CN104860887A - Synthesis method of 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)-ethanol - Google Patents
Synthesis method of 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)-ethanol Download PDFInfo
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- CN104860887A CN104860887A CN201510268020.1A CN201510268020A CN104860887A CN 104860887 A CN104860887 A CN 104860887A CN 201510268020 A CN201510268020 A CN 201510268020A CN 104860887 A CN104860887 A CN 104860887A
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- 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
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Abstract
The invention discloses a synthesis method of 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)-ethanol. The method comprises steps as follows: DMF (dimethylformamide), imidazole, caustic soda flakes and PEG600 are added to a reaction container, evenly mixed, slowly heated to the temperature of 110-115 DEG C, kept at the temperature for 1 h and then cooled to the temperature of 50-55 DEG C; a DMF solution of 2-chloro-1-(2,4'-dichlorophenyl)-ethanol is dropwise added while stirring, the temperature is controlled to range from 50 DEG C to 55 DEG C while addition and kept for 1 h after addition, the mixture is heated to the temperature of 110-115 DEG C and has a reaction for 4 h, the mixture is cooled to the temperature of 60 DEG C, 200 ml of water is added, and the mixture is continuously cooled to the room temperature; a crude 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)-ethanol product is obtained through centrifugal filtration; the crude product is dried and recrystallized with methylbenzene, and a dry product is obtained. According to the method, used equipment is simple, steps are simplified, the production cost is low, and the method is suitable for industrial production.
Description
Technical field
The present invention relates to organic synthesis field, particularly relate to a kind of synthetic method of imidazolyl ethanol.
Background technology
Imidazolyl ethanol: 1-(2,4 dichloro benzene base)-2-(1-imidazolyl)-ethanol is the important intermediate of nitric acid synthesis miconazole, econazole nitrate, for the intermediate of the imidazoles such as antifungal drug and fruit antistaling agent antifungal drug.
Its synthetic method mainly contains at present: be 1. obtained by reacting imidazolyl ethanol with 2,4 dichloro benzene hexadecyl ethylene oxide and imidazoles in the basic conditions, and the reagent that this reaction uses is many, and the three wastes are many.2. make phase-transfer catalyst with PEG-4000, THF is solvent, and the chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol and imidazoles reaction, prepare imidazolyl ethanol, yield is lower.3. use TBAB catalysis, THF is solvent, and the chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol and imidazoles reaction, prepare imidazolyl ethanol, rapid stirring, need use ice, safety coefficient is low, complicated operation.
Summary of the invention
The object of this invention is to provide a kind of synthetic method of imidazolyl ethanol, use equipment simple, easy to operate, be applicable to industrial production.
In technical solutions according to the invention, use high polar solvent dimethyl formamide (DMF), PEG600 is catalyzer, and the chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol and imidazoles reaction, prepare imidazolyl ethanol.In the chemical reaction of the technical program, reactive behavior increases along with the polarity of solvent and increases, and is on the one hand because the solubleness of substrate, catalyzer and solvent increase the extraction efficiency of ion pair Q+Y-; Be on the other hand based on: the halohydrocarbon with moment of dipole forms dipole-dipole key with solvent in dipole organic solvent, also has this effect between the ion pair Q+Y-that non-nucleophilic anion is combined with catalyst cation and solvent.In theory, at the temperature of 50 DEG C-55 DEG C, be applicable temperature of reaction, but the yield of product is low, is not easy to be separated; In specific experiment operation, grope to find by experiment repeatedly, react 110 DEG C-115 DEG C time, keep certain hour, yield significantly improves, and is easily separated.Contrast by experiment, optimization experiment step, make the yield of reaction the highest.
The object of the invention is to be achieved through the following technical solutions:
DMF, imidazoles, sheet alkali are joined in reaction vessel, is uniformly mixed, slowly heat to 110 DEG C-115 DEG C, be incubated 1 hour, cool to 50 DEG C-55 DEG C afterwards; Drip the DMF solution of 2-chloro-1-(2,4 '-dichlorophenyl)-ethanol, dropping limit, limit is stirred, and during dropping, temperature controls at 50 DEG C-55 DEG C, after dropping terminates, be incubated 1 hour, be warmed up to 110 DEG C-115 DEG C, react after 4 hours, be cooled to 60 DEG C, add water 200ml, continues to be cooled to room temperature; Centrifuging, obtains product 1-(2,4 '-dichlorophenyl)-2-(1-imidazolyl)-ethanol crude product.Crude product is dried, and obtains dry product with re crystallization from toluene.
Synthetic route is as follows:
The advantage of the synthetic method of the present invention's imidazolyl ethanol used:
1, present method prepares imidazolyl ethanol, and the equipment of use is simple, and step simplifies, and is applicable to industrial production.
2, present method uses DMF as solvent, respond and terminate after, can recycling, reduce production cost.
3, present method synthesis imidazolyl ethanol, yield is high, and purity is high.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described:
Embodiment 1
Take the chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol 23g to join in 20mLDMF, be uniformly mixed, the DMF solution of the obtained chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol;
Measure DMF:80mL, imidazoles: 8.2g, sheet alkali: 8g, PEG600:1.8g put in four-hole boiling flask, access agitator, thermometer, condensing reflux pipe, stir, heating, is slowly warmed up to 40 DEG C-45 DEG C insulations 1 hour; Drip the chloro-1-(2 of 2-, 4 '-dichlorophenyl) the DMF solution of-ethanol, dropping limit, limit is stirred, and temperature controls at 50 DEG C-55 DEG C, drips and terminates, be incubated 4 hours, add water 200ml, continues to be cooled to room temperature, centrifuging, obtain product 1-(2,4 '-dichlorophenyl)-2-(1-imidazolyl)-ethanol crude product;
Dried by crude product, be weighed as 102g, with re crystallization from toluene, obtain dry product, be weighed as 94g, yield is 41%, surveys fusing point to be: 132.1-133.4 DEG C.
Embodiment 2
Take the chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol 23g to join in 20mLDMF, be uniformly mixed, the DMF solution of the obtained chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol;
Measure DMF:80mL, imidazoles: 8.2g, sheet alkali: 8g, PEG600:1.8g put in four-hole boiling flask, access agitator, thermometer, condensing reflux pipe, stir, heating, is slowly warmed up to 50 DEG C-55 DEG C insulations 1 hour; Drip the chloro-1-(2 of 2-, 4 '-dichlorophenyl) the DMF solution of-ethanol, dropping limit, limit is stirred, and temperature controls at 50 DEG C-55 DEG C, drips and terminates, be incubated 4 hours, add water 200ml, continues to be cooled to room temperature, centrifuging, obtain product 1-(2,4 '-dichlorophenyl)-2-(1-imidazolyl)-ethanol crude product;
Dried by crude product, be weighed as 111g, with re crystallization from toluene, obtain dry product, be weighed as 103g, yield is 45%, surveys fusing point to be: 131.7-132.6 DEG C.
Embodiment 3
Take the chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol 23g to join in 20mLDMF, be uniformly mixed, the DMF solution of the obtained chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol;
Measure DMF:80mL, imidazoles: 8.2g, sheet alkali: 8g, PEG600:1.8g put in four-hole boiling flask, access agitator, thermometer, condensing reflux pipe, stir, and heating, is slowly warmed up to 90 DEG C-100 DEG C, is incubated 1 hour, cools to 50 DEG C-55 DEG C; Drip the DMF solution of 2-chloro-1-(2,4 '-dichlorophenyl)-ethanol, dropping limit, limit is stirred, temperature controls at 50 DEG C-55 DEG C, drips and terminates, be incubated 1 hour, be warmed up to 90 DEG C-100 DEG C afterwards, keep thermotonus 4 hours, be cooled to 60 DEG C after reaction terminates, add water 200ml, continue to be cooled to room temperature, centrifuging, obtains product 1-(2,4 '-dichlorophenyl)-2-(1-imidazolyl)-ethanol crude product;
Dried by crude product, be weighed as 128g, with re crystallization from toluene, obtain dry product, be weighed as 116g, yield is 51%, surveys fusing point to be: 131.7-133.1 DEG C.
Embodiment 4
Take the chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol 23g to join in 20mLDMF, be uniformly mixed, the DMF solution of the obtained chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol;
Measure DMF:80mL, imidazoles: 8.2g, sheet alkali: 8g, PEG600:1.8g put in four-hole boiling flask, access agitator, thermometer, condensing reflux pipe, stir, and heating, is slowly warmed up to 110 DEG C-115 DEG C, is incubated 1 hour, cools to 50 DEG C-55 DEG C; Drip the DMF solution of 2-chloro-1-(2,4 '-dichlorophenyl)-ethanol, dropping limit, limit is stirred, temperature controls at 50 DEG C-55 DEG C, drips and terminates, be incubated 1 hour, be warmed up to 110 DEG C-115 DEG C afterwards, keep thermotonus 4 hours, be cooled to 60 DEG C after reaction terminates, add water 200ml, continue to be cooled to room temperature, centrifuging, obtains product 1-(2,4 '-dichlorophenyl)-2-(1-imidazolyl)-ethanol crude product;
Dried by crude product, be weighed as 220g, with re crystallization from toluene, obtain dry product, be weighed as 210g, yield is 92%, surveys fusing point to be: 132.5-133.8 DEG C.
Embodiment 5
Take the chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol 23g to join in 20mLDMF, be uniformly mixed, the DMF solution of the obtained chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol;
Measure DMF:80mL, imidazoles: 8.2g, sheet alkali: 8g, PEG600:1.8g put in four-hole boiling flask, access agitator, thermometer, condensing reflux pipe, stir, and heating, is slowly warmed up to 120 DEG C-125 DEG C, is incubated 1 hour, cools to 50 DEG C-55 DEG C; Drip the DMF solution of 2-chloro-1-(2,4 '-dichlorophenyl)-ethanol, dropping limit, limit is stirred, temperature controls at 50 DEG C-55 DEG C, drips and terminates, be incubated 1 hour, be warmed up to 120 DEG C-125 DEG C afterwards, keep thermotonus 4 hours, be cooled to 60 DEG C after reaction terminates, add water 200ml, continue to be cooled to room temperature, centrifuging, obtains product 1-(2,4 '-dichlorophenyl)-2-(1-imidazolyl)-ethanol crude product;
Dried by crude product, be weighed as 216g, with re crystallization from toluene, obtain dry product, be weighed as 205g, yield is 90%, surveys fusing point to be: 131.9-133.4 DEG C.
Claims (5)
1. a synthetic method for imidazolyl ethanol, is characterized in that, described imidazolyl ethanol is by the chloro-1-(2 of 2-, 4 '-dichlorophenyl)-ethanol, imidazoles in DMF solvent, in the presence of a base, use PEG600 make catalyzer, reaction generates, and synthesis step comprises following:
(1) prepare the DMF solution of the chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol, be uniformly mixed;
(2) take DMF, imidazoles, sheet alkali, PEG600 respectively, drop in reaction unit, stir, be slowly warmed up to 110 DEG C-115 DEG C, be incubated 1 hour, cool to 50 DEG C-55 DEG C;
(3) the chloro-1-(2 of 2-is dripped, 4 '-dichlorophenyl) the DMF solution of-ethanol, dropping limit, limit is stirred, and temperature controls at 50 DEG C-55 DEG C, drip and terminate, be incubated 1 hour, be warmed up to 110 DEG C-115 DEG C afterwards, keep thermotonus 4 hours, after reaction terminates, be cooled to 60 DEG C, add water, continue to be cooled to room temperature; Centrifuging, obtains product 1-(2,4 '-dichlorophenyl)-2-(1-imidazolyl)-ethanol crude product;
(4) dried by crude product, re crystallization from toluene, obtains dry product.
2. the synthetic method of imidazolyl ethanol according to claim 1, is characterized in that the chloro-1-of described 2-(2,4 '-dichlorophenyl)-ethanol, the mol ratio of imidazoles is 1:1.2.
3. the synthetic method of imidazolyl ethanol according to claim 1, is characterized in that the mass ratio of the chloro-1-of 2-(2,4 '-dichlorophenyl)-ethanol, DMF in described step (1) is 1:1.
4. the synthetic method of imidazolyl ethanol according to claim 1, is characterized in that the mol ratio of imidazoles, sheet alkali, PEG600 in described step (2) is 1.2:2:0.03.
5. the synthetic method of imidazolyl ethanol according to claim 1, it is characterized in that described DMF is solvent, and the mass ratio of reactant is about 1:2.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109111402A (en) * | 2018-10-30 | 2019-01-01 | 徐州工业职业技术学院 | A kind of preparation method of imidazolyl ethanol |
| CN110683992A (en) * | 2019-11-01 | 2020-01-14 | 徐州工业职业技术学院 | Method for synthesizing econazole nitrate by one-pot method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85107116A (en) * | 1985-09-10 | 1986-09-10 | 上海第二制药厂 | A kind of processing method of producing miconazole nitrate with phase transfer reaction |
-
2015
- 2015-05-22 CN CN201510268020.1A patent/CN104860887A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85107116A (en) * | 1985-09-10 | 1986-09-10 | 上海第二制药厂 | A kind of processing method of producing miconazole nitrate with phase transfer reaction |
Non-Patent Citations (2)
| Title |
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| 王明慧等: "咪康唑和益康唑的PEG-400连续催化N-和O-烷基化反应制备", 《中国医药工业杂志》 * |
| 金万祥等: "相转移催化合成1-(2,4-二氯苯基)-2-(1-咪唑基)-乙醇的研究", 《化学世界》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109111402A (en) * | 2018-10-30 | 2019-01-01 | 徐州工业职业技术学院 | A kind of preparation method of imidazolyl ethanol |
| CN109111402B (en) * | 2018-10-30 | 2021-10-15 | 徐州工业职业技术学院 | Preparation method of imidazole ethanol |
| CN110683992A (en) * | 2019-11-01 | 2020-01-14 | 徐州工业职业技术学院 | Method for synthesizing econazole nitrate by one-pot method |
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Application publication date: 20150826 |