Pirlindole Enantiomer Synthesis via Asymmetric Cyclization

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current methods for preparing Pirlindole enantiomers are not economically viable at an industrial scale due to reliance on racemic starting materials and involve unstable reagents that pose safety risks, necessitating a safer and more eco-friendly industrial process.

Innovation Solution

The process involves cyclization of (S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine in 1,3-dimethyl-2-imidazolidinone (DMI) with sodium hydride, followed by catalytic hydrogenolysis, which increases yield and stability, allowing for the recovery and reuse of solvents, and simplifies purification.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If racemic pirlindole is used as starting material for enantiomer preparation, then the process can be performed at industrial scale, but the economic viability deteriorates due to additional resolution steps and lower overall yield

Engineering Contradiction:

Improveindustrial scale production capabilityVSAvoideconomic viability

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

Instead of starting with racemic pirlindole and performing resolution (conventional approach), the invention inverts the sequence by first performing asymmetric synthesis to obtain enantiomerically pure intermediates, then completing the synthesis. This inversion eliminates the need for resolution steps and improves overall yield and economic viability at industrial scale

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention performs asymmetric synthesis and enantiomer separation at an early stage (preliminary action) using chiral auxiliary (S)-(-)-α-methylbenzylamine, before completing the pirlindole synthesis. This preliminary establishment of chirality avoids later resolution steps and improves process efficiency

Inventive Principle:

Principle #10Preliminary action

2Manufacturing precision

If conventional resolution methods using optically active organic acids are employed, then enantiomers can be separated efficiently, but the process complexity and cost increase at industrial scale

Engineering Contradiction:

Improveenantiomer separation efficiencyVSAvoidprocess complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention changes the approach from post-synthesis resolution to asymmetric synthesis with chiral auxiliary, fundamentally altering the process parameters and sequence to achieve simpler, more economical industrial production

Inventive Principle:

Principle #35Parameter changes

3Temperature

If dimsyl anion is used as reagent, then the reaction can proceed at lower temperatures, but safety risks increase due to exothermic decomposition above 40°C

Engineering Contradiction:

Improvereaction temperatureVSAvoidprocess safety

Core Design Contradiction:

TemperatureVSReliability

Solution Approach 1:

The invention replaces the unstable, hazardous dimsyl anion with a more stable alkaline agent (sodium hydride or other alkali metal hydrides) that can be safely handled and stored. The new reagent system, while requiring controlled conditions, eliminates the severe safety risks of dimsyl anion decomposition

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The invention addresses the safety issue by completely replacing the hazardous reagent system with a safer alternative, transforming a harmful process into a safe one, rather than merely mitigating the harm

Inventive Principle:

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

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 significantly enhances the yield and stability of Pirlindole enantiomers, making the process industrially applicable, safe, and environmentally friendly, with high purity crude products requiring minimal additional purification steps.

Implementation Method 1

stereoselective reduction with sodium borohydride in ethanol. According to Andreeva et al. the reaction might occur through directed intramolecular hydride transfer after formation of a complex between compound of formula V and reducing agent to afford (S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine VI

Methodology Applied

Scientific EffectStereoselective reduction: Reduction

Implementation Method 2

The hydrogenolysis reaction was catalysed by Palladium on charcoal (Pd content 0.1g, 9 mol%) and was conducted in methanol. The conversion of compound of formula VII into compound of formula III was performed under a hydrogen pressure of 1.8-2.0 MPa at 22 °C for a period of 17h.

Methodology Applied

Scientific EffectCatalytic hydrogenolysis: Catalysis

Data Source

PatentEP3612535B1Process for the preparation of pirlindole enantiomers and its salts

Publication Date: 2021.09.01 TECNIMEDE SOCIEDADE TECNICO MEDICINAL SA

AI summary

The present invention relates to an improved process for the preparation of Pirlindole enantiomers, or a pharmaceutically acceptable salt thereof.