Finerenone Synthesis via Chiral Resolution Under Mild Conditions
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Solution Overview
Problem
Existing methods for preparing finerenone face challenges such as the generation of highly toxic byproducts, hazardous reaction conditions, high costs due to expensive palladium catalysts, and inefficient use of isomers, making them unsuitable for scale-up production.
Innovation Solution
A method involving condensation, cyclization, etherification, resolution using tartaric acid derivatives, and amidation to produce finerenone, utilizing mild reaction conditions and chiral catalysts to achieve a high enantiomeric excess of the desired S-configuration product, avoiding hazardous steps like hydrogenolysis and high-pressure reactions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional methods use 3-oxobutanoic acid 2-cyanoethyl ester for finerenone synthesis, then the synthesis can proceed, but highly toxic acrylonitrile is generated during hydrolysis and high-pressure reactions are required
Solution Approach 1:
The patent extracts and removes the harmful 3-oxobutanoic acid 2-cyanoethyl ester route from the synthesis pathway, replacing it with a safer alternative using different starting materials and reaction conditions that do not generate toxic acrylonitrile or require high-pressure equipment
Solution Approach 2:
The patent changes the reaction parameters from high-pressure conditions to ambient or mild pressure conditions, and from routes generating toxic byproducts to routes with benign byproducts, fundamentally altering the synthesis parameters to eliminate hazards
2Reliability
If benzyl ester protection is used for carboxylic acid, then protection is achieved, but expensive palladium catalysts are required and side reactions occur at the cyano group
Solution Approach 1:
The patent replaces expensive palladium catalysts with cheaper alternative catalysts or catalyst-free conditions, using disposable, cost-effective reagents that achieve the same protection and transformation goals without requiring precious metal catalysts
Solution Approach 2:
The patent uses different protecting group strategies or reaction intermediaries that avoid the need for benzyl ester hydrogenolysis, employing alternative mediators or pathways that do not trigger side reactions at the cyano group
3Productivity
If racemic mixture is obtained from synthesis, then the synthesis can proceed, but the S/R configuration ratio is 1:1 and the undesired isomer cannot be effectively utilized
Solution Approach 1:
The patent performs preliminary chiral resolution or uses chiral auxiliaries/catalysts during the synthesis to preferentially form the desired S-configur isomer before completion of the synthesis, preventing formation of the undesired R-isomer in the first place and maximizing utilization of all starting materials
Solution Approach 2:
The patent implements effective chiral resolution methods that not only separate but also allow recovery and reuse of the undesired isomer or its precursors, converting what would be waste into reusable materials or valuable byproducts
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 method achieves a finerenone yield with an enantiomeric excess greater than 99.9% and a purity of 99.9%, suitable for industrial production with reduced costs and safety risks.
Implementation Method 1
mixing the compound of Formula 3, a compound of Formula 4, a chiral catalyst, and a second organic solvent, and conducting cyclization, to obtain a compound of Formula 5
Implementation Method 2
mixing the compound of Formula 6, a tartaric acid derivative, and a fourth organic solvent, conducting a first heat preservation by maintaining an obtained mixture at a first temperature, and then cooling a resulting heated product to a second temperature and conducting second heat preservation, to obtain a salt of the tartaric acid derivative
Implementation Method 3
mixing the compound of Formula 7, a sixth organic solvent, and a basic compound, and conducting hydrolysis, to obtain a compound of Formula 8
Implementation Method 4
mixing the compound of Formula 8, N,N-carbonyldiimidazole (CDI), a seventh organic solvent, 4-dimethylaminopyridine (DMAP), and aqueous ammonia, and conducting amidation, to obtain the finerenone
Data Source
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AI summary
The present application belongs to the technical field of preparation and processing of drugs, and particularly relates to finerenone, a preparation method therefor and a finerenone intermediate. In the preparation method provided by the present application, a compound with a diester structure as represented by formula 2 is used as a reaction raw material to carry out a series of reactions, a chiral catalyst is used in the reaction to obtain a product with an S/R configuration ratio of up to 85:15, and the product is resolved by means of using a tartaric acid derivative, so as to prepare a compound with a structure as represented by formula 7, and then the resulting compound is subjected to hydrolysis and amidation reactions to obtain finerenone. A finerenone drug substance with an ee value of >99.9% and a purity of up to 99.9% can be obtained by means of the preparation method of the present application. Moreover, the reactions during the preparation method provided by the present application are all common reactions, not involving dangerous reaction steps such as hydrogenolysis and high-pressure processes. The method has mild reaction conditions, generates no highly toxic by-products, has low requirements for reaction equipment, has low operational costs, and is simple and convenient to operate. Therefore, the method is suitable for industrial production, and has good market prospects.