Development of an Enzymatic Process for the Synthesis of the Key Intermediate of Telotristat Ethyl

Abstract

Abstract(R)‐1‐(4‐chloro‐2‐(3‐methyl‐1H‐pyrazol‐1‐yl)phenyl)‐2,2,2‐trifluoroethan‐1‐ol [(R)‐2] is a key chiral intermediate in the synthesis of telotristat ethyl, an anti‐carcinoid syndrome drug. However, the synthetic methods for (R)‐2 mainly include chemical reductions, rarely involving biocatalysis or bioreduction until now. Here, we report a method for obtaining (R)‐2 by biocatalytic reduction of corresponding prochiral acetophenone (1) with bulky o‐substitution using recombinant Lactobacillus fermentum short‐chain dehydrogenase/reductase 1 (LfSDR1) as a biocatalyst. Further engineering of LfSDR1 variants could access asymmetric reduction of 1 and yield (R)‐2 with a >99% ee and a >99% conversion. In addition, through the test of different co‐solvents and a series of initial substrate concentrations, substrate 1 with the concentration of 60 g/L can be completely converted into (R)‐2 on a preparative scale (1.13 g, 3.93 mmol, 75.6% isolated yield) in 24 hours. This study presents an efficient enzymatic process for the biocatalytic synthesis of key chiral intermediate (R)‐2 in the synthesis of telotristat ethyl.magnified image