Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Abstract

An efficient preparation of a precursor to the neprilysin inhibitor sacubitril is described. The convergent synthesis features a diastereoselective Reformatsky-type carbethoxyallylation and a rhodium-catalyzed stereoselective hydrogenation for installation of the two key stereocenters. Moreover, by integrating machine-assisted methods with batch processes, this procedure allows a safe and rapid production of the key intermediates which are promptly transformed to the target molecule (3·HCl) over 7 steps in 54% overall yield.

Synthesis of Organometallic Compounds in Flow

“…Ley and coworkers reported a Reformatsky like reaction with sulfinylimines under Barbier ’s conditions . A mixture of allylic bromide 15 (1.2 equiv.…”

Recent developments in the asymmetric Reformatsky-type reaction

“…Earlier in 2015, Ley et al reported an efficient synthesis of a precursor of the neprilysin inhibitor sacubitril based on a zinc-mediated aza-Reformatsky-type reaction [ 31 ]. Indeed, this convergent synthesis featured a diastereoselective aza-Reformatsky-type carbethoxyallylation of ( S )- N - tert- butylsulfinyl imine 25u with bromide 35 performed in isopropanol as solvent in the presence of zinc, LiCl and K 2 CO 3 , which afforded the corresponding chiral acrylic ester 36 as single diastereomer (98% de) in 82% yield ( Scheme 14 ).…”

Development of a multistep reaction cascade for the synthesis of a sacubitril precursor in continuous flow

“…An alternative route, also running via formation of intermediate 2, was developed by Hook et al [5], who used L-pyroglutamic acid methyl ester 4 as chiral pool for the synthesis of 2 in batch (Scheme 1, b). Recently, Ley et al [6] published a novel approach applying the concept of continuous flow technology and integrating machine-assisted methods for the synthesis of hydrochloride salt 2*HCl. In contrast to the other groups, their strategy employs exclusively achiral starting materials 5-7 and the two chiral centers are installed by both Rh-catalyzed stereoselective hydrogenation and diastereoselective Reformatsky-type carbethoxyallylation.…”

“…Although apparently a number of different strategies for the synthesis of sacubitril 1 have been developed in the past years, it is conspicuous that almost every approach relies on traditional batch chemistry. As mentioned above, the sole exception is the combined batch and flow process published by Ley and his group [6], involving 5 transformations in continuous flow. Continuous flow methodology offers a plethora of opportunities for the pharmaceutical industry in terms of both process optimization and economics.…”