Substituted Quinolin-4-ol Preparation via Controlled Reaction and Purification
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Solution Overview
Problem
Current methods for preparing substituted quinolin-4-ol compounds at a large scale are not suitable for GMP-compliance kilogram scale production, as they result in excessive byproduct formation and complex purification processes, making them inefficient and industrially unviable.
Innovation Solution
A process involving the reaction of compound Formula (II) with dichlorobenzene at controlled temperatures and concentrations to produce compound Formula (I), followed by a purification process including vacuum concentration, dichloromethane washing, filtration, and water washing to achieve high yields and simplify purification.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional small-scale preparation methods are used, then the compounds can be prepared with existing procedures, but the processes are not suitable for large-scale GMP-compliant production due to excessive byproduct formation and complex purification
Solution Approach 1:
The patent changes the reaction parameters by using a specific molar ratio of reactants (1:1.1 to 1:1.5), controlling reaction temperature (100-150°C), and selecting specific solvents to optimize the reaction conditions for large-scale production, thereby reducing byproduct formation while maintaining high productivity
Solution Approach 2:
The patent introduces a catalyst (Lewis acid or organocatalyst) as an intermediary to facilitate the reaction between compound (II) and dichlorobenzene, enabling the reaction to proceed efficiently at controlled conditions that minimize byproduct formation while suitable for large-scale production
2Ease of manufacture
If conventional preparation methods are used, then existing procedures can be followed, but the purification processes become complex and inefficient for industrial application
Solution Approach 1:
The patent employs extraction techniques where the reaction mixture is treated with water to separate organic and aqueous layers, and further purified by washing with brine and drying over anhydrous sodium sulfate, thereby simplifying the purification process for industrial application
Solution Approach 2:
The patent removes and discards byproducts and impurities through filtration and washing steps, while recovering the pure quinolin-4-ol compound through evaporation and crystallization, thereby simplifying the overall manufacturing process
3Speed
If microwave conditions are used as disclosed in WO 2013/086229, then reaction speed may be improved, but the method is not intended for plant production scale
Solution Approach 1:
The patent replaces microwave heating with conventional thermal heating methods, using oil baths or heating mantles to maintain reaction temperatures, thereby enabling scalable industrial production while maintaining acceptable reaction speeds through optimized reaction conditions and catalysts
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
This method allows for the efficient preparation and purification of substituted quinolin-4-ol compounds on a multi-kilogram scale, reducing byproduct formation and improving yield, making it industrially viable and compliant with GMP standards.
Implementation Method 1
concentrating the reaction mixture under vacuum to provide a solid
Implementation Method 2
stirring the solid of step (a) in dichloromethane (CH2Cl2) to form a mixture; isolating the solid from the mixture of step (b) by filtration
Implementation Method 3
stirring the solid of step (c) in water to form an aqueous mixture; isolating the solid from the aqueous mixture of step (d) by filtration
Implementation Method 4
drying the isolated solid of step (e) to form purified compound of Formula (I)
Data Source
AI summary
The invention relates to a process for preparing substituted quinolin-4-ol compounds useful for preparing protein tyrosine kinase (PTK) inhibitors which are useful in treating cancer.