The Synthesis Route Design And Preparation Of 2,3-dimethoxy Benzaldehyde

Drug price directly affects the people’s burden of medical. The most effective way to lower down the price of drugs is reduction the cost of the drug preparation. Decrease the price of raw materials for synthetic drug and resulting reduce the price ofdrug is an event of the national economy and people’s livelihood. 2,3-dimethoxy-benzaldehyde is a very important pharmaceutical intermediate. It is vital significant to design a high efficiency and environment friendly route to reduce the cost of 2,3-dimethoxy-benzaldehyde preparation. Based on inverse synthetic method, threesynthetic routes forpreparation of 2,3-dimethoxybenzaldehyde have been designed and explored.At the first, 2,3-dihydroxy toluene was synthesized from o-cresol, then etherification to give 2,3-dimethoxy-toluene. Due to the poor selectivity and activity in the oxidation reaction, the route one was gave up. Second one: 3-bromo-5-tert-butyl-2-hydroxy-benzaldehyde was obtained with total yield of 93.5% from the formylation reaction of 4-tertiarybutylphenol, then bromination reaction. But the de-tert-butyl of 3-bromo-5-tert-butyl-2-hydroxy-benzaldehyde to produce 3-bromo-2-hydroxy-benzaldehyde was difficult. So the works have been focused on the third one as following: 2-bromo-4-tertiary-butylphenol was obtained by the bromination of 4-tertiary-butylphenol in the yield of 99.5%. The catalytic properties of different catalysts in thetert-butyltransfer reaction to produce 2-bromophenol were evaluated. When the reaction was run at 40℃ for 5h at molar ratio of 2- bromo-4-tert-butylphenol: Al Cl3: phenol being 1:1:3, the conversion was 69.2%. In this reaction, the tert butyl transferred from 2-bromo-4-tert-butylphenol to phenol, forming 2-bromophenol, while phenol converted to 4-tert-butylphenol. This process realized not only the orientation of Br but also the circulation of t-Butyl. When toluene was used as tert butylreceptor and the solvent, trace amount of water in the reaction system can improve the activity of Al Cl3. When the reaction was run at 40℃ for 5h at molar ratio of 2-bromo-4-tert-butylphenol:Al Cl3:H2O being 1:0.8:0.13, the conversion 2-bromo-4-tertbutylphenol to 2-bromophenol was 96.0%. The combination of hydrogen chloride or hydrogen bromide with Al Cl3 can improve the reactivity of Al Cl3 and reduce the dosage of it. The real catalyst in the tertiary butyl transfer reaction may be aluminum chloride acid forming from the Al Cl3 and HCl. The formylation of 2-bromophenol produced 2-hydroxyl-3-bromo-benzaldehyde in the yield of 94.0%. With cuprous bromide as the catalyst, the methoxylation of 2-hydroxy-3-bromo-benzaldehyde can’t occur when KOH was used as the base, DMC as methyl and methoxyl agent. In stand of the methoxylation of Br group, methyl etherification of phenol hydroxyl was under gone.When using sodium methoxide as base, methoxylation of Br group can be donein solvent of DMF or DMC. When DMC as the solvent in themethoxylation of Br group, methyl etherification reaction of hydroxyl can’t befurther gone. While using DMF as solvent, the 2,3-dimethoxybenzaldehyde can be obtained in “a pot” by themethoxylation of Br group using sodium methoxide as base and further etherification of OH by adding the DMC in the yield of 84.1%.