CN101168542A - Method for preparing 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1-hydro-1,2,4-triazole - Google Patents
Method for preparing 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1-hydro-1,2,4-triazole Download PDFInfo
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- CN101168542A CN101168542A CNA2007101717257A CN200710171725A CN101168542A CN 101168542 A CN101168542 A CN 101168542A CN A2007101717257 A CNA2007101717257 A CN A2007101717257A CN 200710171725 A CN200710171725 A CN 200710171725A CN 101168542 A CN101168542 A CN 101168542A
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Abstract
The invention provides a preparation method for 1-[2-(2,4-difluorophenyl)-2,3-epoxy propyl]-1 hydrogen-1, 2, 4-triazole, and relates to a preparation method for the intermediate of antifungal drug fluconazole. The method is performed in the following two steps: step one, the preparation of oxidant, namely, sulfosalt comprises the steps that dimethyl sulfate, dimethyl sulfide, and organic solvent are added into a reactor, and stirred at 30 to 80 DEG C to react for 2 to 7 hours, thereby obtaining the oxidant, namely, the sulfosalt; step two, raw material, namely, Alpha-(2, 4-difluorophenyl)-Beta-1 hydrogen-1,2,4-triazole acetophenone, the organic solvent, and phase-transfer catalyst are added in the reactor; the oxidant, namely the sulfosalt in step one, and sodium hydroxide water solution with 10 to 50 percent of concentration are stirred to react and obtain the resultant, namely, the 1-[2-(2, 4-difluorophenyl)-2,3-epoxy propyl]-1 hydrogen-1,2,4-triazole. The raw material used by the invention is evenly sold in the market, sources are wide and sufficient, and the price is cheap; the reaction condition of the method is mild, the process is simple, the abuses of high cost, large toxicity, etc. caused by using iodomethane are avoided, and the effectively utilized molar mass is high, thereby the production cost of the intermediate of the fluconazole obtained by the method of the invention is greatly reduced.
Description
Technical field
The present invention relates to a kind of intermediates preparation of fluconazole as antifungal medicine, be specifically related to a kind of preparation 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1 hydrogen-1,2, the method for 4-triazole.
Background technology
1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1 hydrogen-1,2, (structural formula is the formula I of face as follows for the 4-triazole, CAS No.[86386-76-7]) be a kind of key intermediate of antifungal drug fluconazole, fluconazole is the antifungal drug of new generation that is gone on the market by Pfizer Inc. at first, can highly select to suppress the cytochrome P-450 of fungi, makes mycetocyte lose normal sterol, 14 Alpha-Methyl sterols are then accumulated in mycetocyte, play bacteriostatic action.In addition, fluconazole is novel antifungal drug in triazole class, and the broad-spectrum antifungal effect is arranged, and the sterol that can optionally suppress fungi is synthetic.Oral and intravenous injection is to people and various animal fungi infestation, as monilial infection (systemic candidiasis that comprises the humans and animals of the normal or immunocompromised host of immunity), infection by Cryptococcus neoformans (comprising intracranial infection), sugared not plump chlosma, microsporum, trichophyton, Epidermophyton, Blastomyces dermatitidis, posadasis spheriforme (comprising intracranial infection) and histoplasma capsulatum, Fonsecaea pedrosor, Ka Shi branch spore etc. effectively.Studies show that, 50mg of fluconazole, 1 time on the one, took continuously 28, the male blood plasma testosterone concentration or the women of child-bearing age's blood plasma steroid concentrations there is not influence; 0.2～0.4g of fluconazole 1 time on the one, does not make significant difference to the endogenous steroid levels or the thyroliberin effect of healthy male volunteers.Studies show that of drug interaction taken single agent or multi-agent fluconazole 50mg, and the metabolism of quinizine is not all had influence, therefore, is safe, obtained widespread use.
At present, in the main synthetic method of fluconazole, synthetic for intermediate, main methyl-sulphoxide and the iodomethane reaction of adopting, generate the corresponding raw material α of oxygenant oxidation-(2,4 difluorobenzene base)-2,4 difluorobenzene ethyl ketone and obtain target intermediate (English Patent publication number 2099818, U.S. Patent Publication No. 4404216), the shortcoming of this method is that the methyl iodide that will use costs an arm and a leg, toxicity is bigger, and effectively the molar mass of utilizing is little.
Summary of the invention
The objective of the invention is to the deficiency that exists at prior art and a kind of reaction conditions gentleness and technology are provided, equipment is simple and be convenient to operate, raw material sources are extensive and the antifungal drug fluconazole intermediate 1-[2-of harmless environment (2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1 hydrogen-1,2, the preparation method of 4-triazole.
For reaching above-mentioned purpose, we have carried out a series of experiments, have adopted methyl-sulfate and dimethyl thioether to make corresponding oxygenant at last, oxidation raw material α-(2, the 4-difluorophenyl)-2, the 4-difluoro acetophenone obtains the target intermediate, and the method after the improvement has raw material and cheaply is easy to get, the reaction conditions gentleness, and effective molar mass height that utilizes, can reduce the cost of preparation target intermediate greatly, thereby the production cost of fluconazole is significantly reduced, maximum can reduce by 10% cost.
Realize that technical scheme of the present invention is as follows:
A kind of antifungal drug fluconazole intermediate 1-[2-(2,4 difluorobenzene base)-2 with formula (I) expression, the 3-epoxypropyl]-1 hydrogen-1,2, the 4-triazole (CAS No.[86386-76-7]) make according to the following step:
A. oxygenant contains the preparation of sulfosalt: add methyl-sulfate in reactor, dimethyl thioether and organic solvent stir, and temperature of reaction is 30-80 ℃, and the reaction times is 2-7 hour, and the oxygenant that obtains formula (II) expression contains sulfosalt;
B.1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1 hydrogen-1,2, the preparation of 4-triazole: in reactor, add raw material α-(2,4 difluorobenzene base)-β-1 hydrogen-1,2,4-triazole methyl phenyl ketone, organic solvent, phase-transfer catalyst, oxygenant contain sulfosalt (II) and concentration is the aqueous sodium hydroxide solution of 10-50%, and stirring reaction obtains product 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1 hydrogen-1,2, the 4-triazole.
At A of the present invention, the described organic solvent of B step is acetone, or acetonitrile or methylene dichloride, is preferably methylene dichloride.
At the described phase-transfer catalyst of B step of the present invention is quaternary ammonium salt, can be Tetrabutyl amonium bromide, or tetrabutylammonium iodide, or benzyltriethylammoinium chloride, is preferably Tetrabutyl amonium bromide.
One of advantage of the present invention, each step raw materials used all can by commercially available channel obtain and wide material sources, abundance and price relatively cheap.
Advantage of the present invention two, gentleness and technology are simple relatively for reaction conditions, each step reaction is routine operation, has avoided the use methyl iodide to cause the cost height, the bigger drawback of the big grade of toxicity.
Embodiment
How further specify the present invention below by specific embodiment realizes:
Embodiment 1
A, oxygenant contains the preparation of sulfosalt:
Reflux condensing tube is being housed, drying tube, add methyl-sulfate (19ml in the 100ml there-necked flask of permanent inferior dropping funnel and magnetic agitation whipping appts, 0.2mol), drip dimethyl thioether (15ml after methylene dichloride (80ml) stirring and dissolving, 0.2mol), the cooling bath cooling, the dropping process keeps temperature to be no more than 30 degree, after dropwising several minutes, reaction mixture becomes sticky thick, the product oxygenant contains sulfosalt and slowly separates out, continuation stirring reaction 5 hours under 30 ℃ of conditions with the white crystal that obtains, filters, with acetone (each 10ml totally 3 times, be called for short 10ml * 3) washing, vacuum-drying, obtaining the product oxygenant, to contain sulfosalt be white crystal (28.2g), yield 75.0%, m.p.100-104 ℃.
B, 1-[2-(2,4 difluorobenzene base)-2,3-epoxypropyl]-1 hydrogen-1,2, the preparation of 4-triazole:
Reflux condensing tube is being housed, add raw material α-(2 in the 250ml there-necked flask of drying tube and mechanical stirring device, the 4-difluorophenyl)-β-1 hydrogen-1,2,4-triazole methyl phenyl ketone (22.3g, 0.1mol), methylene dichloride (100ml) and Tetrabutyl amonium bromide (0.1g), the back that stirs adds oxygenant and contains sulfosalt (21.7g, 0.115mol) and 50% sodium hydroxide solution (50ml), finish the afterreaction mixture and be warming up to 50 ℃, continue mechanical stirring reaction 24 hours, TLC shows raw material α-(2, the 4-difluorophenyl)-β-1 hydrogen-1,2,4-triazole methyl phenyl ketone disappears, and reaction adds entry (300ml) after finishing, separatory is told organic phase, organic phase is water successively, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1 hydrogen-1,2,4-triazole crude product obtains elaboration (19.4g), yield 81.9% with ethyl alcohol recrystallization.
Embodiment 2
Other steps are identical with embodiment 1, just to contain the preparation method of sulfosalt as follows for the oxygenant of A step: reflux condensing tube is being housed, drying tube, add methyl-sulfate (19ml in the 100ml there-necked flask of permanent inferior dropping funnel and magnetic agitation whipping appts, 0.2mol), drip dimethyl thioether (15ml after acetone (80ml) stirring and dissolving, 0.2mol), the cooling bath cooling, the dropping process keeps temperature to be no more than 30 degree, after dropwising several minutes, reaction mixture becomes sticky thick, the product oxygenant contains sulfosalt and slowly separates out, continuation stirring reaction 5 hours under 30 ℃ of conditions, the white crystal that obtains is filtered, with acetone (10ml * 3) washing, vacuum-drying, obtaining the product oxygenant, to contain sulfosalt be white crystal (26.8g), yield 71.3%.
Embodiment 3
Other steps are identical with embodiment 1, and just to contain the preparation method of sulfosalt as follows for the oxygenant of A step:
Reflux condensing tube is being housed, drying tube, add methyl-sulfate (19ml in the 100ml there-necked flask of permanent inferior dropping funnel and magnetic agitation whipping appts, 0.2mol), drip dimethyl thioether (15ml after methylene dichloride (80ml) stirring and dissolving, 0.2mol), the cooling bath cooling, the dropping process keeps temperature to be no more than 30 degree, after dropwising several minutes, reaction mixture becomes sticky thick, the product oxygenant contains sulfosalt slowly separates out, and continues under 50 ℃ of conditions stirring reaction 5 hours, and the white crystal that obtains is filtered, wash with acetone (10ml * 3), vacuum-drying, obtaining the product oxygenant, to contain sulfosalt be white crystal (25.4g), yield 67.6%.
Embodiment 4
Other steps are identical with embodiment 1, and just to contain the preparation method of sulfosalt as follows for the oxygenant of A step:
Reflux condensing tube is being housed, drying tube, add methyl-sulfate (19ml in the 100ml there-necked flask of permanent inferior dropping funnel and magnetic agitation whipping appts, 0.2mol), drip dimethyl thioether (15ml after methylene dichloride (80ml) stirring and dissolving, 0.2mol), the cooling bath cooling, the dropping process keeps temperature to be no more than 30 degree, after dropwising several minutes, reaction mixture becomes sticky thick, the product oxygenant contains sulfosalt slowly separates out, and continues under 80 ℃ of conditions stirring reaction 5 hours, and the white crystal that obtains is filtered, wash with acetone (10ml * 3), vacuum-drying, obtaining the product oxygenant, to contain sulfosalt be white crystal (25.1g), yield 66.7%.
Embodiment 5
Other steps are identical with embodiment 1, and just to contain the preparation method of sulfosalt as follows for the oxygenant of A step:
Reflux condensing tube is being housed, drying tube, add methyl-sulfate (19ml in the 100ml there-necked flask of permanent inferior dropping funnel and magnetic agitation whipping appts, 0.2mol), drip dimethyl thioether (15ml after methylene dichloride (80ml) stirring and dissolving, 0.2mol), the cooling bath cooling, the dropping process keeps temperature to be no more than 30 degree, after dropwising several minutes, reaction mixture becomes sticky thick, the product oxygenant contains sulfosalt slowly separates out, and continues under 30 ℃ of conditions stirring reaction 2 hours, and the white crystal that obtains is filtered, wash with acetone (10ml * 3), vacuum-drying, obtaining the product oxygenant, to contain sulfosalt be white crystal (24.2g), yield 64.4%.
Embodiment 6
Other steps are identical with embodiment 1, and just to contain the preparation method of sulfosalt as follows for the oxygenant of A step:
Reflux condensing tube is being housed, drying tube, add methyl-sulfate (19ml in the 100ml there-necked flask of permanent inferior dropping funnel and magnetic agitation whipping appts, 0.2mol), drip dimethyl thioether (15ml after methylene dichloride (80ml) stirring and dissolving, 0.2mol), the cooling bath cooling, the dropping process keeps temperature to be no more than 30 degree, after dropwising several minutes, reaction mixture becomes sticky thick, the product oxygenant contains sulfosalt slowly separates out, and continues under 30 ℃ of conditions stirring reaction 7 hours, and the white crystal that obtains is filtered, wash with acetone (10ml * 3), vacuum-drying, obtaining the product oxygenant, to contain sulfosalt be white crystal (28.4g), yield 75.5%.
Embodiment 7
Other steps are identical with embodiment 1, are the 1-[2-(2,4 difluorobenzene base)-2 of B step, the 3-epoxypropyl]-1 hydrogen-1,2, the preparation method of 4-triazole is as follows:
Reflux condensing tube is being housed, add raw material α-(2 in the 250ml there-necked flask of drying tube and mechanical stirring device, the 4-difluorophenyl)-β-1 hydrogen-1,2,4-triazole methyl phenyl ketone (22.3g, 0.1mol), methylene dichloride (100ml) and benzyltriethylammoinium chloride (0.1g), the back that stirs adds oxygenant and contains sulfosalt (21.7g, 0.115mol) and 50% sodium hydroxide solution (50ml), finish the afterreaction mixture and be warming up to 50 ℃, continue mechanical stirring reaction 24 hours, TLC shows raw material α-(2, the 4-difluorophenyl)-β-1 hydrogen-1,2,4-triazole methyl phenyl ketone disappears, and reaction adds entry (300ml) after finishing, separatory is told organic phase, organic phase is water successively, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1 hydrogen-1,2,4-triazole crude product obtains elaboration (18.9g), yield 79.7% with ethyl alcohol recrystallization.
Embodiment 8
Other steps are identical with embodiment 1, are the 1-[2-(2,4 difluorobenzene base)-2 of B step, the 3-epoxypropyl]-1 hydrogen-1,2, the preparation method of 4-triazole is as follows:
Reflux condensing tube is being housed, add raw material α-(2 in the 250ml there-necked flask of drying tube and mechanical stirring device, the 4-difluorophenyl)-β-1 hydrogen-1,2,4-triazole methyl phenyl ketone (22.3g, 0.1mol), acetonitrile (100ml) and Tetrabutyl amonium bromide (0.1g), the back that stirs adds oxygenant and contains sulfosalt (21.7g, 0.115mol) and 50% sodium hydroxide solution (50ml), finish the afterreaction mixture and be warming up to 50 ℃, continue mechanical stirring reaction 24 hours, TLC shows raw material α-(2, the 4-difluorophenyl)-β-1 hydrogen-1,2,4-triazole methyl phenyl ketone disappears, and reaction adds entry (300ml) after finishing, separatory is told organic phase, organic phase is water successively, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1 hydrogen-1,2,4-triazole crude product obtains elaboration (18.4g), yield 77.6% with ethyl alcohol recrystallization.
Embodiment 9
Other steps are identical with embodiment 1, the 1-[2-(2,4 difluorobenzene base)-2 of B step just, 3-epoxypropyl]-1 hydrogen-1,2, be 10% except the concentration of sodium hydroxide solution among the preparation method of 4-triazole, all the other are identical with embodiment 8.Obtain elaboration (16.7g), yield 70.3% with ethyl alcohol recrystallization.
Embodiment 10
Other steps are identical with embodiment 1, are the 1-[2-(2,4 difluorobenzene base)-2 of B step, the 3-epoxypropyl]-1 hydrogen-1,2, the preparation method of 4-triazole is as follows:
Reflux condensing tube is being housed, add raw material α-(2 in the 250ml there-necked flask of drying tube and mechanical stirring device, the 4-difluorophenyl)-β-1 hydrogen-1,2,4-triazole methyl phenyl ketone (22.3g, 0.1mol), acetonitrile (100ml) and Tetrabutyl amonium bromide (0.1g), the back that stirs adds oxygenant and contains sulfosalt (21.7g, 0.115mol) and 10% sodium hydroxide solution (50ml), finish the afterreaction mixture and be warming up to 50 ℃, continue mechanical stirring reaction 24 hours, TLC shows raw material α-(2, the 4-difluorophenyl)-β-1 hydrogen-1,2,4-triazole methyl phenyl ketone disappears, and reaction adds entry (300ml) after finishing, separatory is told organic phase, organic phase is water successively, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1 hydrogen-1,2,4-triazole crude product obtains elaboration (16.4g), yield 69.2% with ethyl alcohol recrystallization.
Embodiment 11
Other steps are identical with embodiment 1, are the 1-[2-(2,4 difluorobenzene base)-2 of B step, the 3-epoxypropyl]-1 hydrogen-1,2, the preparation method of 4-triazole is as follows:
Reflux condensing tube is being housed, add raw material α-(2 in the 250ml there-necked flask of drying tube and mechanical stirring device, the 4-difluorophenyl)-β-1 hydrogen-1,2,4-triazole methyl phenyl ketone (22.3g, 0.1mol), acetonitrile (100ml) and Tetrabutyl amonium bromide (0.1g), the back that stirs adds oxygenant and contains sulfosalt (21.7g, 0.115mol) and 30% sodium hydroxide solution (50ml), finish the afterreaction mixture and be warming up to 50 ℃, continue mechanical stirring reaction 24 hours, TLC shows raw material α-(2, the 4-difluorophenyl)-β-1 hydrogen-1,2,4-triazole methyl phenyl ketone disappears, and reaction adds entry (300ml) after finishing, separatory is told organic phase, organic phase is water successively, saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1 hydrogen-1,2,4-triazole crude product obtains elaboration (17.8g), yield 75.1% with ethyl alcohol recrystallization.
The above is preferred embodiment of the present invention only, is not to be used for limiting scope of the present invention, and is all according to equalization variation and modification that the present invention did, is all claim of the present invention and contains.
Claims (3)
1. a 1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1 hydrogen-1,2, the preparation method of 4-triazole is characterized in that: with the 1-[2-(2,4 difluorobenzene base)-2 of formula (I) expression, 3-epoxypropyl]-1 hydrogen-1,2, the 4-triazole makes according to the following step:
A. oxygenant contains the preparation of sulfosalt
Add methyl-sulfate in reactor, dimethyl thioether and organic solvent stir, and temperature of reaction is 30-80 ℃, and the reaction times is 2-7 hour, and the oxygenant that obtains formula (II) expression contains sulfosalt;
B.1-[2-(2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1 hydrogen-1,2, the preparation of 4-triazole
In reactor, add raw material α-(2, the 4-difluorophenyl)-and β-1 hydrogen-1,2,4-triazole methyl phenyl ketone, organic solvent, phase-transfer catalyst, oxygenant contain sulfosalt (II) and concentration is the aqueous sodium hydroxide solution of 10-50%, and stirring reaction obtains product 1-[2-(2, the 4-difluorophenyl)-2, the 3-epoxypropyl]-1 hydrogen-1,2, the 4-triazole.
2. a kind of 1-[2-according to claim 1 (2,4 difluorobenzene base)-2, the 3-epoxypropyl]-1 hydrogen-1,2, the preparation method of 4-triazole is characterized in that: described organic solvent is acetone, acetonitrile or methylene dichloride.
3. a kind of 1-[2-(2 according to claim 1, the 4-difluorophenyl)-2,3-epoxypropyl]-1 hydrogen-1,2, the preparation method of 4-triazole is characterized in that: the described phase-transfer catalyst of B step is Tetrabutyl amonium bromide, tetrabutylammonium iodide or benzyltriethylammoinium chloride.
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| CNA2007101717257A CN101168542A (en) | 2007-12-04 | 2007-12-04 | Method for preparing 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1-hydro-1,2,4-triazole |
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| CNA2007101717257A CN101168542A (en) | 2007-12-04 | 2007-12-04 | Method for preparing 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1-hydro-1,2,4-triazole |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103059004A (en) * | 2012-12-21 | 2013-04-24 | 泰州职业技术学院 | Method of preparing 1-[Alpha-(2, 4-difluorophenyl)-2, 3-glycidyl]-1H-1, 2, 4-triazole |
| CN103497227A (en) * | 2013-09-13 | 2014-01-08 | 青岛科技大学 | Preparation method for tulathromycin intermediate |
| CN106749202A (en) * | 2016-12-06 | 2017-05-31 | 中节能万润股份有限公司 | A kind of preparation method of Ravuconazole intermediate |
-
2007
- 2007-12-04 CN CNA2007101717257A patent/CN101168542A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103059004A (en) * | 2012-12-21 | 2013-04-24 | 泰州职业技术学院 | Method of preparing 1-[Alpha-(2, 4-difluorophenyl)-2, 3-glycidyl]-1H-1, 2, 4-triazole |
| 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 |
| CN106749202A (en) * | 2016-12-06 | 2017-05-31 | 中节能万润股份有限公司 | A kind of preparation method of Ravuconazole intermediate |
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Open date: 20080430 |