Quinazoline Synthesis via Selective Demethylation and Merging
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Solution Overview
Problem
The existing process for preparing N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy) quinazolin-4-amine dihydrochloride is not commercially viable due to the use of expensive reactants like Isovanillin, low overall yield, requirement of pyrophoric catalysts, and cumbersome work-up procedures.
Innovation Solution
A new process using 6,7-dimethoxyquinazoline-4(3H)-one as a starting material, avoiding expensive reactants and pyrophoric catalysts, and simplifying the work-up procedures by eliminating the need for intermediate isolation, with steps including selective demethylation, acetylation, chlorination, and subsequent reactions to achieve high yields and purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If the existing process using Isovanillin is employed, then the compound can be prepared, but the process is not commercially viable due to expensive reactants and low overall yield
Solution Approach 1:
The patent replaces expensive Isovanillin with cheap and readily available 6,7-dimethoxyquinazoline-4(3H)-one as the starting material. This substitution of costly reactants with inexpensive alternatives directly addresses the commercial viability issue while maintaining the ability to produce the target compound
Solution Approach 2:
The synthesis is divided into multiple discrete steps (demethylation, acetylation, chlorination, condensation) allowing for better process control and intermediate management. This segmentation enables optimization of each individual step's yield while avoiding the cumulative losses of a single-step process
2Ease of manufacture
If the existing process is used, then the compound can be prepared, but it requires pyrophoric catalysts like Raney Nickel and high pressure reactions
Solution Approach 1:
The patent eliminates pyrophoric Raney Nickel catalyst and high-pressure equipment by using conventional reagents and ambient pressure conditions. This substitution of hazardous materials with safer alternatives directly improves process safety while removing the need for specialized handling equipment
Solution Approach 2:
The patent converts potentially harmful reactions into safer alternatives by replacing pyrophoric catalysts with conventional base-catalyzed condensations and high-pressure hydrogenations with ambient pressure reactions using safer reagents like thionyl chloride and morpholinopropyl chloride
3Ease of operation
If the existing process is followed, then the compound can be prepared, but it involves cumbersome work-up procedures and isolation of intermediates
Solution Approach 1:
The patent combines multiple operations into streamlined sequences: demethylation followed by acetylation without full isolation, and chlorination followed by condensation in sequence. This merging of steps reduces the number of isolation and purification operations, simplifying work-up procedures and reducing overall process time
Solution Approach 2:
The patent performs acetylation as a preliminary protective step before chlorination, and conducts chlorination and condensation in sequence without isolating the intermediate. This preliminary action approach allows for smoother process flow and eliminates time-consuming isolation steps
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 new process achieves high yields and purity (>99.9% HPLC) of the compound, making it commercially viable, cost-effective, and scalable, while avoiding the use of expensive reagents and hazardous catalysts, thus improving process timelines and reducing environmental impact.
Implementation Method 1
selective demethylation of 6,7-dimethoxyquinazoline-4(3H)-one using DL-Methionine-sulfuric acid medium to get 6-hydroxy-7-methoxy quinazoline-4(3H)-one
Implementation Method 2
acetylation of 6-hydroxy-7-methoxyquinazoline-4(3H)-one in acetic anhydride medium to get 6-acetoxy-7-methoxyquinazoline-4(3H)-one
Implementation Method 3
reacting 6-acetoxy-7-methoxy-quinazoline-4(3H)-one with thionyl chloride in the presence of DMF in chloroform to get 6-acetoxy-4-chloro-7-methoxyquinazoline hydrochloride
Implementation Method 4
reacting 6-acetoxy-4-chloro-7-methoxyquinazoline hydrochloride in-situ with 3-ethynylaniline of formula-III in isopropanol medium to get 6-acetoxy-4-(3-ethynylanilino)-7-methoxyquinazoline hydrochloride
Implementation Method 5
treating 6-acetoxy-4-(3-ethynylanilino)-7-methoxyquinazoline hydrochloride salt of formula-XVII in-situ with aqueous ammonia in methanol medium to get 4-(3-ethynylanilino)-6-hydroxy-7-methoxyquinazoline
Implementation Method 6
reacting 4-(3-ethynylanilino)-6-hydroxy-7-methoxyquinazoline of formula-XVIII with 3-morpholinopropyl chloride of compound of formula-VI in presence of base in DMF to get N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy) quinazolin-4-amine
Data Source
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AI summary
Present invention relates to an improved process for the preparation of N-(3- ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy) quinazolin-4-amine dihydrochloride of formula-I.