Seki Masahiko, Tapkir Sandeep Ramesharao, Nadiveedhi Maheshwara Reddy, Kalita Subarna Jyoti, Mulani Shaheen Kasim, Mashima Kazushi
R&D Planning Department, Tokuyama Corporation, Tsukuba, Ibaraki 300-4247, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
J Org Chem. 2023 Nov 3;88(21):15367-15373. doi: 10.1021/acs.joc.3c01873. Epub 2023 Oct 20.
Disclosed herein is a novel and efficient synthesis of dapagliflozin and canagliflozin, the most advanced sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors), for the treatment of type 2 diabetes mellitus (T2DM). Per Ac-protected thioester was prepared by the treatment of per Ac d-gluconolactone with 1-dodecanethiol and PrMgCl without affecting labile Ac-protecting groups. Aryl bromide (ArBr) was synthesized through reduction of diaryl ketone to diaryl methane by the TiCl/NaBH/DME-MeOH reduction system. Fukuyama coupling of the thioester with aryl zinc reagent prepared from ArBr gave a multifunctional aryl ketone at 40 °C in a high yield where the use of a limited amount of a mixed solvent (7.2 volumes (v), THF:toluene:DMF = 3v/4v/0.2v) was crucial to achieve the higher yield. After cleavage of the THP group, hydroxy ketone obtained was treated with methanesulfonic acid (MSA) in MeOH to give a methoxy-cyclized product in a single step and in a quantitative yield, which was allowed to silane reduction to furnish dapagliflozin in an excellent yield. By following the same procedure, canagliflozin was synthesized. The current synthetic method is featured by high yields, mild reaction conditions, and the use of inexpensive reagents and readily cleavable protecting groups.
本文公开了一种用于治疗2型糖尿病（T2DM）的新型高效合成达格列净和卡格列净的方法，达格列净和卡格列净是最先进的钠葡萄糖协同转运蛋白2抑制剂（SGLT2抑制剂）。通过用1-十二烷硫醇和PrMgCl处理全乙酰基保护的d-葡萄糖内酯来制备全乙酰基保护的硫酯，而不影响不稳定的乙酰基保护基团。通过TiCl/NaBH/DME-MeOH还原体系将二芳基酮还原为二芳基甲烷来合成芳基溴（ArBr）。硫酯与由ArBr制备的芳基锌试剂的福山偶联在40℃下以高产率得到多功能芳基酮，其中使用有限量的混合溶剂（7.2体积（v），THF：甲苯：DMF = 3v/4v/0.2v）对于实现更高产率至关重要。在THP基团裂解后，将得到的羟基酮在MeOH中用甲磺酸（MSA）处理，一步定量得到甲氧基环化产物，然后进行硅烷还原，以优异的产率得到达格列净。按照相同的程序合成了卡格列净。目前的合成方法具有产率高、反应条件温和以及使用廉价试剂和易于裂解的保护基团的特点。
