Background and overview[1][2]
It belongs to 2-(2-methoxyethoxy)acetaldiol and is a key intermediate in the synthesis of the drug dirithromycin. Dirithromycin is a macrolide antibiotic that is widely used clinically for the treatment of acute exacerbations of chronic bronchitis, acute bronchitis, community-acquired pneumonia, pharyngitis and tonsillitis, as well as simple skin and soft tissue infections. Is a good oral alternative to erythromycin. At present, the reported synthesis method of 2-(2-methoxyethoxy)acetal glycol mainly uses ethylene glycol monomethyl ether as the starting material and solvent, and an appropriate strong base (metal sodium or Sodium hydride), through the Williamson ether synthesis method, the strong basic intermediate 2-methoxyethoxylate is prepared, and then reacted with the glycol of haloacetaldehyde in one pot to prepare 2-(2-methoxyethoxy base) acetal glycol.
Preparation[1]
Add 91.2 g of ethylene glycol monomethyl ether into the reaction bottle, and add 40 g of sodium hydroxide under stirring to obtain a mixture; the mixture was heated to 100-130°C for vacuum distillation and dehydration reaction, and the vacuum degree was -0.09 MPa. React until no more water droplets evaporate, stop heating, and cool down to below 60°C; add 124.5 g of 2-chloroacetaldehyde dimethylacetal, then heat to 130°C for reflux condensation reaction for 8 hours until the solution no longer refluxes; react After completion, cool to room temperature, filter, collect the filtrate, add 18.7g of sodium chloride, heat to 50~60°C and keep stirring for 7 hours, then distill under reduced pressure, vacuum degree -0.09 MPa, collect the 110~116°C fraction, that is Obtain 2-(2-methoxyethoxy)acetaldimethylacetal, 152.3 g, purity 98.5%, yield 92.8%.
Apply[2]
Used in the synthesis of dirithromycin. 
Place (2-methoxyethoxy)acetaldimethylacetal (3.0g, 18.4mmol) in a three-neck flask equipped with a mechanical stirrer, and stir with CH3 containing 4% water. Dilute with CN (15mL). p-Toluenesulfonic acid (50 mg, 0.27 mmol) was added and the mixture was stirred at ambient temperature for at least 8 hours. Add (9S)-erythromycinamine (5.0 g, 6.80 mmol) portionwise over 15-20 minutes. After 30 minutes, the amine was completely dissolved. Stirring was maintained at room temperature for 10 hours, the reaction mixture was cooled to 0°C and stirred for a further 2 hours. Filter the solid, wash with cold CH3CN, and dry to obtain dirithromycin. Crystallized white solid, yield 4.75 g, 84%. Melting point: 186-189℃ (decomposition).
Main reference materials
[1] [Chinese invention, Chinese invention authorization] CN201510380237.1 A preparation method of 2-(2-methoxyethoxy)acetaldehyde glycol [public]
[2]From Synthesis, (11), 1089-91; 1993
