Abstract

The active pharmaceutical ingredient sacubitril acts as a neprilysin inhibitor in the body and is administered to patients suffering from high blood pressure and chronic heart failure. In this paper, we report the development of a three-step setup for the synthesis of an advanced sacubitril precursor in continuous flow. The key transformation of our cascade is a Suzuki-Miyaura coupling facilitated by a heterogeneous palladium catalyst. Its implementation in a packed-bed reactor and the application of continuous flow methodologies allow intensification of the cross-coupling reaction compared to batch processing. The subsequent steps for the synthesis of the target molecule involve Boc-deprotection as well as N-succinylation, which have been optimized using the statistical “Design of Experiments” (DoE) approach. In this way, the individual as well as interactive effects of selected parameters on the output of the reactions could be investigated very efficiently. The consecutive performance of the three reaction steps using an integrated setup enabled the synthesis of a late-stage sacubitril precursor in continuous flow with 81% overall yield.Graphical .

Highlights

  • Among the different medication options for the treatment of hypertension and related cardiovascular complaints [1], drugs affecting the renin-angiotensin-aldosterone system have proved to be highly effective [1]

  • Intensification of Suzuki coupling in continuous flow employing a heterogeneous palladium catalyst implemented in a packed-bed reactor

  • Apart from the mentioned approaches involving the formation of chiral intermediate 2, two alternative strategies for the synthesis of sacubitril 1 have been reported in literature

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Summary

Introduction

Among the different medication options for the treatment of hypertension and related cardiovascular complaints [1], drugs affecting the renin-angiotensin-aldosterone system have proved to be highly effective [1]. Scheme 1 Published literature routes for the synthesis of sacubitril 1 [4,5,6,7,8]. Apart from the mentioned approaches involving the formation of chiral intermediate 2, two alternative strategies for the synthesis of sacubitril 1 have been reported in literature. Xu et al [7] achieved formation of 1 starting from Bettibase and (S)-2-methyloxobutanoic acid, which yielded oxazolidine 8. Upon stereoselective addition of a Grignard reagent to the obtained chiral intermediate 8, the biphenyl motif is installed and 3 more steps give the active pharmaceutical ingredient 1 (Scheme 1, d). The key transformations of their process are epoxide formation as well as an one-flask Staudinger reduction/succinic amide formation, which facilitate formation of sacubitril 1 in a total of 7 steps (Scheme 1, e)

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