Aliskiren Intermediate Purification via Selective Methylation
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Solution Overview
Problem
The synthesis of enantiomerically pure Aliskiren intermediates is challenging due to the presence of chiral carbon atoms, leading to impurities like hydroxy compounds that result in lower yields and impure Aliskiren during the conversion process.
Innovation Solution
An improved process involves condensing compound Formula-A with Formula-B in the presence of an alkali metal or alkaline earth metal, followed by methylation of the reaction mass to remove hydroxy impurities, using methylating agents like methyl iodide and phase transfer catalysts, and subsequent purification through fractional distillation to achieve high purity of Formula-II intermediate.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If flash chromatography is used to purify compound of Formula-II, then purification is achieved, but the process complexity increases and yield is reduced
Solution Approach 1:
The patent extracts and removes the harmful hydroxy impurity (Formula-C) from the reaction mixture through selective methylation, separating it from the desired compound (Formula-II). This extraction approach eliminates the need for complex flash chromatography while achieving high purity.
Solution Approach 2:
The patent converts the harmful hydroxy impurity (Formula-C) into a beneficial methylated compound through methylation reaction. By adding a methyl group to the hydroxy impurity, it transforms into a separable species that can be removed, thereby simplifying the purification process.
2Ease of manufacture
If hydroxy impurity is carried forward to next stages, then process simplicity is maintained, but yield decreases and product purity is reduced
Solution Approach 1:
The patent performs preliminary methylation of the hydroxy impurity during the same reaction stage before the compound proceeds to subsequent stages. This preliminary action prevents the impurity from carrying forward and causing yield loss later, while maintaining overall process simplicity.
Solution Approach 2:
The patent converts the harmful hydroxy impurity into a beneficial methylated form that can be easily removed. This transformation turns the impurity from a yield-reducing factor into a removable byproduct, thereby improving overall yield without complicating the process.
3Manufacturing precision
If methylation is performed on the reaction mass, then hydroxy impurity is removed, but additional reagents and steps are required
Solution Approach 1:
The patent merges the methylation step with the existing reaction protocol, combining multiple functions into a single integrated process. By performing methylation during the same operational sequence, the patent reduces the number of discrete steps while achieving high purity.
Solution Approach 2:
The patent employs a multi-functional approach where the methylation reagent serves dual purposes: it modifies the hydroxy impurity for removal and simultaneously prepares the reaction mass for subsequent purification. This universality reduces the overall number of required steps.
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 process significantly reduces hydroxy impurity levels to less than 0.5%, resulting in higher yields and purer Aliskiren production by ensuring the removal of impurities during the intermediate conversion to Aliskiren or its pharmaceutically acceptable salts.
Implementation Method 1
condensing the compound of Formula-A with Compound of Formula-B in the presence of an alkali metal or alkaline earth metal
Implementation Method 2
methylating the condensed crude product containing the mixture of compound of formula II and compound of Formula-C
Implementation Method 3
subsequent purification through fractional distillation to achieve high purity of Formula-II intermediate
Implementation Method 4
using methylating agents like methyl iodide and phase transfer catalysts
Data Source
AI summary
The present invention relates to an improved process for the preparation of pure compound of Formula-II, which is an intermediate in the preparation of Aliskiren and further conversion of compound of Formula-II into Aliskiren or its pharmaceutically acceptable salts.