Monobactam Synthesis via Dynamic Kinetic Resolution
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Solution Overview
Problem
Current processes for producing monobactam antibiotic Compound X are inefficient due to numerous steps, nitrogen protection/deprotection steps, and the need for chromatographic purification, resulting in poor handling characteristics and low yield.
Innovation Solution
A new process that eliminates the need for nitrogen protecting groups in the final synthesis steps, reducing the number of purification steps and improving handling characteristics by reacting compounds of formulas 22 and 2A in a solvent with a base and coupling agent, and employing asymmetric reduction conditions for intermediate synthesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional processes are used for producing monobactam antibiotic Compound X, then the synthesis can be completed with established methods, but the process requires numerous steps including nitrogen protection/deprotection and chromatographic purification, resulting in low yield and poor handling characteristics
Solution Approach 1:
The invention extracts and eliminates the nitrogen protection/deprotection steps from the conventional synthesis process. By using alternative reaction conditions and reagents, the process directly synthesizes the final compound without requiring intermediate protection groups, thereby reducing the number of process steps and improving overall yield while maintaining product purity
Solution Approach 2:
The invention implements continuous synthesis by eliminating discrete protection and deprotection cycles. The reaction sequence proceeds continuously through fewer intermediate stages, with each step building directly toward the final product without interruption for protecting group manipulation, thereby improving productivity and reducing process complexity
2Stability of the object's composition
If conventional processes with nitrogen protecting groups are used, then intermediate stability can be maintained, but the need for multiple purification steps increases process complexity and reduces yield
Solution Approach 1:
The invention removes the requirement for nitrogen protecting groups entirely from the synthesis pathway. By selecting reaction conditions that maintain intermediate stability without protection groups, the process eliminates the need for multiple chromatographic purification steps, thereby reducing process complexity while preserving intermediate integrity
Solution Approach 2:
The invention changes the reaction parameters (such as solvent selection, temperature control, and reagent choice) to enable stable intermediate formation without nitrogen protection groups. This parameter optimization allows the synthesis to proceed through fewer purification steps while maintaining adequate intermediate stability
3Manufacturing precision
If multiple nitrogen protection/deprotection steps are implemented, then selective reaction control can be achieved, but the overall yield decreases due to the large number of process steps
Solution Approach 1:
The invention extracts and eliminates the nitrogen protection/deprotection steps that were previously necessary for reaction selectivity. By using alternative selective reagents and optimized reaction conditions, the process achieves the required manufacturing precision without the yield-penalty of multiple protection cycles
Solution Approach 2:
The invention performs preliminary optimization of reaction conditions and reagent selection to enable selective transformations without nitrogen protection groups. This preliminary preparation of the reaction system allows subsequent steps to proceed with high selectivity and improved overall yield
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 new process simplifies the synthesis of Compound X, enhancing efficiency and yield by eliminating the need for nitrogen protection and chromatography, resulting in improved handling and manufacturing advantages.
Implementation Method 1
reducing a compound of formula (VII) under asymmetric reduction conditions to produce the compound of formula (VIIc), or a salt thereof
Data Source
AI summary
The present invention provides a process of synthesizing 1-(((Z)-(1-(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)-1-sulfoazetidin-3 yl)amino)ethylidene)amino)oxy)cyclopropanecarboxylic acid (referred to herein as Compound X), or a salt thereof, or a solvate including hydrate thereof, and/or intermediates thereof, and the use of intermediates for preparing Compound X. In particular, the process relates to the preparation of Compound X using dynamic kinetic resolution (DKR) and asymmetric catalytic reduction, thereby providing an improved route to 1-(((Z)-(1-(2-aminothiazol-4-yl)-2-oxo-2-(((3S,4R)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)-1-sulfoazetidin-3 yl)amino)ethylidene)amino)oxy)cyclopropanecarboxylic acid (Compound X) and compositions containing said compound, including the arginine salt, sodium salt and hydrated solid forms of Compound X.