Copanlisib Synthesis via Continuous Microreaction Nitration
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Solution Overview
Problem
Existing synthesis methods for copanlisib, a cancer agent inhibiting Class I phosphatidylinositol-3-kinases, face challenges such as batch nitration safety concerns, formation of explosive nitrogen triiodide, and difficulties in scaling up due to the use of sulfur and standard catalytic reductions, which reduce yield and complicate industrial-scale production.
Innovation Solution
A continuous process using microreaction technology for nitration, replacing ammonia and iodine with ethylenediamine and N-bromosuccinimide, and employing a platinum-iron catalyst for hydrogenation to overcome safety and scalability issues, resulting in improved yield and product quality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If batch nitration is used for copanlisib synthesis, then the traditional synthesis pathway can be maintained, but safety concerns arise due to potential runaway reactions
Solution Approach 1:
The batch nitration process is segmented into a continuous flow process where reagents are fed separately through a packed bed reactor containing nitrobenzenesulfonic acid. This segmentation allows better control of the exothermic reaction by dividing the reaction into smaller stages along the flow path, eliminating safety concerns while maintaining manufacturing feasibility
Solution Approach 2:
Nitrobenzenesulfonic acid is introduced as an intermediary catalyst in the packed bed reactor. This intermediary enables the nitration reaction to proceed under milder, more controllable conditions compared to traditional batch methods, improving safety while simplifying the overall manufacturing process
2Productivity
If ammonia and iodine are used for aldehyde to nitrile conversion, then the reaction can proceed, but explosive nitrogen triiodide is formed
Solution Approach 1:
The harmful iodine component is extracted from the reaction system and replaced with N-bromosuccinimide as the brominating agent. This removal of the problematic reagent eliminates nitrogen triiodide formation while maintaining the efficiency of converting aldehyde to nitrile through the formamidine intermediate
Solution Approach 2:
The method converts potentially harmful reagents (ammonia and iodine) into a safer alternative system using N-bromosuccinimide and ethylenediamine. The harmful explosive byproduct formation is converted into a beneficial safe process that maintains or improves reaction efficiency
3Productivity
If sulfur and standard catalytic reductions are used, then the nitro group can be reduced, but yield is reduced and industrial scaling is complicated
Solution Approach 1:
The reduction conditions are changed by using hydrogen gas with a platinum-iron catalyst instead of sulfur-based reducing agents. This parameter change in the reducing system improves yield and simplifies the process for industrial scaling by eliminating the need for sulfur handling and associated complex workup procedures
Solution Approach 2:
The chemical reduction mechanism using sulfur is substituted with a catalytic hydrogenation system. This replacement uses a platinum-iron catalyst to facilitate hydrogen addition to the nitro group, achieving better yields and simpler processing suitable for industrial manufacturing
4Ease of manufacture
If conventional synthesis methods are used for scale-up, then existing procedures can be followed, but safety and scalability issues arise
Solution Approach 1:
The synthesis is reorganized from batch operations to a continuous flow process with segmented reaction zones. The packed bed reactor segments the nitration step into controlled flow stages, enabling safe scale-up while maintaining reliability. Each reaction step is optimized for continuous processing rather than batch scaling
Solution Approach 2:
The method performs preliminary optimization of reaction conditions for continuous flow before scale-up. By designing the synthesis pathway with flow chemistry principles from the outset, including the selection of appropriate catalysts and reagent feeds, the process achieves both safety and scalability without requiring subsequent re-optimization for industrial scale
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 new process enables safe and efficient large-scale production of copanlisib with reduced side products and regioisomer removal, enhancing the feasibility of industrial-scale synthesis.
Implementation Method 1
a) conversion of an aldehyde to a nitrile with ammonia and iodine as reagents, or with ethylenediamine and N-bromosuccinimide in the presence of a nitrobenzenesulfonic acid catalyst
Implementation Method 2
b) reduction of the nitro group with hydrogen and a platinum-iron catalyst
Implementation Method 3
reduction of the nitro group with hydrogen and a platinum-iron catalyst
Data Source
AI summary
The present invention relates to a novel method of preparing copanlisib, copanlisib dihydrochloride, or hydrates of copanlisib dihydrochloride, to novel intermediate compounds, and to the use of said novel intermediate compounds for the preparation of said copanlisib, copanlisib dihydrochloride, or hydrates of copanlisib dihydrochloride. The present invention also relates to copanlisib dihydrochloride hydrates as compounds.