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Preparing anti-SARS-CoV-2 agent EIDD-2801 by a practical and scalable approach, and quick evaluation via machine
Zhen Qin1, Bin Dong2, Renbing Wang1
1Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211100, China.
Acta Pharmaceutica Sinica. B
|October 27, 2021
Summary
Optimized synthesis of EIDD-2801, a COVID-19 treatment candidate, achieved 99.9% purity and increased yield to 58%. Machine learning identified reagents and temperature as key factors for maximizing yield.
Area of Science:
- Medicinal Chemistry
- Process Chemistry
- Drug Development
Background:
- EIDD-2801 is an orally bioavailable prodrug being considered for Emergency Use Authorization for COVID-19 treatment.
- Optimizing the synthesis of EIDD-2801 is crucial for its potential large-scale application.
Purpose of the Study:
- To develop an optimized, high-yield synthesis for EIDD-2801.
- To identify critical parameters influencing the yield of the deprotection step.
Main Methods:
- A four-step synthesis was optimized, including a one-pot hydroxylamination procedure.
- The deprotection step was analyzed using Shapley value explanation and a decision tree machine learning approach.
- Synthesis was validated at decagram scale (200 g for the first step, 20 g for the final step).
Main Results:
- Achieved a high purity of 99.9% for EIDD-2801.
- Increased the overall synthesis yield from 17% to 58% without requiring column chromatography.
- Identified reagents as the most impactful factor on yield, followed by temperature, in the deprotection step.
Conclusions:
- The optimized synthesis provides a more efficient and scalable route for EIDD-2801 production.
- Understanding the key parameters controlling yield is vital for robust drug manufacturing.
- This work supports the potential emergency use of EIDD-2801 for COVID-19 treatment.
