4-hydroxy-5-methoxy-2-nitrobenzaldehyde

Compound 2 (10 g, 0.03 mol) was added to a 500 mL round bottom flask.Dissolve with 200mL of trifluoroacetic acid, add a small amount of dichloromethane if it is not soluble.Stir at room temperature and react overnight. TLC (DCM) was used to detect the extent of the reaction.After the reaction is over, The solvent was spun and the ethyl acetate dissolved in the dried solid.Alkali to 1 to 10 with 1 mol/L NaOH, The residual trifluoroacetic acid was removed and acidified to a pH of about 5 with 6 mol/L HCl to react the sodium phenolate into a phenolic hydroxyl group. Extracted with ethyl acetate, The combined organic phases were dried over anhydrous sodium sulfate and dried to dryness.N-hexane has poor solubility in the product and good solubility in impurities.Rinse the product with n-hexane and dry.5 g of a yellow solid, Compound 3, was obtained in a yield of 72.9percent.2-Nitrovanilin (2) was synthesized via a flow nitration of vanillin acetate (1 ) in a micro reactor. 3.94 kg of nitric acid (65 wpercent) were added to 5.87 kg of concentrated sulfuric acid at 0 (nitrating acid). 1 .5 kg of va nillin acetate were dissolved in 2.9 kg of dichloromethane (vanillin acetate solution). Both solutions reacted in a micro reactor with flow rates of app. 8.0 mL/min (nitrating acid) and app. 4.0 mL/min (vanillin acetate solution) at 5. The reaction mi xture was directly dosed into 8 kg of water at 3 . After 3h flow rates were increased to 10 mL/min (nitrating acid) and 5.0 mL/min (vanillin acetate solution). After additional 9 h the flow reaction was completed. The layers were separated at r.t., and the aqueous phase was extracted with 2 L of dichloromethane. The combined organic phases were washed with 2 L of saturated sodium bicarbonate, and then 0.8 L of water. The dichloromethane solution was concentrated in vacuum to app. 3 L, 3.9 L of methanol were added and app. the same volume was removed by distillation again. Additional 3.9 L of methanol were added, and the solution concentrated to a volume of app. 3.5 L. 1 .25 kg of methanol were added, followed by 2.26 kg of potassium carbonate. The mixture was stirred at 30 for 3h. 7.3 kg of dichl oromethane and 12.8 kg of aqueous hydrochloric acid (10 wpercent) were added at < 30 (pH 0.5 - 1 ). The mixture was stirred for 15 min, and the layers were separated. The organic layer was filtered, and the filter cake washed with 0.5 L of dichloromethane. The aqueous layer was extracted twice with 4.1 kg of dichloromethane. The combined organic layers were concentrated in vacuum to app. 4 L. 3.41 kg of toluene were added, and the mixture concentrated to a final volume of app. 4 L. The mixture was cooled to 0. After 90 min the suspension was filtered. T he collected solids were washed with cold toluene and dried to give 0.95 kg (62 percent). : Step A1 : Preparation of 4-acetoxy-3-methoxy-2- nitrobenzaldehyde (2) 3.94 kg of nitric acid (65 wpercent) were added to 5.87 kg of concentrated sulfuric acid at 0°C (nitrating acid). 1 .5 kg of vanillin acetate were dissolved in 2.9 kg of dichloromethane (vanillin acetate solution). Both solutions reacted in a micro reactor with flow rates of app. 8.0 mL/min (nitrating acid) and app. 4.0 mL/min (vanillin acetate solution) at 5°C. The reaction mixture was directly dosed into 8 kg of water at 3°C. After 3h flow rates were increased to 10 mL/min (nitrating acid) and 5.0 mL/min (vanillin acetate solution). After additional 9 h the flow reaction was completed. The layers were separated at r.t., and the aqueous phase was extracted with 2 L of dichloromethane. The combined organic phases were washed with 2 L of saturated sodium bicarbonate, and then 0.8 L of water. The dichloromethane solution was concentrated in vacuum to app. 3 L, 3.9 L of methanol were added and app. the same volume was removed by distillation again. Additional 3.9 L of methanol were added, and the solution concentrated to a volume of app. 3.5 L. This solution of 4-acetoxy-3-methoxy-2- nitrobenzaldehyde (2) was directly used in the next step. : Step A2 : Preparation of 4-hydroxy -3-methoxy-2- nitrobenzaldehyde (2-nitro-vanillin) (3) To the solution of 4-acetoxy-3-methoxy-2-nitrobenzaldehyde (2) prepared as described in (see above) 1 .25 kg of methanol were added, followed by 2.26 kg of potassium carbonate. The mixture was stirred at 30°C for 3h. 7.3 kg of dichloromethane and 12.8 kg of aqueous hydrochloric acid (10 wpercent) were added at < 30°C (pH 0.5 - 1 ). The mixture was stirred for 15 min, and the layers were separated. The organic layer was filtered, and the filter cake washed with 0.5 L of dichloromethane. The aqueous layer was extracted twice with 4.1 kg of dichloromethane. The combined organic layers were concentrated in vacuum to app. 4 L. 3.41 kg of toluene were added, and the mixture concentrated to a final volume of app. 4 L. The mixture was cooled to 0°C. After 90 min the suspension was filtered. The collected solids were washed with cold toluene and dried to give 0.95 kg (62 percent). After fuming nitric acid (50 mL) was cooled at -20 ° C., The acetate salt obtained above was added in small portions. Then, After stirring the mixture at -10 to 0 ° C. for 3 hours, Poured into ice cold water (~ 200 mL) and stirred for 10 minutes.The mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, After drying with anhydrous Na 2 SO 4, Evaporation to dryness gave a crude product.The crude product obtained above was added to a 2 M KOH solution (200 mL)Reflux heating was carried out for 15 minutes.After cooling to room temperature, the reaction was stopped by slowly adding concentrated hydrochloric acid at 0 ° C.After filtering the solid matter, washing with cold water and vacuum drying, A mixture of Compound 1 as a brown solid and its regioisomer was obtained (7.6 g,

Molecular Weight:197.14
XLogP3:0.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:197.03242232
Monoisotopic Mass:197.03242232
Topological Polar Surface Area:92.4
Heavy Atom Count:14
Complexity:226
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes