Apalutamide Synthesis with Novel Intermediates for Safer Scale-Up
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Solution Overview
Problem
Existing processes for the production of Apalutamide are inefficient, costly, and hazardous, with low yields and poor stability of polymorphs, making them unsuitable for large-scale industrial production.
Innovation Solution
A novel process using a novel intermediate, such as 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid, is developed, which involves condensation reactions with 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile and subsequent dissolution in suitable solvents, avoiding expensive and hazardous reagents, and allowing for high-purity Apalutamide production with high yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing processes for Apalutamide production are used, then production can be achieved, but the yield is low and the process is costly
Solution Approach 1:
The patent divides the synthesis process into distinct modular stages: (i) preparation of ethyl 4-amino-2-fluorobenzoate, (ii) condensation with bromocyclobutane-1-carboxylic acid to form the spiro cycle, (iii) reaction with 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile, and (iv) cyclization to form the final Apalutamide product. This segmentation allows each step to be optimized independently, improving overall yield and facilitating scale-up while reducing manufacturing costs through standardized procedures.
Solution Approach 2:
The patent optimizes reaction parameters including solvent selection (using ethyl acetate and toluene instead of hazardous reagents), temperature control (reflux conditions), and stoichiometry of reagents. These parameter changes improve reaction efficiency and yield while reducing production costs by eliminating expensive and hazardous materials from the process.
2Productivity
If existing processes for Apalutamide production are used, then production can be achieved, but the process involves hazardous reagents and is inefficient
Solution Approach 1:
The patent replaces expensive and hazardous reagents with cheaper, safer alternatives. Specifically, dimethylformamide is replaced with ethyl acetate and toluene, which are less hazardous and more environmentally friendly. This substitution improves production efficiency by reducing safety precautions and waste treatment requirements while eliminating harmful factors from the process.
Solution Approach 2:
The patent converts potentially hazardous reaction conditions into beneficial outcomes by optimizing the reaction sequence to use milder conditions. The multi-step synthesis allows for controlled formation of intermediates under safe conditions, transforming what would be hazardous direct reactions into a series of manageable, safe steps that improve overall efficiency.
3Stability of the object's composition
If prior-art processes are used, then Apalutamide can be produced, but the polymorphs show poor stability at long term storage
Solution Approach 1:
The patent employs controlled crystallization and solvent removal steps that induce specific phase transitions to form stable polymorphic forms of Apalutamide. The final drying step at controlled temperature and the use of specific solvents promote formation of the thermodynamically stable polymorph, ensuring long-term storage stability and reliability of the 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 process is cost-effective, eco-friendly, and efficient, producing high-purity Apalutamide suitable for large-scale industrial production with improved stability and yield, overcoming the limitations of previous methods.
Implementation Method 1
2-Fluoro-4-aminobenzoic acid ethyl ester (KSM-1) is condensed with bromocyclobutane-1-carboxylic acid (KSM-2) in presence of suitable base that leads to formation of a novel intermediate 1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid (Intermediate-1)
Implementation Method 2
1-[4-(ethoxycarbonyl)-3-fluoroanilino]cyclobutane-1-carboxylic acid (Intermediate-1) is reacted with 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile (KSM-3) in presence of suitable base that leads to formation of ethyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoate (Intermediate-2)
Implementation Method 3
ethyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoate (Intermediate-2) is dissolved in suitable solvent in the presence of suitable base to form Apalutamide
Data Source
AI summary
The present invention relates to novel highly efficient and economic process for large-scale production of Apalutamide. The present invention also relates to novel process that form highly pure Apalutamide through a novel intermediate. This process avoids use of expensive and hazardous reagents and solvents. Along with the ease of performance, the present invention process also gives high-purity final product with high yield. This makes the present invention highly cost-effective and time-efficient.