Imidazopyrrolidinone Synthesis via Segmented Coupling

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Solution Overview

Problem

Existing processes for preparing imidazopyrrolidinone derivatives face challenges in scaling up due to safety issues, loss of process control, and generation of hazardous waste, making them unsuitable for full-size production.

Innovation Solution

A modified process using less hazardous chemicals and reaction conditions, involving specific solvents, bases, and coupling agents, such as N,N'-carbonyldiimidazole, to enhance efficiency and yield, while reducing impurities and side reactions, as described in the provided schemes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If existing processes are scaled up for full-size production, then productivity increases, but safety issues and loss of process control worsen

Engineering Contradiction:
Improveproduction scaleVSAvoidprocess control
Core Design Contradiction:
ProductivityVSReliability

Solution Approach 1:

The synthesis process is divided into multiple discrete steps with isolated workups and purifications between each step. This segmentation allows for better control at each stage, reduced accumulation of hazards, and easier scalability compared to one-pot reactions.

Inventive Principle:
Principle #1Segmentation

Solution Approach 2:

The patent introduces specific intermediates and workup procedures between reaction steps that serve as buffers to control the overall process. These intermediates allow for controlled progression through the synthesis pathway, enabling scale-up while maintaining process reliability.

Inventive Principle:
Principle #24Intermediary (Mediator)

2Productivity

If existing processes are scaled up for full-size production, then productivity increases, but generation of hazardous waste increases

Engineering Contradiction:
Improveproduction scaleVSAvoidhazardous waste
Core Design Contradiction:
ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent converts potentially hazardous byproducts into useful intermediates or recyclable materials. Specific workup procedures are designed to transform harmful substances into benign or valuable products, reducing waste generation while maintaining high productivity at scale.

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

Solution Approach 2:

The synthesis process incorporates steps to recover and reuse valuable materials while properly disposing of hazardous waste. Recyclable intermediates are recovered through specific purification steps, and hazardous byproducts are managed through designated disposal procedures, enabling scalable production with reduced environmental harm.

Inventive Principle:
Principle #34Discarding and recovering

3Ease of manufacture

If conventional chemicals and conditions are used, then ease of manufacture is maintained, but safety and hazard issues worsen

Engineering Contradiction:
Improveprocess simplicityVSAvoidchemical hazard
Core Design Contradiction:
Ease of manufactureVSObject-affected harmful factors

Solution Approach 1:

The patent modifies reaction parameters such as temperature, pressure, concentration, and pH to use safer chemicals and conditions. These parameter changes maintain manufacturing ease while reducing chemical hazards, allowing for safe scale-up without sacrificing process simplicity.

Inventive Principle:
Principle #35Parameter changes

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 process allows for scalable, reproducible, and safer production of high-quality imidazopyrrolidinone derivatives with reduced waste and lower costs, suitable for commercial production scales.

Implementation Method 1

reacting a compound of formula (D6), or a salt thereof, or a solvate thereof, in a solvent in the presence of base and a coupling agent, wherein the coupling agent is N,N'-carbonyldiimidazole

Methodology Applied
Scientific EffectChemical Bonding: Chemical Bonding

Data Source

PatentEP3544982B1Chemical process for preparing imidazopyrrolidinone derivatives and intermediates thereof
Publication Date: 2021.10.20 NOVARTIS AG
  • EP3544982B1 patent drawingFigure 1
  • EP3544982B1 patent drawingFigure 2
  • EP3544982B1 patent drawingFigure 3

AI summary

The present disclosure relates to a method of synthesizing imidazopyrrolidinone derivative, such as compound of formula (I), or a solvate including hydrate thereof, or a co-crystal thereof, and/or intermediates thereof, their use as pharmaceuticals and the use of intermediates.