Isoamyl Nitrite → Nicotinic Acid

HRID 1768906Notes

Reaction equation

HRID 1768906 reaction equation
[Na].C([C:5]1[C:6](CC(C)C)=[C:7]([C:18]([O:20]C)=[O:19])[C:8](C(F)F)=[N:9][C:10]=1C(F)(F)F)(=O)C.N(OCCC(C)C)=O>CO>[N:9]1[CH:10]=[CH:5][CH:6]=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=1

Participants

5

Reactant 3

HCID 8053Isoamyl NitriteHCID 5360545SodiumHCID 20098194Methyl 5-acetyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate

Product 1

HCID 938Nicotinic AcidYield 99%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
25 °C

Procedure

This example illustrates the preparation of Compound 101, an example of the formation of the heterocycle by cycloaddition reaction. Sodium (7.87 g, 0.35 mol) was cautiously added in portions to 250 mL methanol under nitrogen. Methyl 5-acetyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (20 g, 0,057 mol) was added at 25° C., followed by dropwise addition of isoamyl nitrite (33.15 g, 0.283 mol). The mixture was stirred overnight at 25° C., then quenched with ice/concentrated HCl slush, and extracted with ether. The combined ether layers were washed with saturated sodium bicarbonate and dried (MgSO4). The solvent was evaporated in vacuo and the residue purified by HPLC with 10% ethyl acetate-hexane to give 22 g (99%) of 3-pyridinecarboxylic acid, 2-(difluoromethyl)-5-((hydroxyimino)acetyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-, methyl ester, as a yellow solid. m.p. 84°-86° C.

Workup

  1. customquenched with ice/concentrated HCl slush
  2. extractionextracted with ether
  3. washThe combined ether layers were washed with saturated sodium bicarbonate
  4. dry with materialdried (MgSO4)
  5. customThe solvent was evaporated in vacuo
  6. customthe residue purified by HPLC with 10% ethyl acetate-hexane

Sources & evidence

ORD record
ord-5de0b4381bb649149579c061d353de90
Source dataset
uspto-grants-1995_01
Patent number
US05380699

Reaction notes

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