The synthesis of multigram quantities of small molecule PCSK9 inhibitor (R,S)-3 is described. The route features a safe, multikilogram method to prepare 5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazole (10). A three-component dynamic kinetic resolution between tetrazole 10, acetaldehyde, and isobutyric anhydride was catalyzed by a chiral DMAP catalyst to afford enantiomerically enriched hemiaminal ester (S)-12 on multikilogram scale. Magnesiation, transmetalation, and Negishi coupling provided access to Boc-intermediate (R,S)-13, which was deprotected to provide (R,S)-3 in multigram quantities.

中文翻译：

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Tetrazole前体药物的区域和对映选择性制备的可扩展途径：PCSK9抑制剂在多克分子级合成中的应用

描述了数克数量的小分子PCSK9抑制剂（R，S）-3的合成。该路线以安全的多公斤级方法为特征，以制备5-（4-碘-1-甲基-1 H-吡唑-5-基）-2 H-四唑（10）。用手性DMAP催化剂催化四唑10，乙醛和异丁酸酐之间的三组分动态动力学拆分，以多千克级得到对映异构体富集的半缩醛酸酯（S）-12。镁，铁金属和Negishi耦合提供了进入Boc中间体（R，S）-13的通道，将其脱保护得到多克数量的（R，S）-3。