Enzymatic Stereoisomer Separation at Low Temperature for Enzyme Reuse

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Solution Overview

Problem

Existing enzymatic processes for separating (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine suffer from enzyme degradation at high temperatures, limiting the number of separation cycles and increasing costs due to the use of expensive enzymes.

Innovation Solution

A process using Candida antarctica enzyme at lower temperatures (0-50°C) for acylation, followed by hydrogenation and reaction with a base or acid, allowing multiple cycles of isomer separation with enzyme reuse.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Speed

If enantioselective acylation is performed at high temperatures (70-130°C) as disclosed in prior art, then reaction rate is improved, but enzyme longevity deteriorates due to degradation

Engineering Contradiction:
Improvereaction rateVSAvoidenzyme longevity
Core Design Contradiction:
SpeedVSDuration of action of stationary object

Solution Approach 1:

The patent changes the temperature parameter from high (70-130°C in prior art) to low (0-50°C in the invention) to resolve the contradiction. This parameter change maintains enzyme stability and longevity while still achieving effective reaction rates through optimized catalyst selection and reaction conditions.

Inventive Principle:
Principle #35Parameter changes

2Manufacturing precision

If expensive enzymes are used for separation, then separation efficiency is improved, but cost increases and enzyme reuse becomes limited

Engineering Contradiction:
Improveseparation efficiencyVSAvoidcost
Core Design Contradiction:
Manufacturing precisionVSEase of manufacture

Solution Approach 1:

The patent implements enzyme recovery and reuse through immobilization on solid supports. The immobilized enzyme can be filtered, washed, and reused for multiple cycles, transforming a single-use expensive reagent into a recoverable catalyst, thereby reducing costs while maintaining high separation efficiency.

Inventive Principle:
Principle #34Discarding and recovering

3Productivity

If multiple separation cycles are performed, then productivity is improved, but enzyme degradation increases at high temperatures

Engineering Contradiction:
Improvenumber of separation cyclesVSAvoidenzyme stability
Core Design Contradiction:
ProductivityVSReliability

Solution Approach 1:

The patent performs preliminary immobilization of the enzyme on a solid support before the separation cycles. This preliminary action protects the enzyme structure, enables easy recovery, and allows the same enzyme to be reused for multiple cycles without significant degradation, thereby increasing both productivity and reliability.

Inventive Principle:
Principle #10Preliminary action

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

Achieves high purity (at least 95%) (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine with extended enzyme longevity, reducing costs by enabling multiple separation cycles.

Implementation Method 1

reaction of a mixture of the four isomers (1R,1R)-, (1S,2S)-, (1S,2R)- and (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine with an acylating agent, in the presence of an enzyme which is Candida antarctica

Methodology Applied
Scientific EffectEnzyme catalysis: Enzyme

Implementation Method 2

step 3) is the hydrogenation with a metal catalyst of the mixture of the three isomers (1R,1R)-, (1S,2S)- and (15,2R)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine obtained in step 2)

Methodology Applied
Scientific EffectHydrogenation: Hydrogenation

Data Source

PatentEP4692046A1Enzymatic process for the separation of 2,6-dimethyl-2,3-dihydro-1h-inden-1-amine stereoisomers
Publication Date: 2026.02.11 ADAMA AGAN LTD
  • EP4692046A1 patent drawing
  • EP4692046A1 patent drawing
  • EP4692046A1 patent drawing

AI summary

An enzymatic process for the separation of isomers of 2,6-dimethyl-2,3-dihydro-1H-inden-1-amine.