Asymmetric Synthesis of Azaspiro Compounds via Davis-Ellman Imine
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Solution Overview
Problem
Current processes for preparing 1-substituted 2-azaspiro compounds and 1-substituted 2-azaspiro[3.3]heptane compounds result in racemic products with poor yields and require hazardous reagents, making them industrially unfeasible and costly.
Innovation Solution
A scalable and diastereoselective process involving the reaction of cyclobutane carboxylate anion with Davis-Ellman's imine, followed by reduction and cyclization, using non-toxic and cost-effective reagents, to produce enantio-enriched 1-substituted 2-azaspiro[3.3]heptane compounds without the need for additional purification or resolution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional processes are used to prepare 1-substituted 2-azaspiro compounds, then the compounds can be produced, but the products are racemic with poor yields and require hazardous reagents
Solution Approach 1:
The patent applies asymmetry by using a chiral catalyst (Davis-Ellman's imine) in the synthesis process to generate enantiomerically enriched products. The chiral environment provided by the catalyst induces asymmetric induction during the formation of the spiro center, thereby producing non-racemic compounds with high enantiomeric excess while maintaining high yields through the efficiency of the catalytic asymmetric synthesis pathway.
2Ease of manufacture
If conventional processes are used to prepare 1-substituted 2-azaspiro compounds, then the compounds can be produced, but hazardous reagents such as thionyl chloride and oxalyl chloride are required
Solution Approach 1:
The patent converts the harmful effect of using hazardous reagents into a benefit by replacing them with safer alternatives. Instead of using thionyl chloride or oxalyl chloride which require special handling and generate toxic byproducts, the invention employs a catalytic asymmetric synthesis method that uses benign reagents and conditions, thereby eliminating the harmful factors while maintaining or improving the ease of manufacture through a more straightforward and safer process.
3Manufacturing precision
If conventional processes are used to prepare 1-substituted 2-azaspiro compounds, then the compounds can be produced, but additional purification and resolution procedures are required
Solution Approach 1:
The patent applies preliminary action by incorporating the resolution step into the main synthesis pathway through catalytic asymmetric synthesis. Instead of performing racemic synthesis followed by separate resolution procedures, the chiral catalyst is used from the beginning to directly produce enantiomerically enriched products. This preliminary introduction of chirality in the synthesis process eliminates the need for subsequent resolution steps, thereby reducing process complexity while maintaining high product purity.
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 achieves high yields and purity with diastereoselectivity up to 98:2 and 90% yield, making it commercially viable and environmentally friendly for large-scale production of bioactive substances and drug candidates.
Implementation Method 1
addition of a cyclobutane carboxylate anion to a Davis-Ellman's imine
Implementation Method 2
followed by reduction and cyclisation
Implementation Method 3
followed by reduction and cyclization
Data Source
AI summary
The present invention relates to an improved asymmetric synthesis of azaspiro or diazaspiro compound (hereafter referred to as the compound 5, (5A) or (5N)) or their pharmaceutically acceptable salts and derivatives; through the formation of intermediate compounds 4, (4A) or (4N) respectively. The process comprises an unusual substrate specific highly diastereoselective as well as enantio-enriched 1-substituted 2-azaspiro[3.3]heptane or 1-substituted 2-diazaspiro[3.3]heptane compounds with high diastereoselectivity by addition of a cyclobutane carboxylate anion to a Davis-Ellman's imine, followed by reduction and cyclisation resulting in the selective formation of azaspiro or diazaspiro intermediate compound 4, (4A) or (4N); which on subsequently removing the sulfinyl group provides corresponding azaspiro or diazaspiro compound 5, (5A) or (5N) respectively.