Clazosentan Disodium Salt Crystallization for High-Purity Manufacturing
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Solution Overview
Problem
Existing methods for manufacturing clazosentan disodium salt are inefficient, costly, and lack the ability to produce high-purity forms suitable for large-scale pharmaceutical use, particularly in the context of treating cerebral vasospasm and ischemic effects following aneurysmal subarachnoid hemorrhage.
Innovation Solution
A novel process involving specific reaction conditions and solvents, including the use of alkali metal salts and aprotic organic solvents, to produce clazosentan disodium salt with high yields, purity, and crystalline forms that facilitate safe handling and reduce costs in large-scale manufacturing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing methods are used for manufacturing clazosentan disodium salt, then production can be achieved, but the process is inefficient, costly, and produces poor purity and filterability
Solution Approach 1:
The patent applies parameter changes by optimizing reaction conditions including using specific molar ratios of reactants (1:1.05-1.20 for compound of formula 1 and 5-methyl-pyridine-2-sulfonamide), controlling reaction temperature (70-90°C), and selecting specific solvents (acetonitrile, 1,4-dioxane, or their mixtures). These parameter optimizations simultaneously improve both purity (98-99.5%) and productivity (85-95% yield) of clazosentan disodium salt
Solution Approach 2:
The patent employs composite solvent systems combining acetonitrile and 1,4-dioxane in specific ratios to achieve optimal reaction performance. This composite approach enhances both the efficiency of the reaction process and the purity of the final product, resolving the contradiction between manufacturing precision and productivity
2Ease of operation
If existing manufacturing processes are used, then clazosentan disodium salt can be produced, but filterability and handling are difficult
Solution Approach 1:
The patent changes physical parameters including reaction temperature (70-90°C), solvent selection (acetonitrile, 1,4-dioxane, or mixtures), and molar ratios to optimize crystal formation. These changes produce clazosentan disodium salt with superior filterability and handling characteristics while maintaining high purity levels of 98-99.5%
3Reliability
If existing methods are used, then production can proceed, but safety concerns and agglomerate formation occur
Solution Approach 1:
The patent employs an inert atmosphere (nitrogen or argon) during the reaction process to prevent oxidation and degradation of the compound. This creates a safe operating environment that eliminates safety concerns while preventing agglomerate formation, thereby improving both reliability and reducing harmful factors
Solution Approach 2:
The patent optimizes reaction parameters including temperature control (70-90°C), solvent selection, and molar ratios to prevent unwanted side reactions and agglomerate formation. These controlled conditions enhance safety and reliability while eliminating the formation of harmful aggregates
4Productivity
If existing processes are used, then manufacturing can occur, but costs are high and yields are low
Solution Approach 1:
The patent optimizes reaction parameters including using 1.05-1.20 equivalents of 5-methyl-pyridine-2-sulfonamide, controlling temperature at 70-90°C, and selecting cost-effective solvents like acetonitrile and 1,4-dioxane. These optimizations achieve high yields (85-95%) while reducing manufacturing costs through improved efficiency and reduced material waste
Solution Approach 2:
The patent uses readily available, inexpensive solvents such as acetonitrile and 1,4-dioxane that can be easily removed and do not require expensive specialized handling or disposal procedures. This approach reduces manufacturing costs while maintaining high productivity through efficient reaction conditions
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 achieves high-purity clazosentan disodium salt with improved safety, reduced agglomerate formation, and simplified handling, thereby enhancing the effectiveness and cost-effectiveness of pharmaceutical applications.
Implementation Method 1
reacting the compound of formula 1 with 5-methyl-pyridine-2-sulfonamide or a salt (notably alkali metal salt; especially potassium salt) thereof, under basic conditions, to give the compound of formula 2
Implementation Method 2
reacting the compound of formula 2 with ethylene glycol in the presence of an alkali metal hydroxide (especially sodium hydroxide), to give the compound of formula 3
Implementation Method 3
reacting the compound of formula 3 with trimethylsilyl cyanide to give the compound of formula 4
Implementation Method 4
reacting the compound of formula 4 with sodium azide to give the compound of formula 5
Implementation Method 5
reacting the compound of formula 5 with a sodium containing base to give clazosentan disodium salt
Implementation Method 6
produce clazosentan disodium salt with high yields, purity, and crystalline forms that facilitate safe handling
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
The present invention relates to clazosentan disodium salt and a process for the preparation thereof.