CN103059004A - Method of preparing 1-[Alpha-(2, 4-difluorophenyl)-2, 3-glycidyl]-1H-1, 2, 4-triazole - Google Patents
Method of preparing 1-[Alpha-(2, 4-difluorophenyl)-2, 3-glycidyl]-1H-1, 2, 4-triazole Download PDFInfo
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- CN103059004A CN103059004A CN2012105595349A CN201210559534A CN103059004A CN 103059004 A CN103059004 A CN 103059004A CN 2012105595349 A CN2012105595349 A CN 2012105595349A CN 201210559534 A CN201210559534 A CN 201210559534A CN 103059004 A CN103059004 A CN 103059004A
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- difluorophenyl
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Abstract
The invention discloses a method of preparing 1-[Alpha-(2, 4-difluorophenyl)-2, 3-glycidyl]-1H-1, 2, 4-triazole. Alpha-(1H-1, 2, 4 triazole-1-group)-2, 4-difluoroacetophenone is taken as starting raw materials to react with dimethyl sulphate or dimethyl sulfide under an alkaline condition, and the epoxide 1-[Alpha-(2, 4-difluorophenyl)-2, 3-glycidyl]-1H-1, 2, 4-triazole is generated. The method is simple and high-efficiency in operation, temperate in reaction condition, strong in safety, easy to control, high in yield coefficient and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of 1-[α-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1, the preparation method of 2,4-triazole belongs to medical production technical field.
Background technology
Fluconazole (Fluconazole) is novel triazole antifungal agent, and its chemical structural formula is as follows:
Chemistry α by name-(2,4 difluorobenzene base)-α-(1H-1,2,4-triazol-1-yl methyl) 1H-1,2,4 triazol-1-yl methyl alcohol are white or off-white color crystallization or crystalline powder, odorless or little be with special smelly, bitter.This product is easily molten in methyl alcohol, dissolves in ethanol, and slightly soluble in methylene dichloride, water or acetic acid, fusing point are 137
~141 ℃, the sterol of Antifungi is synthetic strongly and constantly, efficient, low toxicity, has a broad antifungal spectrum, and can see through hemato encephalic barrier, be the choice drug of anti-deep fungal.
The synthetic method of fluconazole generally common are following route:
Wherein produce a kind of 1-[of preparation α-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole needs α-(1H-1,2,4 triazoles-1-yl)-2,4-difluoro acetophenone and Trimethylsulfoxonium Iodide reaction obtain, but Trimethylsulfoxonium Iodide is expensive and consumption is large, so that cost increases.
Summary of the invention
The objective of the invention is for above-mentioned problem, provide a kind of 1-[of preparation α-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2,4-triazole method.
For addressing the above problem, the present invention takes following technical scheme to realize:
A kind of 1-[α-(2,4 difluorobenzene base)-2,3-epoxypropyl of preparing]-1H-1,2,4-triazole method comprises the steps:
With α-(1H-1,2,4 triazoles-1-yl)-and the 2,4 difluorobenzene ethyl ketone is starting raw material, reacts under alkaline condition with methyl-sulfate or dimethyl thioether, generate epoxy compounds 1-[α-(2, the 4-difluorophenyl) 2, the 3-epoxypropyl]-1H-1,2, the 4-triazole, concrete reaction formula is as follows:
The concentration of the aqueous sodium hydroxide solution that uses in the described reaction is 10-50 %.
Use α-(1H-1,2,4 triazoles-1-yl)-2,4 difluorobenzene ethyl ketone in the described reaction: methyl-sulfate consumption mol ratio is 1:1-2.
Using the consumption mol ratio of α-(1H-1,2,4 triazoles-1-yl)-2,4 difluorobenzene ethyl ketone and dimethyl thioether in the described reaction is 1:0.5-3.
The temperature of reaction of described reaction is 0-50 ℃.
The invention has the beneficial effects as follows: methyl-sulfate or dimethyl thioether that the present invention is used are cheap, so that reaction cost reduces greatly.The present invention is simple to operate efficient, and reaction conditions is gentle, and high safety is easy to control, and yield is higher, is suitable for suitability for industrialized production.
Embodiment
Now in conjunction with the embodiments, the present invention is further elaborated.
Embodiment 1 preparation 1-[α-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2,4-triazole:
At the 500ml four-hole boiling flask, stirring is housed, temperature is taken into account reflux condensing tube, adds 51.5 g α-(1H-1 in reaction flask, 2,4 triazoles-1-yl)-and the 2,4 difluorobenzene ethyl ketone, 200 g toluene, heated and stirred to 50 ℃ adds 35% sodium hydroxide 90g, methyl-sulfate ((CH
3)
2SO
4) 50g, dimethyl thioether 30 g, 45-48 ℃ of stirring reaction 2 hours, reaction was finished, and slightly calmly put layering.Toluene layer is washed 3 times with the each 100g of clear water.Underpressure distillation is to 1/3rd of original volume after the toluene layer drying, the methylsulfonic acid that adds dry acetic acid second vinegar 150g and drip 16.6g is dissolved in the acetic acid second vinegar solution of 10ml, heating, being cooled to 0 ℃ of crystallization filtered more than 2 hours, filter cake washs with the acetic acid second vinegar of fresh dried, get 51.5g, fusing point 127-129 ℃ after the wet product drying.
Embodiment 2 preparation 1-[α-(2,4 difluorobenzene bases) 2, the 3-epoxypropyl]-1H-1,2,4-triazole:
At the 500ml four-hole boiling flask, stirring is housed, temperature is taken into account reflux condensing tube, adds 200 g toluene in reaction flask, adds 25% sodium hydroxide 90g, dimethyl thioether (CH
3)
2S 60g at 38-40 ℃ of 60ml toluene solution that stirs and drip 51.5 g α-(1H-1,2,4 triazoles-1-yl)-2,4 difluorobenzene ethyl ketone, reacted 3 hours, and reaction is finished, and slightly cooled down and put layering.Toluene layer is washed 3 times with the each 100g of clear water.Underpressure distillation is to 1/3rd of original volume after the toluene layer drying, the methylsulfonic acid that adds dry acetic acid second vinegar 150g and drip 16.6g is dissolved in the acetic acid second vinegar solution of 10ml, heating, being cooled to 0 ℃ of crystallization filtered more than 2 hours, filter cake washs with the acetic acid second vinegar of fresh dried, get 48.5g, fusing point 127-129 ℃ after the wet product drying.
Embodiment 3 preparation fluconazoles:
In the 500ml there-necked flask, add α-(1H-1,2,4 triazoles-1-yl)-2,4 difluorobenzene ethyl ketone 51.5g(0.23mol), methyl-sulfate ((CH
3)
2SO
4) 50g, dimethyl thioether (CH
3)
2S 30g,, add NaOH 24g(0.60mol) 50% isopropanol water solution 300ml(Virahol: water=1:1), add again 4-amino-1H-1,2,4-triazole 21g(0.25mol) put in the ultrasonic oscillation device with water-bath normal temperature 3-4 h, steaming desolventizes.Add water 100ml, drip 30 % HCl 150ml, ice-water bath to 0 ~ 5 ℃ drip NaNO
218g(0.26mol), insulation 30min drops to sodium dihydric hypophosphite NaH with diazonium salt solution
2PO
2H
2O 36g(0.25mol) in the solution that 15% HCl 60ml is made into, stirring at normal temperature 2 h use Na
2CO
3Pressed powder transfers to neutrality, filters, and chloroform extraction 6 times (100ml * 4,50ml * 2) merges organic layer, soda lye wash, Na
2SO
4Drying, steaming desolventizes, and with the Virahol recrystallization of 1:3, activated carbon decolorizing gets fluconazole 38g, yield 55 %, mp138 ~ 141 ℃.
Claims (5)
1. one kind prepares 1-[α-(2,4 difluorobenzene base)-2,3-epoxypropyl]-1H-1,2,4-triazole method comprises the steps:
With α-(1H-1,2,4 triazoles-1-yl)-and the 2,4 difluorobenzene ethyl ketone is starting raw material, reacts under alkaline condition with methyl-sulfate or dimethyl thioether, generate epoxy compounds 1-[α-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2, the 4-triazole, concrete reaction formula is as follows:
2. preparation 1-[α according to claim 1-(2,4 difluorobenzene base) 2, the 3-epoxypropyl]-1H-1,2,4-triazole method is characterized in that: reaction is carried out in basic solution, and the concentration of the aqueous sodium hydroxide solution that uses is 10-50 %.
3. preparation 1-[α-(2 according to claim 1, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole method is characterized in that: use α-(1H-1,2 in the reaction, 4 triazoles-1-yl)-and the 2,4 difluorobenzene ethyl ketone: methyl-sulfate consumption mol ratio is 1:1-2.
4. preparation 1-[α-(2 according to claim 1, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1H-1,2,4-triazole method is characterized in that: use α-(1H-1,2 in the reaction, 4 triazoles-1-yl)-the consumption mol ratio of 2,4 difluorobenzene ethyl ketone and dimethyl thioether is 1:0.5-3.
5. preparation 1-[α according to claim 1-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1H-1,2,4-triazole method is characterized in that: the temperature of reaction of reaction is 0-50 ℃.
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| CN2012105595349A CN103059004A (en) | 2012-12-21 | 2012-12-21 | Method of preparing 1-[Alpha-(2, 4-difluorophenyl)-2, 3-glycidyl]-1H-1, 2, 4-triazole |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497227A (en) * | 2013-09-13 | 2014-01-08 | 青岛科技大学 | Preparation method for tulathromycin intermediate |
| WO2022030622A1 (en) * | 2020-08-06 | 2022-02-10 | 株式会社クレハ | Method for producing compound |
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| US20080027117A1 (en) * | 2003-08-12 | 2008-01-31 | Korea Reserach Instiitute Of Chemical Technology | Antifungal Azole Derivatives Having a Fluorovinyl Moiety and Process for the Preparation Thereof |
| CN101168542A (en) * | 2007-12-04 | 2008-04-30 | 同济大学 | Method for preparing 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1-hydro-1,2,4-triazole |
| CN101768126A (en) * | 2009-12-10 | 2010-07-07 | 中国人民解放军第二军医大学 | Novel triazole antifungal compound and salt thereof |
| CN102491959A (en) * | 2011-12-19 | 2012-06-13 | 江苏澄扬作物科技有限公司 | Preparation method of oxirane derivative |
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2012
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080027117A1 (en) * | 2003-08-12 | 2008-01-31 | Korea Reserach Instiitute Of Chemical Technology | Antifungal Azole Derivatives Having a Fluorovinyl Moiety and Process for the Preparation Thereof |
| CN101168542A (en) * | 2007-12-04 | 2008-04-30 | 同济大学 | Method for preparing 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1-hydro-1,2,4-triazole |
| CN101768126A (en) * | 2009-12-10 | 2010-07-07 | 中国人民解放军第二军医大学 | Novel triazole antifungal compound and salt thereof |
| CN102491959A (en) * | 2011-12-19 | 2012-06-13 | 江苏澄扬作物科技有限公司 | Preparation method of oxirane derivative |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497227A (en) * | 2013-09-13 | 2014-01-08 | 青岛科技大学 | Preparation method for tulathromycin intermediate |
| CN103497227B (en) * | 2013-09-13 | 2015-09-30 | 青岛科技大学 | A kind of preparation method of tulathromycin intermediate |
| WO2022030622A1 (en) * | 2020-08-06 | 2022-02-10 | 株式会社クレハ | Method for producing compound |
| CN116171273A (en) * | 2020-08-06 | 2023-05-26 | 株式会社吴羽 | Process for producing compound |
| JP7427096B2 (en) | 2020-08-06 | 2024-02-02 | 株式会社クレハ | Method for producing compounds |
| CN116171273B (en) * | 2020-08-06 | 2024-05-14 | 株式会社吴羽 | Process for producing compound |
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Application publication date: 20130424 |