Ticagrelor Synthesis via Triazolopyrimidine Intermediate
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Solution Overview
Problem
The existing synthesis methods for ticagrelor are lengthy and involve the use of toxic compounds, with poor chemoselectivity issues and the need for heavy metal catalysts, making them inefficient and economically unfeasible for industrial production.
Innovation Solution
A process involving the use of a compound of formula VI or its salt, which allows for a shorter synthesis by omitting the deprotection step and using non-toxic, basic reagents, enabling the introduction of a hydroxyethyl side chain in 2-3 steps and facilitating the production of ticagrelor with improved purity through one-pot conversions and solid crystalline intermediates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing synthesis methods are used, then ticagrelor can be produced, but the synthesis is lengthy (7-9 steps) and involves toxic compounds
Solution Approach 1:
The invention extracts and removes toxic elements (CHBr3, triflic anhydride, heavy metal catalysts) and lengthy synthesis steps from the process by introducing a novel compound of formula VI that enables direct reaction without protective group deprotection, thereby eliminating harmful substances and reducing synthesis steps to 4-5 steps
Solution Approach 2:
The patent replaces expensive and toxic reagents (triflic anhydride, CHBr3, heavy metal catalysts like Pd/C and Pt/C) with inexpensive, non-toxic alternatives (compound of formula VI, basic reagents), making the process economically feasible and environmentally friendly for industrial production
2Productivity
If existing synthesis methods are used, then ticagrelor can be produced, but poor chemoselectivity issues arise
Solution Approach 1:
The invention applies local quality by designing compound of formula VI with specific functional group characteristics that enable selective reaction at the desired site without affecting other parts of the molecule, achieving high chemoselectivity in the formation of key intermediates and avoiding side reactions
Solution Approach 2:
The patent changes the chemical parameters by introducing compound of formula VI with modified structural parameters (protective group configuration) that alter the reactivity profile, enabling selective reactions under basic conditions and improving chemoselectivity throughout the synthesis pathway
3Productivity
If existing synthesis methods are used, then ticagrelor can be produced, but heavy metal catalysts are required
Solution Approach 1:
The invention extracts and eliminates heavy metal catalysts (Pd/C, Pt/C) from the synthesis process by designing a reaction pathway that uses basic reagents and compound of formula VI, which proceeds without requiring metal catalysis, thereby producing ticagrelor free from heavy metal contamination
Solution Approach 2:
The patent replaces expensive heavy metal catalysts with inexpensive basic reagents and compound of formula VI, eliminating the need for costly metal catalysts while maintaining synthesis efficiency and producing a cleaner product suitable for pharmaceutical applications
4Productivity
If existing synthesis methods are used, then ticagrelor can be produced, but the process is economically unfeasible for industrial production
Solution Approach 1:
The invention replaces expensive reagents (triflic anhydride, CHBr3, heavy metal catalysts, deprotection reagents) with inexpensive alternatives (compound of formula VI, basic reagents), dramatically reducing material costs and making the process economically viable for large-scale industrial production
Solution Approach 2:
The patent extracts and removes costly synthesis steps (protective group deprotection, toxic reagent handling, metal catalyst recovery) by introducing compound of formula VI that enables direct reaction, thereby simplifying the process and reducing both operational and material costs for industrial manufacturing
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 process significantly reduces the number of reaction steps, eliminates the use of toxic substances, and enhances the purity of ticagrelor by avoiding side product formation and stereoisomeric impurities, resulting in an industrially applicable and economically improved method for producing ticagrelor.
Implementation Method 1
converting a compound of formula VIII by nitrosation to a compound of formula IX
Implementation Method 2
coupling the compound of formula IX or IX' with a compound of formula X or a salt thereof in a presence of a base to provide a compound of formula XI
Data Source
AI summary
The present invention relates to the field of organic synthesis and describes the synthesis of specific intermediates suitable for the preparation of triazolopyrimidine compounds such as ticagrelor.