AG-10 Synthesis Process for Industrial Scale-Up
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Solution Overview
Problem
Current methods for synthesizing AG-10 are not suitable for industrial manufacturing and lack additional forms with advantageous pharmacokinetic properties, and existing protein inhibitors like therapeutic monoclonal antibodies are costly and induce immune responses.
Innovation Solution
A multi-step synthetic process for AG-10 involving specific chemical reactions and organic solvents, followed by formation of pharmaceutically acceptable salts, to enhance bioavailability and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic monoclonal antibodies are used to inhibit protein-protein interactions, then the therapeutic effect is achieved, but the manufacturing cost increases and immune response is induced
Solution Approach 1:
The patent replaces expensive, complex monoclonal antibodies with small molecule inhibitors that are cheaper to manufacture and do not induce immune responses. The small molecules (e.g., compounds of Formula I and their salts) serve as simplified, cost-effective alternatives that achieve the same therapeutic goal of inhibiting protein-protein interactions without the drawbacks of biologic drugs.
2Quantity of substance
If the disclosed synthesis method for AG-10 is used, then the compound is produced, but the method is not suitable for industrial manufacturing
Solution Approach 1:
The patent divides the synthesis of AG-10 into distinct modular steps (Steps a-e), each producing a specific intermediate (Formula II through Formula IX). This segmentation allows each step to be independently optimized for industrial scale-up, with clear intermediates that can be isolated, characterized, and controlled. The modular approach enables parallel processing and standardized operational procedures suitable for manufacturing.
Solution Approach 2:
The patent optimizes reaction parameters at each synthesis step, including solvent selection (e.g., dimethylformamide, dichloromethane, ethyl acetate), temperature ranges, and reagent ratios, to improve yields and facilitate industrial manufacturing. The methodology systematically adjusts chemical parameters to achieve conditions that are both effective for synthesis and practical for scale-up production.
3Reliability
If additional forms of AG-10 are developed, then pharmacokinetic properties are improved, but the synthesis complexity increases
Solution Approach 1:
The patent uses common intermediate structures (Formulas II-VIII) that can be diversified to produce multiple final products (AG-10 and its salts). The intermediates serve as versatile building blocks that can be converted into different pharmaceutically acceptable salts (e.g., hydrochloride, mesylate, tosylate) through simple salt formation reactions, avoiding the need for complex separate syntheses for each form.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The process achieves high yields and improved bioavailability of AG-10, providing effective treatment options for protein-related diseases with reduced immune response risks.
Implementation Method 1
contacting a compound of Formula II with a compound of Formula III a first base, and a first organic solvent to provide a compound of Formula IV
Implementation Method 2
contacting a compound of Formula VI with a compound of Formula VII a second base, and an third organic solvent to provide a compound of Formula VIII
Implementation Method 3
contacting a compound of Formula IX with a pharmaceutically acceptable salt forming agent to provide a pharmaceutically acceptable salt of Formula I
Data Source
AI summary
Provided herein are improved processes for the preparation of a compound of Formula IX (AG-10). Also provided herein are pharmaceutically acceptable salts of Formula I and Formula Ibas well as crystalline types of Formula IX (AG-10). The processes described herein provide improved yields and efficiency, while the pharmaceutically acceptable salts and crystalline forms provide unexpected pharmacokinetic properties. Other features and aspects of the present disclosure will be apparent to a person of skill in the art upon reading the remainder of the specification.