Alectinib Synthesis Using Trimethylsilylacetylene and Palladium Catalysis
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Solution Overview
Problem
The existing process for preparing alectinib, an ALK inhibitor for treating non-small-cell lung cancer, has low yields and uses expensive and toxic reagents, making it inefficient and costly.
Innovation Solution
A new process involving the reaction of a compound with trimethylsilylacetylene in the presence of a base and a palladium catalyst, followed by cleavage of the trimethylsilyl group and reduction of the ethynyl group to produce alectinib, using cheaper and less toxic reagents, and potentially as a one-pot reaction to avoid intermediate isolation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the existing process using triisopropylsilylacetylene and TBAF is used, then the synthesis can be completed, but the yield is low (approx. 8.8%) and reagents are expensive and toxic
Solution Approach 1:
The patent replaces expensive and toxic reagents (triisopropylsilylacetylene and TBAF) with cheaper and less toxic alternatives (trimethylsilylacetylene and K2CO3). This substitution maintains the necessary chemical functionality while eliminating harmful effects and reducing costs, directly addressing the contradiction between achieving synthesis and avoiding toxic reagents.
Solution Approach 2:
The patent changes the chemical parameters of the reagents used in the synthesis process. Specifically, it modifies the silyl group from triisopropylsilyl to trimethylsilyl, and changes the base from TBAF to K2CO3. These parameter changes result in improved yield and reduced toxicity, resolving the technical contradiction.
2Productivity
If the existing three-step process for introducing ethyl group is used, then the synthesis can be completed, but the total yield is low (approx. 14%) and the process is complex
Solution Approach 1:
The patent merges multiple steps into a streamlined sequence. Instead of separate steps for coupling, deprotection, and reduction, the patent combines these operations into a more integrated process that proceeds through intermediate compounds more efficiently. This merging reduces the overall complexity while maintaining or improving yield.
Solution Approach 2:
The patent extracts and eliminates unnecessary intermediate steps and reagents from the existing three-step process. By removing the need for TBAF and triisopropylsilylacetylene, and using more direct reagents, the process is simplified while achieving better yields, thus resolving the contradiction between completion and complexity.
3Manufacturing precision
If intermediate compounds are isolated at each step, then purity can be maintained, but time and cost increase
Solution Approach 1:
The patent enables continuous processing by allowing the reaction sequence to proceed without complete isolation of intermediates. The modified reagents and conditions allow for more seamless transitions between steps, maintaining purity while reducing the time and resources required for isolation procedures.
Solution Approach 2:
The patent uses modified intermediate compounds that can be handled more efficiently. The changes in reagents allow these intermediates to be processed through simplified procedures, acting as bridges that maintain purity while enabling more continuous and less time-consuming synthesis.
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 increases the yield of alectinib production, is safer and more cost-effective, and is suitable for plant-scale production by eliminating the need for expensive and toxic reagents like triisopropylsilylacetylene and tetra-n-butylammonium fluoride.
Implementation Method 1
reacting a compound of formula IV with trimethylsilylacetylene (TMS-acetylene) in the presence of a base, a palladium catalyst and a ligand
Implementation Method 2
treating the resulting intermediate compound of formula III with a base, such as K2CO3, in the presence of a solvent
Implementation Method 3
converting the resulting intermediate compound of formula II into alectinib, or a pharmaceutically acceptable salt thereof, preferably the hydrochloride salt, by reduction of the ethynyl group
Data Source
AI summary
The present invention relates to a process for preparing alectinib, or a pharmaceutically acceptable salt thereof, and to related intermediates.