Abstract
(S)-3,5-Bistrifluoromethylphenyl ethanol((S)-BTPE) is a key pharmaceutical intermediate of the NK-1 receptor antagonist. The asymmetric bioreduction of 3,5-bis(trifluoromethyl) acetophenone (BTAP) to (S)-BTPE using Rhodococcus erythropolis XS1012 has been established in a phosphate buffer system. To overcome the problem of unsatisfactory yields at high substrate concentration, deep eutectic solvents (DESs) have been introduced to the buffer system. After screening 13 kinds of choline chloride-based DESs, [choline chloride][urea] ([ChCl][U]) showed great influence on the cell activity and significantly increased the cell membrane permeability. Subsequently, some major parameters for this reaction were determined. A remarkable (S)-BTPE yield of 91.9% was gained at 150 mM substrate concentration under optimized reaction conditions with >99.9% product enantioselectivity. Compared to reduction in a buffer system, the developed [ChCl][U]-containing system increased the yield from 82.6% to 91.9%. It maintains a yield of 80.7% with the substrate concentration up to 300 mM, compared to only 63.0% in buffer system. This study demonstrated that [ChCl][U] is a feasible co-solvent to improve the bioreduction process.
Highlights
Chirality is a significant characteristic of drugs and drug candidates that mainly makes a difference in pharmacokinetics, pharmacodynamics, and toxicity [1,2]. Both optical pure 3,5-bistrifluoromethylphenyl ethanol ((R)- and (S)-BTPE) is an intermediate for the synthesis of NK-1 receptor antagonist, while (S)-BTPE is included in the antagonists currently under clinical evaluation [3]
XS1012 selected as a biocatalyst for the asymmetric reduction of bis(trifluoromethyl) acetophenone (BTAP) to (S)-BTPE
To further understand the effect of deep eutectic solvents (DESs) on R. erythropolis XS1012 cells, cell activity was estimated by the value of sugar metabolic retention (MAR), which can be altered with cell tolerance to the DESs and substrate
Summary
Chirality is a significant characteristic of drugs and drug candidates that mainly makes a difference in pharmacokinetics, pharmacodynamics, and toxicity [1,2]. Ionic liquids (ILs) display many unique characteristics, as almost negligible vapor pressure, tropicalis 104 cells gained a high yield (70.3%) and excellent enantioselectivity at 50 mM substrate excellent chemical and thermal stability, low melting points, low toxicity, and good biocompatibility. The above literature indicates that the biocatalytic reduction of (S)-BTPE in the aqueous phase is performance, generally unsatisfied when at high substrate concentration Because of their superior they have drawn extensive interest and are considered to be al.organic introduced the ionic[11,12]. Points, DESs low generally two or three components, excellent chemical and thermal stability, low melting toxicity, consist and goodof biocompatibility Because of their superior performance, they have drawn extensive interest and are considered to be such as choline chloride with a hydrogen donor (such as urea and amino acids). Choosing a co-solvent appropriately can provide a higher reactant concentration [21], so it is of great interest to carry out the investigation of the influences of and Discussion choline chloride-based DESs on biocatalysis reduction
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