Lithium Borohydride Reduction for Ospemifene Production

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Solution Overview

Problem

Existing methods for producing ospemifene, such as those using lithium aluminum hydride or sodium borohydride, suffer from low yields and safety concerns due to the use of explosive reagents, and face challenges in controlling hydrogen production, making them unsuitable for large-scale industrial production.

Innovation Solution

The method involves reducing a compound using lithium borohydride, which is formed in the reaction system, and performing the reaction in the presence of borane or trimethylsilyl chloride to efficiently produce ospemifene with improved yield and safety, avoiding the use of explosive reagents.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If lithium aluminum hydride is used for reduction, then the reduction reaction can proceed, but the yield is poor (43%) and safety is compromised due to explosive reagent

Engineering Contradiction:

ImproveyieldVSAvoidsafety

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent changes the chemical parameters by substituting lithium aluminum hydride with lithium borohydride, which has different reducing power and safety characteristics. This parameter change resolves the contradiction by achieving comparable reduction efficacy while eliminating the explosive hazard and improving yield

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs a milder, safer reducing agent (lithium borohydride) that can be used in controlled conditions without requiring special safety infrastructure. This allows for safer, more economical large-scale production while maintaining or improving yield

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Productivity

If sodium borohydride is used for reduction, then the reaction can proceed, but hydrogen production cannot be controlled and explosion risk exists

Engineering Contradiction:

Improvereaction efficiencyVSAvoidhydrogen production

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent changes the reducing agent from sodium borohydride to lithium borohydride, which exhibits different reactivity characteristics. This parameter change reduces excessive hydrogen evolution while maintaining reduction efficiency, eliminating the safety hazard of uncontrolled hydrogen production

Inventive Principle:

Principle #35Parameter changes

3Productivity

If lithium borohydride is used alone, then reduction occurs, but carboxylic acid byproduct is formed due to ester hydrolysis

Engineering Contradiction:

Improvereduction efficiencyVSAvoidpurity

Core Design Contradiction:

ProductivityVSManufacturing precision

Solution Approach 1:

The patent introduces borane or trimethylsilyl chloride as an intermediary substance that modifies the reaction pathway. These intermediaries prevent the hydrolysis side reaction that leads to carboxylic acid byproduct formation, thereby improving product purity while maintaining reduction efficiency

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent converts the potentially harmful hydrolysis reaction into a beneficial pathway by using borane or trimethylsilyl chloride to guide the reaction toward the desired alcohol product, eliminating the carboxylic acid byproduct and improving overall manufacturing precision

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

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 results in a higher yield and safer production process, making it more suitable for industrial use with reduced costs and minimal byproducts, thus effectively addressing the limitations of previous methods.

Implementation Method 1

The present inventors discovered that ospemifene can be efficiently produced by reducing a compound represented by the formula (I) with lithium borohydride

Methodology Applied

Scientific EffectReduction reaction: Reduction

Implementation Method 2

lithium hydroxide is produced through the reaction of lithium borohydride with moisture in the solvent or air, and this lithium hydroxide causes the esters to be hydrolyzed, leading to the production of carboxylic acid. The produced carboxylic acid cannot be readily reduced to alcohol with lithium borohydride and becomes a byproduct

Methodology Applied

Scientific EffectHydrolysis prevention: Hydrolysis

Data Source

PatentEP3415491B1Method for producing phenoxyethanol derivative

Publication Date: 2020.11.18 SHIONOGI & CO LTD

AI summary

Provided is a method for producing a phenoxyethanol derivative. This method for producing a compound represented by formula (II) is characterized in that a compound represented by formula (I) (in the formula, R1 is a substituted or unsubstituted alkyl) is reduced in the presence of lithium borohydride.