Aim To optimize the reaction condition for preparation of 3-spiro-1, 3, 4-oxadiazole substituted fructose and hydrolysis of its isopropylidenes stepwisely. Methods Cyclohexane was added to the reaction mixture every 8 h to remove acetic acid at 90 ℃. The isopropylidenes were hydrolyzed in 80% AcOH at 60 ℃ stepwisely in a reaction time- dependent manner. Results The yields of cyclization products 1b and 1c were improved from 53% and 51% to 74% and 79% respectively. The 1, 2-di-O-isopropylidene product 3 was obtained after 1 h and the total deprotected product 4 was obtained after 3 h in 80% AcOH at 60 ℃. Conclusion The yield of 1 is improved by cyclohexane-aided azeotropic removal of AcOH from the reaction mixture. Deprotection of 1 in 80% AcOH at 60 ℃ gives 3 or 4 after different time periods.
