Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent.

Graham R Cumming,Neil Frankish,Helen Sheridan,Tao Zhang,Gaia Scalabrino

doi:10.1021/acs.oprd.7b00258

Graham R Cumming, Neil Frankish + Show 3 more

Open Access

https://doi.org/10.1021/acs.oprd.7b00258

Copy DOI

Abstract

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.

Highlights

The new chiral chemical entity PH46A, 6-(methylamino)-hexane-1,2,3,4,5-pentanol 4-(((1S,2S)-1-hydroxy-2,3-dihydro1H,1′H-[2,2-biinden]-2-yl)methyl)benzoate, was previously synthesized by our research group[1] and shown to have potential therapeutic activity in the areas of inflammation and autoimmune diseases, including inflammatory bowel disease.[2]
The absolute stereochemistry of PH46 had previously been established as an S configuration at both C-1 and C-2.1 This configuration was shown to be fundamental to the potent anti-inflammatory effects of the molecule.[2]
Further investigations using the related, and yet much less common, TiBA were more successful, leading to a robust, selective, and scalable process and insights into the kinetic vs thermodynamic products in our system. This diastereoselective reduction method was successfully employed on multikilo scale in a GMP environment, achieving up to 70% yield and >98% d.e. and purity

Summary

Introduction

The new chiral chemical entity PH46A, 6-(methylamino)-hexane-1,2,3,4,5-pentanol 4-(((1S,2S)-1-hydroxy-2,3-dihydro1H,1′H-[2,2-biinden]-2-yl)methyl)benzoate, was previously synthesized by our research group[1] and shown to have potential therapeutic activity in the areas of inflammation and autoimmune diseases, including inflammatory bowel disease.[2]. The overall yield of the original route (Scheme 1a) was less than satisfactory, due to the generation of the undesired diastereoisomer (rac)-5 and the unwanted enantiomer (R,R)-8. The reduction of ketone 3 (step 3) was carried out using sodium borohydride (NaBH4), which afforded a 60:40 ratio of the unwanted diastereoisomer (rac)-5 and desired diastereoisomer (rac)-6.2 Bulkier reagents, such as L-Selectride, gave even greater selectivity for the undesired isomer, while conceptually different reductants, such as DIP-chloride and CBS reagent, gave poor conversion.[4] The separation of diastereoisomers 5 and 6 proved challenging, especially on larger scales, due to their similar chemical and physical properties. The development of a scalable stereoselective route for the synthesis of PH46A was desirable to eliminate or reduce the cost burdens of generating the undesired diastereoisomer and of carrying out a large scale separation of the enantiomers. The current article describes our initial work toward this goal, which underpinned the kilo-scale

Objectives

Methods

Results

Conclusion