Process Development of the Copper(II)-Catalyzed Dehydration of a Chiral Aldoxime and Rational Selection of the Co-Substrate.

Jannis Nonnhoff,Harald Gröger

doi:10.1002/open.202100230

Abstract

The access towards chiral nitriles remains crucial in the synthesis of several pharmaceuticals. One approach is based on metal‐catalyzed dehydration of chiral aldoximes, which are generated from chiral pool‐derived aldehydes as substrates, and the use of a cheap and readily available nitrile as co‐substrate and water acceptor. Dehydration of N‐acyl α‐amino aldoximes such as N‐Boc‐l‐prolinal oxime catalyzed by copper(II) acetate provides access to the corresponding N‐acyl α‐amino nitriles, which are substructures of the pharmaceuticals Vildagliptin and Saxagliptin. In this work, a detailed investigation of the formation of the amide as a by‐product at higher substrate loadings is performed. The amide formation depends on the electronic properties of the nitrile co‐substrate. We could identify an acceptor nitrile which completely suppressed amide formation at high substrate loadings of 0.5 m even when being used with only 2 equivalents. In detail, utilization of trichloroacetonitrile as such an acceptor nitrile enabled the synthesis of N‐Boc‐cyanopyrrolidine in a high yield of 92 % and with full retention of the absolute configuration.

Highlights

Nitriles represent an important class of compounds for bulk and fine chemicals with a particular focus on their occurrence as chiral building blocks in pharmaceuticals.[1]
This work is focusing on an investigation of the influence of the reaction parameters on the suppression of the undesired amide formation as a side reaction
While no difference was observed between 1 and 5 mol % with respect to the total conversion as well as to the amide formation, the total conversion at a catalyst loading of 0.5 mol % decreased to 38 % (28 % nitrile 5 and 10 % amide 6)

Summary

Introduction

Nitriles represent an important class of compounds for bulk and fine chemicals with a particular focus on their occurrence as chiral building blocks in pharmaceuticals.[1] An example are chiral acylated α-amino nitriles (Figure 1) such as Saxagliptin 1,[2] distributed by AstraZeneca/BMS, and Vildagliptin 2,[3,4] distributed by Novartis, with sales of over $1 billion per year Both pharmaceuticals belong to the class of dipeptidyl peptidase-4 (DPP-4) inhibitors and are used in the treatment of type II diabetes. In previous studies of our group,[3,4,18] an alternative synthesis of enantiomerically highly enriched N-acyl amino nitriles, based on a copper(II) acetate-catalyzed dehydration of aldoximes, was described, using acetonitrile as water acceptor (Scheme 1). An in situ formed nitrile acts as a (formal) water acceptor in the dehydration of further aldoximes.[23]

Results and Discussion

Variation of Catalyst Loading and Temperature

Variation of the Excess of the Acceptor Nitrile

Variation of Acceptor Nitrile

Conclusion

Data Availability Statement