Synthesis of a key intermediate of sacubitril via asymmetric hydrogenation

Sacubitril is a key component of the first-line heart failure and hypertension drug sacubitril/valsartan, and its chiral intermediate is crucial for industrial production. Current synthetic methods suffer from high catalyst cost, harsh conditions, and low chiral resolution efficiency. In this work, an efficient and scalable asymmetric hydrogenation route was developed for the synthesis of the sacubitril key chiral intermediate. Using commercially available chiral ruthenium complex Ru(OAc)2[(S)-dtbm-segphos] as a catalyst with 0.1% w/w loading, the reaction was carried out in methanol at 25 °C under 2.5 MPa H2 for 6 h, achieving >99.9% conversion and up to 91.7% crude enantiomeric excess (ee). After simple recrystallization with ethyl acetate/n-heptane, ee was up to 99.9% with 82% isolated yield. The 200 g scale-up reaction maintained >99.9% conversion, 99.8% ee and 79% yield. This protocol features low cost, simple operation, high stereoselectivity, and good reproducibility, providing a practical industrial route for sacubitril intermediate preparation.