Hydrochloric Acid → Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

HRID 1963416Notes

Reaction equation

HRID 1963416 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12][CH2:11][N:10]1[C:18]([O:20][CH3:21])=[O:19].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:34]([O:36][C:37](=[O:42])[CH2:38]C([O-])=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>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15](=[O:17])[CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:42])[CH2:12][CH2:11][N:10]1[C:18]([O:20][CH3:21])=[O:19]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonate2×HCID 5360315Magnesium Chloride2×HCID 66731707HCID 66731707, compound2×

Product 1

HCID 66731881Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 63.6%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 178479889HCID 178479889, compoundSolvent3×

Procedure

2-(2-Chloro-4-fluorophenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.13 g, 6.75 mmol) (reference compound 21) was dissolved in methyl THF (50 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (1.641 g, 10.12 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 (2.067 g, 12.14 mmol) suspended in methyl THF (25 mL) and magnesium chloride (1.156 g, 12.14 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 15 h using an oversized stirring bar. 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 (1.033 g, 6.07 mmol) suspended in methyl THF (25 mL) and magnesium chloride (0.578 g, 6.07 mmol) was added. The suspension was stirred at 50° C. for 15 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 (gradient 2:1->1:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV). Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.655 g, 63.6%) was isolated as a colorless oil. MS m/z 386 (M+H)+

Workup

  1. customIn a separate flask was
  2. stirringThe suspension was stirred at 50° C. under nitrogen for 15 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 15 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 (gradient 2:1->1:1 heptane:EtOAc, Biotage® KP-SIL 340 g column, 10 CV)

Sources & evidence

ORD record
ord-98288adf9ba94f759c5f82d313d693ec
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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