J. Org. Chem.2019, 84, 4796−4802. DOI:10.1021/acs.joc.8b02751
◆GDC-0908 (1) is one of the therapeutic development agents targeting the PI3K pathway in cancer.
◆We envisioned that GDC-0908 (1) could be accessed via a palladium-catalyzed Negishi coupling of bromodihydrobenzothienooxepine 2 and the organozinc reagent derived from benzoylprotected aminotriazole 3
◆A general synthesis of dihydrobenzothienooxepines in good to excellent yields via palladium-catalyzed intramolecular direct C−H arylation was developed, which tolerates both electronically and sterically diverse substituents on the phenyl ring
◆A thermal monocyclic rearrangement was developed to construct the southern hemisphere substituted 3-amino-1,2,4-triazole
◆Knochel reported that TMPZnCl·LiCl readily deprotonates a variety of arenes and heteroarenes, and more importantly, the resulting arylzinc species can readily undergo Negishi coupling in the presence of a palladium catalyst.
◆To our delight, 95% deuterium incorporation was detected when 2.1 equiv of TMPZnCl·LiCl was employed. For comparison, when a weaker base LDA was used, only 50% deuterium was incorporated in compound 3.
◆Under the optimal Negishi coupling conditions employing bromide 2, 1.1 equiv of aminotriazole 3, 3.3 equiv of TMPZnCl·LiCl,5 mol % of PdCl2(TFP)2, and 10 mol % of TFP in THF at 65°C, the reaction was highly productive with little impurity detected.
◆Quenching the Negishi reaction with aqueous HCl, followed by 5 equiv of concentrated H2SO4 at 65 °C removed the benzoyl group, generating GDC-0908·H2SO4 (1b) in 86% isolated yield over two steps.
招聘上海合成工藝研究員
設計、優化I類新藥的工藝合成路線，各反應條件、參數，包括後處理，撰寫報告、跟蹤並解決GMP生產技術問題
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