The First Asymmetric Pilot-Scale Synthesis of TV-45070,Organic Process Research & Development

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The First Asymmetric Pilot-Scale Synthesis of TV-45070
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2017-09-08 00:00:00 , DOI: 10.1021/acs.oprd.7b00237
Joseph A. Sclafani ₁ , Jian Chen ₁ , Daniel V. Levy ₁ , Harlan Reese ₁ , Mina Dimitri ₁ , Partha Mudipalli ₁ , Michael Christie ₁ , Christopher J. Neville ₁ , Mark Olsen ₁ , Roger P. Bakale ₁

Affiliation

TV-45070 is a small-molecule lactam containing a chiral spiro-ether that has been reported as a potential topical therapy for pain associated with the Na_v1.7 sodium ion channel encoded by the gene SCN9A. A pilot-scale synthesis is presented that is highlighted by an asymmetric aldol coupling at ambient temperature, used to create a quaternary chiral center. Although only a moderate ee is obtained, the removal of the undesired isomer is achieved through preferential precipitation of a near racemic mixture from the reaction, leaving the enantiopure isomer in solution. Cyclization to form the final API uses an uncommon diphenylphosphine-based leaving group which proved successful on the neopentyl system when other traditional leaving groups failed.

中文翻译：

TV-45070的第一个不对称中试合成

TV-45070是一种含有手性螺醚的小分子内酰胺，据报道是潜在的局部疗法，用于治疗与基因SCN9A编码的Na _v 1.7钠离子通道相关的疼痛。提出了中试规模的合成，其突出之处在于在环境温度下的不对称醛醇偶合，用于形成四元手性中心。尽管仅获得适度的ee，但通过从反应中优先沉淀出近消旋混合物，将对映体纯的异构体留在溶液中，从而去除了不需要的异构体。环化形成最终的API使用了一个不常见的基于二苯基膦的离去基团，当其他传统的离去基团失败时，该基团在新戊基系统上被证明是成功的。

更新日期：2017-09-08

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