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

HRID 1963525Notes

Reaction equation

HRID 1963525 reaction equation
[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][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][CH:3]=1.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-].[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>[CH2:35]([O:37][C:38](=[O:43])[CH2:39][C:14]([C@@H:12]1[CH2:11][CH2:10][N:9]([C:17]([O:19][CH3:20])=[O:18])[C@@H:8]([CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=2)[CH2:13]1)=[O:16])[CH3:36].[CH2:35]([O:37][C:38](=[O:43])[CH2:39][C:40]([C@H:12]1[CH2:11][CH2:10][N:9]([C:17]([O:19][CH3:20])=[O:18])[C@@H:8]([CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=2)[CH2:13]1)=[O:42])[CH3:36]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonate2×HCID 5360315Magnesium Chloride2×HCID 667324832-(4-Fluorophenethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×

Product 2

HCID 131730451trans-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylateYield 14%HCID 131730452cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylateYield 60%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 178479889HCID 178479889, compoundSolvent3×

Procedure

2-(4-Fluorophenethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.34 g, 14.03 mmol) (reference compound 41) was dissolved in methyl THF (100 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (3.41 g, 21.05 mmol) added. The suspension was stirred at room temperature for 4 h (flask 1). In a separate flask was potassium 3-ethoxy-3-oxopropanoate (4.30 g, 25.25 mmol) suspended in methyl THF (100 mL) and magnesium chloride (2.404 g, 25.25 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 4 h using an oversized stirring bar (flask 2). The contents of flask 1 was added to flask 2 and the mixture (white suspension) was stirred at room temperature for 19 h. In a new flask was potassium 3-ethoxy-3-oxopropanoate (4.30 g, 25.25 mmol) suspended in methyl THF (100 mL) and magnesium chloride (2.404 g, 25.25 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 4 h using an oversized stirring bar and subsequently added to the reaction mixture. The mixture was stirred at room temperature for another 16 h at room temperature. 0.1 M HCl and DCM was added, the phases separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with satd NaHCO3, filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on 2 Biotage® KP-SIL 340 g columns. Mobile phase 2:1 heptane:EtOAc over 4 CV, then gradient from 2:1->1:1 heptane:EtOAc over 6 CV. Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate (0.74 g, 14%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate (3.17 g, 60%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.24 (t, 3H), 1.50-2.11 (m, 6H), 2.48-2.65 (m, 2H), 2.67-7.77 (m, 1H), 3.03-3.14 (m, 1H), 3.50 (s, 2H), 3.69 (s, 3H), 3.84-3.93 (m, 1H), 4.07 (p, 1H), 4.12-4.22 (m, 2H), 6.95 (t, 2H), 7.08-7.16 (m, 2H). MS m/z 380 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.23-1.32 (m, 3H), 1.41-2.11 (m, 6H), 2.42-2.66 (m, 2H), 2.76-2.96 (m, 2H), 3.45 (s, 2H), 3.69 (s, 3H), 4.01-4.65 (m, 4H), 6.97 (t, 2H), 7.13 (s, br., 2H). MS m/z 380 (M+H)+

Workup

  1. customIn a separate flask was
  2. stirringThe suspension was stirred at 50° C. under nitrogen for 4 h
  3. additionThe contents of flask 1 was added to flask 2
  4. stirringthe mixture (white suspension) was stirred at room temperature for 19 h
  5. customIn a new flask was
  6. stirringThe suspension was stirred at 50° C. under nitrogen for 4 h
  7. additionsubsequently added to the reaction mixture
  8. stirringThe mixture was stirred at room temperature for another 16 h at room temperature
  9. customthe phases separated
  10. extractionthe aqueous phase was extracted with DCM
  11. washThe combined organic layers were washed with satd NaHCO3
  12. filtrationfiltered through a phase separator
  13. customevaporated
  14. customThe residue was purified by automated flash chromatography on 2 Biotage® KP-SIL 340 g columns

Sources & evidence

ORD record
ord-b27082f68fb343ec93939724eb0a4118
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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