Chemo-selective Reduction of Benzoate Ester and Lactone
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Solution Overview
Problem
Existing processes for synthesizing the active metabolite of tolterodine and its phenolic monoesters, such as fesoterodine, are complex and inefficient, requiring numerous steps with unsatisfactory yields due to challenges in selectively reducing the benzoate ester to a primary alcohol without over-reducing the lactone.
Innovation Solution
A chemo-selective reduction reaction is employed using a reducing agent in a molar ratio of 2 or more, preferably diisobutylaluminium hydride, to selectively reduce the benzoate ester while maintaining the lactone at the aldehyde stage, thereby simplifying the synthesis process and improving yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional multi-step synthesis processes are used to produce the active metabolite, then the synthesis can be completed, but the number of steps is large (11-12 steps) and the yield is unsatisfactory
Solution Approach 1:
The patent combines multiple reduction steps into a single chemo-selective reduction reaction. The lactone is reduced to the lactol in one step using diisobutylaluminium hydride, merging what would traditionally require separate reduction steps for the benzoate ester and lactone portions of the molecule.
Solution Approach 2:
The patent changes the chemical parameters of the reduction reaction by using specific conditions (diisobutylaluminium hydride as reducing agent, controlled temperature, molar ratio of 2 or more) to achieve chemo-selectivity. This allows the benzoate ester to be reduced to primary alcohol while the lactone is reduced only to the aldehyde stage, not further.
2Productivity
If the benzoate ester is reduced to primary alcohol, then the synthesis can proceed, but the lactone may be over-reduced which compromises yield
Solution Approach 1:
The patent applies local quality by making different parts of the molecule have different reduction characteristics. The benzoate ester portion is reduced fully to primary alcohol, while the lactone portion is reduced only to the aldehyde stage (lactol), creating different functional groups at different locations in the molecule based on their selective reduction properties.
Solution Approach 2:
The patent uses diisobutylaluminium hydride as an intermediary reducing agent that mediates the selective reduction. This specific reducing agent acts as a mediator that allows controlled reduction of the benzoate ester while stopping at the lactol stage for the lactone, preventing over-reduction.
3Reliability
If multiple reduction steps are used to reduce benzoate ester and lactone separately, then complete reduction can be achieved, but the process becomes complex and yield decreases
Solution Approach 1:
The patent segments the reduction process by treating different functional groups (benzoate ester and lactone) differently within a single reaction step. The benzoate ester undergoes complete reduction to primary alcohol, while the lactone undergoes partial reduction to lactol, achieving complete functional transformation without requiring multiple separate 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 approach reduces the number of steps required in the synthesis, enhances the yield, and allows for the direct conversion of the intermediate to the active metabolite, improving the overall efficiency of the production process.
Implementation Method 1
A chemo-selective reduction reaction is employed using a reducing agent in a molar ratio of 2 or more, preferably diisobutylaluminium hydride, to selectively reduce the benzoate ester while maintaining the lactone at the aldehyde stage
Data Source
AI summary
The compound of formula (I): is provided. It may be produced by subjecting a compound of formula (IV) to a reduction reaction wherein R represents hydrogen, straight or branched C1-C6 alkyl. This compound is a valuable intermediate which may be used in the synthesis of fesoterodine, tolterodine, its active metabolite, and related compounds.