Acetic Acid → 4-Fluoro-1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid ethyl ester

HRID 1465052Notes

Reaction equation

HRID 1465052 reaction equation
Cl.[F:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.O=[C:15]1[CH2:20][CH2:19][O:18][C:17](=O)[CH2:16]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOCC.[OH-].[Na+].C(Cl)Cl>[CH2:12]([O:11][C:9]([C:3]1([F:2])[CH2:4][CH2:5][N:6]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:7][CH2:8]1)=[O:10])[CH3:13]

Participants

8

Reactant 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 9793733Oxane-2,4-dioneHCID 24729616Ethyl 4-Fluoropiperidine-4-carboxylate Hydrochloride

Product 1

HCID 595081294-Fluoro-1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid ethyl ester

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 14798Sodium HydroxideSolvent

Procedure

To a 250 mL RB were added compound B2(I) ethyl 4-fluoropiperidine-4-carboxylate, hydrochloride (1.25 g, 5.91 mmol, 1.0 eq), CH2Cl2 (20 mL), 4-oxotetrahydropyranone B2(II) (0.61 mL, 6.50 mmol, 1.10 eq), and glacial HOAc (0.340 mL, 5.91 mmol, 1.0 eq). After being stirred at rt for 5 to 10 min, sodium triacetoxyborohydride (2.02 g, 9.45 mmol, 1.60 eq) was added in one portion. A cloudy solution was obtained. After being stirred at rt for 12 h, the reaction mixture was diluted with 150 mL Et2O and 200 mL NaOH (1 M aqueous). The resulting suspension was stirred at rt for 1 h. The organic layer was collected, washed with 200 mL brine, dried over Na2SO4, filtered, and concentrated to afford 320 mg of the desired product, 4-fluoro-1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid ethyl ester B2(III) in 21 yield as a colorless oil. 1H NNR (400 MHz, CDCl3, ppm) δ 1.30 (t, J=7.08, 3H), 1.56-1.66 (m, 2H), 1.74-1.78 (m, 2H), 1.94-2.21 (m, 4H), 2.46-2.55 (m, 3H), 2.82-2.85 (m, 2H), 3.38 (ddd, J=1.52, 11.84, 11.84, 2H), 4.03 (dd, J=4.28, 11.08, 2H), 4.24 (q, J=7.05 Hz, 2H); 19F NMR (376 Hz, CDCl3, ppm) δ-166.94.

Workup

  1. customA cloudy solution was obtained
  2. stirringAfter being stirred at rt for 12 h
  3. stirringThe resulting suspension was stirred at rt for 1 h
  4. customThe organic layer was collected
  5. washwashed with 200 mL brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-8224f7f1fa7b41bcb5e431e224c4e74e
Source dataset
uspto-grants-2015_04
Patent number
US08999981B2

Reaction notes

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