The Development of Synthetic Routes Leading to Pharmaceuticals and the Key Intermediates Using Hydroxynitrile Lyase

Area of Science:

• Biocatalysis and Organic Synthesis
• Enzyme Engineering for Pharmaceutical Production
• Asymmetric Synthesis of Chiral Drugs

Background:

• Hydroxynitrile lyases (HNLs) are crucial enzymes for synthesizing chiral building blocks.
• Existing synthetic routes for pharmaceuticals like Cenobamate and Clopidogrel can be limited in efficiency and selectivity.
• Parafontaria laminata hydroxynitrile lyase (PlamHNL) presents a potential biocatalyst for improved pharmaceutical synthesis.

Purpose of the Study:

• To develop novel synthetic routes for active pharmaceutical ingredients (APIs) using PlamHNL.
• To enhance enantioselectivity and regioselectivity in the synthesis of key pharmaceutical intermediates.
• To improve overall yields in the production of Cenobamate (Xcopri), Clopidogrel (Plavix), and Mirabegron (Myrbetriq).

Main Methods:

• Utilized PlamHNL for asymmetric synthesis of chiral mandelates.
• Developed novel synthetic pathways starting from HNL-catalyzed reactions.
• Optimized reaction conditions to achieve high selectivity and yield for target APIs.

Main Results:

• Achieved high enantioselectivity and regioselectivity in HNL-catalyzed reactions.
• Demonstrated efficient synthesis of Cenobamate and Clopidogrel from a common intermediate, (R)-methyl-2-chloro mandelate.
• Reported improved yields for the synthesis of Xcopri, Plavix, and Myrbetriq.

Conclusions:

• PlamHNL is an effective biocatalyst for developing novel and efficient synthetic routes for important pharmaceuticals.
• The developed methods offer significant advantages in selectivity and yield compared to existing approaches.
• This work provides a foundation for the industrial application of PlamHNL in API manufacturing.