Alogabat Manufacturing Process Without Chromatography or Toxic Solvents
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing laboratory-scale processes for manufacturing alogabat, such as those disclosed in WO2018104419, are not suitable for industrial-scale production due to the use of toxic solvents, silica gel chromatography, and low yields, making it challenging to provide this treatment option for Autism Spectrum Disorder (ASD) patients.
Innovation Solution
Alogabat is manufactured using a base such as sodium hydride in an aprotic solvent like 2-methyltetrahydrofuran, followed by purification through filtration with activated charcoal and crystallization, and the synthesis of key intermediates like 6-chloro-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide is optimized with palladium catalysts and bases like N-ethyldiisopropylamine in solvents like 2-propanol, enabling large-scale production under Good Manufacturing Practice (GMP) conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If silica gel chromatography is used for purification, then product purity is improved, but device complexity and manufacturing cost increase significantly
Solution Approach 1:
The invention extracts and eliminates the need for silica gel chromatography from the purification process. Instead of using complex chromatographic separation, the process relies on selective crystallization and filtration to achieve the desired purity, thereby removing the harmful complexity of chromatography while maintaining product quality
Solution Approach 2:
The invention changes the purification parameters from chromatographic separation to crystallization-based purification. By controlling temperature, solvent composition, and crystallization conditions, the process achieves high purity through phase transition rather than adsorption, simplifying the overall manufacturing process
2Productivity
If toxic solvents like DMF are used, then reaction efficiency is improved, but object-affected harmful factors increase
Solution Approach 1:
The invention converts the harmful aspect of solvent use by replacing toxic DMF with safer alternative solvents. The process maintains reaction efficiency by optimizing the alternative solvent system, thereby transforming a harmful process into a beneficial one that eliminates toxic exposure while preserving productivity
Solution Approach 2:
The invention changes the solvent parameter from toxic DMF to safer alternatives, maintaining reaction efficiency through optimized reaction conditions. This parameter change eliminates the harmful effects of toxic solvent exposure while preserving the beneficial aspect of high reaction efficiency
3Manufacturing precision
If laboratory-scale processes are used, then product quality is maintained, but productivity remains low
Solution Approach 1:
The invention creates a universal process that functions effectively at both laboratory and industrial scales. By eliminating scale-dependent steps like chromatography and using robust crystallization-based purification, the process maintains consistent product quality whether producing milligrams or kilograms, achieving multi-scale applicability
Solution Approach 2:
The invention segments the manufacturing process into distinct, scalable stages: reaction, filtration, and crystallization. Each stage can be independently optimized and scaled, allowing the process to transition smoothly from laboratory to industrial production while maintaining product quality through controlled separation of functions
Data Source
AI summary
The invention relates to novel processes for manufacturing 6-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methoxy]-N-tetrahydropyran-4-yl-pyridazine-3-carboxamide (1), or a pharmaceutically acceptable salt thereof. The processes according to the invention are particularly suitable for large-scale manufacturing of the compound of formula 1 under GMP conditions.