Ozanimod Production with tert-Butylsulfinyl Group Retention
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Solution Overview
Problem
Existing processes for producing ozanimod, an optically active compound, suffer from incomplete chiral induction leading to enantiomer contaminants, necessitating costly and time-consuming purification methods like chiral chromatography or diastereomer salt formation.
Innovation Solution
A synthesis pathway where the tert-butylsulfinyl group is maintained until the final step, allowing diastereomer contaminants to be easily separated and removed, eliminating the need for enantiomer-specific purifications by converting the compound into acid addition salts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If chiral synthesis with asymmetrical induction is used to produce ozanimod, then the desired enantiomer is obtained in large majority, but enantiomer contaminants still appear requiring costly purification
Solution Approach 1:
The patent introduces a resolving agent that forms diastereomeric salts as an intermediary step. The resolving agent (such as (R)- or (S)-α-methoxy-α-(trifluoromethyl)phenylacetic acid) acts as a mediator that converts the difficult-to-separate enantiomers into easily separable diastereomeric salts through salt formation, which can then be separated by filtration or crystallization.
Solution Approach 2:
The patent changes the physical and chemical parameters of the mixture by forming salts with resolving agents. This transformation alters the solubility, crystallization behavior, and separation characteristics of the enantiomers, enabling their separation through conventional techniques rather than requiring expensive chiral chromatography.
2Manufacturing precision
If chiral chromatography is used to purify enantiomer contaminants, then high enantiomer purity is achieved, but the process becomes expensive and time-consuming
Solution Approach 1:
The patent employs inexpensive resolving agents that can be used in stoichiometric or slight excess amounts. These resolving agents form temporary diastereomeric salt complexes that are easily separated and discarded, replacing the need for expensive, time-consuming chiral chromatography columns and resins.
Solution Approach 2:
The patent utilizes phase transition differences between diastereomeric salts during crystallization and filtration processes. By controlling temperature and solvent conditions, the desired enantiomer salt crystallizes out of solution while the other remains in solution, enabling separation through simple filtration rather than chromatography.
3Manufacturing precision
If multiple purification steps are introduced to remove enantiomer contaminants, then product purity increases, but the synthesis process becomes more complex
Solution Approach 1:
The patent combines the resolution step with the existing synthesis workflow by integrating salt formation and filtration operations into the sequence. Rather than adding separate purification modules, the resolving agent is introduced at a strategic point where it forms salts that can be separated using standard unit operations already present in the process.
Solution Approach 2:
The patent extracts the enantiomer separation problem from the main synthesis pathway by using a side reaction (salt formation) that selectively removes one enantiomer from the mixture. The unwanted enantiomer is extracted into the solid salt phase, which is then removed by filtration, leaving the desired enantiomer in the filtrate.
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 simplifies and economizes ozanimod production by reducing synthesis steps, enhancing purity through diastereomer separation, and eliminating the need for expensive resolving agents, while achieving high chemical purity without additional purification steps.
Implementation Method 1
Asymmetrical induction occurs during the sodium borohydride reduction, and so compound (VI) is created in the large majority
Implementation Method 2
the C═N bond of the Schiff base (B) formed is reduced with sodium borohydride
Implementation Method 3
the Boc protective group is introduced to the primary amine obtained. The (D) amide produced in this way
Implementation Method 4
the 1,2,4-oxadiazole ring is formed using the appropriate benzoic acid derivative
Data Source
AI summary
The present invention relates a new process for the preparation of ozanimod of the formula and acid addition salts, via new intermediates and a new polimop form of ozanimod base.