Aclidinium Bromide Synthesis via Amide Solvents
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Solution Overview
Problem
The existing processes for preparing aclidinium bromide face challenges such as the use of genotoxic reagents and long reaction times, with high temperatures and solvent boiling points posing operational difficulties.
Innovation Solution
A process involving a transesterification reaction between 3R-quinuclidinol and MDTG, followed by a quaternization reaction with 3-phenoxypropyl bromide in solvents like dimethylformamide (DMF) or dimethylsulfoxide (DMSO) at temperatures below 100°C, reducing reaction time and genotoxic reagent usage while maintaining high purity and controlling particle size.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the process uses 3-phenoxypropyl bromide with large excess (5 equivalents), then the reaction can proceed, but the genotoxic reagent usage increases and purification becomes more difficult
Solution Approach 1:
The patent changes the stoichiometric parameter by reducing 3-phenoxypropyl bromide from 5 equivalents to 1.05-1.2 equivalents, and adjusts the solvent system to amides/sulfoxides with specific boiling points to enable lower temperature operation while maintaining reaction efficiency
Solution Approach 2:
The patent converts the harmful excess reagent into a beneficial controlled amount by using the specific solvent system that allows complete reaction with stoichiometric or near-stoichiometric amounts, eliminating genotoxic impurities while maintaining productivity
2Reliability
If the reaction time is extended to 72 hours, then complete conversion is achieved, but the manufacturing time and productivity are negatively affected
Solution Approach 1:
The patent changes the temperature parameter by enabling reactions at lower temperatures (below 100°C) through the use of amide and sulfoxide solvents, and adjusts the time parameter by reducing reaction time from 72 hours to 8-24 hours while maintaining complete conversion through optimized stoichiometry
3Temperature
If solvents with high boiling points (50°C to 210°C) are used, then the reaction can proceed at higher temperatures, but operational challenges and energy consumption increase
Solution Approach 1:
The patent selects specific solvents with particular properties (amides like DMF, DMA; sulfoxides like DMSO) that have optimal boiling points for the reaction, providing local optimization of temperature control and ease of manipulation rather than using any high boiling point solvent
Solution Approach 2:
The patent uses solvents that are easy to remove by evaporation due to their specific boiling point ranges, facilitating simple workup procedures and reducing operational complexity despite their high boiling points
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 high chemical purity (>99.0%) and consistent polymorphic form, with controlled particle size and reduced reaction time, overcoming the disadvantages of prior methods while operating at lower temperatures and minimizing genotoxic reagent use.
Implementation Method 1
A process for preparing (3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R) yl methyl ester and 3-phenoxypropyl bromide
Implementation Method 2
The preparation of aclidinium bromide involves a transesterification reaction between 3R-quinuclidinol (II) and MDTG (III) to produce N-despropylaclidinium (IV), followed by the reaction of N-despropylaclidinium with 3-phenoxypropyl bromide (V) (quaternization reaction) to synthesize aclidinium bromide
Implementation Method 3
wherein the reaction takes place in a solvent or mixture of solvents that are selected from the group of amides and/or the group of solvents with a sulfoxide group at a temperature below their boiling point. The reaction temperature is below 100° C.
Implementation Method 4
The present process also enables the manufacture of a product with controlled particle size
Data Source
AI summary
A process for preparing (3R)-3-[2-Hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) comprises reacting 2-hydroxy-2,2-dithien-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R) yl methyl ester and 3-phenoxypropyl bromide, wherein the reaction takes place in a solvent or mixture of solvents selected from the group of amides and/or the group of solvents with a sulfoxide group. Also provided is a crystalline aclidinium bromide characterized by a powder XRPD pattern having peaks at 7.7±0.2° 2θ, 10.4±0.2° 2θ, 13.2±0.2° 2θ, 13.8±0.2° 2θ, 19.9±0.2° 2θ, 20.3±0.2° 2θ, 20.8±0.2° 2θ, 24.2±0.2° 2θ, 25.7±0.2° 2θ, 26.1±0.2° 2θ, 29.2±0.2° 2θ, 30.8±0.2° 2θ. A pharmaceutical composition comprises aclidinium bromide according to the invention and a pharmaceutically acceptable excipient.