Synthesis of Substituted Indene Derivative AQX-1125
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Solution Overview
Problem
Current methods for preparing AQX-1125, a substituted indene derivative with anti-inflammatory activity, are inefficient with low yields and require multiple steps and expensive reagents, necessitating a more cost-effective and streamlined synthesis.
Innovation Solution
The development of new synthetic methods involving specific chemical transformations such as lactone and oxime O-ether reduction, acetate salt formation, carbonyl protection, hydroxyl protection, allylic oxidation, carbonyl reduction, and hydroboration-oxidation steps to produce AQX-1125 with increased yield and reduced reagent usage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If current synthetic methods for preparing AQX-1125 are used, then the compound can be produced, but the overall yield is low and the process requires multiple steps with expensive reagents
Solution Approach 1:
The synthesis is divided into distinct modular stages: (a) carbonyl protection of compound 1 to form compound 2, (b) hydroxyl protection to form compound 3, (c) allylic oxidation to form compound 4, (d) carbonyl reduction and hydroboration-oxidation to form compound 5, (e) carbonyl deprotection to form compound 6, and (f) lactone and oxime O-ether reduction followed by acetate salt formation to produce AQX-1125. Each stage uses specific protecting groups and reagents that can be systematically applied and removed, improving overall yield while maintaining manageable complexity.
Solution Approach 2:
Protecting groups are installed early in the synthesis sequence before key transformations. The carbonyl group is protected as a ketal (compound 2) and the hydroxyl group is protected as a silyl ether (compound 3) before performing the allylic oxidation and subsequent reductions. This preliminary protection prevents side reactions and improves the yield of subsequent steps, allowing the synthesis to proceed more efficiently through multiple transformations.
2Ease of manufacture
If current synthetic methods are used, then AQX-1125 can be prepared, but expensive reagents and multiple steps increase the cost of production
Solution Approach 1:
The synthesis employs systematic changes in reaction conditions and reagent selection to improve cost-effectiveness. For example, the allylic oxidation uses a catalytic system with copper iodide and tert-butyl hydroperoxide rather than stoichiometric reagents. The reductions use lithium aluminum hydride in tetrahydrofuran under controlled temperature conditions. These parameter optimizations reduce reagent costs and improve atom economy while maintaining high yields.
Solution Approach 2:
The methodology uses readily available, inexpensive starting materials and common reagents. Compound 1 (the starting material with steroid backbone) is commercially accessible, and the protecting groups (ethylene glycol for carbonyl, tert-butyldimethylsilyl chloride for hydroxyl) are standard, low-cost reagents. The catalytic oxidant system uses inexpensive copper salts rather than precious metal catalysts, significantly reducing the overall cost of the synthesis.
3Loss of time
If current methods are used, then synthesis can proceed, but the process is time-consuming due to multiple steps
Solution Approach 1:
The synthesis is designed with continuous progression through each transformation stage. Each reaction is optimized to proceed to completion with high yield, and the product of one step becomes the substrate for the next without requiring extensive purification intermediates. The protecting group strategies are designed to be orthogonal, allowing selective deprotection when needed. This continuous action minimizes idle time and maximizes productivity through the six-step sequence.
Solution Approach 2:
The synthesis employs periodic protection and deprotection cycles to enable selective transformations. The carbonyl is protected early (step a), then the hydroxyl is protected (step b), allowing independent manipulation of each functional group. Later, the carbonyl protecting group is removed (step e) while the hydroxyl remains protected, enabling selective reactions. This periodic activation and protection of functional groups streamlines the synthesis by preventing side reactions and eliminating the need for intermediate purifications, thereby reducing total synthesis time.
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
These methods enhance the overall yield of AQX-1125, reduce the number of steps, and utilize less expensive starting materials, providing a more efficient and cost-effective route to the compound.
Implementation Method 1
treating compound 53A having the formula: (structure) under suitable lactone and oxime O-ether reduction conditions to provide compound 16 having the formula: (structure)
Implementation Method 2
treating compound 16 under suitable acetate salt formation conditions to provide AQX-1125
Implementation Method 3
These methods enhance the overall yield of AQX-1125, reduce the number of steps, and utilize less expensive starting materials, providing a more efficient and cost-effective route to the compound
Data Source
AI summary
This invention is directed to methods of preparing AQX-1125 having the formula:This invention is also directed to intermediates utilized in the methods of preparing AQX-1125.