Paper
ZHAI Lihai, ZHOU Youchun, GUO Lihong, XIA Xianglai, ZHANG Guimin
The impurity, [(3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[[1,3]dioxolo)- [4,5-b:4',5'-d]pyran-3a-yl]methyl][(3aS,5aS,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis([1,3]dioxolo)- [4,5-b:4',5'-d]pyran-3a-yl]methyl]sulfamate(4), was found in the synthesis of topiramate(1). Its structure was confirmed by NMR and MS. In this paper, it was proved that 4 was resulted from the reaction of residual 2,3:4,5-bis- O-(1-methylethylidene)-β-D-fructopyranoside(3) in the oily 2,3:4,5-bis-O-(1-methyethylidene)-β-D-fructopyranose chlorosulfonate(2) with 1. Therefore, the synthetic process of 2 was improved. Compound 3 reacted with sulfuryl chloride in DCM/toluene to give the oily 2, which was purified with isopropyl ether to obtain the solid form of 2 for the first time. The content of 3 in solid 2 was reduced to 0.05%. Then the solid 2 reacted with NH3 to give 1 in a purity of 99.93% and a total yield of 87%(based on 3), which did not need the further purification. This process was easy to remove the impurities, and the intermediate 2 obtained was solid, which was convenient for storage and sampling.