225920-05-8 | (S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol

CAS:225920-05-8 | (S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol,Description

Asymmetric Bioreduction of 3,5-Bis(trifluoromethyl) Acetophenone

The compound "(S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol" is a significant chiral intermediate in the pharmaceutical industry, particularly for the synthesis of NK-1 receptor antagonists. The asymmetric bioreduction of its precursor, 3,5-bis(trifluoromethyl) acetophenone, has been studied to produce this alcohol with high enantiomeric excess (e.e.).

Synthesis Analysis

The synthesis of "(S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol" has been achieved through biocatalytic methods. Candida tropicalis 104 cells were used to catalyze the asymmetric reduction of 3,5-bis(trifluoromethyl) acetophenone. The study found that several reaction parameters, such as substrate concentration, co-substrate type and concentration, biomass, and reaction time, significantly affect the yield. Optimal conditions were identified, leading to a maximum yield of 70.3% with 100% enantiomeric excess.

Molecular Structure Analysis

The molecular structure of "(S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol" is characterized by the presence of two trifluoromethyl groups attached to a phenyl ring, which is further connected to an ethanol moiety. This structure is crucial for its activity as an NK-1 receptor antagonist. The stereochemistry of the alcohol function is particularly important, and the synthesis methods focus on achieving a high enantiomeric purity.

Chemical Reactions Analysis

The enzymatic reduction of the ketone precursor to "(S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol" is a key chemical reaction. The isolated enzyme alcohol dehydrogenase from Rhodococcus erythropolis has been shown to reduce the substrate with excellent enantiomeric excess (>99.9%) and high conversion (>98%). This reaction is an example of an asymmetric enzymatic reduction where the enzyme's chiral environment drives the production of one enantiomer over the other.

Physical and Chemical Properties Analysis

While the specific physical and chemical properties of "(S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol" are not detailed in the provided papers, the general properties of such compounds include poor water solubility due to the hydrophobic trifluoromethyl groups. The high enantiomeric excess achieved in the synthesis indicates that the compound has a specific three-dimensional arrangement, which is critical for its biological activity.

Relevant Case Studies

The studies provided focus on the synthesis of "(S)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol" at different scales. The second paper demonstrates the process up to a pilot scale with high substrate concentration and an effective isolation process. The space-time yield was significantly improved in preparative scale experiments, indicating the potential for efficient industrial-scale production.

Scientific Research Applications

Enantioselective Synthesis

• Efficient Synthesis Processes : (R)-[3,5-Bis(trifluoromethyl)phenyl] ethanol, a chiral intermediate for aprepitant synthesis, can be efficiently synthesized using biocatalysts like Leifsonia xyli CCTCC M 2010241 and Trichoderma asperellum ZJPH0810. These processes utilize isopropanol and glycerol as co-substrates for cofactor recycling, leading to high product yields and enantiometric excess (e.e.) (Ouyang et al., 2013); (Li et al., 2013).
• Catalyst Development : Burkholderia cenocepacia-derived enzymes exhibit excellent anti-Prelog’s stereoselectivity for converting 3,5-bis(trifluoromethyl) acetophenone to (R)-3,5-Bis(trifluoromethyl)phenyl ethanol. This approach could be a potential alternative in pharmaceutical applications for producing aromatic chiral alcohols (Yu et al., 2018).
• Biocatalytic Reduction and Kinetic Resolution : Leifsonia xyli HS0904 was used for the asymmetric reduction of 3,5-bis(trifluoromethyl) acetophenone to (1R)-[3,5-bis(trifluoromethyl)phenyl] ethanol. This process explored various factors including buffer pH and substrate concentration for optimization (Wang et al., 2011).
• Photoenzyme-Catalyzed Synthesis : A biohybrid photocatalytic system was developed for synthesizing (R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol, utilizing TiO2 nanotubes and Cp*Rh(bpy) photoenzyme. This method showed high yield and enantiomeric excess, highlighting its potential for sustainable drug production (Yin et al., 2021).

Chiral Alcohol Production

• Novel Bacterial Strains for Bioreduction : Sphingomonas sp. LZ1 was identified for its efficient reduction of 3,5-bis(trifluoromethyl) acetophenone to enantiopure (S)-[3,5-bis(trifluoromethyl)phenyl]ethanol. This discovery provides a new potential biocatalyst for the production of valuable chiral alcohols in the industry (Wang et al., 2020).
• Ionic Liquid-Enhanced Bioreduction : Ionic liquids were used as co-solvents in the asymmetric bioreduction of 3,5-bis(trifluoromethyl)acetophenone, catalyzed by recombinant Escherichia coli cells. This method improved the efficiency of bioreduction and demonstrated potential for various biocatalytic reactions (Wang et al., 2015).

More Information