Hydrochloric Acid → 2-(Difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid

HRID 241431Notes

Reaction equation

HRID 241431 reaction equation
[F:1][CH:2]([F:21])[C:3]1[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][C:6]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:5][N:4]=1.O.[OH-].[Li+].Cl>O1CCOCC1>[F:21][CH:2]([F:1])[C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:5][N:4]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 3939Lithium HydroxideHCID 71059744Ethyl 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinate

Product 1

HCID 710598402-(Difluoromethyl)-5-(isobutyramidomethyl)nicotinic acidYield 94.7%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

Dissolve ethyl 2-(difluoromethyl)-5-{[(2-methylpropanoyl)amino]methyl}pyridine-3-carboxylate (414 g, 1.38 mol, 1.0 equiv) in 1,4-dioxane (4.97 L). Add water (2.48 L) and lithium hydroxide (125.6 g, 2.96 mol, 2.5 equiv); then stir the resulting mixture for 60 min at room temperature. Concentrate the 1,4-dioxane solution to ½ volume under reduced pressure, and add hydrochloric acid (5 N, 1.16 L, 5.79 mol, 4.2 equiv) slowly to maintain temperature at less than 20° C. until the pH is 2. Collect the solids by filtration; air dry for 18 hours; and then in a vacuum oven at 40° C. for 18 hours to give a white solid, (355.4 g, 94.7% yield). MS (m/z) 303 (M+1).

Workup

  1. concentrationConcentrate the 1,4-dioxane solution
  2. temperatureto maintain temperature at less than 20° C. until the pH is 2
  3. customCollect the solids
  4. filtrationby filtration
  5. customair dry for 18 hours
  6. customand then in a vacuum oven at 40° C. for 18 hours to give a white solid, (355.4 g, 94.7% yield)

Sources & evidence

ORD record
ord-f84b6cf067d94450a290f699b2478cc6
Source dataset
uspto-grants-2014_02
Patent number
US08648200B2

Reaction notes

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