Hydrochloric Acid → HCID 131730435, compound

HRID 1963486Notes

Reaction equation

HRID 1963486 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[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:32]([O:34][C:35](=[O:40])[CH2:36][C:37]([O-:39])=O)[CH3:33].[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.CC(OC)(C)C>[CH2:32]([O:34][C:35](=[O:40])[CH2:36][C:11]([C@@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:13])[CH3:33].[CH2:32]([O:34][C:35](=[O:40])[CH2:36][C:37]([C@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:39])[CH3:33]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonate2×HCID 5360315Magnesium Chloride2×HCID 66732502HCID 66732502, compound2×

Product 2

HCID 131730434HCID 131730434, compoundYield 19%HCID 131730435HCID 131730435, compoundYield 62%

Reagents, catalysts & solvents 2

HCID 15413tert-Butyl methyl etherSolventHCID 178479889HCID 178479889, compoundSolvent3×

Procedure

1-(Methoxycarbonyl)-2-phenylpiperidine-4-carboxylic acid (5.133 g, 19.50 mmol) (reference compound 34) was dissolved in methyl THF (90 mL) and di(1H-imidazol-1-yl)methanone (4.74 g, 29.24 mmol) was added. The suspension was stirred at room temperature under nitrogen overnight (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (5.97 g, 35.09 mmol) was suspended in methyl THF (90 mL) and magnesium chloride (3.34 g, 35.09 mmol) was added. The suspension was stirred at room temperature under nitrogen overnight (flask 2). Then, the slightly yellow suspension in flask 1 was added to the white suspension in flask 2. The resulting white suspension was stirred under nitrogen at room temperature for 6 h 30 min. In the meantime, potassium 3-ethoxy-3-oxopropanoate (5.97 g, 35.09 mmol) was suspended in methyl THF (90 mL) and magnesium chloride (3.34 g, 35.09 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 2 h and then added to the reaction mixture. The resulting white suspension was stirred at room temperature under nitrogen for 3 days. The mixture was acidified to pH 1 with 1 M HCl and MTBE was added. The phases were separated and the organic phase washed with water, satd NaHCO3 and water. The solvents were evaporated to yield a yellow oil. The diastereoisomers were separated by column chromatography on silica (Biotage, gradient 0%=>50% EtOAc in heptane; Biotage® KP-SIL 340 g column) to yield trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-phenylpiperidine-1-carboxylate (1.14 g, 19%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-phenylpiperidine-1-carboxylate (3.77 g, 62%). Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22-1.31 (m, 3H), 1.84-2.11 (m, 3H), 2.26-2.35 (m, 1H), 2.82-2.92 (m, 1H), 3.28-3.48 (m, 3H), 3.63 (s, 3H), 4.12-4.21 (m, 3H), 4.96-5.04 (m, 1H), 7.17-7.35 (m, 5H). MS m/z 334 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.13-1.25 (m, 3H), 1.44-1.95 (m, 3H), 2.45-2.66 (m, 2H), 2.78-2.88 (m, 1H), 3.39 (s, 2H), 3.68 (s, 3H), 3.98-4.34 (m, 3H), 5.55 (s, br., 1H), 7.10-7.23 (m, 3H), 7.26-7.34 (m, 2H). MS m/z 334 (M+H)+.

Workup

  1. stirringThe suspension was stirred at room temperature under nitrogen overnight (flask 2)
  2. additionThen, the slightly yellow suspension in flask 1 was added to the white suspension in flask 2
  3. stirringThe resulting white suspension was stirred under nitrogen at room temperature for 6 h 30 min
  4. stirringThe suspension was stirred at 50° C. under nitrogen for 2 h
  5. additionadded to the reaction mixture
  6. stirringThe resulting white suspension was stirred at room temperature under nitrogen for 3 days
  7. additionwas added
  8. customThe phases were separated
  9. washthe organic phase washed with water
  10. customThe solvents were evaporated
  11. customto yield a yellow oil
  12. customThe diastereoisomers were separated by column chromatography on silica (Biotage, gradient 0%=>50% EtOAc in heptane; Biotage® KP-SIL 340 g column)

Sources & evidence

ORD record
ord-a9f431d2e35249ee95b141c8304773ab
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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