Boronic Ester Synthesis via Continuous Flow Chemistry

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Solution Overview

Problem

Current methods for synthesizing beta-lactamase inhibitors, such as boronic esters, face challenges in large-scale production due to the need for rigorous control of temperature, exclusion of water, and careful stoichiometry of base and Lewis acid, which complicates the process and leads to the formation of undesired side products like dichloroketone.

Innovation Solution

A continuous flow process is developed involving the mixing of a compound of Formula (II) with dichloromethane and a base like lithium diisopropylamide, followed by treatment with a Lewis acid, in a coordinating ethereal solvent, to produce the compound of Formula (III) with controlled temperatures and stoichiometries, minimizing side product formation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If conventional methods are used to synthesize boronic esters, then the desired compound can be produced, but the process requires rigorous control of temperature, exclusion of water, and careful stoichiometry, leading to complex process requirements and formation of undesired side products

Engineering Contradiction:

Improvecontrol of temperature and stoichiometryVSAvoidprocess complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent introduces a flow chemistry system with an intermediary mixing chamber that facilitates controlled interaction between reactants. The continuous flow system acts as an intermediary mechanism that enables precise control of reaction conditions without requiring complex manual intervention, thereby reducing process complexity while maintaining manufacturing precision.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent employs continuous flow chemistry to dynamically adjust reaction parameters such as temperature and stoichiometry in real-time. By changing the mode of reaction delivery from batch to continuous flow, the system achieves better control over reaction conditions, reducing the formation of side products while simplifying the overall process requirements.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If conventional batch methods are used, then the synthesis can be performed, but large-scale production is complicated by the need for rigorous control of reaction conditions

Engineering Contradiction:

Improvelarge-scale production capabilityVSAvoidcontrol requirements

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent replaces traditional batch mechanical mixing and heating systems with a continuous flow chemistry system. This substitution enables large-scale production by using pump-driven flow control and automated temperature management, thereby increasing productivity while reducing the complexity of manual control requirements.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The continuous flow system maintains continuous reaction conditions without interruption, enabling consistent large-scale production. The uninterrupted flow of reactants through the mixing chamber and reaction zone ensures steady-state operation, improving productivity while simplifying control compared to batch methods that require repeated heating, mixing, and monitoring cycles.

Inventive Principle:

Principle #20Continuity of useful action

3Quantity of substance

If conventional synthesis methods are used, then the compound can be synthesized, but undesired side products like dichloroketone are formed

Engineering Contradiction:

Improveyield of desired compoundVSAvoidside product formation

Core Design Contradiction:

Quantity of substanceVSObject-generated harmful factors

Solution Approach 1:

The continuous flow system rapidly transports reactants through the mixing chamber and reaction zone, minimizing the time available for side reactions. By rushing the reaction through the flow system quickly and maintaining optimal conditions throughout, the patent maximizes the yield of the desired compound while minimizing the formation of harmful side products like dichloroketone.

Inventive Principle:

Principle #21Skipping (Rushing through)

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 process achieves high yields of the desired compound with reduced impurities, facilitating the pharmaceutical development of beta-lactamase inhibitors by simplifying the synthesis and increasing efficiency.

Implementation Method 1

reacting a compound of Formula (II) with a base to form a reactive intermediate

Methodology Applied

Scientific EffectNucleophilic attack: Chemical Bonding

Implementation Method 2

treating the reactive intermediate with a Lewis acid

Methodology Applied

Scientific EffectLewis acid coordination: Chemical Bonding

Implementation Method 3

in a coordinating ethereal solvent

Methodology Applied

Scientific EffectSolvation: Solvation

Data Source

PatentUS11560392B2Boron-containing compounds

Publication Date: 2023.01.24 VENATORX PHARMACEUTICALS INC

AI summary

Described herein are boron-containing compounds, compositions, and methods for their preparation.