Nicotinic Acid → 2-[Cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-3-pyridin-3-yl-propionic acid ethyl ester

HRID 545340Notes

Reaction equation

HRID 545340 reaction equation
[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:24](=[O:31])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH3:2]

Participants

5

Reactant 2

HCID 938Nicotinic AcidHCID 67133328[Cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester2×

Product 1

HCID 671330912-[Cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-3-oxo-3-pyridin-3-yl-propionic acid ethyl esterYield 58%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-30 °C

Procedure

To solution of 12.7 ml (1 M in THF, 13 mmol) of lithium hexamethyldisilylazide cooled to −78° C. under Ar was added, drop wise, a solution of 3.8 g (12 mmol) of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) in 20 ml of THF. The mixture was brought to −30° C. and stirred for 1 h. Separately, 0.6 g (5 mmol) of nicotinic acid was added to 0.8 g (5 mmol) of 1,1-carbonyl diimidazole in 10 ml of CH2Cl2 and the mixture stirred for 1 h after which time it was concentrated to dryness. The crude residue was re-dissolved in 10 ml of THF under Ar and cooled to −30° C. The enolate solution of intermediate 7B (described above) was then added by cannula to the crude imidazolide solution and the mixture was allowed to reach room temperature. After 2 h the reaction was diluted with EtOAc, washed with saturated ammonium chloride solution, the organic phase dried with sodium sulfate and concentrated. Purification by flash column chromatography [n-heptane/EtOAc 1:1] afforded 1.2 g (58%) of the title compound as an orange oil. MS: 437.2 (MH+).

Workup

  1. additionwas added
  2. customwas brought to −30° C.
  3. stirringthe mixture stirred for 1 h after which time it
  4. concentrationwas concentrated to dryness
  5. dissolutionThe crude residue was re-dissolved in 10 ml of THF under Ar
  6. additionThe enolate solution of intermediate 7B (described above) was then added by cannula to the crude imidazolide solution
  7. customto reach room temperature
  8. additionAfter 2 h the reaction was diluted with EtOAc
  9. washwashed with saturated ammonium chloride solution
  10. dry with materialthe organic phase dried with sodium sulfate
  11. concentrationconcentrated
  12. customPurification by flash column chromatography [n-heptane/EtOAc 1:1]

Sources & evidence

ORD record
ord-55b4bd089aa74b6499e5ade24586afcd
Source dataset
uspto-grants-2011_05
Patent number
US07935707B2

Reaction notes

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