Hydrochloric Acid → HCID 131730500, compound

HRID 1963646Notes

Reaction equation

HRID 1963646 reaction equation
[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH:6]1[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=1)=[O:4].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:36]([O:38][C:39](=[O:44])[CH2:40][C:41]([O-:43])=O)[CH3:37].[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>[CH2:36]([O:38][C:39](=[O:44])[CH2:40][C:11]([C@@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([CH2:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)[CH2:7]1)=[O:13])[CH3:37].[CH2:36]([O:38][C:39](=[O:44])[CH2:40][C:41]([C@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([CH2:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)[CH2:7]1)=[O:43])[CH3:37]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66732169HCID 66732169, compound2×

Product 2

HCID 131730499HCID 131730499, compoundYield 7.46%HCID 131730500HCID 131730500, compoundYield 47.5%

Reagents, catalysts & solvents 3

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

Procedure

1-(Methoxycarbonyl)-2-(3,4,5-trifluorobenzyl)piperidine-4-carboxylic acid (3.42 g, 10.32 mmol) (reference compound 60) was dissolved in methyl THF (60 mL) and di(1H-imidazol-1-yl)methanone (2.51 g, 15.49 mmol) added. The suspension was stirred at room temperature under nitrogen for 6 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (3.16 g, 18.58 mmol) was suspended in methyl THF (60.0 mL) and magnesium chloride (1.769 g, 18.58 mmol) added. The suspension was stirred under nitrogen for 6 h (flask 2). The white suspension in flask 2 was then added to the brown suspension in flask 1. The resulting suspension was stirred at room temperature for 18 h. The mixture was acidified to pH 1 with 3 M HCl. MTBE (250 mL) and water (250 mL) were added, shaken and the phases separated. The organic phase was washed with water (250 mL), satd NaHCO3 (250 mL) and brine (250 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 20% EtOAc in heptane over 2 CV followed by 20% to 60% of EtOAc in heptane over 8 CV was used as mobile phase. Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorobenzyl)-piperidine-1-carboxylate (0.309 g, 7.46%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (1.967 g, 47.5%) were isolated. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.19-1.30 (m, 3H), 1.62-1.96 (m, 4H), 2.61-2.68 (m, 1H), 2.68-2.76 (m, 1H), 2.80-2.87 (m, 1H), 2.96-3.04 (m, 1H), 3.46 (s, 2H), 3.65 (s, 3H), 3.83-3.94 (m, 1H), 4.09-4.20 (m, 3H), 6.76-6.84 (m, 2H). MS m/z 402 (M+H)+. Trans-isomer: MS m/z 402 (M+H)+

Workup

  1. stirringThe suspension was stirred under nitrogen for 6 h (flask 2)
  2. additionThe white suspension in flask 2 was then added to the brown suspension in flask 1
  3. stirringThe resulting suspension was stirred at room temperature for 18 h
  4. stirringshaken
  5. customthe phases separated
  6. washThe organic phase was washed with water (250 mL), satd NaHCO3 (250 mL) and brine (250 mL)
  7. dry with materialdried with Na2SO4
  8. filtrationfiltered
  9. customevaporated in vacuo
  10. customThe residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column

Sources & evidence

ORD record
ord-9bf5d87566d24d528c400e5458de8570
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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