3-NITROISONICOTINALDEHYDE Chemical Properties

Melting point:

53-54 °C

Boiling point:

310.0±27.0 °C(Predicted)

Density 

1.432±0.06 g/cm3(Predicted)

storage temp. 

Inert atmosphere,Store in freezer, under -20°C

pka

-0.78±0.18(Predicted)

Appearance

Light yellow to yellow Solid

Safety Information

HS Code 

2933399990

3-NITROISONICOTINALDEHYDE Usage And Synthesis

Uses

3-Nitro-4-pyridinaldehyde is used in laboratory research and development and in chemical and pharmaceutical synthesis processes.

Synthesis Reference(s)

Tetrahedron Letters, 35, p. 219, 1994 DOI: 10.1016/S0040-4039(00)76515-4

Synthesis

General procedure for the synthesis of 3-nitropyridine-4-carbaldehyde from the compound (CAS: 908847-23-4): 1. Preparation of intermediate 12: (3R/S)-3-Amino-L-FF(4R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl-3,4-dihydro-1,7-naphthyridin-2(1H)-one (1.43 g, 10.36 mmol) was dissolved in anhydrous DMF (5 mL), and dimethylformamide dimethyl acetal (2.0 g. 16.8 mmol). The mixture was heated at 140 °C for 2 h under nitrogen protection and evaporated under reduced pressure to give (E)-N,N-dimethyl-2-(3-nitropyridin-4-yl)ethylideneamine as a dark red solid. 2. Oxidation reaction: The above product was added to a stirred THF/water (1:1, 100 mL) solution of sodium periodate (6.61 g, 31 mmol) in one go at room temperature. After stirring for 2 h at room temperature, the reaction mixture was filtered and the solid was washed with ethyl acetate (100 mL). The washings and filtrate were combined and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (100 mL), the organic layers were combined and washed sequentially with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL), dried (MgSO?) and evaporated under reduced pressure to give a brown solid. Purification by column chromatography (DCM) gave 3-nitroisonicotinaldehyde (960 mg, 61%). 3. 1H NMR data: δ 7.8 (d, 1H); 9.15 (d, 1H); 9.4 (s, 1H); 10.4 (s, 1H). 4. methyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (1.73 g, 5.82 mmol) was dissolved in anhydrous THF (20 mL) and cooled to -78 °C under nitrogen protection. Tetramethylguanidine (638 mg, 5.55 mmol) was added and stirred at -78 °C for 10 min. Anhydrous THF (5 mL) solution of 3-nitroisonicotinic acid hydrazide (804 mg, 5.29 mmol) was added dropwise. The dark red solution was stirred at -78 °C for 2 h and poured into a mixture of ethyl acetate (100 mL) and water (50 mL). The organic layer was separated, washed with water (2 x 50 mL) and brine (25 mL), dried (MgSO?) and evaporated under reduced pressure to give a yellow oil. Purification by column chromatography (EtOAc:isohexane 1:1) afforded methyl-2-[(tert-butoxycarbonyl)amino]-3-(3-nitropyridin-4-yl)acrylate as a 10:1 mixture of Z/E isomers (1.57 g, 92%). 5. 1H NMR data: δ 1.3 (s, 9H); 1.4 (s, 0.9H); 3.55 (s, 0.3H); 3.8 (s, 3H); 6.6 (s, 0.1H); 7.2 (s, 1H); 7.25 (d, 0.1H); 7.5 (d, 1H); 8.75 (d, 0.1H); 8.8 (s, 1.1H); 8.85 (d, 1H); 9.2 (s, 0.1H); 9.25 (s, 1H); MS m/z 322. 6. 2-[(tert-butoxycarbonyl)amino]-3-(3-nitropyridin-4-yl)acrylic acid methyl ester (10:1 mixture of Z/E isomers) (1.57 g, 4.83 mmol) was dissolved in ethanol and 10% palladium/carbon catalyst (250 mg) was added. The mixture was stirred for 6 h at room temperature under 1 atm hydrogen. After diatomaceous earth filtration to remove the catalyst, the filtrate was concentrated under reduced pressure to give a yellow oil. Purification by column chromatography (eluent DCM/MeOH gradient 0-10%) afforded tert-butyl (2-oxo-1,2,3,4-tetrahydro-1,7-diazanaphthalen-3-yl) carbamate (284 mg, 22%). 7. 1H NMR data: δ 1.4 (s, 9H); 3.0 (m, 2H); 4.2 (m, 1H); 7.0 (d, 1H); 7.2 (d, 1H); 8.1 (m, 2H); 10.36 (s, 1H); MS m/z 264. 8. tert-Butyl (2-oxo-1,2,3,4-tetrahydro-1,7-diazanaphthalen-3-yl) carbamate (284 mg) was dissolved in DCM (10 mL) and trifluoroacetic acid (5 mL) was added. After stirring at room temperature for 1 h, the reaction mixture was evaporated under reduced pressure and the residue was ground with ether (20 mL) to give a light brown solid. It was collected by filtration, washed with ether and dried to give 3-amino-3,4-dihydro-1,7-diazanaphthalen-2(1H)-one (346 mg, 82%) as trifluoroacetic acid bis salt. 9. 1H NMR data: δ 3.2 (m, 2H); 4.3 (m, 1H); 7.4 (d, 1H); 8.2 (s, 1H); 8.25 (d, 1H); 8.6 (b, 3H); 11.0 (s, 1H). 10. Sodium hydride (1.18 g, 60% dispersion in oil, 29.4 mmol) was added to a solution of (3R/S)-3-amino-3,4-dihydro-1,7-diazanaphthalen-2(1H)-one (2.24 g, 9.4 mmol) in anhydrous DMF (40 mL), and the mixture was heated to 80 °C and stirred for 30 min. [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl] methyl methanesulfonate (2 mL, 10.4 mmol) was added and the reaction was stirred at 80 °C for 19 hours. After cooling, the mixture was diluted with DCM (450 mL) and purified by fast column chromatography (SiO?, eluent: DCM to DCM:MeOH, 85:15 to DCM:MeOH:NH?OH, 80:20:0.7), and the solvent was removed under reduced pressure to give 3-nitropyridine-4-carbaldehyde (1.1 g, 42%) as an oil. 11. 1H NMR data: δ 1.23 (m, 3H), 1.26 (s, 1.8H), 1.28 (s, 1.2H), 3.52 (m, 1H), 3.68 (m, 1H), 4.02 (m, 2H), 4.15 (m, 1H), 4.31 (m, 1H), 7.27 (br d, 1H), 8.21 (d, 1H). 8.55 (d, 1H); MS m/z 278.

References

[1] Tetrahedron Letters, 1994, vol. 35, # 2, p. 219 - 222
[2] Patent: WO2005/20987, 2005, A1. Location in patent: Page/Page column 58
[3] Patent: WO2003/74532, 2003, A1. Location in patent: Page/Page column 112

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