CN117924046B - Method for preparing chlorphenesin and application thereof - Google Patents
Method for preparing chlorphenesin and application thereof Download PDFInfo
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- CN117924046B CN117924046B CN202311821704.0A CN202311821704A CN117924046B CN 117924046 B CN117924046 B CN 117924046B CN 202311821704 A CN202311821704 A CN 202311821704A CN 117924046 B CN117924046 B CN 117924046B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
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Abstract
The invention discloses a method for preparing chlorphenesin and application thereof, comprising the following steps: adding glycerol and boric acid into a reaction bottle, and obtaining a diglycerol borate intermediate after dehydration reaction; adding a proper amount of solvent into the diglycerol borate intermediate in the step a, uniformly stirring, cooling to 0-5 ℃, dropwise adding solvent solution of p-toluenesulfonyl chloride, stirring for a period of time at room temperature after the dripping, and sampling and GC analysis until the p-toluenesulfonyl chloride is consumed, so as to obtain a diester intermediate; and c, adding sodium parachlorophenol into the diester intermediate in the step b, continuing stirring at room temperature for a period of time, controlling the GC until the sodium parachlorophenol is completely consumed, removing the solvent, and adding a proper amount of water for hydrolysis to obtain the target compound, namely the chlorphenyl glycinate. The preparation method disclosed by the invention has the advantages of mild process conditions, high yield, environment-friendly production process and reduced generation of byproducts through the application of the diglycerol borate structure.
Description
Technical Field
The invention relates to a method for synthesizing chlorophenylglycol ether through a novel synthetic route and application thereof, in particular to application of a diglycerol borate structure, thereby obtaining the chlorophenylglycol ether with high yield.
Background
Chlorophenylglycol is a preservative which is widely used in cosmetics, and Europe has been allowed to be used as a preservative in cosmetics since 1996, japan, and the United states.
The principal of its operation is to block nerve impulses from being sent to the brain. In cosmetics, it is used as a preservative because it has antifungal, antibacterial properties. As a preservative, it can prevent various products from suffering from such problems as viscosity change, PH change, demulsification, visible microbial growth, color change and generation of offensive odors. In addition to being used to treat fungal nail problems, the ingredients are most commonly used in facial moisturizers, anti-aging essences, sunscreens, foundations, eye creams, facial cleansers, mascaras, and concealers. In medicine, the clomazone-related formulation is an antigen-related immunosuppressant that inhibits igChemicalbooke-mediated histamine release. The chlorphenesin also belongs to antifungal medicines, is applicable to antifungal, bacterial, vaginal mould and trichomonas diseases, and has multiple medicine dosage forms. In the aspect of cosmetics, the chlorphenyl glycine ether is used as a cosmetic bactericide in International cosmetic raw materials dictionary and handbook, can effectively resist gram-positive and gram-negative bacteria, has stronger bactericidal activity on Aspergillus niger iml149007 and Penicillium pinophilum imi87160 (fungi), and has good inhibition effect on candida albicans ncpf3179 and Saccharomyces cerevisiae ncpf3275 (yeast).
The production of chlorophenylglycol is very popular, and the methods are different, but have advantages and disadvantages. British patent GB628497 reports that: the preparation method comprises the steps of reacting p-chlorophenol with glycidol in the presence of pyridine, and refining the p-chlorophenol with chloroform or diethyl ether-petroleum ether after post-treatment to obtain the chlorobenzeneglycerol ether. The method uses diethyl ether low-boiling-point substances, and the large-scale production is at risk. Chinese patent CN 101445436A adopts epichlorohydrin to hydrolyze in dilute sulfuric acid and then reacts with sodium parachlorophenol to prepare chlorphenesin, and the method has simple process, but involves the use of sulfuric acid and has high requirements on equipment.
Therefore, in combination with the above-mentioned technical problems, it is necessary to provide a new technical solution.
Disclosure of Invention
In order to at least solve one of the technical problems existing in the prior art and realize green production of the chlorphenyl glyceryl ether, the inventor research and development team invents a new method for preparing the chlorphenyl glyceryl ether and application thereof, and the method comprises the following steps:
the specific scheme of the synthetic route is as follows:
a: adding glycerol and boric acid into a reaction bottle, and obtaining a diglycerol borate intermediate after dehydration reaction;
b: adding a proper amount of solvent into the diglycerol borate intermediate in the step a, uniformly stirring, cooling to 0-5 ℃, dropwise adding solvent solution of p-toluenesulfonyl chloride, stirring for a period of time at room temperature after the dripping, and sampling and GC analysis until the p-toluenesulfonyl chloride is consumed, so as to obtain a diester intermediate;
c: and c, adding sodium parachlorophenol into the diester intermediate in the step b, continuing stirring at room temperature for a period of time, controlling the GC until the sodium parachlorophenol is completely consumed, removing the solvent, and adding a proper amount of water for hydrolysis to obtain the target compound, namely the chlorphenyl glycinate.
As a preferred embodiment of the method for preparing chlorphenesin according to the present invention, in the step a, the molar ratio of boric acid to glycerin is 1:2.
As a preferable scheme of the method for preparing the chlorphenesin ether, in the step a, glycerin and boric acid are added into a reaction bottle, and the temperature is raised by 100 ℃, and the vacuum dehydration reaction is performed under reduced pressure.
As a preferred embodiment of the method for preparing chlorophenylglycerol ether of the present invention, in the step b, the molar ratio of p-toluenesulfonyl chloride to glycerin in the step a is 1:1.
As a preferred embodiment of the process for preparing chlorophenylglycerol ether of the present invention, in step b, the solvent used is methylene chloride.
As a preferred embodiment of the process for preparing chlorophenylglycerol ethers of the present invention, in step c, the molar ratio of sodium parachlorophenate to glycerol in step a is 1:1.
As a preferable scheme of the method for preparing the chlorphenyl glyceryl ether, in the step c, a specific condition of adding a proper amount of water for hydrolysis is that the target compound chlorphenyl glyceryl ether can be obtained by directly adding water and stirring at room temperature.
On the one hand, the application of the chlorphenesin prepared by the method in preservative is provided.
Compared with the prior art, the invention has at least one or more of the following beneficial effects:
The preparation method disclosed by the invention is mild in technological conditions, high in yield and environment-friendly in production process.
The preparation method reduces the generation of byproducts through the application of the diglycerol borate structure.
The invention relates to multi-step reaction, but each step of reaction process is simple, reduces cost and is beneficial to realizing large-scale production.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
Embodiments of the present invention will be described in detail below, and technical solutions in the embodiments of the present invention will be clearly and completely described, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In one aspect, the invention provides a method for preparing chlorphenesin, and the synthetic route scheme of the target compound specifically comprises the following steps:
a: adding glycerol and boric acid into a reaction bottle, and obtaining a diglycerol borate intermediate after dehydration reaction;
b: adding a proper amount of solvent into the diglycerol borate intermediate in the step a, uniformly stirring, cooling to 0-5 ℃, dropwise adding solvent solution of p-toluenesulfonyl chloride, stirring for a period of time at room temperature after the dripping, and sampling and GC analysis until the p-toluenesulfonyl chloride is consumed, so as to obtain a diester intermediate;
c: and c, adding sodium parachlorophenol into the diester intermediate in the step b, continuing stirring at room temperature for a period of time, controlling the GC until the sodium parachlorophenol is completely consumed, removing the solvent, and adding a proper amount of water for hydrolysis to obtain the target compound, namely the chlorphenyl glycinate.
Preferably, in step a, the molar ratio of boric acid to glycerol is 1:2.
Preferably, in step a, glycerin and boric acid are added into a reaction bottle, the temperature is raised by 100 ℃, and the vacuum dehydration reaction is performed under reduced pressure. Further preferably, after the dehydration reaction is completed, a diglycerol borate intermediate is obtained, which is cooled to room temperature for use.
Preferably, in step b, the molar ratio of p-toluenesulfonyl chloride to glycerol in step a is 1:1.
Preferably, in step b, the solvent used is dichloromethane.
Preferably, in step c, the molar ratio of sodium parachlorophenate to glycerol in step a is 1:1.
Preferably, the specific condition of adding a proper amount of water for hydrolysis is that the target compound of the chlorphenyl glycin ether can be obtained by directly adding water and stirring at room temperature.
The synthetic process route of the invention is as follows:
in one aspect, the fatty acid alkanolamides prepared by the method provided by the invention are applied to preservatives.
EXAMPLE 1 Synthesis of Chlorophenyl glyceryl ether
13.8G (150 mmol) of glycerol and 4.65g (75 mmol) of boric acid are added into a 250ml three-port reaction bottle, the temperature is raised to 100 ℃, the vacuum dehydration reaction is carried out for 6 hours, after the dehydration reaction is completed, the temperature is reduced to room temperature, 100ml of dichloromethane is added, the mixture is stirred uniformly, after the temperature is reduced to 0-5 ℃, a dichloromethane solution of p-toluenesulfonyl chloride (28.6 g,150 mmol) is added dropwise, the mixture is stirred for 30 minutes at room temperature after the dropwise addition, and the mixture is sampled and is controlled until the consumption of the p-toluenesulfonyl chloride is completed by GC (gas chromatography); then adding sodium parachlorophenol (22.9 g,150 mmol) into the reaction bottle, continuing stirring at room temperature for 2h, controlling the GC until the sodium parachlorophenol is consumed, adding 50ml of deionized water, stirring at 60 ℃ for 3h, sampling for GC analysis, stopping layering, washing an oil layer with 50ml multiplied by 2 water twice, collecting an anhydrous sodium sulfate oil layer, drying, and spin-drying a solvent to obtain 28.3g of chlorphenicol solution.
Through testing, the GC content of the product is 91.5%, and the yield is 85.2%.
EXAMPLE 2 Synthesis of Chlorophenylglycol
55.2G (600 mmol) of glycerin and 18.6g (300 mmol) of boric acid are added into a 1L three-port reaction bottle, the temperature is raised to 100 ℃, the vacuum dehydration reaction is carried out for 6 hours under reduced pressure, after the dehydration reaction is completed, the temperature is reduced to room temperature, 500ml of dichloromethane is added, the mixture is stirred uniformly, after the temperature is reduced to 0-5 ℃, a dichloromethane solution of p-toluenesulfonyl chloride (114.4 g,600 mmol) is added dropwise, the mixture is stirred for 30 minutes after the dropwise conversion to room temperature, and the mixture is sampled and controlled in a GC until the p-toluenesulfonyl chloride is consumed; then adding sodium parachlorophenol (91.6 g,600 mmol) into a reaction bottle, continuing stirring at room temperature for 2h, controlling the GC until the sodium parachlorophenol is consumed, adding 200ml of deionized water, stirring at 60 ℃ for 3h, sampling for GC analysis, stopping layering, washing an oil layer 200ml multiplied by 2 twice, collecting an anhydrous sodium sulfate oil layer, drying, and spin-drying a solvent to obtain 112.5g of a chlorphenicol solution.
Through testing, the GC content of the product is 93.4%, and the yield is 86.4%.
While embodiments of the invention have been illustrated and described above, it should be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that any modifications, equivalent substitutions, improvements, etc. that fall within the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (7)
1. A process for preparing a chlorophenylglycerol ether comprising the steps of:
a: adding glycerol and boric acid into a reaction bottle, and obtaining a diglycerol borate intermediate after dehydration reaction;
b: adding a proper amount of solvent into the diglycerol borate intermediate in the step a, uniformly stirring, cooling to 0-5 ℃, dropwise adding solvent solution of p-toluenesulfonyl chloride, stirring for a period of time at room temperature after the dripping, and sampling and GC analysis until the p-toluenesulfonyl chloride is consumed, so as to obtain a diester intermediate;
c: adding sodium parachlorophenol into the diester intermediate in the step b, continuing stirring at room temperature for a period of time, controlling the GC until the sodium parachlorophenol is completely consumed, removing the solvent, adding a proper amount of water for hydrolysis to obtain the target compound chlorphenicol ether,
The specific structure of the boric acid diglycerol ester intermediate is as follows:
The structure of the diester intermediate is as follows:
2. The process for preparing chlorophenylglycerol ether of claim 1, wherein in step a, the molar ratio of boric acid to glycerin is 1:2.
3. The process for preparing chlorophenylglycerol ether according to claim 1 or 2, wherein in step a, glycerin and boric acid are added into a reaction flask, and the temperature is raised by 100 ℃, and the vacuum dehydration reaction is performed under reduced pressure.
4. The process for preparing chlorophenylglycerol ether of claim 1, wherein in step b, the molar ratio of p-toluenesulfonyl chloride to glycerin in step a is 1:1.
5. The process for preparing chlorobenzeneglycerine ethers according to claim 1, wherein in step b, the solvent used is methylene chloride.
6. The process for preparing chlorophenylglycerol ethers of claim 1,2, 4 or 5, wherein in step c the molar ratio of sodium parachlorophenate to glycerol in step a is 1:1.
7. The method for preparing the chlorphenyl glyceryl ether according to claim 1, wherein in the step c, a proper amount of water is added for hydrolysis, and the specific condition is that the chlorphenyl glyceryl ether is directly added with water and stirred at room temperature to obtain the target compound.
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| CN202311821704.0A CN117924046B (en) | 2023-12-27 | 2023-12-27 | Method for preparing chlorphenesin and application thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105016989A (en) * | 2015-08-18 | 2015-11-04 | 北京桑普生物化学技术有限公司 | Synthetic method of chlorobenzene glyceryl ether |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB788278A (en) * | 1955-05-24 | 1957-12-23 | Bayer Ag | Process for the manufacture of ª-phenylglycerol ethers |
| FR1458922A (en) * | 1963-10-02 | 1966-04-29 | Angeli Inst Spa | Process for preparing glyceryl ethers of acylphenols |
| DK154192D0 (en) * | 1992-12-23 | 1992-12-23 | Neurosearch As | HETEROCYCLIC COMPOUNDS |
| CN1328240C (en) * | 2005-08-31 | 2007-07-25 | 四川大学 | Preparation of benzoyl oxy-aldehyde |
| EP2184367A1 (en) * | 2008-10-31 | 2010-05-12 | Biosynth AG | Non-hydrolytic microbial probes |
| CN115850110B (en) * | 2022-12-27 | 2024-02-20 | 苏州元素集化学工业有限公司 | Synthesis method of ceramide-like compound containing glyceride structure |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105016989A (en) * | 2015-08-18 | 2015-11-04 | 北京桑普生物化学技术有限公司 | Synthetic method of chlorobenzene glyceryl ether |
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