Anthranilamide Synthesis via Cyanamide Condensation
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Solution Overview
Problem
Current methods for synthesizing anthranilamides, particularly anthranilamide pyridinureas, are inefficient, costly, and pose safety concerns due to multi-step processes, low yields, and the difficulty in eliminating palladium from the final product, making them unsuitable for pharmaceutical use on an industrial scale.
Innovation Solution
A novel method involving the generation of an anilide derivative, building the urea part, and forming an imine intermediate, which is then reduced to produce anthranilamides with improved yields and safety, eliminating the need for chromatographic purification and reducing the use of hazardous reagents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If palladium-catalysed carbon-nitrogen coupling is used as the last synthetic step, then the anthranilamide can be synthesized, but the palladium is difficult to eliminate from the final product making it less suitable as a pharmaceutical agent
Solution Approach 1:
The patent removes the palladium-catalysed carbon-nitrogen coupling step from the synthesis pathway. Instead, it uses a condensation reaction between an aniline derivative and a cyanamide derivative followed by hydrolysis, which eliminates palladium contamination and produces pharmaceutical-grade anthranilamides without harmful metal residues.
Solution Approach 2:
The patent replaces expensive palladium catalyst with simple, inexpensive reagents (cyanamide derivatives and acid catalysts) that do not require special removal procedures. The new methodology uses readily available chemicals that leave no persistent harmful residues in the final product.
2Manufacturing precision
If a multi-step synthesis with chromatographic purification is used, then the anthranilamide can be synthesized with high purity, but the process is long and has low overall yield
Solution Approach 1:
The patent implements a continuous synthesis process where the condensation reaction produces an intermediate that is directly hydrolyzed in situ to form the final anthranilamide product. This eliminates the need for isolating and purifying intermediate compounds through chromatography, maintaining continuous productive action throughout the synthesis.
Solution Approach 2:
The patent changes the reaction parameters by using cyanamide derivatives and acid-catalyzed hydrolysis conditions that directly produce the desired anthranilamide with high purity. The reaction conditions are optimized to achieve complete conversion without requiring chromatographic separation, thereby improving both yield and efficiency.
3Ease of manufacture
If hazardous reagents such as 2-nitrobenzoyl chloride and tert-butyl nitrite are used, then the synthesis can proceed, but safety concerns arise
Solution Approach 1:
The patent replaces hazardous reagents like 2-nitrobenzoyl chloride and tert-butyl nitrite with safe, inexpensive cyanamide derivatives and common acid catalysts. These substituted reagents are non-hazardous, readily available, and eliminate safety concerns while maintaining synthesis feasibility.
Solution Approach 2:
The patent converts potentially harmful nitro and nitrite groups into benign cyanamide and carboxylic acid functional groups through hydrolysis. This transformation eliminates the hazardous nature of the reagents while preserving the synthetic utility and producing the desired pharmaceutical product.
4Ease of manufacture
If expensive reagents such as trimethyloxonium tetrafluoroborate, Xanthphos and Pd 2 (dba) 3 are used, then the synthesis can be completed, but the cost is very high
Solution Approach 1:
The patent replaces expensive reagents (trimethyloxonium tetrafluoroborate, Xanthphos, Pd 2 (dba) 3) with inexpensive cyanamide derivatives and simple acid catalysts. The new methodology uses readily available, low-cost chemicals that complete the synthesis just as effectively without the high material costs.
Solution Approach 2:
The patent uses simple cyanamide molecules as substitutes for complex palladium catalyst systems. The cyanamide derivatives perform the essential function of building the anthranilamide structure through condensation and hydrolysis, providing a cost-effective copy of the synthetic capability previously requiring expensive metals and ligands.
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 method significantly increases overall yield from 20% to 63%, achieves 98.5% purity, and simplifies the process by eliminating chromatographic steps, making it more efficient and economical for industrial production while ensuring safety.
Implementation Method 1
The imine of formula IIa is the precursor for the generation of anthranilamides of formula I by reduction of the C=N double bond
Implementation Method 2
The imine of formula IIa is the precursor for the generation of anthranilamides of formula I by reduction of the C=N double bond
Data Source
AI summary
The present invention relates to a novel method of preparing anthranilamides of formula I : in which R1 , R2 , R3 , A, E, Q, X, and W are defined in the claims, to a novel intermediate compound, and to the use of said novel intermediate compound for the preparation of said anthranilamides of formula I.