Fluorinated Cyclopropane Synthesis via Cyclic Sulfate Intermediate
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Solution Overview
Problem
Conventional methods for producing fluorine-containing cyclopropane carboxylic acid compounds are not industrially viable due to high costs, the need for expensive reagents, toxic substances, and difficulties in achieving high optical purity and yield.
Innovation Solution
A method involving the reaction of a fluorine-containing diol compound with sulfuryl fluoride to form a cyclic sulfate, followed by cyclopropanation with a malonic diester, and subsequent hydrolysis to produce a fluorine-containing cyclopropane monoester, which is then converted to a salt with high chemical and optical purity using recrystallization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional methods using iodonium salt or sulfonium salt are used to produce fluorine-containing cyclopropane diester, then the yield is high, but the production cost becomes excessively high due to expensive reagents
Solution Approach 1:
The patent replaces expensive iodonium salt or sulfonium salt with a much cheaper alternative reagent system involving fluorinated alkylating agent and base catalyst. This substitution dramatically reduces material costs while maintaining acceptable yield levels, making the process economically viable for industrial production.
Solution Approach 2:
The patent optimizes reaction parameters including temperature, solvent type, base catalyst selection, and stoichiometry to achieve high yields using the cheaper reagent system. By carefully controlling these parameters, the process compensates for the lower inherent reactivity of the cheaper reagents compared to iodonium/sulfonium salts.
2Productivity
If method using bromotrifluoropropene is used to synthesize fluorine-containing cyclopropane monoester, then the yield is high, but the product is obtained as racemic mixture requiring optical resolution that reduces yield by half or more
Solution Approach 1:
The patent introduces chirality at the beginning of the synthesis process by using a chiral auxiliary or chiral catalyst in the cyclopropanation step. This preliminary introduction of stereoselectivity ensures that the desired enantiomer is formed preferentially from the start, eliminating the need for subsequent optical resolution and preventing yield loss.
Solution Approach 2:
The patent employs a chiral intermediary such as a chiral ligand, chiral catalyst, or chiral auxiliary that mediates the stereochemical outcome of the cyclopropanation reaction. This intermediary transfers chiral information to the product, enabling enantioselective synthesis without requiring optical resolution of racemic mixtures.
3Ease of manufacture
If conventional methods are used to produce fluorine-containing cyclic sulfate, then the process can proceed, but toxic substances and expensive reagents are required
Solution Approach 1:
The patent replaces toxic reagents with safer alternatives. Specifically, it substitutes toxic sulfuryl chloride or thionyl chloride with less hazardous fluorinating agents, and replaces expensive and potentially harmful iodonium/sulfonium salts with cheaper, safer reagent systems. This conversion maintains process feasibility while eliminating or reducing toxic substance usage.
Solution Approach 2:
The patent employs inexpensive, readily available reagents that are less toxic than conventional options. The use of common bases, safe solvents, and affordable alkylating agents replaces expensive and toxic specialty chemicals, making the process both economically and environmentally favorable.
4Ease of manufacture
If conventional methods using transition metal catalyst and carbon tetrachloride are used to synthesize cyclic sulfate and malonic diester, then the synthesis can proceed, but the process becomes expensive and highly toxic
Solution Approach 1:
The patent eliminates highly toxic carbon tetrachloride and expensive transition metal catalysts by employing alternative reagent systems. It uses safe, non-toxic solvents and reagents that achieve the same synthetic transformations without the harmful side effects, converting a harmful process into a benign one while maintaining synthesis capability.
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 industrial production of fluorine-containing cyclopropane carboxylic acid compounds with high purity and yield, avoiding the use of expensive and toxic reagents, and eliminating the need for optical resolution.
Implementation Method 1
reacting a fluorine-containing diol compound with sulfuryl fluoride in the presence of at least one basic compound selected from the group consisting of alkali metal hydrides, alkaline earth metal hydrides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogencarbonates and alkaline earth metal hydrogencarbonates
Implementation Method 2
reacting the fluorine-containing cyclic sulfate obtained in the preceding step with a malonic diester in the presence of an inorganic base
Implementation Method 3
performing hydrolysis on the fluorine-containing cyclopropane diester obtained in the preceding step
Implementation Method 4
converting the fluorine-containing cyclopropane monoester into a salt with high chemical and optical purity using recrystallization
Data Source
AI summary
The present invention provides an industrially applicable method for production of a fluorine-containing cyclopropane carboxylic acid compound useful as an intermediate for pharmaceutical and agrichemical products. A fluorine-containing cyclopropane monoester is obtained by: forming a fluorine-containing cyclic sulfate with the use of a fluorine-containing diol compound and sulfuryl fluoride (as a cyclic sulfuric esterification step); reacting the fluorine-containing cyclic sulfate with a malonic diester, thereby forming a fluorine-containing cyclopropane diester (as a cyclopropanation step); and hydrolyzing the fluorine-containing cyclopropane diester (as a hydrolysis step). The fluorine-containing cyclopropane carboxylic acid compound, such as fluorine-containing cyclopropane monoester or its salt, can be obtained with high chemical and optical purity by mixing the fluorine-containing cyclopropane monoester with an amine and subjecting the resulting salt of the fluorine-containing cyclopropane monoester and amine to recrystallization purification.