CN113512003B - Preparation method of 4- (imidazole-1-yl) phenol - Google Patents
Preparation method of 4- (imidazole-1-yl) phenol Download PDFInfo
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- CN113512003B CN113512003B CN202110751078.7A CN202110751078A CN113512003B CN 113512003 B CN113512003 B CN 113512003B CN 202110751078 A CN202110751078 A CN 202110751078A CN 113512003 B CN113512003 B CN 113512003B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
Abstract
The invention discloses a preparation method of 4- (imidazole-1-yl) phenol, belonging to the field of in vitro diagnosis. Taking p-bromoanisole and imidazole as raw materials, carrying out Ullmann reaction under the conditions of a catalyst, alkali and a reaction solvent, extracting after the reaction is finished to obtain an organic phase, adding saturated salt water into the organic phase, stirring, separating, drying, and crystallizing by utilizing methyl tert-butyl ether to obtain 1- (4-methoxyphenyl) -1H-imidazole; and then boron tribromide is used for demethylating the 1- (4-methoxyphenyl) -1H-imidazole, and recrystallization is carried out to obtain the 4- (imidazole-1-yl) phenol. The method has simple post-treatment process, does not need a large amount of solvent extraction and column chromatography purification, can obtain the product only by recrystallization, has no copper ion residue in the prepared product, has white appearance, and can better meet the market demand.
Description
Technical Field
The invention belongs to the field of in vitro diagnosis, and particularly relates to a preparation method of 4- (imidazole-1-yl) phenol.
Background
The luminol system can be oxidized by some oxidants under alkaline conditions to generate chemiluminescence reaction, the chemiluminescence with the maximum emission wavelength of 425nm is radiated, and the luminol system can be widely applied to the fields of criminal investigation, biological engineering, chemical tracing and the like. Among them, 4- (imidazol-1-yl) phenol is a luminol system enhancer and is very important for in vitro diagnostics.
Currently, the synthesis of 4- (imidazol-1-yl) phenol involves: 1) wen Chen et al (Journal of the American Chemical Society, 2007, 129, 13879-13886) reported the one-step synthesis of 4- (imidazol-1-yl) phenol by the Ullmann reaction starting from p-bromophenol and imidazole. 2) Pratt, Derek A. et al (Organic Letters, 2005, 7, 2735-. The product prepared by the method has the problems of difficult post-treatment, residual copper ions, poor product color (such as yellow/green/brown), and the like. Although the reaction conversion rate and the product selectivity are good, the post-treatment difficulty greatly increases the industrial cost, and the product residual copper ions influence the product appearance, so that the product cannot meet higher consumption requirements. Therefore, the establishment of a method for preparing 4- (imidazole-1-yl) phenol with excellent quality has important significance.
Disclosure of Invention
[ problem ] to provide a method for producing a semiconductor device
The existing method for synthesizing 4- (imidazole-1-yl) phenol has the problems that the difficulty in post-treatment is high, the product and water form hydrogen bonds, the product is difficult to extract in a water phase, and the product color caused by copper ion residues is poor (greenish grey or brown grey).
[ technical solution ] A
In order to solve the technical problems, the invention provides a preparation method of 4- (imidazole-1-yl) phenol, the method has simple post-treatment process, and the prepared product has no copper ion residue and is white in appearance.
Specifically, the invention provides a preparation method of 4- (imidazole-1-yl) phenol, and the route of the preparation method is as follows:
the method comprises the following steps:
(1) taking p-bromoanisole and imidazole as raw materials, carrying out Ullmann reaction under the conditions of a catalyst, alkali and a reaction solvent, extracting after the reaction is finished to obtain an organic phase, adding saturated salt water into the organic phase, stirring, separating, drying, and crystallizing by using methyl tert-butyl ether to obtain 1- (4-methoxyphenyl) -1H-imidazole;
(2) demethylating 1- (4-methoxyphenyl) -1H-imidazole by using boron tribromide, and recrystallizing to obtain the 4- (imidazole-1-yl) phenol.
In one embodiment of the present invention, in step (1), the molar ratio of bromoanisole to imidazole is 1: 1 to 1.5.
In one embodiment of the present invention, in step (1), the reaction solvent comprises one or more of N, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), or Dimethylsulfoxide (DMSO), preferably NMP; the catalyst is one or two of CuO or CuI; the base is Na 2 CO 3 、K 2 CO 3 、Cs 2 CO 3 Or one or more of NaOH.
In one embodiment of the invention, the catalyst is added in an amount of 5 to 10 mol% and the base is added in an amount of 1 to 2 equivalents.
In one embodiment of the invention, the reaction temperature of the Ullmann reaction is 110-140 ℃; the reaction time is 6-15 h.
In one embodiment of the invention, the extraction is by ethyl acetate; the specific operation is preferably as follows: after the Ullmann reaction is finished, filtering to remove solids; adding NaOH aqueous solution, stirring, and filtering again to remove solids; ethyl acetate was added to the aqueous phase to extract, and an organic phase was obtained.
In one embodiment of the invention, the concentration of the aqueous NaOH solution is between 8 and 10%.
In one embodiment of the invention, in step (2), the molar ratio of 1- (4-methoxyphenyl) -1H-imidazole to boron tribromide is 1: 1.5 to 3.
In one embodiment of the invention, in the step (2), the temperature of the reaction system is controlled to be-10 to 5 ℃ when the boron tribromide is fed.
In one embodiment of the present invention, in step (2), the reaction solvent is CH 2 Cl 2 (ii) a The reaction temperature is 20-30 ℃; the reaction time is 6-12 h.
In one embodiment of the present invention, in step (2), recrystallization using t-butanol or ethanol yields 4- (imidazol-1-yl) phenol as a white solid.
In one embodiment of the present invention, the reaction of step (2) is performed under the protection of inert atmosphere, and the inert atmosphere comprises nitrogen, argon, etc.
The invention also provides the application of the preparation method in the fields of criminal investigation, bioengineering and chemical tracing.
Compared with the prior art, the invention has the following advantages and effects:
1. the method has simple post-reaction treatment, does not need a large amount of solvent extraction and column chromatography purification, can obtain the product only by recrystallization, is more beneficial to industrial production and has lower cost.
2. The method can avoid the problem of residual metal copper ions in the product, so that the product has higher quality, is white solid in appearance and can better meet the market demand.
3. The total yield of the 4- (imidazole-1-yl) phenol prepared by the method can reach 60 percent, and the purity is as high as more than 99.5 percent.
4. The method selects p-bromoanisole as a starting material, has low industrial price, can easily extract the generated intermediate 3 by using common solvents (ethyl acetate, dichloromethane and the like) in the post-treatment, and can effectively avoid the residue of metal ions.
Drawings
FIG. 1 is a reaction scheme of the production process of the present invention.
FIG. 2 preparation of 4- (imidazol-1-yl) phenol obtained in example 1 1 H NMR。
FIG. 3 HPLC of the 4- (imidazol-1-yl) phenol prepared in example 1.
FIG. 4 is a product diagram of 4- (imidazol-1-yl) phenol prepared by different methods, wherein (a) is 4- (imidazol-1-yl) phenol synthesized by one step through Ullmann reaction by using p-bromophenol and imidazole as raw materials in the prior art; (b) is sold in the market; (c) inventive example 1.
Detailed Description
The present invention is further described below with reference to examples, but the embodiments of the present invention are not limited thereto.
Example 1
Step (1): in a reactor, 1kg of p-bromoanisole, 0.5kg of imidazole, 70g of cuprous oxide, 1kg of potassium carbonate and 2LNMP were added and stirred. The reaction temperature is increased to 120 ℃ and the reaction lasts for 12 hours. After the reaction is finished, filtering, leaching with 500mL of ethyl acetate, and removing solids; 2L of 8% aqueous NaOH solution was added, stirring was carried out until a solid was formed, and the solid was removed by filtration. To the liquid, ethyl acetate (3 × 1L) was added for extraction, and the organic phases were combined. Adding saturated saline solution into the organic phase, stirring, separating liquid, drying, removing the solvent by rotation, and recrystallizing by using methyl tert-butyl ether to obtain 500g of 1- (4-methoxyphenyl) -1H-imidazole; the yield is 53 percent;
step (2): in a reactorAdding 1- (4-methoxyphenyl) -1H-imidazole 0.5kg, dissolving in dichloromethane, stirring, cooling to 0 deg.C with ice salt bath, and adding BBr 4.3L1.0M dropwise under the protection of nitrogen 3 Dichloromethane solution. After finishing dropping, the reaction system is naturally heated to 25 ℃ and reacts for 12 h. After the reaction, the reaction solution was slowly added to an ice-water mixture and quenched. Adjusting the alkali with sodium bicarbonate, separating out white solid, filtering, and recrystallizing with tert-butyl alcohol to obtain 350g of 4- (imidazole-1-yl) phenol; the yield is 76 percent, and the purity is 99.8 percent.
As can be seen from fig. 3: the purity of the product prepared by the method is as high as 99.8%.
As can be seen from fig. 4, the 4- (imidazol-1-yl) phenol prepared by the present invention is white, while the 4- (imidazol-1-yl) phenol synthesized by ullmann reaction (prior art) using p-bromophenol and imidazole as raw materials is grayish green, and the commercially available product is pale yellow.
Example 2
Step (1): in the reactor, 1kg of p-bromoanisole, 0.5kg of imidazole, 70g of cuprous oxide, 1kg of cesium carbonate and 2LNMP were added and stirred. The reaction temperature is raised to 120 ℃ and the reaction lasts for 12 h. After the reaction, filtering, adding NaOH aqueous solution, stirring and filtering. Extraction with ethyl acetate and combination of the organic phases. Adding saturated saline solution into the added organic phase, stirring, separating liquid, drying, removing the solvent by rotation, and crystallizing methyl tert-butyl ether to obtain 700g of 1- (4-methoxyphenyl) -1H-imidazole; the yield thereof was found to be 74%.
Step (2) was the same as in example 1.
Example 3
Step (1): in the reactor, 1kg of p-bromoanisole, 0.5kg of imidazole, 70g of cuprous iodide, 1kg of cesium carbonate and 2LDMF were added and stirred. The reaction temperature is increased to 120 ℃ and the reaction lasts for 12 hours. After the reaction, filtering, adding NaOH aqueous solution, stirring and filtering. Extraction with ethyl acetate and combination of the organic phases. Adding saturated saline solution into the added organic phase, stirring, separating liquid, drying, removing solvent by rotation, and crystallizing methyl tert-butyl ether to obtain 450g of 1- (4-methoxyphenyl) -1H-imidazole; the yield thereof was found to be 48%.
Step (2) was the same as in example 1.
Example 4
Step (1): in the reactor, 1kg of p-bromoanisole, 0.5kg of imidazole, 70g of cuprous iodide, 1kg of cesium carbonate and 2LNMP were added and stirred. The reaction temperature is increased to 140 ℃ and the reaction is carried out for 8 h. After the reaction, filtering, adding NaOH aqueous solution, stirring and filtering. Extraction with ethyl acetate and combination of the organic phases. Adding saturated salt solution into the organic phase, stirring, separating liquid, drying, removing solvent, and crystallizing methyl tert-butyl ether to obtain 1- (4-methoxyphenyl) -1H-imidazole;
step (2): adding 0.5kg of 1- (4-methoxyphenyl) -1H-imidazole into a reactor, dissolving in dichloromethane, stirring, cooling the system to-10 ℃ by using a ice salt bath, and dropwise adding 4.3L1.0M BBr under the protection of nitrogen 3 Dichloromethane solution. After finishing dropping, the reaction system is naturally heated to 20 ℃ and reacts for 12 h. After the reaction, the reaction solution was slowly added to an ice-water mixture and quenched. Adjusting the alkali with sodium bicarbonate, separating out white solid, filtering, and recrystallizing with tert-butanol to obtain 4- (imidazole-1-yl) phenol; the purity is 99.9%.
Comparative example 1
Step (1) same as example 1;
step (2): 50g of 1- (4-methoxyphenyl) -1H-imidazole was charged into the reactor, 48% HBr200mL was added thereto, and the mixture was stirred and reacted at 100 ℃ for 6 hours. After the reaction, the reaction solution was slowly added to an ice-water mixture and quenched. Adjusting the alkali of sodium bicarbonate, separating out a solid, and filtering to obtain a pink solid; the solid obtained after recrystallization from tert-butanol was yellowish, 30g of solid was obtained, and the yield was 65%.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (7)
1. A preparation method of 4- (imidazole-1-yl) phenol is characterized in that the route of the preparation method is as follows:
the method comprises the following steps:
(1) takes p-bromoanisole and imidazole as raw materials, and cuprous oxide and alkali Cs are added in a catalyst 2 CO 3 Carrying out Ullmann reaction with a reaction solvent NMP, extracting to obtain an organic phase after the reaction is finished, adding saturated saline solution into the organic phase, stirring, separating, drying, and crystallizing by using methyl tert-butyl ether to obtain 1- (4-methoxyphenyl) -1H-imidazole; wherein, the adding amount of the catalyst is 5-10 mol%; alkali Cs 2 CO 3 Is 1 equivalent; the reaction time is 6-15 h;
(2) demethylating 1- (4-methoxyphenyl) -1H-imidazole by using boron tribromide, and recrystallizing to obtain the 4- (imidazole-1-yl) phenol.
2. The production method according to claim 1, wherein in the step (1), the molar ratio of p-bromoanisole to imidazole is 1: 1 to 1.5.
3. The method according to claim 1, wherein the Ullmann reaction is carried out at a reaction temperature of 110 to 140 ℃.
4. The method according to claim 1, wherein in the step (2), the molar ratio of 1- (4-methoxyphenyl) -1H-imidazole to boron tribromide is 1: 1.5 to 3.
5. The process according to claim 1, wherein in the step (2), the reaction solvent is CH 2 Cl 2 (ii) a The reaction temperature is 20-30 ℃; the reaction time is 6-12 h.
6. The process according to claim 1, wherein in the step (2), 4- (imidazol-1-yl) phenol is obtained as a white solid by recrystallization from t-butanol or ethanol.
7. The preparation method according to any one of claims 1 to 6, wherein the reaction in step (2) is carried out under the protection of inert gases, and the inert gases comprise nitrogen and argon.
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