The Supply Chain Status in China

As of August 26, 2024, there are 36 potential suppliers manufacturing Zavegepant intermediate methyl (2R)-2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate;dihydrochloride (CAS No. 1414976-14-9), including 9 traders, 1 reagent distributors, 26 factories and 0 labs. Among factories and labs:

- The 25th percentile has an average registered capital of 1 million CNY;

- The 50th percentile has an average registerd capital of 4 million CNY;

-  The 75th percentile has an average registered capital of 17.50 million CNY.

Feeling overwhelmed? Contact Unibest if you need us to quality-check other sources to strengthen your supply chain or to find a tailored solution for your specific procurement request.

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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.

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

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).