Ferroquine Synthesis via Convergent Reductive Amination

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Solution Overview

Problem

The existing method for synthesizing ferroquine is hazardous due to the use of unstable and explosive reagents like hydroxylamine and LiAlH4, and is costly due to the use of expensive reagents and low productivity, making it challenging to produce this antimalarial drug on an industrial scale, especially for regions where it is most needed.

Innovation Solution

A new method involving a convergent reductive amination process that directly synthesizes ferroquine from aldehyde-amino ferrocene and 7-chloroquinolin-4-amine, reducing the number of stages and using safer, less expensive reagents, with a one-pot process that includes condensation, reduction, and hydrolysis in the presence of suitable solvents and catalysts.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If the existing method using hydroxylamine and LiAlH4 is employed, then ferroquine can be synthesized, but the process becomes hazardous and costly with low productivity

Engineering Contradiction:

Improvesafety of synthesis processVSAvoidproductivity of ferroquine synthesis

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent removes the hazardous reagents hydroxylamine and LiAlH4 from the synthesis pathway, extracting the dangerous elements while preserving the core synthetic transformation through a safer alternative method using sodium triacetoxyborohydride

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the chemical parameters of the reduction step by substituting LiAlH4 with sodium triacetoxyborohydride, a milder and safer reducing agent that operates under less restrictive conditions, thereby improving safety without sacrificing productivity

Inventive Principle:

Principle #35Parameter changes

2Manufacturing precision

If expensive reagents like LiAlH4 are used, then reduction to amine is achieved, but manufacturing cost increases significantly

Engineering Contradiction:

Improvereduction efficiency to amineVSAvoidmanufacturing cost

Core Design Contradiction:

Manufacturing precisionVSEase of manufacture

Solution Approach 1:

The patent replaces the expensive reagent LiAlH4 with a cheaper alternative, sodium triacetoxyborohydride, which achieves the same reduction function at lower cost, making the manufacturing process more economically viable while maintaining adequate reduction efficiency

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Manufacturing precision

If multiple synthesis stages are used, then complete transformation is achieved, but process complexity and time increase

Engineering Contradiction:

Improvecompleteness of transformationVSAvoidsynthesis time

Core Design Contradiction:

Manufacturing precisionVSLoss of time

Solution Approach 1:

The patent combines the condensation and reduction steps into a streamlined sequence, eliminating the need for isolating and characterizing intermediate oxime compounds, thereby reducing the number of discrete stages and overall synthesis time while maintaining complete transformation

Inventive Principle:

Principle #5Merging (Combining)

4Manufacturing precision

If rigorous anhydrous conditions are maintained, then reduction reaction proceeds correctly, but operational complexity and safety risks increase

Engineering Contradiction:

Improvereaction accuracyVSAvoidoperational simplicity

Core Design Contradiction:

Manufacturing precisionVSEase of operation

Solution Approach 1:

The patent employs sodium triacetoxyborohydride, a reagent that is less sensitive to moisture than LiAlH4, allowing the reaction to proceed under less stringent anhydrous conditions, thereby simplifying operational procedures and reducing safety risks associated with rigorous moisture exclusion

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

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 method significantly reduces the cost and improves safety by achieving higher yields and productivity, making ferroquine more accessible and affordable for widespread use, particularly in poor countries where it is needed most.

Implementation Method 1

a reaction of reductive amination, in which reaction: (i) the aldhehyde-amino ferrocene of formula (III) is condensed with 7-chloroquinolin-4-amine

Methodology Applied

Scientific EffectCondensation reaction:

Implementation Method 2

the product of condensation thus obtained of formula (II), is reduced, in the presence of metal hydride

Methodology Applied

Scientific EffectReduction: Reduction

Implementation Method 3

the reaction mixture is hydrolyzed

Methodology Applied

Scientific EffectHydrolysis: Hydrolysis

Data Source

PatentEP2580224B1Method of synthesis of ferroquine by convergent reductive amination

Publication Date: 2014.05.28 SANOFI SA(FR)

AI summary

The invention relates to a method of synthesis of ferroquine of formula (F) or of its metabolite of formula (Fm): comprising a reaction of reductive amination, said reaction comprising: (i) a stage of condensation of the aldhehyde-amino ferrocene of formula (1 ), which R represents a hydrogen atom or a methyl group, with the 7-chloroquinolin- amine of formula (2) as shown below, followed by (ii) a stage of reduction of the product of condensation obtained in the preceding stage (iii) then a stage of hydrolysis of the reaction mixture in the presence of an aqueous solution of ammonia or of citric acid.