We describe the process research and development of a practical synthesis of glucokinase activator 1 as a potential drug for treating type 2 diabetes mellitus. The key structure, a 3,4-cis-difluorinated cyclopentane moiety, was constructed via diastereoselective epoxidation, followed by one-pot difluorination with Et₃N·3HF and perfluorobutanesulfonyl fluoride (PBSF). Julia olefination of benzothiazol-2-yl sulfone with glyoxylate furnished an E/Z mixture of acrylate, followed by isomerization of the alkene to the desired E configuration during the formation of the acid chloride in the final step. This development achieved a highly practical process route to 1 (15% overall yield, 12 steps). This process route overcomes the drawbacks of the original medicinal chemistry synthetic route, which used hazardous and costly reagents (LiAlH₄, OsO₄, and Deoxo-Fluor) and had low efficiency (<4% overall yield, 20 steps).

中文翻译：

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实用和可扩展性合成的葡萄糖激酶激活剂通过一锅二氟化和朱莉娅Olefination

我们描述了作为一种潜在药物治疗2型糖尿病的实用合成葡萄糖激酶激活剂1的过程研究和开发。通过非对映选择性环氧化，然后用Et ₃ N·3HF和全氟丁烷磺酰氟（PBSF）一锅二氟化，构建了关键结构3,4-顺式-二氟环戊烷部分。苯并噻唑-2-基砜与乙醛酸酯的朱莉亚烯化反应提供丙烯酸酯的E / Z混合物，然后在最后一步的酰氯形成过程中将烯烃异构化为所需的E构型。这一发展取得了非常实用的工艺路线，以1（15％的总产率，12个步骤）。该工艺路线克服了原始药物化学合成路线的弊端，该路线使用了危险且昂贵的试剂（LiAlH ₄，OsO ₄和Deoxo-Fluor）并且效率低（总产率<4％，20个步骤）。