2-Methoxy-5-nitro-3-picoline Chemical Properties

Boiling point:

279.7±35.0 °C(Predicted)

Density 

1.247±0.06 g/cm3(Predicted)

storage temp. 

Sealed in dry,Room Temperature

pka

-0.34±0.20(Predicted)

Appearance

Off-white to light yellow Solid

InChI

InChI=1S/C7H8N2O3/c1-5-3-6(9(10)11)4-8-7(5)12-2/h3-4H,1-2H3

InChIKey

HEDKXDCXKNQWEX-UHFFFAOYSA-N

SMILES

C1(OC)=NC=C([N+]([O-])=O)C=C1C

CAS DataBase Reference

89694-10-0(CAS DataBase Reference)

Safety Information

HS Code 

2933399990

2-Methoxy-5-nitro-3-picoline Usage And Synthesis

Chemical Properties

Off-white solid

Uses

2-Methoxy-3-methyl-5-nitropyridine is used in the preparation of heteroaromatic cyanoindoline derivative for use as NIK inhibitors.

Synthesis

1. 3-Methyl-5-nitropyridin-2-ol (134 g, 0.872 mol) was divided equally into three equal portions and placed in three 1L round bottom flasks. Phosphorus oxychloride (POCl3, 200mL) was added to each flask and the mixture was heated to reflux for 2 hours. Upon completion of the reaction, the solution was cooled and the excess POCl3 was removed under vacuum. the residue was slowly poured into ice water (1 L) under stirring, the precipitate was collected by filtration, and air-dried for 20 minutes. The products were combined and recrystallized using a hexane solution of 10% ethyl acetate (300 mL) and air dried to give 2-chloro-3-methyl-5-nitropyridine (139 g, 92% yield) as a white solid, which could be used in the next reaction without further purification. Product characterization data: 1H NMR (300MHz, CDCl3) δ 9.04 (d, J=2.5Hz, 1H), 8.33 (d, J=2.2Hz, 1H), 2.50 (s, 3H). 2. 2-Chloro-3-methyl-5-nitropyridine (139 g, 0.806 mol) prepared in the above steps was divided into two equal portions and placed in two 2L round-bottomed flasks and methanol (500 mL) was added. The solution was cooled in a dry ice/isopropanol bath and solid sodium methanol (26.5 g, 0.467 mol) was added in batches, controlling the reaction temperature below 20 °C. After the addition was completed, the mixture was heated to reflux for 1 hour. At the end of the reaction, the mixture was cooled and diluted with ice water (500 mL) to produce a white precipitate, which was collected by filtration. The combined filter cake was washed with water and air dried to give 2-methoxy-3-methyl-5-nitropyridine (127 g, 97% yield) as a white solid. Product characterization data: 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J=2.0 Hz, 1H), 8.16 (s, 1H), 4.06 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.83,141.91,139.37,132.92, 121.77,54.83,15.84. The analyzed sample was recrystallized from hexane to obtain white needle-like crystals with the melting point of 95-96.5 ℃. Elemental analysis results (C7H8N2O3): calculated value C 50.00, H 4.79, N 16.66; measured value C 49.73, H 5.02, N 16.48.

References

[1] Patent: US2010/29684, 2010, A1. Location in patent: Page/Page column 5; 14
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 23, p. 7653 - 7668
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3056 - 3062

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