5-substituted isoxazole-3-carboxylic acid ester compounds are widely used in the study of active molecules such as drugs,bactericides and herbicides, Therefore, it is particularly important to study and develop large-scale preparation routes for these compounds. In this paper, 27 5-alkyl or aryl substituted methyl isoxazol-3-carboxylate molecules are synthesized by one-pot method, The intermediate products do not require separation and purification treatment, and the operating process is simple. At the same time, reaction processes can be carried out in a single solvent methanol, which is easy to handle and recover. This process avoids the use of flammable base, such as butyl lithium, sodium hydride, or easily hygroscopic tertbutanol potassium, and more cheaper and milder sodium methoxide are used, which is safer and more operable in industrial scale production. At the same time, it also avoids the use of high cost solvents such as tetrahydrofuran, which are compatible with butyl lithium, sodium hydride, and potassium tertbutanol, reducing production costs. Most importantly, after the end of the reaction, most of the solid products are precipitated in the form of crystals, which can be obtained by direct filtration without further purification, and the purity can basically reach more than 95%. The whole synthesis process is safe and simple, suitable for large-scale batch preparation.