4-FLUORO-2-METHOXYBENZALDEHYDE Chemical Properties

Melting point:

55 °C

Boiling point:

224.6±20.0 °C(Predicted)

Density 

1.192±0.06 g/cm3(Predicted)

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

solubility 

soluble in Methanol

form 

powder to lump

color 

White to Orange to Green

Sensitive 

Air Sensitive

CAS DataBase Reference

450-83-9(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xi,Xn

Risk Statements 

36/37/38-52-41-37/38-22

Safety Statements 

26-36-39

Hazard Note 

Irritant

HS Code 

29124990

4-FLUORO-2-METHOXYBENZALDEHYDE Usage And Synthesis

Uses

4-Fluoro-2-methoxy-benzaldehyde is used in the synthesis of imidazopyridazinones acting as novel PDE7 inhibitors for application towards Parkinson’s disease treatment.

Synthesis

3-Fluorophenol (20 g, 0.2 mol) was dissolved in molecular sieve-dried acetonitrile (500 mL), stirred under argon protection, and anhydrous magnesium chloride (102 g, 1.1 mol) was added. after 5 min, triethylamine (225 mL, 1.6 mol) was added, and an exothermic mixture was observed. After continued stirring for 30 min, paraformaldehyde (63 g) was added and the reaction was carried out for 3 h at 50 °C. Upon completion of the reaction, the pH was adjusted to 4 with 1N aqueous hydrochloric acid and the mixture was subsequently extracted with ethyl acetate (3 x 150 mL). The organic phases were combined, dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 49.9 g of a dark red oily crude product (containing 4-fluoro-2-methoxybenzaldehyde and 2-fluoro-6-methoxybenzaldehyde), which was subsequently solidified. The crude product was dissolved in tetrahydrofuran (100 mL), potassium carbonate (81.2 g, 0.6 mol) and dimethyl sulfate (25.4 mL, 0.3 mol) were added, and the reaction was carried out at 40 °C overnight. Complete consumption of the raw materials was confirmed by TLC. Potassium carbonate was removed by filtration and the solid was washed with ethyl acetate (3 x 100 mL). The organic phases were combined, dried and concentrated with anhydrous magnesium sulfate. The residue was purified by column chromatography (eluent was petroleum ether/ethyl acetate, 15:1, v/v) to afford the intermediate 4-fluoro-2-methoxybenzaldehyde (15.8 g) and the by-product 2-fluoro-6-methoxybenzaldehyde (2.8 g), both as pale yellow solids, in an overall yield of 68%. 4-fluoro-2-methoxybenzaldehyde: melting point: °C; 1H NMR (300 MHz. CDCl3) δ 10.4 (1H, s), 7.85 (1H, dd, J = 8.4 Hz, 6.9 Hz), 6.75-6.67 (2H, m), 3.93 (3H, d, J =11.0 Hz), 13C NMR (75MHz, CDCl3) δ 130.9 (d, J =11.6 Hz), 121.6 (d, J = 2.7 Hz), 108.1 (d, J =22.1 Hz), 99.7 (d, J =25.7 Hz), 56.0. 2-Fluoro-6-methoxybenzaldehyde: melting point: 60-61 °C; 1H NMR (300 MHz, CDCl3) δ 10.3 (1H, s), 7.41 (1H, dd, J =15.0 Hz, 8.4 Hz), 6.71-6.61 (2.2). 6.71-6.61 (2H, m), 3.85 (3H, s), 13C NMR (75MHz, CDCl3) δ 187.4 (d, J = 3.4 Hz), 163.3 (d, J = 260.5 Hz), 162.2 (d, J = 5.4 Hz), 136.2 (d, J = 12.0 Hz), 114.0, 108.6 ( d, J = 21.3 Hz), 107.3 (d, J = 3.5 Hz), 56.3.

References

[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[2] Patent: CN104557654, 2017, B. Location in patent: Paragraph 0086-0088

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