Pyridine → Ethyl 2-acetamidopyridine-4-carboxylate

HRID 1870661Notes

Reaction equation

HRID 1870661 reaction equation
C([C:3]1[C:11]([NH2:12])=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])C.[C:13](Cl)(=[O:15])[CH3:14].N1C=CC=[CH:19][CH:18]=1>>[C:13]([NH:12][C:11]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH2:18][CH3:19])=[O:6])(=[O:15])[CH3:14]

Participants

4

Reactant 3

HCID 1049PyridineHCID 6367Acetyl chlorideHCID 18767899HCID 18767899, compound

Product 1

HCID 18768010Ethyl 2-acetamidopyridine-4-carboxylate

Procedure

Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-(2-acetamido)-pyridyl))-propionate: A solution of 2-chloroisonicotinic acid (25.0 g, 0.16 mol) in 65 mL of concentrated ammonium hydroxide was warmed to 205 Celsius in a steel bomb for 72 h. After cooling to 23 C, the solution was acidified to a pH of 1 using 6N HCl and subsequently filtered to remove unreacted starting material. The solution was concentrated to one fourth the original volume (approx 200 mL) in vacuo, and carefully adjusted to a pH of 6 using 1 N NaOH. After storing the cloudy solution at 0 C for 20 h, the desired 2-aminoisonicotinic acid was filtered off. To a suspension of 2-aminoisonicotinic acid in ethanol (600 mL) was added 47.1 mL of 4 N anhydrous HCl in dioxane. After warming to achieve reflux for 20 h, an additional 47.1 mL of 4 N anhydrous HCl in dioxane was added and the reaction was warmed to -reflux for an additional 20 h. Concentration with a stream of nitrogen in the hood was followed by further concentration in vacuo, the remaining solid was diluted with saturated bicarbonate (200 mL), extracted with ethyl acetate (2×200 mL), dried (Na2SO4). After concentration in vacuo, the desired ethyl 2-aminoisonicotinate was obtained. To a solution of ethyl 2-aminoisonicotinic acid in pyridine (45 mL) at 0 C under an argon atmosphere was added acetyl chloride dropwise over 5 min. After 2 h at 0 C, the reaction was pored into over ice 300 g, extracted with ethyl acetate (2×300 mL), washed with water (2×100 ml) followed by brine (2×100 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by application of flash chromatography (step gradient ethyl acetate: hexane 1:4 then ethyl acetate: hexane 1:1) to afford ethyl 2-acetamidoisonicotinate.

Workup

  1. extractionextracted with ethyl acetate (2×300 mL)
  2. washwashed with water (2×100 ml)
  3. dry with materialdried (Na2SO4)
  4. concentrationAfter concentration in vacuo
  5. customthe residue was purified by application of flash chromatography (step gradient ethyl acetate: hexane 1:4

Sources & evidence

ORD record
ord-ba0c59d356c943ea80aa79d346788598
Source dataset
uspto-grants-2000_08
Patent number
US06096753

Reaction notes

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