Hydrochloric Acid → cis-Methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

HRID 1963611Notes

Reaction equation

HRID 1963611 reaction equation
[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH2:7][N:6]1[C:14]([O:16][CH3:17])=[O:15].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:35]([O:37][C:38](=[O:43])[CH2:39][C:40]([O-:42])=O)[CH3:36].[K+].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.O.CC(OC)(C)C>[F:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:13])[CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:43])[CH2:8][CH2:7][N:6]1[C:14]([O:16][CH3:17])=[O:15].[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:40](=[O:42])[CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:43])[CH2:8][CH2:7][N:6]1[C:14]([O:16][CH3:17])=[O:15]

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 667316802-(2,6-Difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×

Product 2

HCID 131730485trans-Methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 7%HCID 131730486cis-Methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 41%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 15413tert-Butyl methyl etherSolventHCID 178479889HCID 178479889, compoundSolvent2×

Procedure

2-(2,6-Difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.72 g, 15.07 mmol) (reference compound 55) was dissolved in methyl THF (108 mL) and di(1H-imidazol-1-yl)methanone (3.66 g, 22.60 mmol) was added. The suspension was stirred at room temperature for 3 h 45 min under nitrogen (flask 1). In a separate flask was to a suspension of potassium 3-ethoxy-3-oxopropanoate (4.62 g, 27.12 mmol) in methyl THF (108 mL) magnesium chloride (2.58 g, 27.12 mmol) added. The suspension was stirred with a large stirring bar for 3.5 h at 50° C. under nitrogen (flask 2). The suspension in flask 1 was added to the suspension in flask 2 and the reaction mixture was then stirred at room temperature overnight. The reaction mixture was acidified to pH 1 with 2 M HCl. MTBE and water were added and the phases were separated. The organic phase was washed with water, satd NaHCO3 and water before it was dried and concentrated. The residue was purified in 2 runs by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient from 15% to 50% of EtOAc in heptane over 8 CV (3 CV initial waste+5 CV collected) was used as mobile phase. Trans-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.405 g, 7%) and cis-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.404 g, 41%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.33 (m, 3H), 1.68-2.05 (m, 4H), 2.65-2.89 (m, 2H), 2.93-3.16 (m, 2H), 3.49 (s, 5H), 3.96 (dd, 1H), 4.14-4.22 (m, 2H), 4.27-4.40 (m, 1H), 6.77-6.89 (m, 2H), 7.09-7.20 (m, 1H). MS m/z 384 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22-1.34 (m, 3H), 1.41-2.01 (m, 4H), 2.75-3.20 (m, 4H), 3.37-3.70 (m, 5H), 4.02-4.32 (m, 3H), 4.55-4.85 (m, 1H), 6.81-6.92 (m, 2H), 7.11-7.23 (m, 1H). MS m/z 384 (M+H)+

Workup

  1. additionadded
  2. stirringThe suspension was stirred with a large stirring bar for 3.5 h at 50° C. under nitrogen (flask 2)
  3. additionThe suspension in flask 1 was added to the suspension in flask 2
  4. stirringthe reaction mixture was then stirred at room temperature overnight
  5. customthe phases were separated
  6. washThe organic phase was washed with water
  7. customwas dried
  8. concentrationconcentrated
  9. customThe residue was purified in 2 runs by automated flash chromatography on a Biotage® KP-SIL 340 g column
  10. customA gradient from 15% to 50% of EtOAc in heptane over 8 CV (3 CV initial waste+5 CV collected)

Sources & evidence

ORD record
ord-af8e888e3dd2432aa769e0a3838485d0
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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