Abstract: Monoglyceride is a crucial intermediate for preparing high-value fatliquors for leather and bio-plasticizers for PVC synthetic leather. However, the products obtained by using the traditional synthesis method are the mixture of mono-, di- and tri-glycerides, in which the content of monoglycerides is generally lower than 50%. Meanwhile, extracting the monoglycerides from the mixture is also a challenge. The high-purity monoglycerides can be directly synthesized by using the dihydroxyl protection method, but the deprotection reaction condition, which is the most crucial for the purity of the final products, is difficult to control. Here, using lauric acid as a representative, isopropylidene glyceryl laurate was synthesized by using the dihydroxyl protection method, and the deprotection reaction conditions were optimized by using the response surface methodology. The theoretical prediction fitted well with the experimental results. It was demonstrated that the purity of glycerol monolaurate prepared by using the dihydroxy protection method could reach 95.5% under the optimal deprotection reaction conditions, i.e., 3.4 molar ratio of water to isopropyl glycerol laurate, reaction temperature of 44 ℃, reaction time of 5 h, and the hydrochloric acid concentration of 0.9%. The present effort may lay the foundation for leather industry to prepare monoglyceride-based high-value leather chemicals.