Macrocyclic Chelant Purification for High-Purity Gadolinium Complexes
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Solution Overview
Problem
Existing processes for synthesizing Gadoteridol and Calteridol calcium are cumbersome, require multiple steps, lack desired purity, and are not suitable for industrial scale due to expensive purification methods and use of various solvents, making them inefficient and costly.
Innovation Solution
A novel process involving the reaction of 1,4,7,10-tetraazacyclododecane with tert-butyl 2-bromoacetate, followed by hydrolysis and alkylation with propylene oxide to form 2,2′,2″-(10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, which is then complexed with Gadolinium or calcium ions, and purified using acidic and basic resins to achieve high purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If existing purification methods (preparative HPLC, ion exchange column cascade) are used to prepare Gadoteridol and Calteridol calcium, then the desired purity is achieved, but the process becomes expensive, cumbersome, and not suitable for industrial scale
Solution Approach 1:
The invention changes the purification parameters by using a two-stage ion exchange chromatography process with specifically selected resins (strong cation exchange resin in first stage, weak cation exchange resin in second stage) and controlled pH conditions (elution at pH 3.0-4.0 then pH 7.0-8.0), replacing the complex preparative HPLC and ion exchange column cascade methods while achieving ≥98% purity for Gadoteridol and ≥99% purity for Calteridol calcium
Solution Approach 2:
The invention extracts and removes impurities selectively through two sequential ion exchange stages: first removing metal ions and strongly basic impurities with strong cation exchange resin, then removing weakly basic impurities with weak cation exchange resin, achieving high purity without requiring expensive preparative HPLC equipment
2Ease of manufacture
If multiple solvents and reagents are used in existing synthesis processes, then the desired chemical transformations are achieved, but the process becomes costly and inefficient for industrial application
Solution Approach 1:
The invention recovers and reuses the ion exchange resins after purification by regenerating them with appropriate solutions (HCl for strong cation exchange resin, NaOH for weak cation exchange resin), allowing multiple cycles of use and significantly reducing material costs for industrial production while maintaining purification efficiency
Solution Approach 2:
The ion exchange resins serve multiple functions: they act as purification agents during chromatography, can be regenerated and reused multiple times, and the same resin types can be applied to purify both Gadoteridol and Calteridol calcium products, reducing overall process complexity and material costs
3Manufacturing precision
If traditional multi-step synthesis and purification processes are used, then the desired product purity is achieved, but the production time and operational complexity increase significantly
Solution Approach 1:
The invention performs preliminary purification actions by conducting the two-stage ion exchange chromatography process with pre-selected resins and pH conditions before final product formulation, ensuring that impurities are removed in advance and the product meets purity specifications (≥98% for Gadoteridol, ≥99% for Calteridol calcium) without requiring additional time-consuming purification steps later in the process
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 yields Gadoteridol and Calteridol calcium with purities greater than 98.0% and 99.0%, respectively, with reduced impurities and metal content, making it suitable for industrial applications.
Implementation Method 1
purified by ion exchange column by using 10% ammonia solution as eluent
Data Source
AI summary
The present invention relates to an improved process for the preparation of macrocyclic chelant 2,2′,2″-(10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid of formula (1). The present invention further relates to the process for the preparation of metal complexes of macrocyclic chelant 2,2′,2″-(10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid of formula (1) with purity greater than 99.0% by HPLC. The present invention also relates to an improved process for the preparation of gadolinium complex of formula (1a) with macrocyclic chelant 2,2′,2″-(10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid of formula (1). The present invention further relates to a novel process for the preparation of calcium complex of formula (1b) with macrocyclic chelant 2,2′,2″-(10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid of formula (1).