Siponimod Intermediate Synthesis Without Chromatographic Purification
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Solution Overview
Problem
Existing processes for synthesizing Siponimod suffer from low yields and require numerous purification steps, making them unsuitable for large-scale industrial production.
Innovation Solution
A novel process that introduces the cyclohexyl group in the final steps of the synthesis, eliminating the need for intermediate purification and isolation, thereby increasing yield and reducing solvent use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional purification steps on chromatographic column are used, then product purity is improved, but total yield decreases
Solution Approach 1:
The invention extracts and eliminates the chromatographic purification steps from the synthesis process. By removing these purification operations, the process achieves both high yield (90% or more) and acceptable purity without the yield loss associated with column chromatography, directly resolving the contradiction between purity and productivity
Solution Approach 2:
Instead of following the conventional approach of purifying each intermediate, the invention inverts the strategy by using crude intermediates directly in subsequent reactions. This reversal of the purification paradigm eliminates yield loss while maintaining product quality through the final purification step
2Manufacturing precision
If multiple purification steps are performed, then product quality is improved, but number of synthesis steps increases
Solution Approach 1:
The invention merges multiple purification operations into a single final purification step. By combining the purification function across all synthesis stages into one operation at the end, the process reduces the number of steps while maintaining product quality, directly addressing the contradiction between quality and complexity
3Manufacturing precision
If intermediate purification and isolation are performed, then reaction purity is improved, but solvent usage increases
Solution Approach 1:
The invention extracts and removes intermediate purification and isolation steps from the synthesis pathway. By eliminating these steps, the process dramatically reduces solvent consumption while maintaining reaction purity through the final purification, directly resolving the contradiction between purity and substance loss
Solution Approach 2:
The invention maintains continuous synthesis by using crude intermediates directly in subsequent reactions without interruption for purification. This continuous approach minimizes solvent usage while preserving product quality, as the only purification occurs at the final stage where the product can be isolated in high purity
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 yields and industrial scalability with minimal solvent usage, making it economically and ecologically advantageous.
Implementation Method 1
an attempt was made to introduce the cyclohexyl group into the molecule through an organometallic coupling reaction on a different synthesis intermediate
Implementation Method 2
Said intermediate can then be directly transformed into Siponimod via a reductive amination reaction known from the literature
Implementation Method 3
converting the thus obtained compound of formula (III) into the compound of formula (IV) by the hydrolysis of the R1 group
Data Source
AI summary
The present invention relates to a process for the preparation of a key intermediate and other intermediates useful for the synthesis of Siponimod, a drug used for the treatment of multiple sclerosis. Object of the invention are also said novel intermediates.