Microreactor Synthesis of Quinolone Intermediates

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Solution Overview

Problem

Existing methods for synthesizing dimethyl (2S,4S)-2-tert-butyloxycarbonylamino-4-methyl-glutarate are hindered by harsh reaction conditions, complex processing operations, and low efficiency, making them unsuitable for large-scale production.

Innovation Solution

A microreactor-based method for continuously synthesizing dimethyl (2S,4S)-2-tert-butyloxycarbonylamino-4-methyl-glutarate, which involves reacting compound i with a hydrogen-pulling reagent and a methylation reagent at controlled temperatures, followed by quenching with an acid solution, to achieve mild reaction conditions and improved efficiency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If conventional batch synthesis method is used with LiHMDS reagent at low temperature, then methylation reaction can be achieved, but reaction time is long (2-4 days) and operation is complex

Engineering Contradiction:

Improvereaction timeVSAvoidprocessing operation complexity

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The patent replaces the conventional batch mechanical stirring and manual quenching system with a continuous flow microreactor system. The microreactor enables automatic mixing and continuous processing, eliminating the need for manual quenching operations with alcohol and acid water, thereby reducing both reaction time and operational complexity

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent implements continuous flow synthesis instead of batch processing. Reactants are continuously fed into the microreactor, allowing the methylation reaction to proceed continuously without interruption. This continuous operation significantly reduces the overall reaction time from 2-4 days to a much shorter duration while simplifying the workflow

Inventive Principle:

Principle #20Continuity of useful action

2Manufacturing precision

If low temperature (less than -78°C) is used for methylation reaction, then reaction selectivity is improved, but energy consumption increases and operation becomes more difficult

Engineering Contradiction:

Improvereaction selectivityVSAvoidenergy consumption

Core Design Contradiction:

Manufacturing precisionVSUse of energy by moving object

Solution Approach 1:

The patent changes the temperature parameter from extreme low temperature (less than -78°C) to a milder range (-40°C to 0°C) by utilizing the continuous flow characteristics of the microreactor. This parameter change maintains reaction selectivity while significantly reducing energy consumption for cooling and simplifying operational requirements

Inventive Principle:

Principle #35Parameter changes

3Productivity

If conventional batch synthesis is used, then reaction can be completed, but reaction time is long (3-4 days for 80-100 kg scale)

Engineering Contradiction:

Improveproduction efficiencyVSAvoidreaction time

Core Design Contradiction:

ProductivityVSLoss of time

Solution Approach 1:

The patent implements continuous flow synthesis where reactants are continuously fed through the microreactor system, eliminating the batch-wise processing interruptions. This continuous operation maintains constant reaction conditions and significantly reduces the production time from 3-4 days to a much shorter duration, thereby improving production efficiency

Inventive Principle:

Principle #20Continuity of useful action

Solution Approach 2:

The patent divides the reaction process into distinct segments within the microreactor system, with each segment performing a specific function (mixing, reaction, quenching). This segmentation allows for optimized residence time in each zone and enables parallel processing, thereby reducing the overall reaction time while maintaining high productivity

Inventive Principle:

Principle #1Segmentation

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 microreactor method significantly reduces reaction time, increases conversion rate to over 95%, and yields a product with high purity and yield, making it suitable for industrial production while minimizing environmental impact and operational complexity.

Implementation Method 1

reacting compound i with a hydrogen-pulling reagent and a methylation reagent at controlled temperatures

Methodology Applied

Scientific EffectMixing:

Implementation Method 2

followed by quenching with an acid solution

Methodology Applied

Scientific EffectQuenching:

Data Source

PatentEP4345093B1A process method for synthesizing quinolones intermediates by use of a microreactor

Publication Date: 2025.05.14 ZHE JIANG MEDICINE CO LTD XINCHANG PHARMA FAB

Figure 1

AI summary

The present disclosure discloses a method for synthesizing quinolones intermediates by a continuous flow reaction. Specifically, according to the method, a microchannel reactor is used, which improves the selectivity and conversion rate of the reaction, and the conversion rate of compound ii is increased to more than 95% and the yield is increased to more than 85%; avoids the use of a solvent such as methanol, and methyl tert-butyl ether, etc., in the intermittent reaction process, which simplifies the post-processing method, shortens the overall operation time from about 24 hours to a few minutes, greatly improving the production efficiency, and realizing the continuity and automation of the whole process; and thus makes the product have high purity and high yield, which is suitable for industrial production.