An asymmetric synthesis of the tetrahydronaphthyridine scaffold of TAK-828F as a RORγt inverse agonist has been developed. The synthesis features a newly discovered atom-economical protocol for Heck-type vinylation of chloropyridine using ethylene gas, an unprecedented formation of dihydronaphthyridine directly from 2-vinyl-3-acylpyridine mediated by ammonia, and a ruthenium-catalyzed enantioselective transfer hydrogenation as key steps. This represents the first example of the enantioselective synthesis of a 5,6,7,8-tetrahydro-1,6-naphthyridine compound. The new synthesis is also free of chromatography or distillation purification processes and therefore qualifies for extension to large-scale manufacture.

中文翻译：

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5,6,7,8-四氢-1,6-萘啶骨架的不对称合成导致有效的类视黄醇相关孤儿受体γt反向激动剂TAK-828F。

已经开发了TAK-828F的四氢萘吡啶骨架作为RORγt反向激动剂的不对称合成。该合成具有一个新发现的原子经济方案，该方案使用乙烯气体进行氯吡啶的Heck型乙烯基化，氨气直接从2-乙烯基-3-酰基吡啶直接形成前所未有的二氢萘吡啶，以及钌催化的对映选择性转移氢化为关键步骤。这代表了5,6,7,8-四氢-1,6-萘啶化合物的对映选择性合成的第一个例子。新的合成方法也没有色谱法或蒸馏提纯方法，因此有资格扩展到大规模生产。