A key step in the synthesis of CAS No. 1414976-14-6 is a transfer of amine from Alanine to the substrate, catalyzed by D-transaminase. The reference synthesis plan of Cas No. 1414976-14-9 is as follows:
The synthesis of Zavegepant intermediate with enzymatic catalysis
Although metal catalysts such as rhodium-catalyst, enzymatic catalysis is preferred for the following reasons.
Metal Catalysis (Rh-catalyzed asymmetric hydrogenation)
Pros:
Fast reaction (1 h) with excellent yield (96%) and enantioselectivity (>99.8% ee)
Fewer linear steps (6 steps) and good overall yield (25%) to amino ester product
High volumetric efficiency (8 L/kg)
Clean reaction with no byproducts
Cons:
Requires expensive, limited availability proprietary catalyst (Et-FerroTANE-Rh)
Sensitive to impurities that deactivate catalyst, requiring intensive substrate purification
Concerns about removing residual Rh and Pd metals from intermediates and API
High substrate purity required to achieve good turnover number
Enzyme Catalysis (D-transaminase)
Pros:
Uses readily available, non-proprietary enzyme catalyst
More tolerant of impurities in starting material (95% purity sufficient)
No issues with residual metals in API
Engineered enzyme developed with improved efficiency
Cons:
Slower reaction (21 h) and moderate yield (79%)
More linear steps (8 steps) but comparable overall yield (34%)
Generates pyruvate byproduct that must be disposed of
Requires more solvent for substrate preparation
In summary, while the metal catalysis was faster and more efficient, the enzyme catalysis avoided issues with metals andsubstrate purity that outweighed those advantages for this large-scale API synthesis.
References
Cann, R. O. et al. Selection of an Enantioselective Process for the Preparation of a CGRP Receptor Inhibitor. Org. Process Res. Dev. 16, 1953–1966 (2012).
