托吡酯的合成工艺改进

本研究发现在托吡酯(1)的合成过程中可生成杂质[(3aS,5aR,8aR,8bS)-2,2,7,7-四甲基四氢-3aH-双[[1,3]二氧戊环]-并[4,5-b:4',5'-d]吡喃-3a-基]甲基[(3aS,5aS,8aR,8bS)-2,2,7,7-四甲基四氢-3aH-双[[1,3]二氧杂戊环]并[4,5-b:4',5'-d]吡喃-3a-基)甲基]氨基磺酸酯(4),其结构经核磁和质谱鉴定确证,证明4是由油状物2,3:4,5-双-O-(1-甲基亚乙基)-β-D-吡喃果糖氯磺酸酯(2)中残余的2,3:4,5-双-O-(1-甲基亚乙基)-β-D-吡喃果糖苷(3)与1反应引起。因此,对2合成工艺进行了改进。将3与磺酰氯在二氯甲烷/甲苯混合溶剂中反应得油状物2,经异丙醚精制首次制得固体2,其中3的含量降至0.05%。将固体2与氨气反应得1,产品无需精制,纯度99.93%,总收率87%(以3计)。该工艺易于除去杂质,所得中间体2为固体,存储取样方便。

Improved Synthetic Process of Topiramate

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.