Vilanterol Trifenatate Purification Without Column Chromatography
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Solution Overview
Problem
Existing processes for the production of Vilanterol are inefficient, require extensive column chromatography, and are difficult to scale up for industrial production, leading to challenges in achieving high purity and economic viability.
Innovation Solution
A novel process involving bromination, etherification, and subsequent reactions with specific catalysts and solvents, followed by solvent washing and anti-solvent precipitation, to produce Vilanterol Trifenatate with high purity and reduced impurities, eliminating the need for chromatography.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If column chromatography is used for purification of intermediates and final product, then purity can be achieved, but device complexity and difficulty of scaling up increase
Solution Approach 1:
The patent changes the purification parameters by using solvent-based extraction and crystallization instead of column chromatography. Specifically, it employs selective solubility parameters and temperature-controlled crystallization to achieve purification, replacing the physical adsorption mechanism of chromatography with solution-based separation mechanisms.
Solution Approach 2:
The patent replaces the mechanical separation system of column chromatography (which requires columns, solvents, and manual fraction collection) with a simpler chemical separation system based on differential solubility and crystallization. This substitution eliminates the need for complex chromatographic equipment while achieving comparable or superior purity.
2Manufacturing precision
If column chromatography is used for all intermediates and final compounds, then purity is maintained, but productivity decreases due to tedious purification
Solution Approach 1:
The patent extracts and removes impurities through selective solvent extraction and crystallization processes. By taking out impurities in earlier stages through controlled extraction, the need for extensive purification at later stages is eliminated, thereby increasing overall productivity while maintaining purity.
Solution Approach 2:
The patent applies preliminary purification actions during the synthesis of intermediates, removing impurities early in the process rather than waiting for the final stage. This preliminary action prevents impurity accumulation and reduces the need for time-consuming purification steps later, thus improving productivity.
3Device complexity
If chiral purity of key intermediate is not maintained, then production process is simpler, but manufacturing precision deteriorates due to difficult-to-separate isomeric impurities
Solution Approach 1:
The patent applies preliminary anti-action by using chiral catalysts or chiral resolving agents in the synthesis step to prevent the formation of unwanted isomeric impurities from the beginning. This proactive approach ensures chiral purity is built into the synthesis process rather than requiring subsequent separation, maintaining both simplicity and precision.
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 achieves Vilanterol Trifenatate with purity greater than 99.5%, significantly reducing known and unknown impurities below 0.15% and 0.10%, respectively, making it suitable for industrial scalability and cost-effectiveness.
Implementation Method 1
Brominating 2,6 Dichlorophenyl methanol with a brominating agent at a temperature of 40-85°C to obtain 2-(Bromomethyl)-1,3-dichlorobenzene
Implementation Method 2
Reacting the 2-(Bromomethyl)-1,3-dichlorobenzene in ethylene glycol with Potassium salt of ethylene glycol at 40 to 70°C to obtain 2-(2, 6-dichlorobenzyloxy) ethanol
Implementation Method 3
Reacting the 2-(2, 6- dichlorobenzyloxy) ethanol with 1,6-Dibromohexane in toluene presence of KOH and Catalytic amount of Tetra butyl Ammonium Hydrogen Sulphate (TBAHS) at 40-65°C to obtain 2-((2-((6-bromohexyl)oxy)ethoxy)methyl)-1,3-dichlorobenzene
Implementation Method 4
Reacting the 2-((2-((6-bromohexyl)oxy)ethoxy)methyl)-1,3-dichlorobenzene with (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one in DMF at ambient temperature, followed by extracting the reaction mass into methylene dichloride
Implementation Method 5
Purifying the crude (R)-3-(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one by treating with acetonitrile and hexane
Implementation Method 6
Cleaving the (5R)-3-(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one with Potassium trimethyl silanolate in THF at 50-70°C to obtain (1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol
Implementation Method 7
Deprotecting the ( 1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol in presence of HCl in acetone to obtain Vilanterol
Implementation Method 8
Treating the Vilanterol with Tri phenyl acetic acid in acetone at 45-65°C to yield crude Vilanterol Trifenatate
Implementation Method 9
Treating the Vilanterol with Tri phenyl acetic acid in acetone at 45-65°C to yield crude Vilanterol Trifenatate; and i) Purifying the crude Vilanterol Trifenatate
Data Source
AI summary
The invention discloses an improved process for preparation of Vilanterol or a pharmaceutically acceptable salt thereof with good yields and high purity.