Efinaconazole Purification via pH-Controlled Liquid-Liquid Extraction
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Solution Overview
Problem
Existing methods for producing and purifying efinaconazole on an industrial scale face challenges in shortening reaction time and simplifying operations while managing impurities, leading to increased impurity content and difficulty in controlling impurity levels.
Innovation Solution
The method involves reacting epoxytriazole with an acid addition salt of 4-methylenepiperidine in toluene, adjusting the pH of the aqueous layer to remove impurities, and using multiple liquid-liquid separations to achieve high-purity efinaconazole through specific solvent and pH control, allowing for efficient conversion to p-toluenesulfonate and subsequent crystallization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the reaction time is shortened or the work-up operation is simplified, then productivity is improved, but the manufacturing precision deteriorates due to increased impurity content
Solution Approach 1:
The patent applies preliminary action by conducting the ring-opening addition reaction in toluene solvent first, then performing liquid-liquid separation with aqueous acid solution to remove basic impurities before final purification. This preliminary removal of impurities allows for shorter reaction times while maintaining product purity, as the impurity removal steps are optimized to be efficient and targeted.
Solution Approach 2:
The patent utilizes parameter changes by adjusting the pH of the aqueous layer during work-up to control the distribution of impurities. By optimizing the pH conditions during liquid-liquid separation, the method achieves effective impurity removal without requiring excessive reaction time or complex operations, thus resolving the contradiction between productivity and manufacturing precision.
2Ease of operation
If the work-up operation is simplified, then ease of operation is improved, but the manufacturing precision deteriorates due to increased impurity content
Solution Approach 1:
The patent segments the work-up operation into distinct liquid-liquid separation steps: first separating the organic layer containing the product from the aqueous layer, then treating the organic layer with aqueous acid solution to remove basic impurities, and finally performing crystallization. This segmentation allows each step to be simple and efficient while collectively achieving high purification effectiveness.
Solution Approach 2:
The patent uses toluene as an intermediary solvent that facilitates the ring-opening addition reaction and enables efficient liquid-liquid separation during work-up. Toluene's properties allow for easy phase separation and effective impurity removal, simplifying the overall work-up operation while maintaining high manufacturing precision.
3Measurement precision
If specific impurities are used as indices, then measurement precision is improved, but the device complexity increases due to additional monitoring requirements
Solution Approach 1:
The patent extracts and identifies specific impurities (such as compound (IV) and other by-products) as key indices for monitoring reaction progress and purification effectiveness. By focusing on these specific impurities rather than monitoring all possible contaminants, the method achieves high measurement precision using standard analytical techniques without requiring complex monitoring systems.
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 approach enables the production of high-purity efinaconazole in high yield by reducing impurity levels and simplifying the work-up operation, ensuring a purity of at least 98% and optimizing the yield of efinaconazole.
Implementation Method 1
washing the reaction mixture more than once or washing so that the pH of the aqueous layer after the washing operation is between 3 and 5
Implementation Method 2
mixing the toluene solution of crude efinaconazole with 2-propanol and p-toluenesulfonic acid or a hydrate thereof to precipitate p-toluenesulfonate of efinaconazole
Implementation Method 3
crystallizing the efinaconazole; further adding water and isolating the efinaconazole that has precipitated out
Data Source
AI summary
The present invention provides efinaconazole producing and purifying methods adapted to industrial scale that provide high-purity efinaconazole in high yield by simple operations using specific impurities as indices. The efinaconazole producing method comprises: step A of forming a toluene solution comprising compound (II), compound (III), an inorganic base, and toluene in a volume (L) which is 2 to 5 times the mass (kg) of compound (II); step B of subjecting the toluene solution to reaction under heating; step C of washing the reaction mixture from step B to obtain a toluene solution of crude efinaconazole in which the residual amount of 4-MP is not more than 5 wt% of efinaconazole.