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

HRID 1963506Notes

Reaction equation

HRID 1963506 reaction equation
[CH:1]1([O:7][CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12][CH2:11][N:10]2[C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.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.C(Cl)Cl>[CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@H:13]([C:15](=[O:17])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:12][CH2:11][N:10]2[C:18]([O:20][CH3:21])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:39](=[O:41])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:12][CH2:11][N:10]2[C:18]([O:20][CH3:21])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonate2×HCID 5360315Magnesium Chloride2×HCID 595365632-(Cyclohexyloxymethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×

Product 2

HCID 131730442trans-Methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 7%HCID 131730443cis-Methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 38%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 178479889HCID 178479889, compoundSolvent3×

Procedure

2-(Cyclohexyloxymethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.425 g, 8.1 mmol) (reference compound 38) was dissolved in methyl THF (60 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (1.970 g, 12.15 mmol) was added. The suspension was stirred at room temperature for 3 h (flask 1). In a separate flask was potassium 3-ethoxy-3-oxopropanoate (2.482 g, 14.58 mmol) suspended in methyl THF (30 mL) and magnesium chloride (1.388 g, 14.58 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 22 h using an oversized stirring bar (flask 2). The contents of flask 1 was added to flask 2 and the resulting white suspension was stirred at room temperature for 20 h. In a separate flask was potassium 3-ethoxy-3-oxopropanoate (1.241 g, 7.29 mmol) suspended in methyl THF (30 mL) and magnesium chloride (0.694 g, 7.29 mmol) was added. The suspension was stirred at 50° C. for 5 h and then added to the reaction mixture. The mixture was stirred at room temperature for 15 h. 0.1 M HCl and DCM were added and the phases separated. The aqueous phase was extracted with DCM, the combined organic layers filtered through a phase separator and evaporated. The residue was purified via Biotage (5:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV). Trans-methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (210 mg, 7%) and cis-methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.13 g, 38%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.14-2.14 (m, 17H), 2.70-2.79 (m, 1H), 3.11-3.30 (m, 2H), 3.34-3.62 (m, 4H), 3.69 (s, 3H), 3.82-3.91 (m, 1H), 4.07-4.24 (m, 3H). MS m/z 370 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.16-2.19 (m, 17H), 2.80-3.10 (m, 2H), 3.16-3.32 (m, 1H), 3.44-3.64 (m, 4H), 3.66-3.74 (m, 3H), 3.97-4.27 (m, 3H), 4.33-4.57 (m, 1H). MS m/z 370 (M+H)+

Workup

  1. customIn a separate flask was
  2. stirringThe suspension was stirred at 50° C. under nitrogen for 22 h
  3. additionThe contents of flask 1 was added to flask 2
  4. stirringthe resulting white suspension was stirred at room temperature for 20 h
  5. customIn a separate flask was
  6. stirringThe suspension was stirred at 50° C. for 5 h
  7. additionadded to the reaction mixture
  8. stirringThe mixture was stirred at room temperature for 15 h
  9. customthe phases separated
  10. extractionThe aqueous phase was extracted with DCM
  11. filtrationthe combined organic layers filtered through a phase separator
  12. customevaporated
  13. customThe residue was purified via Biotage (5:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV)

Sources & evidence

ORD record
ord-6d3b16ae284c47fbb18dac67f7f4841b
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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