Monohydrochloride Crystal Form for High-Purity Nilotinib Intermediate
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Solution Overview
Problem
Existing methods for preparing nilotinib intermediates, such as 3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylaniline, are cumbersome and costly, requiring multiple recrystallization steps and the use of free base forms.
Innovation Solution
A method involving the direct conversion of the free base form of 3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylaniline to its monohydrochloride anhydrous form through mixing with hydrochloric acid in specific organic solvents, followed by filtration and drying, to produce a stable crystal form A with low moisture content.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If the conventional method using free base form and multiple recrystallization steps is used, then the product purity can be improved, but the process complexity and production cost increase significantly
Solution Approach 1:
The invention changes the chemical form parameter from free base to monohydrochloride salt, which fundamentally alters the solubility and crystallization behavior of the compound. This parameter change enables direct crystallization from reaction mixture without multiple recrystallization steps, achieving both high purity and process simplification
Solution Approach 2:
The invention extracts the compound in its monohydrochloride salt form directly from the reaction mixture and precipitates it by adding alkali to free the compound. This extraction approach eliminates the need for multiple recrystallization steps while maintaining high purity, as the salt formation and precipitation steps effectively separate the product from impurities
2Manufacturing precision
If multiple recrystallization steps are performed, then the product purity is improved, but the production time and operational steps increase
Solution Approach 1:
The invention performs salt formation with hydrochloric acid as a preliminary action before the main crystallization step. This preliminary salt formation creates a compound with optimized solubility characteristics that enables direct crystallization, eliminating the need for subsequent multiple recrystallization steps and significantly reducing production time
Solution Approach 2:
The invention merges the salt formation, purification, and crystallization steps into a single integrated process. By forming the monohydrochloride salt and directly crystallizing it from the reaction mixture, multiple operations are combined into one efficient workflow, reducing both time and operational complexity
3Productivity
If the free base form is used for synthesis, then the reaction can proceed, but additional steps for salinization and neutralization are required
Solution Approach 1:
Instead of using the conventional free base form and then converting to salt, the invention inverts the sequence by directly using the monohydrochloride salt form in the synthesis reaction. This inversion eliminates the need for separate salinization and neutralization steps, as the salt form is directly applicable and simplifies the overall synthetic pathway
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 approach simplifies the preparation process, enhances product stability and purity, and reduces production costs by eliminating the need for recrystallization, resulting in high yields and efficient synthesis of nilotinib.
Implementation Method 1
mixing 3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylaniline free base with hydrochloric acid in an organic solvent
Implementation Method 2
mixing 3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylaniline free base with hydrochloric acid in an organic solvent, wherein the organic solvent is two selected from methanol, toluene, and acetone
Implementation Method 3
cooling and stirring to afford a suspension
Implementation Method 4
filtering to collect the solid
Implementation Method 5
the obtained solids are dried at 50-80°C under 10-20mmHg until the moisture content is 0.50% or less
Data Source
Figure 1~2
AI summary
The present invention relates to a crystal form of 3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylaniline monohydrochloride and the use thereof. Specifically, disclosed are a crystal form A of a monohydrochloride anhydrous substance of 3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethylaniline monohydrochloride, a method for preparing the crystal form A and the use of the crystal form in the synthesis of nilotinib. The crystal form A of the present invention has good stability and purity, and can be directly used in the preparation and production of nilotinib. The method for preparing nilotinib in the present invention is easy to operate and has high industrial application value.