新型Na^+依赖性葡萄糖共转运体2(SGLT2)抑制剂6-脱氧canagliflozin的简便合成方法及其晶型研究

A Facile Synthetic Route and Study of Crystalline Form of Novel SGLT2 Inhibitor 6-Deoxycanagliflozin

目的开发一条合成新型Na+依赖性葡萄糖共转运体2(SGLT2)抑制剂6-脱氧canagliflozin的简便实用的路线,并研究其可供药用的晶型。方法利用6-脱氧葡萄糖片段和含噻吩的苷元片段作为起始原料,经过3步反应合成了目标分子6-脱氧canagliflozin。使用从溶剂中结晶的方法来制备不同晶型,使用粉末X-射线衍射和差热分析来测定晶型。结果得到了一条简便实用的合成6-脱氧canagliflozin的路线,并获得了其2个晶型和1个与L-脯氨酸的共结晶。结论新合成路线具有步骤短、产率高的优点。6-脱氧canagliflozin的晶型B比较稳定,可以作为其最佳药用形式。

OBJECTIVE To develop a facile synthetic route of novel SGLT2 inhibitor 6-deoxycanagliflozin and find its pharmaceutically acceptable crystalline forms. METHODS 6-Deoxycanaglifiozin was synthesized from a 6-deoxyglucose fragment and a thio- phene-bearing aglycone in 3 steps. The crystalline forms were prepared by crystallization from a variety of solvents and characterized by power X-Ray diffraction and differential thermal analysis. RESULTS A facial synthetic route of 6-deoxycanagliflozin was developed. Two crystalline forms of 6-deoxycanaglifiozin and a cocrystal of 6-deoxycanagliflozin with L-proline were obtained. CONCLUSION The synthetic route is highlighted by less steps and higher yield. The crystalline form B is very stable and therefore can be used as a pharmaceutically acceptable form for API.