METHYL 3-FORMYL-4-HYDROXYBENZOATE Chemical Properties

Melting point:

80-84 °C

Boiling point:

299.3±25.0 °C(Predicted)

Density 

1.310±0.06 g/cm3(Predicted)

storage temp. 

Keep in dark place,Sealed in dry,Room Temperature

form 

solid

pka

6.56±0.18(Predicted)

color 

Pale yellow

InChI

InChI=1S/C9H8O4/c1-13-9(12)6-2-3-8(11)7(4-6)5-10/h2-5,11H,1H3

InChIKey

ADSJCWKOKYOJSZ-UHFFFAOYSA-N

SMILES

C(OC)(=O)C1=CC=C(O)C(C=O)=C1

Safety Information

Hazard Codes 

Xn

Risk Statements 

22-36/37/38

Safety Statements 

26

WGK Germany 

3

RTECS 

DH1421520

Hazard Note 

Harmful

HS Code 

29189900

METHYL 3-FORMYL-4-HYDROXYBENZOATE Usage And Synthesis

Uses

Methyl 3-Formyl-4-hydroxybenzoate is a useful synthetic intermediate in the synthesis of 1,2-Benzisoxazole-5-carboxylic Acid (B197900). Also a useful synthetic intermediate in the synthesis of Roflumilast (R639700); a selective phosphodiesterase 4 (PDE4) inhibitor and antiasthmatic in the treatment of chronic obstructive pulmonary disease.

Synthesis

The general procedure for the synthesis of methyl 3-formyl-4-hydroxybenzoate from formaldehyde and methyl nipagin was as follows: methyl 4-hydroxybenzoate (3.00 g, 19.7 mmol) and magnesium chloride (2.81 g, 29.5 mmol) were dissolved in 100 mL of acetonitrile and mixed by stirring. Subsequently, triethylamine (TEA, 10.3 mL, 73.9 mmol) was slowly added via syringe. Next, paraformaldehyde (12.0 g, 133 mmol) was added all at once and the reaction mixture was heated to reflux. After keeping the reaction stirred under reflux conditions for 24 hours, it was cooled to room temperature. Upon completion of the reaction, the reaction was quenched by addition of about 100 mL of 1N hydrochloric acid (HCl) and the mixture was poured into ethyl acetate (EtOAc). The organic and aqueous layers were separated and the organic layer was washed with saturated brine. The aqueous layer was back-extracted with ethyl acetate (EtOAc). All organic layers were combined, dried with anhydrous magnesium sulfate (MgSO4), filtered and concentrated in vacuum by rotary evaporator. The crude product was purified by fast column chromatography. Pure grades collected and confirmed by thin layer chromatography (TLC) were concentrated under vacuum to give 2.06 g (58% yield) of the target product, methyl 3-formyl-4-hydroxybenzoate. The structure of the product was confirmed by 1H NMR (400 MHz, DMSO-d6): δ 11.54 (s, 1H), 10.27 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.03 (dd, J = 8.8, 2.4 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 3.79 (s, 3H).

References

[1] Organic Syntheses, 2005, vol. 82, p. 64 - 68
[2] Journal of the American Chemical Society, 2009, vol. 131, # 43, p. 15608 - 15609
[3] Patent: US2008/300242, 2008, A1. Location in patent: Page/Page column 36
[4] Patent: WO2004/62661, 2004, A1. Location in patent: Page/Page column 35-36
[5] Tetrahedron Letters, 2016, vol. 57, # 52, p. 5914 - 5918

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