Chroman Compound Synthesis Without Costly Chiral Resolution
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Solution Overview
Problem
The existing methods for synthesizing 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid and its salts are complicated, costly, and not suitable for industrial scale due to the difficulty and cost of chiral resolution of intermediates, affecting overall yield.
Innovation Solution
A cost-effective and industrially advantageous enantioselective synthesis method involving novel intermediates and steps such as coupling, asymmetric hydrogenation, and selective reductions, using catalysts and ligands like SEGPHOS and palladium catalysts, to control stereochemistry and obtain the desired compound.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If chiral resolution of racemic chroman-2-carboxylic acid is performed to obtain desired (R) chroman-2-carboxylic acid, then enantiomeric purity is improved, but manufacturing complexity and cost increase, and overall yield decreases
Solution Approach 1:
The patent applies preliminary action by incorporating the chiral center during the synthesis of chroman-2-carboxylic acid itself, rather than starting with racemic material and performing resolution later. This enantioselective synthesis approach establishes the desired (R) configuration early in the synthetic route, avoiding the need for subsequent chiral resolution steps and their associated complexity and yield losses
2Manufacturing precision
If chiral resolution of intermediate is performed to obtain desired stereochemistry, then stereochemical purity is improved, but manufacturing cost and complexity increase
Solution Approach 1:
The patent performs preliminary enantioselective synthesis to establish the correct stereochemistry at the chroman-2-carboxylic acid stage, before proceeding with subsequent synthetic steps. This preliminary establishment of chirality eliminates the need for intermediate chiral resolution, thereby improving manufacturing ease while maintaining stereochemical purity
Solution Approach 2:
The patent employs chiral auxiliaries or enantioselective catalysts as intermediaries during the synthesis of chroman-2-carboxylic acid to control stereochemistry. These chiral intermediaries facilitate the formation of the desired enantiomer during the synthesis process itself, rather than requiring resolution of racemic mixtures later
3Manufacturing precision
If chiral resolution steps are included in the synthesis route, then enantiomeric purity is improved, but overall yield decreases
Solution Approach 1:
The patent implements preliminary enantioselective synthesis to generate the desired (R) chroman-2-carboxylic acid directly with high enantiomeric purity from the outset. This approach avoids the material loss inherent in chiral resolution processes, thereby maintaining high overall yield while achieving the required enantiomeric purity for the final product
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 provides a facile and efficient synthesis of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid and its salts, overcoming the limitations of chiral resolution and improving yield and cost-effectiveness.
Implementation Method 1
enantioselective reduction of the double bond of Compound 3 by asymmetric hydrogenation to obtain the optically active Compound 4 using one or more optically active diphosphine ligands
Implementation Method 2
coupling Compound 9 with methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate in the presence of one or more palladium catalysts to give methyl-5-((R)-2-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-2H-chromen-4-yl)-2-methylbenzoate (Compound 10)
Implementation Method 3
hydrolyzing the ester group of Compound 12 using one or more hydroxide bases followed by aqueous reaction of the resultant carboxylate salt into the carboxylic acid
Data Source
AI summary
This disclosure describes an economical and scalable method and process to synthesize the Calcium sensing receptor (CaSR) modulating agent 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid, its intermediates and pharmaceutically acceptable salts therefor. Uses of said intermediates for synthesis of compounds which may be intermediates to the synthesis of 2-methyl-5-((2R,4S)-2-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)chroman-4-yl)benzoic acid are also described herein.