Picolinamide Fungicide Crystallization for Stable Low-Impurity Forms

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Solution Overview

Problem

Existing methods fail to produce stable crystalline forms of (S)-1,1-bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoyl)-L-alaninate (Compound I), leading to agglomerated solids and high impurity profiles, which complicates storage, transportation, and biological activity.

Innovation Solution

A process involving distillation of an aprotic solvent followed by crystallization with a protic solvent and seed Compound I, controlling temperature and solvent exchange to achieve stable crystalline forms A and B, with purity exceeding 97.0% and reduced impurities.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Shape

If conventional crystallization methods are used on Compound I, then crystalline formation is attempted, but the compound forms agglomerated solids instead of proper crystals

Engineering Contradiction:

Improvecrystalline formVSAvoidcrystallization success

Core Design Contradiction:

ShapeVSReliability

Solution Approach 1:

The patent applies parameter changes by systematically varying temperature, solvent composition, and concentration parameters during crystallization to transform Compound I from forming agglomerated solids to forming proper crystalline structures. Specific temperature ranges (e.g., cooling from 60°C to 25°C) and solvent ratios are optimized to achieve reliable crystallization.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses seed crystals as an intermediary to induce and guide crystallization of Compound I. The seed crystals provide a template that facilitates proper crystal lattice formation, preventing agglomeration and ensuring reliable crystalline structure development.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Ease of manufacture

If amorphous material is isolated from organic layer, then compound is obtained, but it forms agglomerated solid with poor flowability

Engineering Contradiction:

Improveisolation simplicityVSAvoidflowability

Core Design Contradiction:

Ease of manufactureVSEase of operation

Solution Approach 1:

The patent employs phase transition from amorphous to crystalline state through controlled crystallization conditions. By transitioning Compound I from amorphous isolated material to crystalline form via temperature control and solvent exchange, the patent simultaneously improves flowability while maintaining ease of manufacture through a straightforward crystallization protocol.

Inventive Principle:

Principle #36Phase transitions

3Quantity of substance

If oil concentration is increased during crystallization, then crystallization is promoted, but agglomerates form inside reactor

Engineering Contradiction:

Improveoil concentrationVSAvoidcrystal structure

Core Design Contradiction:

Quantity of substanceVSShape

Solution Approach 1:

The patent applies preliminary action by performing solvent exchange and temperature conditioning before the main crystallization step. This preliminary preparation of the system at controlled temperatures and solvent compositions prevents premature agglomeration while allowing proper crystal structure development when crystallization is initiated.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent uses seed crystals as an intermediary to mediate between high oil concentration conditions and proper crystal structure formation. The seeds provide a controlled nucleation pathway that allows high concentration crystallization without agglomerate formation inside the reactor.

Inventive Principle:

Principle #24Intermediary (Mediator)

4Reliability

If multiple screening experiments are performed to find crystalline forms, then polymorphs are identified, but process complexity increases

Engineering Contradiction:

Improvecrystalline form stabilityVSAvoidscreening process

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent systematically varies crystallization parameters (temperature, solvent type, concentration) to identify and characterize different polymorphs of Compound I. This methodical parameter exploration reveals stable crystalline forms (Forms A and B) with predictable properties, establishing a reliable framework for manufacturing while organizing the screening process into manageable parameter sets.

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 yields stable, flowable crystalline forms of Compound I with high purity and improved biological activity, suitable for plant disease control, maintaining stability over 12-48 hours at various temperatures.

Implementation Method 1

distilling an aprotic organic solvent from a mixture containing Compound I

Methodology Applied

Scientific EffectDistillation: Distillation

Implementation Method 2

crystallizing Compound I from a protic organic solvent containing Compound I and seed Compound I

Methodology Applied

Scientific EffectCrystallization: Crystallisation

Data Source

PatentUS20260049058A1Crystalline forms of picolinamide fungicide compound

Publication Date: 2026.02.19 CORTEVA AGRISCIENCE LLC

AI summary

The present technology relates to processes useful for making crystalline S)-1,1-bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoyl)-L-alaninate (Compound I). Processes disclosed herein describe more stable, storage compatible preparations of Compound I. Also disclosed are preparations of Compound I which have fewer (trace) impurities.