LCZ696 is a novel treatment for patients suffering from heart failure that combines the two active pharmaceutical ingredients sacubitril and valsartan in a single chemical compound. While valsartan is an established drug substance, a new manufacturing process suitable for large-scale commercial production had to be developed for sacubitril. The use of chemocatalysis, biocatalysis, and flow chemistry as state-of-the-art technologies allowed to efficiently build up the structure of sacubitril and achieve the defined performance targets.

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A hazardous side reaction between N-bromosuccinimide (NBS) and 2-methyltetrahydrofuran (2-MeTHF) was identified during the thermal safety analysis toward a bromination process. A delay reaction owing to a preferred free-radical initiation was observed. The progress of the side reaction and influence of NBS concentration on the reaction heat were studied by means of different calorimeters. The heat flow of the desired reaction was measured by the reaction calorimeter (RC1), indicating the bromination could be controlled under a semibatch mode with appropriate feeding program of NBS. On the basis of these investigations, two consecutive brominating processes with 106 kg starting material were safely scaled up in the pilot plant with expected yields.