Avibactam Synthesis via Disposable Catalyst and One-Pot Steps
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Solution Overview
Problem
Existing methods for synthesizing avibactam are complex, costly, and environmentally unfriendly due to the use of expensive catalysts and the generation of significant waste, with low atom economy and industrial operability.
Innovation Solution
A simplified process involving condensation, reduction, hydrolysis, urea cyclization, deprotection, sulfation, and ion exchange steps, using inexpensive starting materials and avoiding the need for palladium-on-carbon catalysts, to produce avibactam with high yields and reduced waste.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If palladium-on-carbon catalysis is used for debenzylation, then the intermediate can be converted to avibactam, but the process becomes costly and generates catalyst poisoning
Solution Approach 1:
The patent replaces expensive palladium-on-carbon catalyst with a disposable, inexpensive alternative catalyst system that can be easily removed. The new method uses a short-lived catalytic system that does not require expensive metal catalysts, thereby reducing manufacturing costs while maintaining conversion reliability.
Solution Approach 2:
The patent changes the reaction parameters by using a different catalytic system with altered physical and chemical properties. Instead of palladium-on-carbon, the method employs a catalyst that operates under different conditions, avoiding the cost and poisoning issues associated with the traditional catalyst while achieving the same debenzylolation transformation.
2Reliability
If complex multi-step synthesis is used for avibactam preparation, then the reaction can proceed, but the process complexity and waste generation increase
Solution Approach 1:
The patent merges multiple synthesis steps into a more streamlined process. By combining certain reaction steps and eliminating unnecessary intermediate stages, the method reduces process complexity while maintaining reaction feasibility. The synthesis pathway is consolidated to minimize the number of operational steps required.
Solution Approach 2:
The patent extracts and removes unnecessary intermediate steps from the synthesis pathway. By identifying and eliminating redundant operations, the method simplifies the overall process while retaining the essential chemical transformations needed to produce avibactam, thereby reducing complexity without sacrificing reaction feasibility.
3Reliability
If traditional synthesis methods are used, then avibactam can be produced, but atom economy is poor and environmental friendliness is reduced
Solution Approach 1:
The patent changes the reaction parameters and reagent selection to improve atom economy. By choosing reagents and reaction conditions that maximize the incorporation of all atoms into the final product, the method reduces waste generation while maintaining reliable avibactam production. The chemical transformations are optimized to minimize byproduct formation.
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 process is cost-effective, environmentally friendly, and facilitates industrial production with high yields, simplifying the synthesis steps and reducing waste generation.
Implementation Method 1
the compound of formula III is subjected to reduction with a reducing agent in the presence of concentrated sulphuric acid and ethyl acetate
Implementation Method 2
the compound of formula IV is hydrolyzed in the presence of base b and in solvent b to obtain the compound of formula V
Implementation Method 3
the compound of the formula VII is subjected to ion exchange to obtain avibactam (I)
Data Source
Figure 1~2
Figure 3~4
Figure 5~6
AI summary
The present invention provides a simple process of preparing avibactam. Piperidine-5-one-2S-carboxylate II as the raw material is subjected to condensation reaction with O-protecting hydroxylamine hydrochloride; the resulting compound is subjected to reduction and chiral resolution to obtain 5R-substituted oxyaminopiperidine-2S-carboxylic acid V in a basic condition; then, the compound of formula V is subjected to urea cyclization, acyl chlorination, and amidation with phosgene, solid phosgene, or diphosgene in a "one-pot" process, and then subjected to deprotection, sulfation, and tetrabutylammonium salt formation reaction to obtain (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]oxy}sulfonyl tetra-n-butyl ammonium salt VII, and finally, the compound of formula VII is subjected to ion exchange to obtain avibactam I. The present invention has a simple preparing scheme, ease of operation, inexpensive starting materials, and a low cost; besides, the present invention discharges less waste water, waste gas, and waste residuals, such that it is environment friendly; the yields of its respective steps are high, which facilitate industrial production of avibactam.