The synthesis of the chiral, nonracemic 3-aryl piperidine, OSU 6162 (1), a potential CNS agent from Pharmacia Corporation, is presented. The key construction in the described synthesis is a palladium-catalyzed aryl cross-coupling reaction between bromosulfone (4) and pyridyl borane (14). Initially developed conditions for this Suzuki reaction, conducted in tetrahydrofuran/aqueous hydroxide, delivered free base (6) or hydrochloride salt (15a) in reproducible 80% yield. However, by changing the solvent to toluene and the base to carbonate, significant decreases in catalyst requirement were realized, and the methane sulfonate salt (15b) of the coupled product could be obtained in reproducible 92−94% yield on 200-kg input. The success of the Suzuki reaction was critically dependent on a bulk source of the pyridyl borane coupling partner. Cryogenic conditions were developed for its generation via lithium−halogen exchange to generate thermally labile 3-lithiopyridine followed by transmetalation with diethylmeth...

中文翻译：

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OSU 6162 的合成：Suzuki 联轴器的高效、大规模实施

介绍了手性非外消旋 3-芳基哌啶 OSU 6162 (1) 的合成，它是 Pharmacia Corporation 的一种潜在 CNS 剂。所述合成中的关键结构是溴砜 (4) 和吡啶基硼烷 (14) 之间的钯催化芳基交叉偶联反应。最初为该 Suzuki 反应开发的条件，在四氢呋喃/氢氧化物水溶液中进行，以可重现的 80% 产率提供游离碱 (6) 或盐酸盐 (15a)。然而，通过将溶剂改为甲苯，将碱改为碳酸盐，催化剂需求显着降低，并且在 200-kg 投入量下，偶联产物的甲磺酸盐 (15b) 可以重现性 92-94% 的产率获得。Suzuki 反应的成功很大程度上取决于吡啶基硼烷偶联伙伴的大量来源。