SAGE-718 Synthesis Route With Achiral Epimer Separation
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Solution Overview
Problem
The existing synthesis and purification methods for SAGE-718, a neuroprotective agent for treating neurological diseases, are not suitable for industrial-scale production due to high operating costs and complexity, particularly the use of supercritical CO2 and chiral stationary phases in chromatographic resolution.
Innovation Solution
A simplified synthesis process involving a series of chemical transformations (Wittig reaction, oxidation, Grignard reaction, hydroboration-oxidation, and Wittig reaction) followed by a chromatographic separation using a non-chiral stationary phase for industrial-scale production of SAGE-718.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If chromatographic resolution on preparative column with chiral stationary phase and supercritical CO2 is used, then enantiomeric separation is achieved, but operating costs and equipment complexity increase significantly
Solution Approach 1:
The patent changes the separation mechanism from chiral stationary phase recognition to diastereomeric salt formation through derivatization. By converting enantiomers to diastereomers via reaction with a chiral resolving agent, the separation can be achieved using conventional achiral stationary phases, eliminating the need for complex chiral columns and supercritical fluid equipment.
2Manufacturing precision
If chromatographic resolution on preparative column with chiral stationary phase and supercritical CO2 is used, then enantiomeric separation is achieved, but operating costs increase
Solution Approach 1:
The patent employs conventional, inexpensive achiral stationary phases instead of expensive chiral stationary phases. The resolving agent is used in stoichiometric amounts to form transient diastereomeric salts that are easily separated by standard chromatography, significantly reducing material and equipment costs compared to maintaining supercritical CO2 systems with chiral columns.
3Quantity of substance
If the synthesis route from the article by Hill is used, then the compound SAGE-718 is obtained, but the overall yield is only 4%
Solution Approach 1:
The patent optimizes reaction parameters including solvent selection, temperature control, and reagent ratios throughout the synthesis pathway. By systematically improving each transformation step from the starting material through intermediate compounds to the final product, the overall yield is doubled from 4% to 8%, making the process economically viable for industrial production.
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 an overall yield of 8%, improving upon the 4% yield of the previous method, and allows for cost-effective, scalable production of SAGE-718 without the need for supercritical CO2 and chiral stationary phases.
Implementation Method 1
introduction of a methylene group in position 20 of the compound 5-pregnenolone via Wittig reaction, obtaining intermediate 8
Implementation Method 2
oxidation to carbonyl of the hydroxyl in position 3 of intermediate 8 obtaining intermediate 9
Implementation Method 3
introduction of a methyl group in position 3 of intermediate 9 via Grignard reaction obtaining intermediate 10
Implementation Method 4
hydroboration-oxidation of the methylene group in position 21 of intermediate 10 obtaining intermediate 11
Implementation Method 5
oxidation to carbonyl of the hydroxyl in position 22 of intermediate 11 obtaining intermediate 12
Implementation Method 6
a Wittig reaction obtaining intermediate 13
Implementation Method 7
reduction of the double bond in position 22 of intermediate 13 obtaining intermediate 14
Implementation Method 8
introduction of a trifluoromethyl radical in position 24 of intermediate 14 obtaining the epimeric mixture 15
Implementation Method 9
esterification of the hydroxyl in position 3 of said epimeric mixture 15 with a protected aliphatic amino acid obtaining intermediate 16
Implementation Method 10
chromatographic separation of the epimeric mixture 16 obtaining two epimers 17 and 18
Implementation Method 11
removal by hydrolysis of the ester in position 3 of intermediate 17 obtaining the desired product SAGE-718
Data Source
AI summary
The present invention relates to a process for the industrial scale preparation of (3β,24S)-25,25,25-trifluoro-3-methyl-26,27-dinorergost-5-ene-3,24-diol, useful in counteracting the progression of highly disabling neurological diseases such as Alzheimer's, Parkinson's, and Huntington's disease, and having the structure shown below:The invention also relates to an improved method for the separation of two epimers that are obtained during the synthesis.