Hydrochloric Acid → cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate

HRID 1963451Notes

Reaction equation

HRID 1963451 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]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[F:22])=[O:4].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:35]([O:37][C:38](=[O:43])[CH2:39]C([O-])=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.O.CC(OC)(C)C>[CH2:35]([O:37][C:38](=[O:43])[CH2:39][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]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:7]1)=[O:13])[CH3:36]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 667323461-(Methoxycarbonyl)-2-(2,4,5-trifluorophenyl)piperidine-4-carboxylic acid2×

Product 1

HCID 131730419cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylateYield 64.4%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 15413tert-Butyl methyl etherSolventHCID 178479889HCID 178479889, compoundSolvent2×

Procedure

1-(Methoxycarbonyl)-2-(2,4,5-trifluorophenyl)piperidine-4-carboxylic acid (2.388 g, 7.53 mmol) (reference compound 27) was dissolved in methyl THF (50 mL) and di(1H-imidazol-1-yl)methanone (1.831 g, 11.29 mmol) added. The suspension was stirred at room temperature under nitrogen for 6 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (2.306 g, 13.55 mmol) was suspended in methyl THF (50.0 mL) and magnesium chloride (1.290 g, 13.55 mmol) added. The suspension was stirred at 50° C. under nitrogen for 5.5 h using an oversized stirring bar (flask 2). The suspension in flask 1 was now added to the white suspension in flask 2. The resulting beige suspension was stirred under nitrogen at room temperature overnight. The mixture was acidified to pH 1 with 3.8 M HCl and MTBE and water added. The phases were separated and the organic phase washed with water, satd NaHCO3 and water and was evaporated. Traces of water were azeotropically removed by MeCN to yield a yellow oil. The residue was purified on Biotage (20%=>50% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column). Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate (1.877 g, 64%) was isolated as colorless oil. 1H NMR (600 MHz, cdcl3) δ 1.19-1.29 (m, 3H), 1.49-2.19 (m, 3H), 2.22-2.29 (m, 1H), 2.82-2.91 (m, 1H), 3.34 (ddd, 1H), 3.39-3.48 (m, 2H), 3.62 (s, 3H), 4.05-4.20 (m, 3H), 5.00-5.06 (m, 1H), 6.85-7.00 (m, 2H). MS m/z 388 (M+H)+.

Workup

  1. stirringThe suspension was stirred at 50° C. under nitrogen for 5.5 h
  2. additionThe suspension in flask 1 was now added to the white suspension in flask 2
  3. stirringThe resulting beige suspension was stirred under nitrogen at room temperature overnight
  4. additionadded
  5. customThe phases were separated
  6. washthe organic phase washed with water
  7. customwas evaporated
  8. customTraces of water were azeotropically removed by MeCN
  9. customto yield a yellow oil
  10. customThe residue was purified on Biotage (20%=>50% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column)

Sources & evidence

ORD record
ord-2090d74962784da2a3314031a762f969
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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