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Synthesis of Sacubitril
Application of Transition-Metal Catalysis, Biocatalysis, and Flow Chemistry as State-of-the-Art Technologies in the Synthesis of LCZ696.
J. Org. Chem. 2020;
21 July 2020 (online)
Key wordssacubitril - LCZ696 - asymmetric hydrogenation - rhodium catalysis - flow reactor - Ivanov reaction - transaminase
Sacubitril is a nephrilysin inhibitor used in combination with the angiotensin II inhibitor valsartan. The combination drug (LCZ696), marketed under the brand name Entresto®, was approved by the FDA in 2015 for the treatment of heart failure. A noteworthy step in the synthesis of sacubitril depicted features a flow reactor to perform the Ivanov reaction (Synthesis 1975, 83) by which the carboxylic acids B and D were condensed to give γ-ketoacid derivative G in 79% yield on a 15.1 mol scale.
The (R,R)-Ph-BPE-derived rhodium complex in methanol at 30 °C and a hydrogen pressure of 10 bar provided the best performance among the catalyst systems screened for the asymmetric hydrogenation of A. Complete conversion into B was observed in concentrations as high as 1.3 g/mL and catalyst loadings as low as S/C 74,000:1, providing the product in high purity and excellent enantioselectivity (er = 99.7:0.3).