![Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-phosphinetriyltripiperidine]}palladium Under Mild Reaction Conditions](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F51444.jpg&w=3840&q=50)
Efficient Syntheses of KLS-13019 Using Palladium Mediated Cross Couplings
William A Kinney1, Mark E McDonnell1, Stanley Freeman2
1Kannalife Sciences, Inc., 3805 Old Easton Road, Doylestown, PA 18902, United States.
Tetrahedron Letters
|March 20, 2023
Summary
KLS-13019, a cannabidiol analogue, effectively prevents and reverses neurotoxicity. New scalable syntheses improve yield and efficiency, overcoming limitations of the original method.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Neuropharmacology
Background:
- Paclitaxel-induced neurotoxicity is a significant challenge in cancer therapy.
- KLS-13019, a cannabidiol analogue, demonstrates promise in preclinical models.
- The original synthesis of KLS-13019 lacked scalability and efficiency.
Purpose of the Study:
- To develop a scalable and efficient synthesis for KLS-13019.
- To improve the regioselectivity and overall yield of KLS-13019 production.
- To establish a streamlined process for generating high-purity KLS-13019.
Main Methods:
- Utilized palladium-catalyzed cross-coupling reactions for key bond formations.
- Employed an advanced intermediate (compound 5) to shorten the synthetic route.
- Developed a one-pot procedure for Boc-cleavage and acetylation.
Main Results:
- Achieved a significantly shortened synthetic route (3-4 steps).
- Dramatically improved the overall yield and regioselectivity of KLS-13019 synthesis.
- Minimized impurity generation through a one-pot processing technique.
Conclusions:
- The developed synthetic strategies provide a scalable and efficient method for KLS-13019 production.
- These advancements facilitate the further development of KLS-13019 as a therapeutic agent.
- The improved synthesis addresses critical manufacturing challenges for KLS-13019.
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