Avacopan Intermediate Chiral Resolution by Imine Reductase

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Solution Overview

Problem

Existing processes for preparing Avacopan suffer from low chemical and enantiomeric purity and yield, making them unsuitable for large-scale commercial operations.

Innovation Solution

The use of imine reductase enzymes for kinetic resolution of racemic cis-ethyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)piperidine-3-carboxylate, allowing selective oxidation of one enantiomer to imine/enamine while leaving the desired 2R,3S enantiomer untouched, followed by ex-situ recycling of the undesired enantiomer, enhancing yield and purity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If L-DTTA salt crystallization is used for optical resolution, then enantiomeric separation is achieved, but the yield is low (14.1-20.2%)

Engineering Contradiction:

Improveenantiomeric purityVSAvoidyield

Core Design Contradiction:

Manufacturing precisionVSProductivity

Solution Approach 1:

Instead of using the conventional L-DTTA salt crystallization method for optical resolution, the invention employs imine reductase enzymes to perform kinetic resolution through enantioselective oxidation. This inverted approach uses biological catalysis to selectively oxidize one enantiomer while leaving the desired (2R,3S) enantiomer untouched, thereby achieving both high enantiomeric purity and high yield without the limitations of crystallization-based methods

Inventive Principle:

Principle #13The other way round (Inversion)

2Manufacturing precision

If conventional optical resolution methods are used, then enantiomeric separation is achieved, but chemical and enantiomeric purity remain low

Engineering Contradiction:

Improveenantiomeric purityVSAvoidchemical purity

Core Design Contradiction:

Manufacturing precisionVSReliability

Solution Approach 1:

The invention replaces the mechanical/chemical crystallization process with an enzymatic biological system. Imine reductase enzymes provide highly selective biocatalysis that oxidizes only the undesired enantiomer, achieving superior enantiomeric and chemical purity compared to conventional L-DTTA salt crystallization methods through specific enzyme-substrate recognition and catalytic mechanisms

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Ease of manufacture

If conventional processes are used for Avacopan preparation, then synthesis is achieved, but hazardous reagents like trimethyl aluminum are required

Engineering Contradiction:

Improvesynthesis feasibilityVSAvoidhazardous reagents

Core Design Contradiction:

Ease of manufactureVSObject-affected harmful factors

Solution Approach 1:

The invention replaces hazardous reagents like trimethyl aluminum with biodegradable enzymatic catalysts. The imine reductase enzymes and cofactor regeneration systems provide a safer, more environmentally friendly alternative that maintains synthesis feasibility while eliminating the need for pyrophoric and water-sensitive reagents, making the process suitable for large-scale commercial production

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The invention changes the reaction parameters from conventional chemical catalysis to enzymatic catalysis, operating under milder conditions with biological catalysts. This parameter change eliminates the need for hazardous reagents while maintaining synthesis efficiency, using enzyme-specific conditions such as aqueous buffers, controlled pH, and temperature to achieve the same synthetic transformation safely

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

This process achieves high enantiomeric purity and yield of the desired 2R,3S enantiomer of Avacopan intermediate, facilitating efficient large-scale production by recycling and reducing the need for hazardous reagents like trimethyl aluminum.

Implementation Method 1

imine reductase enzymes are able to provide stereochemical control in the resolution of two vicinal stereogenic centres in a cyclic amine system through enantioselective oxidation of the cyclic amine

Methodology Applied

Scientific EffectEnzymatic oxidation: Oxidation

Implementation Method 2

by reversing their usual mode of action, oxidative kinetic resolution of racemic-cis-2,3-substituted piperidines can be effected

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Data Source

PatentUS20250236897A1Processes for preparation of avacopan and intermediates thereof

Publication Date: 2025.07.24 ASSIA CHEM IND

AI summary

The present disclosure encompasses a process for chiral resolution of racemic amines, particularly ethyl 2-(4-((tert-butoxycarbonyl)amino)phenyl)piperidine-3-carboxylate, into its desired isomer, ethyl (2R,3S)-2-(4-((tert-butoxycarbonyl)amino)phenyl)-piperidine-3-carboxylate, which is an intermediate useful in the synthesis of Avacopan.