Pyrazole-4-carboxamide Synthesis via Base-Catalyzed Aminolysis

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Solution Overview

Problem

Conventional methods for producing pyrazole-4-carboxamide derivatives are lengthy, involve hazardous reagents, generate difficult-to-separate wastes, and require additional steps like hydrolysis and acid chloride formation, making them inefficient and unsafe for industrial production.

Innovation Solution

An aminolysis reaction between pyrazole carboxylic acid ester and an amine in the presence of a base, where the reaction is completed without removing by-produced alcohol or phenol from the system, simplifying the process and reducing waste production.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If conventional methods (hydrolysis + acid chloride formation) are used to produce pyrazole-4-carboxamide derivatives, then the carboxamide derivative can be obtained, but the production process becomes lengthy and requires hazardous reagents

Engineering Contradiction:

Improveproduction efficiencyVSAvoidnumber of production steps

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The invention extracts and eliminates the problematic intermediate steps (hydrolysis and acid chloride formation) from the conventional production pathway. By directly reacting the carboxylic acid with the amine in the presence of a base, the method bypasses the complex multi-step sequence and hazardous reagents, achieving a streamlined one-step synthesis that maintains product yield while improving safety and efficiency

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

Instead of following the conventional sequence (ester → hydrolysis → acid chloride → carboxamide), the invention inverts the approach by directly coupling the carboxylic acid with the amine using a base catalyst. This reverse engineering of the synthesis pathway eliminates the need for hazardous chlorinating agents and multiple purification steps, achieving the same target molecule through a safer, more efficient route

Inventive Principle:

Principle #13The other way round (Inversion)

2Productivity

If acid chloride preparation is used, then the carboxamide derivative can be formed, but hazardous reagents must be handled

Engineering Contradiction:

Improvecarboxamide formation efficiencyVSAvoidsafety in operation

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The invention replaces expensive and hazardous reagents (thionyl chloride, oxalyl chloride) with a simple, safe, and inexpensive base catalyst. The base serves its catalytic function and can be easily removed, eliminating the need to handle dangerous acid chlorides while maintaining efficient carboxamide formation

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The base acts as an intermediary that facilitates the direct reaction between carboxylic acid and amine without requiring the formation of hazardous acid chloride intermediates. The base mediates the nucleophilic attack of the amine on the carboxylic acid, enabling carboxamide formation through a safer pathway that avoids toxic reagents

Inventive Principle:

Principle #24Intermediary (Mediator)

3Productivity

If conventional production methods are used, then the carboxamide derivative can be obtained, but large quantities of waste acid and waste water are generated

Engineering Contradiction:

Improvecarboxamide derivative yieldVSAvoidwaste production

Core Design Contradiction:

ProductivityVSLoss of substance

Solution Approach 1:

The invention eliminates the generation of large quantities of waste acid and waste water by avoiding the hydrolysis and acid chloride formation steps. The base-catalyzed direct coupling method produces minimal waste that can be easily handled, and the base itself can be recovered or neutralized without generating substantial wastewater streams

Inventive Principle:

Principle #34Discarding and recovering

Solution Approach 2:

The invention changes the reaction parameters from conventional acid chloride chemistry to base-catalyzed direct coupling. This parameter change fundamentally alters the waste profile of the reaction, transforming a process that generates large volumes of acidic waste into one that produces minimal, easily manageable waste streams while maintaining high product yield

Inventive Principle:

Principle #35Parameter changes

4Productivity

If condensing agents are used for carboxylic acid and amine reaction, then the carboxamide can be obtained, but wastes difficult to separate from target material are generated

Engineering Contradiction:

Improvecarboxamide synthesis efficiencyVSAvoidpurification difficulty

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The invention replaces complex condensing agents (N,N'-dicyclohexylcarbodiimide, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride) with a simple base catalyst. The base leaves no difficult-to-separate waste products, and any excess base can be easily neutralized or removed, dramatically simplifying the purification process while maintaining efficient carboxamide synthesis

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

5Productivity

If bis(2-oxazolidinyl)phosphoryl chloride is used as condensing agent, then the carboxamide can be formed, but carcinogenicity and handling danger increase

Engineering Contradiction:

Improvecarboxamide formation capabilityVSAvoidcarcinogenicity and safety risk

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The invention replaces the carcinogenic condensing agent bis(2-oxazolidinyl)phosphoryl chloride with a simple, non-toxic base catalyst. The base performs the same function of facilitating carboxamide formation without the carcinogenic side effects, and can be safely handled and disposed of without special precautions

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The base serves as a safe intermediary that enables carboxamide formation without requiring the carcinogenic condensing agent. It mediates the reaction between carboxylic acid and amine through a benign mechanism that eliminates exposure to carcinogenic substances while maintaining synthetic efficiency

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 allows for the production of pyrazole-4-carboxamide derivatives in high yield and high purity with a shorter process, safer operations, and reduced waste, making it suitable for industrial use as an agricultural fungicide.

Implementation Method 1

a method of producing a pyrazole-4-carboxamide derivative through an aminolysis reaction of a pyrazole carboxylic acid ester and an amine in a solvent in the presence of a base

Methodology Applied

Scientific EffectAminolysis reaction: Chemical Bonding

Data Source

PatentEP3677572B1Production method for pyrazole-4-carboxamide derivative

Publication Date: 2023.06.07 NIPPON FINE CHEM CO LTD

AI summary

The present invention relates to a method of producing a pyrazole-4-carboxamide derivative including subjecting a pyrazole-4-carboxylic acid ester and an amine to an aminolysis reaction in a solvent in the presence of a base, provided that the reaction is completed without removing a by-produced alcohol or phenol outside the system. An industrial production method of a pyrazole-4-carboxamide derivative which is useful as an agricultural fungicide, simply and in high yield and high purity as compared with the conventional method, is provided.