the reaction stopped bubbling. Aqueous layer was then extracted with DCM (1×) and EtOAc (3×). Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was absorbed onto silica gel and purified by flash chromatography to give title compound of step C (28.95 g, 94%). 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. stirringthe reaction was stirred for an additional 30 min
  2. stirringThe reaction was stirred overnight
  3. customstopped bubbling
  4. extractionAqueous layer was then extracted with DCM (1×) and EtOAc (3×)
  5. dry with materialCombined organic layers were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe resulting crude product was absorbed onto silica gel
  9. custompurified by flash chromatography

Sources & evidence

ORD record
ord-6b61fea9dace4bc697635b5b9d2ba3aa
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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