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Published on: April 7, 2023
Practical and Scalable Manufacturing Process for the Key Intermediate of Poly(ADP-Ribose) Polymerase Inhibitor
Zhaohang Chen1, Shuai Wang1, Kangjie Liu1
1State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China.
Abstract:
Olaparib (Lynparza) is a potent, highly selective inhibitor of poly(ADP-ribose)polymerase enzymes, approved by the U.S. FDA and EMA for the treatment of ovarian cancer. Herein, we report a practical, economical, and scalable process for the synthesis of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid, a key intermediate for olaparib. The low-cost industrial byproduct phthalhydrazide was used as the starting material to construct the phthalazinone moiety, which allowed access to the key intermediate by the Negishi coupling reaction. Optimization of each step has enabled the development of an environmentally benign and robust process with effective control of impurities.
Insights
A new, cost-effective synthesis for a key olaparib intermediate was developed using phthalhydrazide. This practical process is scalable and environmentally friendly, ensuring high purity for the cancer drug intermediate.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Process Chemistry
Background:
- Olaparib (Lynparza) is a crucial poly(ADP-ribose)polymerase inhibitor for ovarian cancer treatment.
- Existing synthesis routes for olaparib intermediates may lack cost-effectiveness or scalability.
Purpose of the Study:
- To develop a practical, economical, and scalable synthesis for 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid, a key olaparib intermediate.
- To optimize the synthetic process for environmental friendliness and impurity control.
Main Methods:
- Utilized phthalhydrazide, a low-cost industrial byproduct, to construct the phthalazinone core.
- Employed Negishi coupling reaction for efficient intermediate synthesis.
- Optimized individual reaction steps for yield and purity.
Main Results:
- Successfully synthesized the target intermediate with high purity.
- Developed a scalable process suitable for industrial application.
- Achieved effective control over process impurities.
Conclusions:
- The developed synthesis offers a practical and economical route to a key olaparib intermediate.
- This environmentally benign process is robust and scalable, supporting olaparib production.
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