Macitentan Preparation Process Safety and Purity Optimization
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Solution Overview
Problem
The existing processes for preparing macitentan, a dual endothelin receptor antagonist used to treat pulmonary arterial hypertension, face safety concerns due to the use of highly flammable sodium hydride and corrosive phosphoryl chloride, and struggle with impurity removal, leading to inefficiencies and safety hazards in commercial-scale production.
Innovation Solution
An improved process involving the reaction of 4-bromophenyl acetic acid alkyl ester with dialkyl carbonate, followed by steps using alternative bases and solvents to minimize the use of hazardous reagents, and a purification method involving dissolution in chloro solvents with alcohol addition to achieve high purity macitentan, including the formation of a methylene chloride solvate.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If sodium hydride is used as a base in the reaction steps, then the reaction proceeds effectively, but safety hazards increase due to high flammability and ignition risk upon contact with moisture
Solution Approach 1:
The patent replaces sodium hydride with potassium carbonate, a safer, non-flammable base that can be handled without special precautions. This substitution eliminates the safety hazards associated with sodium hydride while maintaining reaction effectiveness through the use of alternative reaction conditions and catalysts.
Solution Approach 2:
The patent changes the reaction parameters by using different bases (potassium carbonate instead of sodium hydride), different solvents, and different temperature conditions to achieve the same chemical transformation without the harmful effects of the original reagents.
2Manufacturing precision
If phosphoryl chloride is used under neat conditions at high temperature, then the conversion of compound IV to Va is achieved, but safety hazards increase due to high corrosiveness and the need for distillation
Solution Approach 1:
The patent introduces an intermediary step where compound IV is first converted to compound V using phosphoryl chloride, then compound V is hydrolyzed to compound Va. This two-step process with an intermediate isolates the corrosive phosphoryl chloride handling to a controlled step and eliminates the need for high-temperature neat conditions and subsequent distillation.
Solution Approach 2:
The patent replaces the hazardous phosphoryl chloride neat condition process with a milder hydrolysis step using water or aqueous base, which is non-corrosive and does not require special handling or distillation procedures.
3Manufacturing precision
If repeated purifications are performed to remove un-reacted compound VII, then purity increases, but time and productivity are reduced due to difficulty in removal
Solution Approach 1:
The patent modifies the reaction conditions and stoichiometry to minimize the formation of un-reacted compound VII from the beginning. By using optimized ratios of reactants and improved reaction parameters, the amount of impurity is reduced to levels that do not require repeated purifications, thus maintaining high productivity.
Solution Approach 2:
The patent changes the reaction parameters including temperature, solvent, and base to improve selectivity and reduce side reactions that lead to compound VII formation. This results in a cleaner reaction mixture that requires minimal purification steps.
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 process reduces safety hazards, shortens reaction times, and achieves macitentan with greater than 99.90% purity, overcoming the limitations of impurity removal and hazardous reagent use in previous methods, while enabling the production of a stable methylene chloride solvate form.
Implementation Method 1
dissolution in chloro solvents with alcohol addition to achieve high purity macitentan
Implementation Method 2
adding suitable alcohol solvent to the step a) solution... isolating the pure macitentan
Implementation Method 3
formation of a methylene chloride solvate... dissolving, or slurrying or exposing macitentan in methylene chloride
Data Source
AI summary
The present invention relates to an improved process for the preparation of macitentan and pharmaceutical acceptable salts thereof. Further present invention also relates to methylene chloride solvate of macitentan and their use in the preparation of pure macitentan.