Method for the preparation of androgen receptor antagonists and intermediates thereof
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Solution Overview
Problem
Existing processes for producing AR antagonist intermediates like 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile are costly due to the use of expensive soluble palladium catalysts and result in residual catalysts in the product.
Innovation Solution
A method using heterogeneous palladium catalysts immobilized on solid supports, allowing for easy recovery and recycling, reducing production costs and catalyst residues in the end product.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If homogeneous palladium catalyst is used in Suzuki reaction, then reaction efficiency is improved, but production cost increases and catalyst residues remain in product
Solution Approach 1:
The patent applies the discarding and recovering principle by implementing a heterogeneous palladium catalyst system where the catalyst can be easily separated from the reaction mixture through filtration and then recovered for reuse. This resolves the contradiction by maintaining high reaction efficiency while enabling catalyst recovery, thereby reducing production costs and eliminating catalyst residues in the final product.
Solution Approach 2:
The patent changes the physical state parameter of the palladium catalyst from homogeneous (soluble) to heterogeneous (insoluble/particulate). This parameter change allows the catalyst to maintain its catalytic activity while enabling easy separation through filtration, thus resolving the contradiction between reaction efficiency and production cost by facilitating catalyst recovery and reuse.
2Productivity
If homogeneous palladium catalyst is used in Suzuki reaction, then reaction efficiency is improved, but catalyst residues contaminate the end product
Solution Approach 1:
The patent implements catalyst separation and recovery through filtration, effectively discarding the catalyst from the product stream. This resolves the contradiction by maintaining high reaction efficiency with heterogeneous catalyst while ensuring product purity through complete catalyst removal, eliminating residues in the final pharmaceutical intermediate.
Solution Approach 2:
The patent changes the solubility parameter of the palladium catalyst from soluble (homogeneous) to insoluble (heterogeneous). This parameter change enables easy separation by filtration, resolving the contradiction between reaction efficiency and product purity by allowing complete catalyst removal while maintaining catalytic activity during the reaction.
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 high purity of the end product with reduced catalyst residues, making it more economical and practical for large-scale production.
Implementation Method 1
reacting a compound of formula (Ia) or (Ib) with 4-bromo-2-chlorobenzonitrile of formula (II) at an elevated temperature in the presence of heterogeneous palladium catalyst
Data Source
AI summary
The present invention relates to an improved process for the preparation of 2-chloro-4-(1-tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) which is useful as an intermediate in preparation of carboxamide structured androgen receptor antagonists. The process comprises preparation of compound (III) using heterogeneous palladium catalyst.