Ethyl cyanoacetate → trans-1-[2-(4-Fluorophenyl)ethyl]-4-methyl-2,6-dioxopiperidine-3-carbonitrile

HRID 896547Notes

Reaction equation

HRID 896547 reaction equation
[C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:23])/[CH:20]=[CH:21]/[CH3:22])=[CH:12][CH:11]=1.CC(C)([O-])C.[K+].O1CCCC1>C(O)(C)(C)C.Cl>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][N:18]2[C:19](=[O:23])[CH2:20][C@@H:21]([CH3:22])[C@H:3]([C:1]#[N:2])[C:4]2=[O:6])=[CH:14][CH:15]=1

Participants

7

Reactant 4

HCID 7764Ethyl cyanoacetateHCID 8028TetrahydrofuranHCID 23665647Potassium tert-butoxideHCID 86591719(2E)-N-[2-(4-Fluorophenyl)ethyl]-2-butenamide

Product 1

HCID 69737879trans-1-[2-(4-Fluorophenyl)ethyl]-4-methyl-2,6-dioxopiperidine-3-carbonitrileYield 93.5%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
80 °C

Procedure

A solution of ethyl cyanoacetate (4.26 mL, 40 mmol) and trans-2-butenoic acid [2-(4-fluoro-phenyl)ethyl]amide (4.15 g, 20 mmol) in tert-butanol (60 mL) was treated with a solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 40 mL, 40 mmol) and the mixture was heated at 80° C. The mixture was cooled to room temperature after 16.5 hours and diluted with 1.0 N aqueous hydrochloric acid. The mixture was concentrated under vacuum to remove the organic solvents, providing a suspension of solid in the aqueous residue. This was collected by filtration, dried, and purified by recrystallization from 95% ethanol to provide a white solid (5.13 g, 93%). 1H NMR (300 MHz, CDCl3) δ7.19 (m, 2H), 7.00 (t, J=9 Hz, 2H), 4.02 (m, 2H), 3.41 (d, J=11 Hz, 1H), 2.91 (m, 1H), 2.83 (t, J=8 Hz, 2H), 2.5-2.3 (m, 2H), 1.31 (d, J=6 Hz, 3H). Mass spec (CI) m/z 275.0 (M+H+, 100%).

Workup

  1. temperatureThe mixture was cooled to room temperature after 16.5 hours
  2. concentrationThe mixture was concentrated under vacuum
  3. customto remove the organic solvents
  4. customproviding
  5. additiona suspension of solid in the aqueous residue
  6. filtrationThis was collected by filtration
  7. customdried
  8. custompurified by recrystallization from 95% ethanol

Sources & evidence

ORD record
ord-7f0fa0855d534997a13186fcbc025e64
Source dataset
uspto-grants-2005_07
Patent number
US06919356B2

Reaction notes

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