Cholic Acid Synthesis via Oxidation and Ethylene Attachment
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Solution Overview
Problem
Current methods for preparing cholic acid compounds as FXR ligands have low yields, making them unsuitable for industrial applications.
Innovation Solution
A new preparation method involving specific steps such as oxidation, protection, reaction with acetaldehyde, reduction, conversion of cyano groups, and removal of formyl groups, using CDCA as a raw material, with optimized conditions for solvents, catalysts, and temperatures to achieve high yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If the conventional preparation route (oxidation, protection, ethylene attachment, reduction, hydrolysis, formylation, cyano conversion, formyl removal) is used, then the compound of formula I can be obtained, but the yield is low (34.9% or 13.1%)
Solution Approach 1:
The patent applies preliminary action by performing the oxidation step first to convert the hydroxyl group to a ketone group before any other transformations. This preliminary oxidation enables subsequent reactions to proceed more efficiently and in fewer steps, ultimately improving the overall yield from 34.9% to 68.5%
Solution Approach 2:
The patent extracts and eliminates unnecessary intermediate steps from the conventional synthesis route. By removing the formylation and formyl removal steps, the synthesis pathway is shortened from 8 steps to 5 steps, reducing complexity while maintaining high yield through the optimized sequence of oxidation, ethylene attachment, reduction, and cyano-to-carboxyl conversion
2Manufacturing precision
If multiple protection and deprotection steps are included, then the compound structure can be controlled, but the number of steps increases and yield decreases
Solution Approach 1:
The patent extracts and removes the formylation protection step and the corresponding formyl removal step from the synthesis route. The optimized method achieves sufficient structural control through oxidation, ethylene attachment, reduction, and cyano-to-carboxyl conversion without requiring additional protection/deprotection cycles, thereby eliminating 2 steps and improving overall yield
Solution Approach 2:
The oxidation step is performed preliminarily at the beginning of the synthesis to establish the correct ketone structure at position 7. This preliminary structural establishment eliminates the need for later protection/deprotection steps to maintain structural integrity, as the oxidized intermediate is stable and directly applicable to subsequent transformations
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 method achieves a high yield and reduces the need for purification operations, making it suitable for industrial production of cholic acid compounds.
Implementation Method 1
oxidizing a hydroxyl group at position 7
Implementation Method 2
reducing it to ethyl
Data Source
AI summary
The present application relates to a method for preparing a cholic acid compound. Specifically, the method prepares a compound as shown in formula I, including subjecting a compound of formula 2 to an oxidization reaction to obtain a compound of formula 3; attaching a trimethylsilyl group to the compound of formula 3 to obtain a compound of formula 4; reacting the compound of formula 4 with acetaldehyde to obtain a compound of formula 5; subjecting the compound of formula 5 to a catalytic hydrogenation reaction to obtain a compound of formula 6; and converting a cyano group of the compound of formula 6 to a carboxyl group to give the compound of formula I.