CN104860992A - Preparation method of high-purity fosfluconazole - Google Patents
Preparation method of high-purity fosfluconazole Download PDFInfo
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- CN104860992A CN104860992A CN201410063937.3A CN201410063937A CN104860992A CN 104860992 A CN104860992 A CN 104860992A CN 201410063937 A CN201410063937 A CN 201410063937A CN 104860992 A CN104860992 A CN 104860992A
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Abstract
A fosfluconazole preparation method used in the invention adopts two steps: the first step comprises a reaction of fluconazole and phosphorus trichloride, wherein reaction conditions are mild and easy to control, and the yield is high; and the second step comprises oxidization of fluconazole phosphite with a strong oxidant, wherein the reaction time is short, the post-treatment is simple, and the method is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of high purity good fortune department fluconazole preparation method, this kind of simple and practical yield of preparation method is high, and impurity is especially applicable to suitability for industrialized production less.
Background technology
Fluconazole is a kind of triazole antifungal drug, and the clinical treatment deep that is mainly used in is due to candidiasis, cryptococcus and other opportunistic yeast or fungus-caused infection.
The antifungal drug of new generation of Pfizer Inc.'s listing, fluoro triazole species broad-spectrum antifungal medicine, antimicrobial spectrum is similar with KETOKONAZOL, long-acting, effective to deep infection fungi medicine, and antifungic action is strong, and oral absorption is good.Be mainly used in white containing ball, beads coccus disease and torulosis, also effective to the oropharynx monilial infection of cancer patients; Its mechanism of action is Antifungi cytolemma neccessary composition ergosterol synthetic enzyme, makes ergosterol biosynthesis block, destroys the integrity of fungal cell, thus affects growth, the breeding of fungi.Extremely strong anti-microbial effect is had to fungies such as Candida albicans, trichophyton mentagrophytes, the little leopard bacterium of dog, acrothesium floccosum, mouse coccidioides immitis, Histoplasma capsulatum, Cryptococcus neoformans, aspergillus fumigatuses.
Good fortune department fluconazole is the prodrug of fluconazole, and good fortune department fluconazole in vivo energy metabolism is that fluconazole plays drug action, and it is water-soluble is better than fluconazole, equal dosage, and good fortune department fluconazole only needs very small volume, thus reduces volume load.
Summary of the invention
The object of the present invention is to provide one to prepare high purity good fortune department fluconazole method, this kind of simple and practical yield of preparation method is high, and impurity is especially applicable to suitability for industrialized production less.
Another object of the present invention provides a kind of midbody compound (I) preparing good fortune department fluconazole, and structural formula is as follows:
(Ⅰ)
A kind of method preparing good fortune department fluconazole of the present invention is implemented as follows:
1, fluconazole is added in methylene dichloride under acid binding agent exists again and react with phosphorus trichloride;
2, after the first step reaction terminates, water is slowly joined in reactions steps 1 reaction that is hydrolyzed, the midbody compound (I) of preparation good fortune department fluconazole;
3, midbody compound (I) and alkali are joined at the aqueous solution, stir clearly molten, slowly adding oxidant reaction;
4, after three-step reaction terminates, filtering reacting liquid, regulates reaction solution pH1 ~ 2 by pH adjusting agent, and-10 DEG C ~ 10 DEG C are stirred 4 hours, filter, get Fu Si fluconazole crude product.
Concrete reaction equation is as follows:
Temperature of reaction wherein described in step 1-10 DEG C ~ 30 DEG C; Described acid binding agent is 1-Methylimidazole, 1H-TETRAZOLE, pyridine, 4-dimethylaminopyridine, triethylamine, quadrol, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium acetate, its consumption is 1 ~ 5 times amount of fluconazole molar weight, preferably 4 times amount.
The temperature of the hydrolysis described in step 2 is-20 DEG C ~ 20 DEG C.
Alkali described in step 3 is triethylamine, quadrol, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium acetate, and its consumption is 1 ~ 4 times amount of fluconazole phosphorous acid ester molar weight, preferably 2 times amount.Oxygenant is permanganic acid or its salt, perchloric acid or its salt, ferric acid or its salt, high sulfuric acid or its salt; Its consumption is 1 ~ 2 times amount of fluconazole phosphorous acid ester molar weight, preferably 1 times amount.Oxidizing reaction temperature is 0 DEG C ~ 20 DEG C.
PH adjusting agent described in step 4 is hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid.
The midbody compound (I) that the preparation good fortune department fluconazole that the present invention relates to is new also comprises hydrate and the anhydrate of this compound.
Preparation method of the present invention has following advantage compared with the prior art:
The present invention and prior art are prepared good fortune department fluconazole and are compared, and prior art synthesis good fortune department fluconazole step is complicated, and the reaction times is longer, and use high-pressure hydrogenation still, this safety coefficient after industrial production reduces, and uses precious metal palladium, add production cost in the step of hydrogenation; And the good fortune department fluconazole preparation method that my company invents is simple, only used two steps, just target product can be obtained, and the gentle practical yield of reaction conditions is high, reaction times is short, and under environmental pollution, the good fortune department fluconazole purity obtained is high, do not use high-pressure hydrogenation still and palladium charcoal, be especially applicable to suitability for industrialized production.
Below in conjunction with embodiment, the present invention is described in further detail, but the non-scope being only limitted to these embodiments of scope of the present invention should be understood.
Embodiment 1: the preparation of good fortune department fluconazole
Get fluconazole 10g and 10.7g1-Methylimidazole is dissolved in 100ml methylene dichloride, phosphorus trichloride solution 5.4g is slowly dripped under 0 DEG C of condition, drip and finish, 20 DEG C of stirring reactions 1 hour, are cooled to 0 DEG C, slowly add 6ml water, stir hydrolysis reaction 30 minutes, removing water layer, dichloromethane layer decompression steams solvent, resistates is fluconazole phosphorous acid ester, obtains fluconazole phosphorous acid ester 9g.Get 9g fluconazole phosphorous acid ester and sodium carbonate 2.6g is dissolved in 18ml water, put into ice bath and stir, slowly add potassium permanganate 4g, 15 DEG C of stirring reactions 2 hours, filter, about the pH to 2 with hydrochloric acid conditioning solution, stir, have a large amount of solid to separate out, filter the solid of separating out and obtain good fortune department fluconazole 7.2g.
Embodiment 2: the preparation of good fortune fluconazole
Get fluconazole 200g and 161g1-Methylimidazole is dissolved in 1800ml methylene dichloride, phosphorus trichloride solution 135g is slowly dripped under 5 DEG C of conditions, drip and finish, 10 DEG C of stirring reactions 1 hour, are cooled to-5 DEG C, slowly add 235ml water, stir hydrolysis reaction 50 minutes, removing water layer, dichloromethane layer decompression steams solvent, resistates is fluconazole phosphorous acid ester, obtains fluconazole phosphorous acid ester 195g.Get 195g fluconazole phosphorous acid ester and sodium bicarbonate 44g is dissolved in 600ml water,-5 DEG C of stirrings, slowly add potassium permanganate 125g, 10 DEG C of stirring reactions 2 hours, filter, about the pH to 2 with hydrochloric acid conditioning solution, 0 DEG C is stirred 4 hours, there is a large amount of solid to separate out, filter the solid of separating out and obtain good fortune department fluconazole 136g.
Embodiment 3: the preparation of good fortune department fluconazole
Get fluconazole 50g and 33g triethylamine is dissolved in 1500ml methylene dichloride, phosphorus trichloride solution 25g is slowly dripped under 10 DEG C of conditions, drip and finish, 20 DEG C of stirring reactions 1 hour, are cooled to 10 DEG C, slowly add 25ml water, stir hydrolysis reaction 30 minutes, removing water layer, dichloromethane layer decompression steams solvent, resistates is fluconazole phosphorous acid ester, obtains fluconazole phosphorous acid ester 40g.Get 40g fluconazole phosphorous acid ester and diethylamine 31g is dissolved in 400ml water,-10 DEG C of stirrings, slowly add potassium permanganate 34g, 0 DEG C of stirring reaction 2 hours, filter, about the pH to 2 with acetic acid regulator solution ,-10 DEG C are stirred 4 hours, there is a large amount of solid to separate out, filter the solid of separating out and obtain good fortune department fluconazole 21g.
Embodiment 4: the preparation of good fortune department fluconazole
Get fluconazole 100g and 70g sodium bicarbonate is dissolved in 500ml methylene dichloride, phosphorus trichloride solution 55g is slowly dripped under 20 DEG C of conditions, drip and finish, 20 DEG C of stirring reactions 1 hour, are cooled to 10 DEG C, slowly add 100ml water, stir hydrolysis reaction 30 minutes, removing water layer, dichloromethane layer decompression steams solvent, resistates is fluconazole phosphorous acid ester, obtains fluconazole phosphorous acid ester 91g.Get 91g fluconazole phosphorous acid ester and salt of wormwood 50g is dissolved in 100ml water,-10 DEG C of stirrings, slowly add potassium permanganate 70g, 0 DEG C of stirring reaction 2 hours, filter, about the pH to 2 with phosphoric acid regulator solution ,-10 DEG C are stirred 4 hours, there is a large amount of solid to separate out, filter the solid of separating out and obtain good fortune department fluconazole 88g.
Embodiment 5: the preparation of good fortune department fluconazole
Get fluconazole 100g and 40g pyridinium dissolution in 400ml methylene dichloride, phosphorus trichloride solution 60g is slowly dripped under-5 DEG C of conditions, drip and finish, 0 DEG C of stirring reaction 1 hour, is cooled to 10 DEG C, slowly add 40ml water, stir hydrolysis reaction 20 minutes, removing water layer, dichloromethane layer decompression steams solvent, resistates is fluconazole phosphorous acid ester, obtains fluconazole phosphorous acid ester 88g.Get 88g fluconazole phosphorous acid ester and sodium acetate 60g is dissolved in 200ml water,-10 DEG C of stirrings, slowly add potassium permanganate 70g, 0 DEG C of stirring reaction 2 hours, filter, about the pH to 2 with hydrochloric acid conditioning solution ,-10 DEG C are stirred 4 hours, there is a large amount of solid to separate out, filter the solid of separating out and obtain good fortune department fluconazole 73g.
Embodiment 6: the preparation of good fortune department fluconazole
Get fluconazole 500g and 400g1-Methylimidazole is dissolved in 2500ml methylene dichloride, phosphorus trichloride solution 290g is slowly dripped under 0 DEG C of condition, drip and finish, 20 DEG C of stirring reactions 1 hour, are cooled to 10 DEG C, slowly add 25ml water, stir hydrolysis reaction 30 minutes, removing water layer, dichloromethane layer decompression steams solvent, resistates is fluconazole phosphorous acid ester, obtains fluconazole phosphorous acid ester 486g.Get 486g fluconazole phosphorous acid ester and sodium hydroxide 50g is dissolved in 500ml water,-10 DEG C of stirrings, slowly add potassium permanganate 311g, 0 DEG C of stirring reaction 2 hours, filter, about the pH to 2 with sulfuric acid regulation solution, 0 DEG C is stirred 4 hours, there is a large amount of solid to separate out, filter the solid of separating out and obtain good fortune department fluconazole 410g.
Embodiment 7: the preparation of fluconazole phosphorous acid ester hydrate
Get the isopropanol water solution of 90% of fluconazole phosphorous acid ester 10g 5 times amount, stir 30 minutes under 50 DEG C of conditions, filter, filtrate room temperature crystallization 24 hours, filters to obtain fluconazole phosphorous acid ester hydrate.
Embodiment 8: the preparation of fluconazole phosphorous acid ester hydrate
Get the isopropanol water solution of 90% of fluconazole phosphorous acid ester 100g 8 times amount, stir 15 minutes under 50 DEG C of conditions, filter, filtrate room temperature crystallization 24 hours, filters to obtain fluconazole phosphorous acid ester hydrate.
Embodiment 9: the preparation of fluconazole phosphorous acid ester hydrate
Get the isopropanol water solution of 90% of fluconazole phosphorous acid ester 100g 4 times amount, stir 20 minutes under 60 DEG C of conditions, filter, filtrate room temperature crystallization 24 hours, filters to obtain fluconazole phosphorous acid ester hydrate.
Embodiment 10: the preparation of fluconazole phosphorous acid ester anhydrate
Get the Virahol of fluconazole phosphorous acid ester 100g 10 times amount, stir 40 minutes under 60 DEG C of conditions, filter, filtrate room temperature crystallization 24 hours, filters to obtain fluconazole phosphorous acid ester anhydrate.
Embodiment 11: the preparation of fluconazole phosphorous acid ester anhydrate
Get the Virahol of fluconazole phosphorous acid ester 100g 15 times amount, stir 30 minutes under 50 DEG C of conditions, filter, filtrate room temperature crystallization 24 hours, filters to obtain fluconazole phosphorous acid ester anhydrate.
Embodiment 12: the preparation of fluconazole phosphorous acid ester anhydrate
Get the acetone of fluconazole phosphorous acid ester 100g 10 times amount, stir 60 minutes under 40 DEG C of conditions, filter, filtrate room temperature crystallization 24 hours, filters to obtain fluconazole phosphorous acid ester anhydrate.
Embodiment 13: the preparation of fluconazole phosphorous acid ester anhydrate
Get the acetone of fluconazole phosphorous acid ester 100g 12 times amount, stir 50 minutes under 50 DEG C of conditions, filter, filtrate room temperature crystallization 24 hours, filters to obtain fluconazole phosphorous acid ester anhydrate.
Embodiment 14: pharmacology pharmacodynamic is tested
1, monilial infection in rat body
All use in all experiments not containing the rat (body weight is 200-300g) of specific pathogen.Conduit is inserted in the left jugular vein of the animal of venous perfusion process to be subjected, vein is combined, and connect the conductive pipe on trace control filling pump.By animal via by the lateral vein of penis or via the conduit implanted, infect with candidiasis (4,000CFU/g body weight).In latter 1 hour of infection, carry out intravenous therapy (5mg/kg/ days).To often organizing laboratory animal (often organizing laboratory animal number to be shown in " N " hurdle), be recorded in the interior mean survival time of each number of days (MST), and percentage survival (%surv).Each group is survived but the animal be killed afterwards in the animal of duration of test death and in test, in research its deep tissues of counting (liver,spleen,kidney, lung are in brain), candidiasis quantity.Measure the CFU/g of remnants in culture positive hepatic, and after being shown in the process of table 1(intravenously), represent with average log10CFU/g." %neg " in table 1 is the deep tissues percentage of culture-feminine gender after being shown in process.Therefore, in " MST ", " %surv " and " %neg " each hurdle of more effective test compound, there is high value, and in " CFU/g " hurdle, there is low value.
Table 1
Known by data, good fortune department fluconazole and fluconazole phosphorous acid ester all have the ability of stronger anti-fungal infection.
Claims (11)
1. the preparation method of good fortune department fluconazole is as described below:
Get fluconazole and acid binding agent is dissolved in methylene dichloride, slowly phosphorus trichloride solution is dripped at-10 DEG C ~ 30 DEG C, drip and finish, stirring reaction 1 hour, be cooled to 20 DEG C ~-20 DEG C again, slowly drip water,-20 DEG C ~ 20 DEG C are stirred hydrolysis reaction 5 ~ 120 minutes, removing water layer, organic layer decompression steams solvent, resistates is fluconazole phosphorous acid ester, then by fluconazole phosphorous acid ester and alkali dissolution in water,-20 DEG C ~ 20 DEG C stirrings, slowly add oxygenant, add rear 0 DEG C ~ 40 DEG C stirring reactions 2 hours, filter, regulate pH to 1 ~ 2 of reaction solution with acid about,-10 DEG C ~ 10 DEG C are stirred 4 hours, a large amount of solid is had to separate out, filter the solid of separating out and obtain good fortune department fluconazole.
2. fluconazole phosphorous acid ester according to claim 1, its structural formula is as follows:
。
3. the fluconazole phosphorous acid ester according to claim 1,2, it comprises fluconazole phosphorous acid ester anhydrate, fluconazole phosphorous acid ester 0.5 ~ 7 hydrate.
4. acid binding agent according to claim 1, comprises 1-Methylimidazole, 1H-TETRAZOLE, pyridine, 4-dimethylaminopyridine, triethylamine, quadrol, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium acetate; It is characterized in that weak base amount used is 1 ~ 5 times amount of fluconazole molar weight, preferably 4 times amount.
5. methylene dichloride according to claim 1, is characterized in that amount used is 1 to 30 times amount of fluconazole (w/v), preferably 10 times amount.
6. phosphorus trichloride according to claim 1, is characterized in that amount used is 1 ~ 1.5 times of fluconazole mol ratio, preferably 1.2 times.
7. the water that hydrolysis according to claim 1 is used, is characterized in that amount used is 2 ~ 50 times of fluconazole mol ratio, preferably 10 times.
8. alkali according to claim 1, comprises triethylamine, quadrol, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium acetate; It is characterized in that alkali amount used is 1 ~ 4 times amount of fluconazole phosphorous acid ester molar weight, preferably 2 times amount.
9. be oxidized water used according to claim 1, it is characterized in that amount used is 1 ~ 10 times of fluconazole phosphorous acid ester (w/v).
10. oxygenant according to claim 1, comprises permanganic acid or its salt, perchloric acid or its salt, ferric acid or its salt, high sulfuric acid or its salt; It is characterized in that oxygenant amount used is 1 ~ 2 times amount of fluconazole phosphorous acid ester molar weight, preferably 1 times amount.
11. acid according to claim 1, it comprises hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237569A (en) * | 2015-10-21 | 2016-01-13 | 西南科技大学 | Synthesizing method for preparing 2,4-difluoro-alpha, alpha-bi(1hydrogen-1,2,4-triazole-1-methyl) benzyl alcohol dibenzyl phosphate |
| CN106496270A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of high-purity good fortune department fluconazole preparation method |
| CN106546668A (en) * | 2015-09-22 | 2017-03-29 | 陕西合成药业股份有限公司 | A kind of HPLC methods for separating good fortune department's fluconazole or its pharmaceutical salts about material |
| CN111171075A (en) * | 2020-04-03 | 2020-05-19 | 北京四环生物制药有限公司 | Preparation method of fosfluconazole |
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| CN1210540A (en) * | 1996-02-02 | 1999-03-10 | 辉瑞研究开发公司 | Triazole derivatives useful in therapy |
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| CN1210540A (en) * | 1996-02-02 | 1999-03-10 | 辉瑞研究开发公司 | Triazole derivatives useful in therapy |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106546668A (en) * | 2015-09-22 | 2017-03-29 | 陕西合成药业股份有限公司 | A kind of HPLC methods for separating good fortune department's fluconazole or its pharmaceutical salts about material |
| CN105237569A (en) * | 2015-10-21 | 2016-01-13 | 西南科技大学 | Synthesizing method for preparing 2,4-difluoro-alpha, alpha-bi(1hydrogen-1,2,4-triazole-1-methyl) benzyl alcohol dibenzyl phosphate |
| CN106496270A (en) * | 2016-08-31 | 2017-03-15 | 安徽省润生医药股份有限公司 | A kind of high-purity good fortune department fluconazole preparation method |
| CN111171075A (en) * | 2020-04-03 | 2020-05-19 | 北京四环生物制药有限公司 | Preparation method of fosfluconazole |
| CN111171075B (en) * | 2020-04-03 | 2022-07-12 | 北京四环生物制药有限公司 | Preparation method of fosfluconazole |
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Application publication date: 20150826 |