Mild Carbon-Sulfur Fluorination for Fast 18F Radiolabelling
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Solution Overview
Problem
Current methods for incorporating fluorine into molecules, particularly biomolecules and aliphatic substrates, are slow, require harsh conditions, and are not compatible with common functional groups, limiting their applicability and efficiency, especially for late-stage introduction of fluorine isotopes like 18F.
Innovation Solution
A process involving the use of activator compounds such as N-halosuccinimides and sources of fluoride to convert a carbon-SG bond to a carbon-F bond under mild conditions, suitable for biomolecules and other functional groups, allowing fast and enantioselective fluorination.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing fluorination methods are used, then fluorine can be introduced into molecules, but the reaction requires harsh conditions and long reaction times, leading to degradation of biomolecules and low efficiency
Solution Approach 1:
The patent changes the chemical parameters of the fluorination reaction by using N-halosuccinimide activators and fluoride sources under mild conditions (room temperature, neutral pH), transforming the reaction from requiring harsh conditions to proceeding under physiological conditions, thus resolving the contradiction between molecule stability and reaction speed
Solution Approach 2:
The patent introduces N-halosuccinimide as an intermediary activator that mediates between the fluoride source and the substrate, enabling the fluorination to proceed under mild conditions without direct harsh reagent-substrate interaction, thus protecting biomolecules while maintaining reaction efficiency
2Reliability
If existing fluorination methods are used, then fluorine incorporation can be achieved, but the process requires harsh conditions that are not compatible with common functional groups in biomolecules
Solution Approach 1:
The patent changes the reaction conditions from harsh (high temperature, strong bases/acids) to mild (room temperature, neutral pH), making the process compatible with sensitive functional groups in biomolecules while maintaining high fluorine incorporation efficiency through the activator mechanism
Solution Approach 2:
The N-halosuccinimide activator serves as an intermediary that enables selective fluorine incorporation at the sulfur-bearing carbon without affecting other functional groups, achieving both compatibility and precision
3Productivity
If existing fluorination methods are used, then fluorine can be introduced into molecules, but the reaction times are long and yields are low, especially for 18F radiolabelling
Solution Approach 1:
The patent changes the reaction kinetics by using N-halosuccinimide activators that enable fast fluorine transfer under mild conditions, achieving high yields (often >90%) in minutes rather than hours, which is critical for 18F radiolabelling with its 109-minute half-life
Solution Approach 2:
The activator intermediary facilitates rapid fluorine transfer through a low-energy pathway, dramatically reducing reaction time while increasing yield, making the process suitable for time-sensitive radiolabelling applications
4Ease of manufacture
If existing fluorination methods are used, then fluorine incorporation can be achieved, but the process requires multi-step synthesis and extensive purification, increasing handling steps and potential degradation
Solution Approach 1:
The patent changes the reaction to proceed under mild, aqueous-compatible conditions that eliminate the need for extensive purification steps, allowing direct use in biological systems and reducing handling steps that could degrade the molecule
Solution Approach 2:
The N-halosuccinimide activator enables the reaction to proceed with high selectivity and cleanliness, minimizing byproducts and eliminating the need for complex purification, thus simplifying the manufacturing process and preserving molecule integrity
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 achieves high yields and fast reaction times, enabling the efficient introduction of fluorine into molecules, particularly suitable for radiolabelling agents, with compatibility for common functional groups and minimal degradation.
Implementation Method 1
converting a compound of Formula (I) into a compound of Formula (II)... converting a carbon-SG bond to a carbon-F bond
Data Source
AI summary
The present disclosure relates to processes for the fluorination of molecules. One aspect provides a process for incorporating a fluorine atom into a molecule, said process comprising converting a compound of formula X-SG into a compound of formula X-F, wherein G is an optionally substituted C1-C6 alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, and X is an organic group; and wherein the SG group is attached to a secondary or tertiary carbon atom in the organic group X; said process comprising treating said compound of formula X-SG with (i) an activator compound selected from the group consisting of N-halosuccinimides, N-halobenzenesulfonimides, N-halobenzenesulfonamides, dialkylaminodihalosulfinium salts, heterocyclylaminodihalosulfinium salts, dialkylaminosulfur trihalides, XeF2, difluoroiodotoluene, di- and tri-bromoisocyanuric acids, bromine, chlorine, hypervalent iodine compounds with I2; and other sources of Br+, Cl+, F+, I+, bromonium, iodonium, or chloronium; and (ii) a source of fluoride. Uses of the process in the preparation of various fluorinated molecules as well as uses of certain compounds as intermediates in the processes of the present disclosure are also provided.