Report on two preparation methods of 2-acetyl-4-methylpyridine_Industrial Additives

Background and overview of two preparation methods of 2-acetyl-4-methylpyridine

2-Acetyl-4-methylpyridine is an organic intermediate in the form of colorless needle-shaped crystals. 2-Acetyl-4-methylpyridine can be obtained by reacting 2-nitrile-4-methylpyridine with methylmagnesium iodide or by reacting 4-methylpyridine with paraldehyde.

Two preparation methods of 2-acetyl-4-methylpyridine reported

Two preparation methods of 2-acetyl-4-methylpyridine reported one,

Stir 2-nitrile-4-methylpyridine (31.19 g, 229 mmol) in anhydrous benzene (300 mL)-anhydrous Et₂O (230 mL). Add 2 M MeMgI/Et₂O solution (149.0 mL, 298 mmol) dropwise over 1 hour at 0°C and N₂. The reaction mixture was warmed to room temperature. The mixture was stirred under nitrogen for 1 hour. Cool the mixture to 0°C.

Add aqueous NH4Cl solution (120 mL) dropwise to the mixture at 0°C. Warm the resulting mixture to room temperature and stir for 1 hour.

The aqueous layer was removed and the organic layer was washed with water. Dry each layer with anhydrous MgSO₄. Filter and concentrate in vacuo. The residue was purified by flash column chromatography (silica gel, hexane/AcOEt = 8:1) to obtain 2-acetyl-4-methylpyridine.

Two preparation methods of 2-acetyl-4-methylpyridine report 2,

Add 4-methylpyridine (20 g, 215 mmol), trifluoroacetic acid (TFA, 24.5 g, 215 mmol), tert-butyl hydroperoxide (53.4 mL of 70 wt% aqueous solution, 415 mmol, Acros), A solution of iron (II) sulfate heptahydrate (1.0 g, 3.60 mmol) and paraldehyde (142 g, 1.07 mol) in MeCN (120 mL) was heated to reflux for 4 h. The reaction mixture was concentrated by distillation, cooled to room temperature, neutralized with saturated aqueous Na2CO3, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc: n-hexane = 1:4) to obtain the title compound as colorless needles, yield (5.80 g, 20%).

TLC (EtOAc:n-hexane = 1:4) R_f = 0.50; ¹H NMR (CDCl₃) δ 8.54 (d, J = 4.8, 1H), 7.86 (s, 1H), 7.30 (dd, J = 4.8, 0.9, 1H), 2.72 (s, 3H), 2.43 (s, 3H).

References

[1] Hayashi S , Ueno N , Murase A , et al. Novel acid-type cyclooxygenase- 2 inhibitors: Design, synthesis, and structure-activity relationship for anti-inflammatory drug.[J]. European Journal of Medicinal Chemistry, 2012, 50(none):179-195.

[2] Choi J S , Kang C W , Jung K , et al. Synthesis of DNA Triangles with Vertexes of Bis(terpyridine)iron(II) Complexes[J]. Jou Basic Magnesium Carbonate RNA of the American Chemical Society, 2004, 126(28):8606-7.