Purification of AXL Kinase Inhibitor Free Base via pH Adjustment
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for obtaining the free base of compound A are expensive, not amenable to scaling-up, and result in higher solvent residues, particularly ethanol and dichloromethane, due to complex and inefficient purification processes.
Innovation Solution
A process involving dissolving crude compound A in a mixed solvent of C1-5 alcohol and water with an acid, followed by increasing the pH to precipitate the free base, which avoids the use of harmful organic solvents and additional steps, achieving high purity and low solvent residues, specifically below 10,000 ppm ethanol.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If complex purification procedures involving multiple solvent exchanges and salt formation are used, then the purity of compound A free base can be improved, but the process complexity and solvent residue levels increase
Solution Approach 1:
The invention changes the pH parameter of the solution to precipitate the free base of compound A directly from the reaction mixture. By adjusting pH to basic conditions, the compound transitions from its salt form to free base form, which has lower solubility and precipitates out, achieving purification without complex solvent exchanges or additional salt formation steps
Solution Approach 2:
The invention utilizes phase transition by precipitating the free base of compound A from the aqueous reaction mixture through pH adjustment. The compound transitions from dissolved state in acidic conditions to solid precipitate in basic conditions, enabling simple filtration and purification while avoiding multiple solvent exchanges
2Object-affected harmful factors
If multiple solvent exchange steps are performed to reduce solvent residues, then the solvent residue levels can be improved, but the processing time and cost increase
Solution Approach 1:
The invention changes the pH parameter to precipitate the free base directly in the aqueous reaction medium, eliminating the need for solvent exchange steps. The compound is purified by filtration from the aqueous phase, and solvent residues are reduced by simple evaporation or drying, significantly reducing processing time while achieving acceptable solvent residue levels
Solution Approach 2:
The invention extracts the free base of compound A from the aqueous reaction mixture by precipitation through pH adjustment. The precipitated free base is separated by filtration, removing it from the aqueous phase without requiring multiple solvent exchanges, thus reducing both time and complexity while controlling solvent residues
3Ease of manufacture
If traditional purification methods involving toluene and dichloromethane are used, then the compound can be isolated, but harmful solvent residues remain in the final product
Solution Approach 1:
The invention changes the pH parameter to precipitate the free base directly from the aqueous reaction mixture, eliminating the need for toluene and dichloromethane. The compound is isolated by filtration from water-soluble impurities, and harmful solvent residues are avoided by using water as the sole solvent medium throughout the process
Solution Approach 2:
The invention converts the water-solubility of impurities into a benefit by performing the purification in aqueous medium. Impurities that would require organic solvents to remove are instead left dissolved in water while the free base precipitates, allowing easy separation by filtration and eliminating harmful organic solvent residues
Data Source
Figure 1
Figure 2
AI summary
A process for purifying 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3- (7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5- diamine free base is described, the process comprising a) dissolving a quantity of crude 1-(6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3-(7-(pyrrolidin-1-yl)-6,7,8,9- tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine in a mixed solvent of C1-5alcohol and water, together with an acid, and b) increasing the pH of the solution resulting from (a) until 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-yl)-N 3-(7-(pyrrolidin-1-yl)-6,7,8,9- tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine free base is precipitated from the alcohol-water mixed solvent.