Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent.,Organic Process Research & Development

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Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent.
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2017-11-27 , DOI: 10.1021/acs.oprd.7b00258
Graham R Cumming ₁ , Tao Zhang ₂ , Gaia Scalabrino ₂ , Neil Frankish _{2,

3} , Helen Sheridan _{2,

3}

Affiliation

PH46A, belonging to a class of 1,2-Indane dimers, has been developed by our research group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases. The initial synthetic route to PH46A gave a low overall yield, due in large part to the generation of undesired diastereoisomer 5 and the unwanted enantiomer (R,R)-8 during the synthesis. The aim of this work was to carry out a comprehensive investigation into the stereoselective synthesis of PH46A. Significant progress was made on the ketone reduction step, where the use of triisobutylaluminum [TiBA, Al(iBu)3] afforded high selectivity for the target diastereoisomer (rac)-6, compared to the unfavorable ratio obtained using a previous process. This enabled a multikilo scale synthesis of PH46A in a GMP environment. Further, a brief proof-of-principle investigation was carried out using an achiral phase transfer catalyst (PTC) for alkylation at the methine carbon of the parent indanone.

中文翻译：

新型潜在抗炎药茚满二聚体PH46A的立体选择性合成研究。

PH46A属于1，2-茚满二聚体，是我们的研究小组开发的，可作为治疗炎症和自身免疫性疾病的潜在治疗剂。最初合成PH46A的途径总产率较低，这在很大程度上是由于合成过程中产生了非所需的非对映异构体5和不需要的对映异构体（R，R）-8。这项工作的目的是对PH46A的立体选择性合成进行全面的研究。酮还原步骤取得了重大进展，与使用先前方法获得的不利比例相比，使用三异丁基铝[TiBA，Al（iBu）3]对目标非对映异构体（rac）-6的选择性高。这使得能够在GMP环境中进行PH46A的多千克级合成。进一步，

更新日期：2017-12-06

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