Purifying cis-5-Hydroxy-2-Piperidinecarboxylic Acid via Lactone Crystallization

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Solution Overview

Problem

Current methods for producing highly pure cis-5-hydroxy-2-piperidinecarboxylic acid are inefficient due to difficulties in selectively synthesizing and purifying the compound from isomers, often requiring expensive catalysts, complex processes, and excessive reagents, making them unsuitable for industrial production.

Innovation Solution

A method involving the reaction of cis-5-hydroxy-2-piperidinecarboxylic acid with an acid halide and/or acid anhydride to convert it into a lactone, followed by crystallization and solvent extraction to separate impurities, allowing for the regeneration of highly pure cis-5-hydroxy-2-piperidinecarboxylic acid.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If chemical synthesis methods using L-amino acid are used to fix stereochemistry, then stereoselectivity is improved, but device complexity and cost increase due to expensive catalysts and complex processes

Engineering Contradiction:
ImprovestereoselectivityVSAvoidprocess complexity
Core Design Contradiction:
Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent extracts the purification step from the synthesis pathway by converting the crude mixture into a derivative form (lactone or ester) that enables simple separation of isomers through crystallization or extraction, avoiding complex synthesis procedures

Inventive Principle:
Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the chemical form of the compound by converting cis-5-hydroxy-2-piperidinecarboxylic acid into its derivative (lactone or ester), which alters the physical and chemical properties to enable effective separation of isomers through crystallization or extraction

Inventive Principle:
Principle #35Parameter changes

2Manufacturing precision

If ion-exchange column separation is used to separate isomers, then purity is improved, but productivity decreases due to excessive amounts of filler and eluent required

Engineering Contradiction:
ImprovepurityVSAvoidproduction efficiency
Core Design Contradiction:
Manufacturing precisionVSProductivity

Solution Approach 1:

The patent utilizes phase transition (crystallization) to separate isomers, where the derivative of the desired isomer crystallizes from the solution while impurities remain in the mother liquor, providing simple and efficient separation without requiring large amounts of column materials

Inventive Principle:
Principle #36Phase transitions

Solution Approach 2:

The patent replaces expensive and cumbersome ion-exchange columns with simple, inexpensive operations such as crystallization and solvent extraction that can be performed in standard laboratory equipment, making the process suitable for industrial production

Inventive Principle:
Principle #27Cheap short-living objects (Disposable)

3Manufacturing precision

If lactonization is used to purify the compound, then separation of isomers is improved, but harmful factors increase due to side reactions between lactone and residual trans isomer

Engineering Contradiction:
Improveisomer separationVSAvoidside reactions
Core Design Contradiction:
Manufacturing precisionVSObject-generated harmful factors

Solution Approach 1:

The patent performs preliminary protection of the amino group before lactonization to prevent side reactions during the subsequent steps, ensuring that the lactone formation proceeds cleanly without unwanted reactions with residual trans isomer

Inventive Principle:
Principle #10Preliminary action

Solution Approach 2:

The patent introduces an intermediate protected derivative form that mediates between the crude mixture and the final pure compound, allowing selective transformation and separation while minimizing harmful side reactions

Inventive Principle:
Principle #24Intermediary (Mediator)

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 method effectively purifies cis-5-hydroxy-2-piperidinecarboxylic acid by selectively converting it into a lactone or ester, enabling the removal of impurities and achieving high purity levels with reduced costs and process complexity, suitable for industrial production.

Implementation Method 1

reacting cis-5-hydroxy-2-piperidinecarboxylic acid with an acid halide and/or acid anhydride to convert the cis-5-hydroxy-2-piperidinecarboxylic acid into a compound of Formula (1)

Methodology Applied
Scientific EffectChemical reaction: Chemical Bonding

Implementation Method 2

crystallization and solvent extraction to separate impurities

Methodology Applied
Scientific EffectCrystallization: Crystallisation

Implementation Method 3

crystallization and solvent extraction to separate impurities

Methodology Applied
Scientific EffectSolvent extraction: Liquid-Liquid Extraction

Data Source

PatentEP2889288B1METHOD FOR PRODUCING cis-5-HYDROXY-2-PIPERIDINECARBOXYLIC ACID DERIVATIVE, AND METHOD FOR PURIFYING cis-5-HYDROXY-2-PIPERIDINECARBOXYLIC ACID
Publication Date: 2018.07.25 API CORP (JP)
  • EP2889288B1 patent drawingFigure 1
  • EP2889288B1 patent drawingFigure 2
  • EP2889288B1 patent drawingFigure 3

AI summary

The present invention aims to provide a method for purifying cis-5-hydroxy-2-piperidinecarboxylic acid with high purity, and a method for producing its derivative. The present invention provides a method for producing a cis-5-hydroxy-2-piperidinecarboxylic acid derivative, which method comprises a step of converting cis-5-hydroxy-2-piperidinecarboxylic acid into a compound(s) of Formula (1) and/or Formula (2) (wherein R1 represents a protective group for an amino group, and R2 represents a C1-C6 alkyl group), and a method for purifying cis-5-hydroxy-2-piperidinecarboxylic acid.