Olefin Metathesis in Continuous Flow Reactor Employing Polar Ruthenium Catalyst and Soluble Metal Scavenger for Instant Purification of Products of Pharmaceutical Interest.

Ren Wei Toh,Tomasz Nienałtowski,Karol Grela,Michał Patrzałek,Anna Kajetanowicz,Jie Wu,Jakub Piątkowski

doi:10.1021/acssuschemeng.1c06522

Abstract

In recent years, the development of continuous-flow reactors has attracted growing attention from the synthetic community. Moreover, findings in the precise control of the reaction parameters and improved mass/heat transfer have made the flow setup an attractive alternative to batch reactors, both in academia and industry, enabling safe and easy scaling-up of synthetic processes. Even though a majority of the pharmaceutical industry currently rely on batch reactors or semibatch reactors, many are integrating flow technology because of easier maintenance and lower risks. Herein, we demonstrate an operationally simple flow setup for homogeneous ring-closing metathesis, which is applicable to the synthesis of active pharmaceutical ingredients precursors or analogues with high efficiency, low residence time, and in a green solvent. Furthermore, through the addition of a soluble metal scavenger in the subsequent step within the flow system, the level of ruthenium contamination in the final product can be greatly reduced (to less than 5 ppm). To ensure that this method is applicable for industrial usage, an upscale process including a 24 h continuous-flow reaction for more than 60 g of a Sildenafil analogue was achieved in a continuous-flow fashion by adjusting the tubing size and flow rate accordingly.

Highlights

One of the objectives in organic synthesis is the production of complex polyfunctional bioactive drug molecules with high purity
The usage of catalysts based on rare earth metals is common for the synthesis of active pharmaceutical ingredients (API) in the pharmaceutical industry.[1−4] One such process that is finding more and more applications in the synthesis of biologically active compounds is olefin metathesis.[5−7] It enables the formation of new C−C
The reliance on heavy metals for organic synthesis potentially leads to metal contamination because traditional purification methods like column chromatography and recrystallization is inefficient in purifying complex polyfunctional chemical substances such as APIs in downstream processes.[12]

Summary

■ INTRODUCTION

One of the objectives in organic synthesis is the production of complex polyfunctional bioactive drug molecules with high purity. We report a highly efficient ring-closing metathesis (RCM) in flow that uses the commercially available shcoamveonggeenreo(u1s,4-Sbtisic(k3y-iCsoactyaPnFo6procpatyal)lypsitp5e7razainnde)2S2n,3a4−tc3h6 Ctaot continuously produce advanced functionalized products, resembling in their complexity selected API substances, with low ruthenium content. With this system, without ethylene removal, we conducted a number of RCM reactions of highly functionalized substrates and managed to upscale the flow process to produce 62 g of a Sildenafil analogue in 24 h with a very low ruthenium content of 0.5 ppm with an environmentalfriendly green solvent, ethyl acetate.

EtOAc Ru2

■ CONCLUSION

■ ACKNOWLEDGMENTS

■ REFERENCES