1,1'-Carbonyldiimidazole → cis-Methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

HRID 1963625Notes

Reaction equation

HRID 1963625 reaction equation
[Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([O-:11])=O)[CH3:5].[K+].[F:14][C:15]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:16]=1[CH2:17][CH:18]1[CH2:23][CH:22]([C:24]([OH:26])=O)[CH2:21][CH2:20][N:19]1[C:27]([O:29][CH3:30])=[O:28].N1(C(N2C=CN=C2)=O)C=CN=C1>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O>[F:14][C:15]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:16]=1[CH2:17][C@H:18]1[CH2:23][C@H:22]([C:9](=[O:11])[CH2:8][C:7]([O:6][CH2:4][CH3:5])=[O:12])[CH2:21][CH2:20][N:19]1[C:27]([O:29][CH3:30])=[O:28].[F:14][C:15]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:16]=1[CH2:17][C@H:18]1[CH2:23][C@@H:22]([C:24](=[O:26])[CH2:8][C:7]([O:6][CH2:4][CH3:5])=[O:12])[CH2:21][CH2:20][N:19]1[C:27]([O:29][CH3:30])=[O:28]

Participants

7

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 667324712-(2,4-Difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×

Product 2

HCID 131730490trans-Methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 13%HCID 131730491cis-Methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 45%

Reagents, catalysts & solvents 1

HCID 178479889HCID 178479889, compoundSolvent2×

Conditions

Temperature
50 °C

Procedure

Magnesium chloride (4.55 g, 47.75 mmol) and potassium 3-ethoxy-3-oxopropanoate (8 g, 47.00 mmol) were dissolved in methyl THF (100 mL) under nitrogen and the resulting suspension was stirred at 50° C. with an oversized stirring bar for 6 h 30 min, then cooled to room temperature (flask 1). To a suspension of 2-(2,4-difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (7.48 g, 23.88 mmol) (reference compound 57) in methyl THF (100 mL) was added di(1H-imidazol-1-yl)methanone (5.81 g, 35.81 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 1 h 20 min (flask 2). The contents of flask 2 is transferred into flask 1 by transfer needle. Wash with methyl THF (30 mL). The resulting suspension was stirred at room temperature for 16 h. 3.8 M HCl was added (ca. 200 mL) and the resulting biphasic mixture stirred vigorously for 30 min. Water and MTBE were added and the phases separated. The organic phase was washed with water, satd NaHCO3 and water, then dried over MgSO4 and evaporated. The residue was purified via Biotage (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes, then 20%=>60% over 7 CV). Trans-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.18 g, 13%) and cis-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (4.17 g, 45%) were isolated as yellow oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.32 (m, 3H), 1.59-1.99 (m, 4H), 2.66-3.12 (m, 4H), 3.48 (s, 2H), 3.55 (s, 3H), 3.89-3.98 (m, 1H), 4.07-4.29 (m, 3H), 6.71-6.83 (m, 2H), 7.05-7.17 (m, 1H). MS m/z 384 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.19-1.35 (m, 3H), 1.42-2.02 (m, 4H), 2.65-3.11 (m, 4H), 3.38-3.75 (m, 5H), 4.02-4.34 (m, 3H), 4.45-4.70 (m, 1H), 6.73-6.89 (m, 2H), 7.03-7.34 (m, 1H). MS m/z 384 (M+H)+

Workup

  1. temperaturecooled to room temperature (flask 1)
  2. stirringThe resulting mixture was stirred at room temperature for 1 h 20 min (flask 2)
  3. customThe contents of flask 2 is transferred into flask
  4. washWash with methyl THF (30 mL)
  5. stirringThe resulting suspension was stirred at room temperature for 16 h
  6. addition3.8 M HCl was added (ca. 200 mL)
  7. stirringthe resulting biphasic mixture stirred vigorously for 30 min
  8. additionWater and MTBE were added
  9. customthe phases separated
  10. washThe organic phase was washed with water
  11. dry with materialdried over MgSO4
  12. customevaporated
  13. customThe residue was purified via Biotage (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes

Sources & evidence

ORD record
ord-04de35107fc648ad90aa6deb7fa44bcc
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

Loading…