Alectinib Total Synthesis with Lower-Cost Copper Catalysis
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Solution Overview
Problem
Existing synthetic routes for alectinib are costly, use expensive reagents, and involve inconvenient operation conditions, necessitating an improvement for a more efficient and industrially viable process.
Innovation Solution
A novel synthesis method involving copper-catalyzed C—N coupling, Friedel-Crafts alkylation and acylation, and cyclization steps, utilizing cheaper and less toxic reagents, with the option of a one-pot reaction to directly produce alectinib or its pharmaceutically acceptable salt.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional synthetic routes are used, then alectinib can be produced, but production costs are high and reagents are expensive
Solution Approach 1:
The patent replaces expensive reagents and catalysts with cheaper alternatives. Specifically, it uses inexpensive copper catalysts (CuI, CuBr, CuCl) instead of precious metal catalysts, and employs readily available reagents like K2CO3, KI, and various solvents (EtOH, H2O, DCM) that are significantly less costly than the reagents used in conventional routes.
Solution Approach 2:
The patent optimizes reaction parameters including temperature (ranging from room temperature to reflux conditions), solvent systems (water, ethanol, dichloromethane), and catalyst loadings to achieve high yields while minimizing costs. The multi-step optimization of these parameters enables cost-effective production without sacrificing yield or purity.
2Ease of operation
If conventional synthetic routes are used, then alectinib can be produced, but operation conditions are inconvenient
Solution Approach 1:
The synthesis is divided into distinct modular steps: Step 1 (copper-catalyzed C-N coupling), Step 2 (Friedel-Crafts alkylation), and Step 3 (cyclization). Each step uses different optimized conditions and can be independently controlled, making the overall process easier to operate and troubleshoot compared to conventional one-pot or tightly coupled sequences.
Solution Approach 2:
The patent employs intermediate compounds (compounds of formulas II, III, IV, V, and VI) that can be isolated and characterized at each stage. These intermediates serve as stable handles for process control and quality assurance, simplifying operation and enabling flexible process adjustments without compromising the final product.
3Productivity
If conventional synthetic routes are used, then alectinib can be produced, but production time is long
Solution Approach 1:
The patent employs continuous reaction sequences where each step flows into the next with minimal interruption. The copper-catalyzed coupling, Friedel-Crafts alkylation, and cyclization are performed in sequence with optimized timing, eliminating unnecessary isolation and purification steps between reactions, thereby reducing overall production time while maintaining high yields.
4Object-affected harmful factors
If conventional synthetic routes are used, then alectinib can be produced, but reagents are toxic
Solution Approach 1:
The patent replaces toxic reagents with environmentally benign alternatives. Conventional routes often use toxic solvents and heavy metal catalysts, whereas this invention employs copper catalysts (less toxic than precious metals), and uses green solvents like water and ethanol in many steps, significantly reducing the toxicological burden while maintaining reagent effectiveness.
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 method reduces production time and costs while maintaining high yield, providing a cost-effective and efficient route for alectinib synthesis.
Implementation Method 1
Reacting a compound of formula II with 4-(piperidin-4-yl)morpholine in the presence of a base, a copper catalyst and a ligand to form the compound of formula III
Implementation Method 2
Reacting a compound of formula III with CH3CH2Y in the presence of a catalyst to form a compound of formula IV
Implementation Method 3
Reacting a compound of formula VI with acetone in the presence of a dehydrating reagent and a catalyst to form the alectinib
Data Source
AI summary
The present invention relates to a process for preparing alectinib or a pharmaceutically acceptable salt thereof. The present invention also relates to intermediate compounds which are useful in such process and to the preparation of such intermediate compounds.