Hydrochloric Acid → HCID 131730407, compound

HRID 1963420Notes

Reaction equation

HRID 1963420 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11][CH2:10][N:9]2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][C:3]=1[F:21].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:34]([O:36][C:37](=[O:42])[CH2:38][C:39]([O-:41])=O)[CH3:35].[K+].[Cl-].[Mg+2].[Cl-].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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14](=[O:16])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:11][CH2:10][N:9]2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][C:3]=1[F:21].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:39](=[O:41])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:11][CH2:10][N:9]2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][C:3]=1[F:21]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 667316632-(4-Chloro-3-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×

Product 2

HCID 131730407HCID 131730407, compoundYield 66%HCID 131730408HCID 131730408, compoundYield 6.12%

Reagents, catalysts & solvents 3

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

Procedure

2-(4-Chloro-3-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (1.430 g, 4.53 mmol) (reference compound 22) was dissolved in methyl THF (20 mL) and di(1H-imidazol-1-yl)methanone (1.102 g, 6.79 mmol) added. The reaction was stirred at room temperature for 6 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (1.388 g, 8.15 mmol) was suspended in methyl THF (20.00 mL) and magnesium chloride (0.776 g, 8.15 mmol) added. The suspension was stirred at 50° C. for 6 h (flask 2). The white suspension from flask 2 was added to flask 1. A white suspension was formed. The suspension was stirred at room temperature for 18 h. The suspension was acidified to pH 1 with 3 M HCl. MTBE (100 mL) and water (150 mL) were added, shaken and the phases separated. The organic phase was washed with water (150 mL), satd NaHCO3 (150 mL) and brine (150 mL), dried with Na2SO4, filtered and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient of 20% EtOAc in heptane over 2 CV followed by 20-60% of EtOAc in heptane over 10 CV was used as mobile phase. Cis-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.153 g, 66.0%) and trans-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.107 g, 6.12%) were isolated as colorless oils. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.19-1.30 (m, 3H), 1.73-1.97 (m, 2H), 2.00-2.16 (m, 1H), 2.20-2.27 (m, 1H), 2.81-2.89 (m, 1H), 3.24-3.48 (m, 3H), 3.60-3.65 (m, 3H), 4.04-4.20 (m, 3H), 4.84-4.98 (m, 1H), 6.86-7.01 (m, 2H), 7.28-7.34 (m, 1H). MS m/z 386 (M+H)+. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.19-1.29 (m, 3H), 1.38-2.98 (m, 6H), 3.39-3.49 (m, 2H), 3.63-3.82 (m, 3H), 4.00-4.37 (m, 3H), 5.56 (s, br., 1H), 6.86-7.02 (m, 2H), 7.33-7.39 (m, 1H). MS m/z 386 (M+H)+

Workup

  1. stirringThe suspension was stirred at 50° C. for 6 h (flask 2)
  2. additionThe white suspension from flask 2 was added to flask 1
  3. customA white suspension was formed
  4. stirringThe suspension was stirred at room temperature for 18 h
  5. stirringshaken
  6. customthe phases separated
  7. washThe organic phase was washed with water (150 mL), satd NaHCO3 (150 mL) and brine (150 mL)
  8. dry with materialdried with Na2SO4
  9. filtrationfiltered
  10. customevaporated in vacuo
  11. customThe residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column

Sources & evidence

ORD record
ord-f26a4ce866ee4f81a43b3c937d743760
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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