Hydrochloric Acid → HCID 66732173, compound

HRID 1963481Notes

Reaction equation

HRID 1963481 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][CH:16](C(O)=O)[CH2:15][CH2:14][N:13]2[C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:37]([O:39][C:40](=[O:45])[CH2:41][C:42]([O-])=[O:43])[CH3:38].[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>[CH2:37]([O:39][C:40](=[O:45])[CH2:41][C:42]([CH:16]1[CH2:15][CH2:14][N:13]([C:21]([O:23][CH3:24])=[O:22])[CH:12]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([F:1])[CH:3]=2)[CH2:17]1)=[O:43])[CH3:38]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonate2×HCID 5360315Magnesium Chloride2×HCID 66731620HCID 66731620, compound2×

Product 1

HCID 66732173HCID 66732173, compoundYield 59.3%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 178479889HCID 178479889, compoundSolvent3×

Procedure

2-(3-Fluoro-4-(trifluoromethyl)phenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.07 g, 8.8 mmol) (reference compound 33) was dissolved in methyl THF (60 mL) under nitrogen atmosphere and di(1H-imidazol-1-yl)methanone (2.140 g, 13.20 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 (2.70 g, 15.84 mmol) suspended in methyl THF (30 mL) and magnesium chloride (1.508 g, 15.84 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 transferred into 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 (1.348 g, 7.92 mmol) suspended in methyl THF (30 mL) and magnesium chloride (0.754 g, 7.92 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). The product methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (2.190 g, 59.3%) was isolated as a colorless oil. MS m/z 420 (M+H)+

Workup

  1. customIn a separate flask was
  2. stirringThe suspension was stirred at 50° C. under nitrogen for 22 h
  3. customThe contents of flask 1 was transferred into flask
  4. stirring2 and the 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-fce05e935134423ba724dd129ef25cde
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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