Pimavanserin Purification via Integrated Washing
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Solution Overview
Problem
Current processes for preparing pimavanserin and its hemitartrate form require multiple steps and intermediates, leading to inefficiencies in yield, purity, and environmental impact, with a need for optimization to reduce the number of purification steps and increase chemical yield and purity.
Innovation Solution
A process involving the formation of an acid addition salt solution in an organic solvent, followed by washing with an alcohol/water/acid mixture, dissolution in an aqueous solvent, washing with an organic solvent, and conversion to pimavanserin using a base, which simplifies the purification and increases yield and purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If multiple purification steps are used to remove impurities, then product purity is improved, but process complexity and time consumption increase
Solution Approach 1:
The patent combines multiple purification operations into a single integrated washing step. The crude pimavanserin is washed directly with a specific solvent system (ethyl acetate, water, and hydrochloric acid) that simultaneously removes multiple types of impurities (unreacted amine, isocyanate homodimer, and other byproducts) in one operation, eliminating the need for sequential purification steps while achieving high product purity
Solution Approach 2:
The patent introduces a specific solvent system as an intermediary medium to facilitate impurity removal. The washing solution comprising ethyl acetate, water, and hydrochloric acid acts as a mediator that selectively dissolves and removes impurities from the crude product without affecting the desired pimavanserin, enabling efficient purification in a single step
2Manufacturing precision
If multiple intermediates are isolated, then product purity is improved, but productivity and yield are reduced
Solution Approach 1:
The patent extracts and removes impurities directly from the reaction mixture without isolating intermediate compounds. By washing the crude pimavanserin with the specified solvent system, the process eliminates the need to separate and purify individual intermediates (such as unreacted amine or isocyanate homodimer), thereby streamlining the production process and improving overall productivity while maintaining high product purity
Solution Approach 2:
The patent performs preliminary purification of impurities during the reaction workup phase rather than requiring separate intermediate isolation steps. The washing operation is designed to remove all impurities in advance of the final product isolation, allowing the process to proceed directly to product recovery without intermediate purification steps
3Productivity
If traditional reagents like phosgene are used, then reaction efficiency is improved, but environmental harm increases
Solution Approach 1:
The patent replaces the highly toxic and environmentally harmful reagent phosgene with di-tert-butyl dicarbonate, which achieves the same chemical transformation (formation of the carbamate linkage in pimavanserin) but with significantly reduced environmental impact and improved safety. This substitution converts a harmful process into a benign one while maintaining reaction efficiency and product 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 process achieves high purity and improved yield of pimavanserin with reduced steps, utilizing fewer intermediates and potentially more environmentally friendly reagents, such as di-tert-butyl dicarbonate instead of phosgene, and allows for the direct conversion to a pharmaceutically acceptable acid addition salt.
Implementation Method 1
washing the solution provided in step (i) with an alcohol/water/acid mixture
Implementation Method 2
washing the aqueous solution obtained in step (iii) with an organic solvent
Data Source
AI summary
This invention relates to a process for the preparation of pimavanserin comprising: (i) providing an acid addition salt of pimavanserin; (ii) dissolving the acid addition salt of pimavanserin in an aqueous solvent to form an aqueous solution; (iii) washing the aqueous solution obtained in step (ii) with an organic solvent; and (iv) adding a base to the washed aqueous solution to form pimavanserin. The invention also relates to a process for the preparation of an acid addition salt of pimavanserin additionally comprising step (v) of converting pimavanserin into an acid addition salt of pimavanserin. The invention also relates to pimavanserin or an acid addition salt thereof obtainable by the process, and to the use of pimavanserin hydrochloride, pimavanserin hydrogen sulfate or pimavanserin acetate for preparing pimavanserin or an acid addition salt thereof.