Triethylamine → (R)-tetrahydrofuran-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide

HRID 2062282Notes

Reaction equation

HRID 2062282 reaction equation
[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:6]([C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:8])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 65578Oxalyl chloride2×HCID 2734707Tetrahydro-2-furoic acid, (+)-HCID 125944831-Benzylpiperidin-4-amine dihydrochloride

Product 1

HCID 1246648(R)-tetrahydrofuran-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amideYield 88.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of (R)-tetrahydro-2-furoic acid (58.5 g, 504 mmol) and oxalyl chloride (86 mL, 1.0 mol) in 100 mL CH2Cl2 were refluxed for 2 hours in a flask equipped with a CaCl2 guard tube. After the solution was cooled to room temperature the solvents and excess oxalyl chloride were removed by evaporation under reduced pressure. The resulting acid chloride was dissolved in 200 mL CH2Cl2 and added dropwise to a solution of 1-benzyl-4-amino piperidine dihydrochloride (142 g, 539 mmol) and triethylamine (240 mL, 1.7 mol) in 300 mL CH2Cl2 cooled in an ice bath. The resulting mixture was stirred for 2 hours at room temperature and subsequently washed twice with 300 mL portions of 5% aq. NaHCO3 and 300 mL saturated aq. NaCl solution, dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure. The solid residue was triturated with 500 mL heptanes, collected by filtration, and washed twice with 200 mL portions of heptanes. The solid was air-dried at 45° C. to yield (R)-tetrahydrofuran-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide (128 g, 88%) as an off-white solid. 1H-NMR (300 MHz, CDCl3): δ 7.35-7.20 (m, 5H), 6.58 (bs, 1H), 4.29 (dd, J=5.9, 8.4 Hz, 1H), 3.92-3.77 (m, 2H), 3.48 (s, 2H), 2.82-2.74 (m, 2H), 2.32-2.21 (m, 1H), 2.19-1.95 (m, 3H), 1.94-1.78 (m, 4H), 1.58-1.40 (m, 2H) ppm.

Workup

  1. customequipped with a CaCl2 guard tube
  2. customwere removed by evaporation under reduced pressure
  3. dissolutionThe resulting acid chloride was dissolved in 200 mL CH2Cl2
  4. temperaturecooled in an ice bath
  5. washsubsequently washed twice with 300 mL portions of 5% aq. NaHCO3 and 300 mL saturated aq. NaCl solution
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. customevaporated to dryness under reduced pressure
  9. customThe solid residue was triturated with 500 mL heptanes
  10. filtrationcollected by filtration
  11. washwashed twice with 200 mL portions of heptanes
  12. customThe solid was air-dried at 45° C.

Sources & evidence

ORD record
ord-b993b352d7c74d47887dccf01774f4d1
Source dataset
uspto-grants-2012_10
Patent number
US08283354B2

Reaction notes

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