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Cas No. 1414976-14-9, methyl (2R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate dihydrochloride

  • 1414976-14-9

  • C12H17Cl2N3O2

  • 306.19

  • 0.992

  • 98.0% min (HPLC); 99.0% e.e (HPLC)

  • 113.2

  • Off-white solid

  • Migraine

  • Zavegepant

  • 10/7/2031 (Zavegepant)

  • CGRP

  • N

  • ISO 9001;ISO 14001;ISO 45001; GMP

Availability:

Background

Zavegepant offers a transformative approach to migraine treatment by targeting the underlying cause of migraine attacks. With its efficacy in reducing migraine severity and frequency, Zavegepant holds immense value in the field of neurology. Seamlessly incorporate our intermediates into your manufacturing process, ensuring a consistent supply of this exceptional medication. Join us in revolutionizing the management of migraines and improving the lives of millions of sufferers. Embrace Zavegepant and redefine the future of migraine therapy.

Product Description

Cas No. 1414976-14-9 (di-HCl), is a key intermediate of Zavegepant. It contains a single chiral center, whose formation is catalyzed by transaminase. It reacts with CAS No. 855778-84-6 and forms the N-1 Zavegepant intermediate.


final steps of Zavegepant synthesis

The role of Cas No. 1414976-14-9 in the synthesis of Zavegepant HCl API.


ROS Reference

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:


synthesis of Zavegepant with enzymatic catalysis

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).


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