CN101891693B - New method for preparing fluconazole - Google Patents
New method for preparing fluconazole Download PDFInfo
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- CN101891693B CN101891693B CN 201010246142 CN201010246142A CN101891693B CN 101891693 B CN101891693 B CN 101891693B CN 201010246142 CN201010246142 CN 201010246142 CN 201010246142 A CN201010246142 A CN 201010246142A CN 101891693 B CN101891693 B CN 101891693B
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- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 229960004884 fluconazole Drugs 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- -1 2,4-difluorobromobenzene Grignard reagent Chemical class 0.000 claims abstract description 22
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 11
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims abstract description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 54
- 238000003756 stirring Methods 0.000 claims description 42
- 238000010792 warming Methods 0.000 claims description 35
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 30
- HBAZRGCNSUQWNN-UHFFFAOYSA-N 1-(1,2,4-triazol-1-yl)propan-2-one Chemical compound CC(=O)CN1C=NC=N1 HBAZRGCNSUQWNN-UHFFFAOYSA-N 0.000 claims description 29
- 239000000706 filtrate Substances 0.000 claims description 29
- 239000012043 crude product Substances 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 18
- 235000011152 sodium sulphate Nutrition 0.000 claims description 18
- OLGLPMIHSCHZMK-UHFFFAOYSA-N BrC1(C(C(=O)O)C=CC(=C1C(=O)O)C)Br Chemical compound BrC1(C(C(=O)O)C=CC(=C1C(=O)O)C)Br OLGLPMIHSCHZMK-UHFFFAOYSA-N 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 14
- 239000012044 organic layer Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000002608 ionic liquid Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000001953 recrystallisation Methods 0.000 claims description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 238000004821 distillation Methods 0.000 claims description 10
- 239000011777 magnesium Substances 0.000 claims description 10
- 229910052749 magnesium Inorganic materials 0.000 claims description 10
- 230000001105 regulatory effect Effects 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- 239000011630 iodine Substances 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 238000013019 agitation Methods 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- JHLKSIOJYMGSMB-UHFFFAOYSA-N 1-bromo-3,5-difluorobenzene Chemical compound FC1=CC(F)=CC(Br)=C1 JHLKSIOJYMGSMB-UHFFFAOYSA-N 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 238000009835 boiling Methods 0.000 claims description 5
- 239000000284 extract Substances 0.000 claims description 5
- 230000000977 initiatory effect Effects 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 5
- 230000000843 anti-fungal effect Effects 0.000 abstract description 2
- 229940121375 antifungal agent Drugs 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract 2
- LQQKDSXCDXHLLF-UHFFFAOYSA-N 1,3-dibromopropan-2-one Chemical compound BrCC(=O)CBr LQQKDSXCDXHLLF-UHFFFAOYSA-N 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 7
- 238000012423 maintenance Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 3
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a new method for preparing fluconazole and relates to a method for preparing the fluconazole which is a broad-spectrum antifungal medicament. The method comprises the following steps of: firstly, performing the ketal reaction of 1,3-dibromoacetone serving as a raw material and ethanediol, performing the substitution reaction of the product of the ketal reaction and 1H-1,2,4-triazole; secondly, performing a hydrolysis reaction under the strong acid condition; and finally, reacting the product of the hydrolysis reaction with a prepared 2,4-difluorobromobenzene Grignard reagent to obtain the fluconazole. In the invention, a novel synthesis route is provided, reaction conditions of all steps are easy to operate, the process is simple, the reactions of all steps are regularly operated, so that the high-priced raw materials are avoided and the product cost is reduced.
Description
Technical field
The present invention relates to the more widely preparation method of spectrum antifungal drug of a kind of application, be specifically related to a kind of method for preparing fluconazole.
Background technology
In the development of modern medicine and chemistry, antifungal drug synthetic obtains people always and pays close attention to widely, fluconazole is the kind that occurs in this class medicine early, this product has obtained widely clinical application, effect has obtained doctors and patients' generally approval, therefore further improve its production technique, reduce the emphasis that cost becomes this area research.
In known references, the method for synthetic fluconazole mainly contains two kinds, a kind of as document (" new preparation of fluconazole research ", the Chinese Journal of Modern Applied Pharmacy magazine, the 1st phase of the 23rd volume February in 2006,35-37), patent (CN1861582; CN1699351) described in, for by m-difluorobenzene as raw material, successively with chloroacetyl chloride and 1H-1,2, after the reaction of 4-triazole, form epoxy compounds with trimethylammonium iodate sulfone or Trimethylsulfoxonium Iodide reaction again, generate product by open loop at last, the method is used commonplace now, but wherein need to use trimethylammonium iodate sulfone or Trimethylsulfoxonium Iodide, this expensive raw material price, and this step yield is not very high, directly causes the production cost of the finished product fluconazole to be difficult to reduce.
Another kind of such as document (" synthesizing of fluconazole ", West China pharmaceutical journal, the 3rd phase of the 20th volume in 2005,241-242; " synthetic method of fluconazole and analogue thereof is improved ", Chinese Journal of Pharmaceuticals, the 4th phase of the 21st volume nineteen ninety, mention 152-153), adopt m-difluorobenzene as raw material, direct with 1 by grignard reaction, after the 3-Dichloro acetone reaction again with 1H-1,2,4-triazole reaction preparation product, it is lower that the method respectively goes on foot yield, and with the reaction process of 1,3-DCA in poor selectivity, by product is more, separation difficulty, yield are very low, so this method does not have industrial prospect.
After having consulted a large amount of pertinent literatures both at home and abroad and patent, we have designed a synthetic route synthesising target compound fluconazole that has independent intellectual property right, novel method adopts good reaction selectivity and the facile various raw materials of domestic appearance, each goes on foot the reaction conditions gentleness, technique is simple, and used the new catalyst ionic liquid, improve yield and the selectivity of reaction, simplified last handling process.And each step reaction is routine operation, has effectively avoided adopting expensive raw material, has reduced the cost of product.
Summary of the invention
The object of the present invention is to provide that a kind of equipment is simple, reaction conditions is gentle, the application of convenient operation and the harmless environment new preparation process of spectrum fluconazole as antifungal medicine more widely.
For reaching above-mentioned purpose, we have carried out series of experiments, have proposed a brand-new synthetic route.
Realize that technical scheme of the present invention is as follows:
A kind of preparation method of fluconazole is characterized in that: the fluconazole that represents with formula I obtains in accordance with the following steps:
(Ⅳ) (Ⅰ)
A.2,2-dibromo methyl isophthalic acid, the preparation of 3-dioxolane (II)
In reactor, add 1,1 times of 3-dibromoacetone, toluene 4-8 is (weight ratio) doubly, ethylene glycol 0.31-0.38 is (weight ratio) and catalyzer p-methyl benzenesulfonic acid 0.01-0.03 times (weight ratio) doubly, is warming up to 100 ℃ of stirring reactions, then reflux water-dividing under this temperature, until distillate is clear liquid, about 6 hours, then be cooled to room temperature, remove by filter insolubles, filtrate is warming up to 120 ℃ of distillations and removes toluene, the resistates that obtains is 2,2-dibromo methyl isophthalic acid, 3-dioxolane crude product, 121-124 ℃/10mmHg cut is collected in underpressure distillation, namely 2,2-dibromo methyl isophthalic acid, 3-dioxolane (II).
B.1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1, the preparation of 3-dioxolane (III)
In reactor, add methylene dichloride 3-6 doubly (weight ratio), under agitation condition, add 1H-1,2,4-triazole 0.53-0.59 is (weight ratio) doubly, ionic liquid 0.1 times (weight ratio) and yellow soda ash 0.81-0.90 are doubly or salt of wormwood 1.06-1.17 doubly (weight ratio), stirring at room 1 hour, then drip 2,2-dibromo methyl isophthalic acid, 1 times of 3-dioxolane (II), reaction mixture constantly stirs in the dropping process, be warming up to 35 ℃ after dropwising and continued stirring reaction 10-20 hour, then be cooled to room temperature, remove by filter insolubles, organic layer is used anhydrous sodium sulfate drying after using the saturated common salt water washing, after removing by filter the siccative anhydrous sodium sulphate, filtrate is warming up to 50 ℃ of desolventizings, and the resistates that obtains is 1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1,3-dioxolane (III) crude product, this step product do not need to be further purified and can be directly used in next step reaction.The ionic liquid that relates in this step refers to 3-methyl isophthalic acid-ethyl imidazol(e) hydrosulfate, a kind of in the middle of 1,3-diethyl imidazole bisulfate and the 3-butyl-1-ethyl imidazol(e) hydrosulfate.
C.1, the preparation of 3-two (1H-1,2,4-triazole-1-yl) acetone (IV)
In reactor, add 1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1,1 times of 3-dioxolane (III), concentration be 20% or concentration be 25% hydrochloric acid soln 4-6 doubly (weight ratio), post-heating to 100 ℃ reaction 24-36 hour that stirs, reaction finishes the afterreaction mixture and is cooled to room temperature, remove by filter insolubles, filtrate is regulated pH to 12 with 5% aqueous sodium hydroxide solution, and then mixed solution is used anhydrous sodium sulfate drying with 5 times of (weight ratio) extractions of methylene dichloride 2 times behind the merging organic layer, after removing by filter the siccative anhydrous sodium sulphate, filtrate is warming up to 50 ℃ of desolventizings, obtains 1,3-, two (1H-1,2,4-triazole-1-yl) acetone (IV) crude product obtains elaboration 1,3-two (1H-1 behind 3 times of (weight ratio) recrystallizations of ethanol, 2,4-triazole-1-yl) acetone (IV).
D. the preparation of fluconazole (I)
In reactor, add 3,5-difluoro bromobenzene 1.10-1.21 is (weight ratio) doubly, anhydrous tetrahydro furan 3-4 is (weight ratio) doubly, magnesium chips 0.13-0.15 is (weight ratio) and 0.05 times of iodine (weight ratio) doubly, is heated to backflow, and (iodine color fade) regulated heating unit and made mixture maintenance slight boiling condition after the initiation reaction, until the magnesium chips primitive reaction is complete, about 4 hours, prepare 3,5-difluoro bromobenzene grignard reagent is stand-by.
In another reactor, add 1,3-two (1H-1,2,4-triazole-1-yl) acetone (IV) is 1 times, anhydrous tetrahydro furan 2-3 is (weight ratio) doubly, the rear dropping that stirs is above-mentioned prepare 3,5-difluoro bromobenzene grignard reagent, the dropping process keeps mixture temperature to be no more than 50 ℃, dropwise rear continuation stirring at room reaction 8-10 hour, reaction finishes, and adds saturated aqueous ammonium chloride cancellation reaction, separatory, water extracts 2 times with ethyl acetate 3 times (weight ratios), merge organic phase, the rear anhydrous sodium sulfate drying of using, remove by filter the siccative anhydrous sodium sulphate after, filtrate is warming up to 80 ℃ of desolventizings, obtain fluconazole (I) crude product, crude product obtains elaboration fluconazole (I) with 3 times of (weight ratio) recrystallizations of isopropanol water solution of 75%.
Advantage of the present invention has:
1, the used route of the present invention has avoided using expensive trimethylammonium iodate sulfone or the Trimethylsulfoxonium Iodide in the traditional technology, employing respectively to go on foot the raw material reaction selectivity better, domestic have a large amount of supplies, and moderate, can effectively reduce the production cost of the finished product.
2, second step of the present invention adopts ionic liquid to replace traditional phase-transfer catalyst, has not only simplified operating process and Reaction time shorten, and has obtained preferably reaction result.Also widened simultaneously the range of application of ionic liquid.
3, reaction conditions of the present invention is temperature relatively, and each step reaction is conventional operation, obtains product through four-step reaction, is easy to control, need not complicated and special equipment.
How further specify the present invention below by specific embodiment realizes:
Embodiment 1
A.2,2-dibromo methyl isophthalic acid, the preparation of 3-dioxolane
In reactor, add 1,3-DBA (216g, 1.0mol), toluene (1980ml), ethylene glycol (80.6g, 1.3mol) and catalyzer p-methyl benzenesulfonic acid (6.48g) are warming up to 100 ℃ of stirring reactions, then reflux water-dividing under this temperature, until distillate is clear liquid, about 6 hours, then be cooled to room temperature, remove by filter insolubles, filtrate is warming up to 120 ℃ of distillations and removes toluene, and the resistates that obtains is 2,2-dibromo methyl isophthalic acid, 3-dioxolane crude product, 121-124 ℃/10mmHg cut is collected in underpressure distillation, and namely 2,2-dibromo methyl isophthalic acid, 3-dioxolane (239g), yield 91.9%.
B.1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1, the preparation of 3-dioxolane
In reactor, add methylene dichloride (1560g), under agitation condition, add 1H-1,2,4-triazole (151.8g, 2.2mol), ionic liquid 3-methyl isophthalic acid-ethyl imidazol(e) hydrosulfate (26g) and yellow soda ash (233.2g, 2.2mol), stirring at room 1 hour, then drip 2,2-dibromo methyl isophthalic acid, 3-dioxolane (260g, 1mol), reaction mixture constantly stirs in the dropping process, be warming up to 35 ℃ after dropwising and continued stirring reaction 20 hours, then be cooled to room temperature, remove by filter insolubles, organic layer is used anhydrous sodium sulfate drying after using the saturated common salt water washing, after removing by filter the siccative anhydrous sodium sulphate, filtrate is warming up to 50 ℃ of desolventizings, and the resistates that obtains is 1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1,3-dioxolane crude product, about 207.6g, yield 88.0%, this step product do not need to be further purified and can be directly used in next step reaction.
C.1, the preparation of 3-two (1H-1,2,4-triazole-1-yl) acetone
In reactor, add 1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1,3-dioxolane (236g, 1mol), concentration is 25% hydrochloric acid soln (1415g), post-heating to the 100 ℃ reaction 36 hours that stirs, and reaction finishes the afterreaction mixture and is cooled to room temperature, remove by filter insolubles, filtrate is regulated pH to 12 with 5% aqueous sodium hydroxide solution, and then mixed solution is used anhydrous sodium sulfate drying with methylene dichloride (1180g) extraction 2 times behind the merging organic layer, after removing by filter the siccative anhydrous sodium sulphate, filtrate is warming up to 50 ℃ of desolventizings, obtains 1,3-, two (1H-1,2,4-triazole-1-yl) acetone crude product obtains faint yellow solid behind ethanol (708g) recrystallization, be elaboration 1,3-two (1H-1,2,4-triazole-1-yl) acetone (172.4g), yield 89.8%.1H-NMR (CDCl3，500MHz) δ：4.93(s, 4H), 8.14(s, 2H), 8.47(s, 2H)。FAB-MS(m/z)：193(M+H)。
D. the preparation of fluconazole
In reactor, add 3,5-difluoro bromobenzene (231.6g, 1.2mol), anhydrous tetrahydro furan (765g), magnesium chips (28.8g, 1.2mol) and iodine (9.6g), being heated to backflow, (iodine color fade) regulated heating unit and made mixture maintenance slight boiling condition after the initiation reaction, until the magnesium chips primitive reaction is complete, about 4 hours, prepare 3,5-difluoro bromobenzene grignard reagent is stand-by.
In another reactor, add 1,3-two (1H-1,2,4-triazole-1-yl) acetone (192g, 1mol), anhydrous tetrahydro furan (575g), the rear dropping that stirs is above-mentioned prepare 3,5-difluoro bromobenzene grignard reagent, the dropping process keeps mixture temperature to be no more than 50 ℃, dropwise rear continuation stirring at room reaction 10 hours, reaction finishes, and adds saturated aqueous ammonium chloride cancellation reaction, separatory, water extracts 2 times with ethyl acetate (576g), merge organic phase, the rear anhydrous sodium sulfate drying of using, remove by filter the siccative anhydrous sodium sulphate after, filtrate is warming up to 80 ℃ of desolventizings, obtain the fluconazole crude product, crude product obtains white crystalline powder with 75% isopropanol water solution (576g) recrystallization after the oven dry, be elaboration fluconazole (263.1g), yield 86.0%.M.P.138-141℃。1H-NMR (CDCl3，500MHz) δ：4.41(d, 2H), 4.78(d, 2H), 6.72-6.88(m, 2H), 7.47-7.53(m, 1H), 7.89(s, 2H) , 8.02(s, 2H)。FAB-MS(m/z)：307(M+H)。
Embodiment 2
Other steps are identical with embodiment 1, are 2 of A step, 2-dibromo methyl isophthalic acid, and the preparation method of 3-dioxolane is as follows:
In reactor, add 1,3-DBA (216g, 1.0mol), toluene (995ml), ethylene glycol (67.5g, about 1.1mol) and catalyzer p-methyl benzenesulfonic acid (2.16g) are warming up to 100 ℃ of stirring reactions, then reflux water-dividing under this temperature, until distillate is clear liquid, about 6 hours, then be cooled to room temperature, remove by filter insolubles, filtrate is warming up to 120 ℃ of distillations and removes toluene, and the resistates that obtains is 2,2-dibromo methyl isophthalic acid, 3-dioxolane crude product, 121-124 ℃/10mmHg cut is collected in underpressure distillation, and namely 2,2-dibromo methyl isophthalic acid, 3-dioxolane (227g), yield 87.3%.
Embodiment 3
Other steps are identical with embodiment 1, are 2 of A step, 2-dibromo methyl isophthalic acid, and the preparation method of 3-dioxolane is as follows:
In reactor, add 1,3-DBA (216g, 1.0mol), toluene (1200ml), ethylene glycol (74.4g, 1.2mol) and catalyzer p-methyl benzenesulfonic acid (4.32g) are warming up to 100 ℃ of stirring reactions, then reflux water-dividing under this temperature, until distillate is clear liquid, about 6 hours, then be cooled to room temperature, remove by filter insolubles, filtrate is warming up to 120 ℃ of distillations and removes toluene, and the resistates that obtains is 2,2-dibromo methyl isophthalic acid, 3-dioxolane crude product, 121-124 ℃/10mmHg cut is collected in underpressure distillation, and namely 2,2-dibromo methyl isophthalic acid, 3-dioxolane (236.2g), yield 90.8%.
Embodiment 4
Other steps are identical with embodiment 1, are 1 of B step, 1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1, and the preparation method of 3-dioxolane is as follows:
In reactor, add methylene dichloride (780g), under agitation condition, add 1H-1,2,4-triazole (138g, 2.0mol), ionic liquid 3-methyl isophthalic acid-ethyl imidazol(e) hydrosulfate (26g) and yellow soda ash (212g, 2.0mol), stirring at room 1 hour, then drip 2,2-dibromo methyl isophthalic acid, 3-dioxolane (260g, 1mol), reaction mixture constantly stirs in the dropping process, be warming up to 35 ℃ after dropwising and continued stirring reaction 10 hours, then be cooled to room temperature, remove by filter insolubles, organic layer is used anhydrous sodium sulfate drying after using the saturated common salt water washing, after removing by filter the siccative anhydrous sodium sulphate, filtrate is warming up to 50 ℃ of desolventizings, and the resistates that obtains is 1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1,3-dioxolane crude product, about 195.2g, yield 82.7%, this step product do not need to be further purified and can be directly used in next step reaction.
Embodiment 5
Other steps are identical with embodiment 1, are 1 of B step, 1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1, and the preparation method of 3-dioxolane is as follows:
In reactor, add methylene dichloride (1560g), under agitation condition, add 1H-1,2,4-triazole (145g, 2.1mol), ionic liquid 1,3-diethyl imidazole bisulfate (26g) and salt of wormwood (303.6g, 2.2mol), then stirring at room 1 hour drips 2,2-dibromo methyl isophthalic acid, 3-dioxolane (260g, 1mol), reaction mixture constantly stirs in the dropping process, is warming up to 35 ℃ after dropwising and continues stirring reaction 12 hours, then be cooled to room temperature, remove by filter insolubles, organic layer is used anhydrous sodium sulfate drying with after the saturated common salt water washing, remove by filter the siccative anhydrous sodium sulphate after, filtrate is warming up to 50 ℃ of desolventizings, the resistates that obtains is 1,1'-(2,2-dimethylene-two 1H-1,2, the 4-triazole)-1,3-dioxolane crude product, about 203.3g, yield 86.1%, this step product do not need to be further purified and can be directly used in next step reaction.
Embodiment 6
Other steps are identical with embodiment 1, are 1 of B step, 1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1, and the preparation method of 3-dioxolane is as follows:
In reactor, add methylene dichloride (1250g), under agitation condition, add 1H-1,2,4-triazole (145g, 2.1mol), ionic liquid 3-butyl-1-ethyl imidazol(e) hydrosulfate (26g) and salt of wormwood (276g, 2.0mol), stirring at room 1 hour, then drip 2,2-dibromo methyl isophthalic acid, 3-dioxolane (260g, 1mol), reaction mixture constantly stirs in the dropping process, be warming up to 35 ℃ after dropwising and continued stirring reaction 15 hours, then be cooled to room temperature, remove by filter insolubles, organic layer is used anhydrous sodium sulfate drying after using the saturated common salt water washing, after removing by filter the siccative anhydrous sodium sulphate, filtrate is warming up to 50 ℃ of desolventizings, and the resistates that obtains is 1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1,3-dioxolane crude product, about 198.9g, yield 84.3%, this step product do not need to be further purified and can be directly used in next step reaction.
Embodiment 7
Other steps are identical with embodiment 1, are 1 of B step, 1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1, and the preparation method of 3-dioxolane is as follows:
In reactor, add methylene dichloride (780g), under agitation condition, add 1H-1,2,4-triazole (145g, 2.1mol), ionic liquid 1,3-diethyl imidazole bisulfate (26g) and yellow soda ash (222g, 2.1mol), then stirring at room 1 hour drips 2,2-dibromo methyl isophthalic acid, 3-dioxolane (260g, 1mol), reaction mixture constantly stirs in the dropping process, is warming up to 35 ℃ after dropwising and continues stirring reaction 15 hours, then be cooled to room temperature, remove by filter insolubles, organic layer is used anhydrous sodium sulfate drying with after the saturated common salt water washing, remove by filter the siccative anhydrous sodium sulphate after, filtrate is warming up to 50 ℃ of desolventizings, the resistates that obtains is 1,1'-(2,2-dimethylene-two 1H-1,2, the 4-triazole)-1,3-dioxolane crude product, about 201.7g, yield 85.5%, this step product do not need to be further purified and can be directly used in next step reaction.
Embodiment 8
Other steps are identical with embodiment 1, are 1 of C step, and the preparation method of 3-two (1H-1,2,4-triazole-1-yl) acetone is as follows:
In reactor, add 1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1,3-dioxolane (236g, 1mol), concentration is 25% hydrochloric acid soln (945g), post-heating to the 100 ℃ reaction 24 hours that stirs, and reaction finishes the afterreaction mixture and is cooled to room temperature, remove by filter insolubles, filtrate is regulated pH to 12 with 5% aqueous sodium hydroxide solution, and then mixed solution is used anhydrous sodium sulfate drying with methylene dichloride (1180g) extraction 2 times behind the merging organic layer, after removing by filter the siccative anhydrous sodium sulphate, filtrate is warming up to 50 ℃ of desolventizings, obtains 1,3-, two (1H-1,2,4-triazole-1-yl) acetone crude product obtains faint yellow solid behind ethanol (708g) recrystallization, be elaboration 1,3-two (1H-1,2,4-triazole-1-yl) acetone (162.8g), yield 84.8%.1H-NMR (CDCl3，500MHz) δ：4.93(s, 4H), 8.14(s, 2H), 8.47(s, 2H)。FAB-MS(m/z)：193(M+H)。
Embodiment 9
Other steps are identical with embodiment 1, are 1 of C step, and the preparation method of 3-two (1H-1,2,4-triazole-1-yl) acetone is as follows:
In reactor, add 1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1,3-dioxolane (236g, 1mol), concentration is 20% hydrochloric acid soln (1415g), post-heating to the 100 ℃ reaction 24 hours that stirs, and reaction finishes the afterreaction mixture and is cooled to room temperature, remove by filter insolubles, filtrate is regulated pH to 12 with 5% aqueous sodium hydroxide solution, and then mixed solution is used anhydrous sodium sulfate drying with methylene dichloride (1180g) extraction 2 times behind the merging organic layer, after removing by filter the siccative anhydrous sodium sulphate, filtrate is warming up to 50 ℃ of desolventizings, obtains 1,3-, two (1H-1,2,4-triazole-1-yl) acetone crude product obtains faint yellow solid behind ethanol (708g) recrystallization, be elaboration 1,3-two (1H-1,2,4-triazole-1-yl) acetone (151.4g), yield 78.9%.1H-NMR (CDCl3，500MHz) δ：4.93(s, 4H), 8.14(s, 2H), 8.47(s, 2H)。FAB-MS(m/z)：193(M+H)。
Embodiment 10
Other steps are identical with embodiment 1, are 1 of C step, and the preparation method of 3-two (1H-1,2,4-triazole-1-yl) acetone is as follows:
In reactor, add 1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1,3-dioxolane (236g, 1mol), concentration is 20% hydrochloric acid soln (945g), post-heating to the 100 ℃ reaction 30 hours that stirs, and reaction finishes the afterreaction mixture and is cooled to room temperature, remove by filter insolubles, filtrate is regulated pH to 12 with 5% aqueous sodium hydroxide solution, and then mixed solution is used anhydrous sodium sulfate drying with methylene dichloride (1180g) extraction 2 times behind the merging organic layer, after removing by filter the siccative anhydrous sodium sulphate, filtrate is warming up to 50 ℃ of desolventizings, obtains 1,3-, two (1H-1,2,4-triazole-1-yl) acetone crude product obtains faint yellow solid behind ethanol (708g) recrystallization, be elaboration 1,3-two (1H-1,2,4-triazole-1-yl) acetone (160.3g), yield 83.5%.1H-NMR (CDCl3，500MHz) δ：4.93(s, 4H), 8.14(s, 2H), 8.47(s, 2H)。FAB-MS(m/z)：193(M+H)。
Embodiment 11
Other steps are identical with embodiment 1, and just the preparation method of the fluconazole of D step is as follows:
In reactor, add 3,5-difluoro bromobenzene (212.3g, 1.1mol), anhydrous tetrahydro furan (580g), magnesium chips (26.4g, 1.1mol) and iodine (9.6g), being heated to backflow, (iodine color fade) regulated heating unit and made mixture maintenance slight boiling condition after the initiation reaction, until the magnesium chips primitive reaction is complete, about 4 hours, prepare 3,5-difluoro bromobenzene grignard reagent is stand-by.
In another reactor, add 1,3-two (1H-1,2,4-triazole-1-yl) acetone (192g, 1mol), anhydrous tetrahydro furan (385g), the rear dropping that stirs is above-mentioned prepare 3,5-difluoro bromobenzene grignard reagent, the dropping process keeps mixture temperature to be no more than 50 ℃, dropwise rear continuation stirring at room reaction 8 hours, reaction finishes, and adds saturated aqueous ammonium chloride cancellation reaction, separatory, water extracts 2 times with ethyl acetate (576g), merge organic phase, the rear anhydrous sodium sulfate drying of using, remove by filter the siccative anhydrous sodium sulphate after, filtrate is warming up to 80 ℃ of desolventizings, obtain the fluconazole crude product, crude product obtains white crystalline powder with 75% isopropanol water solution (576g) recrystallization after the oven dry, be elaboration fluconazole (242.6g), yield 79.3%.M.P.138-141℃。1H-NMR (CDCl3，500MHz) δ：4.41(d, 2H), 4.78(d, 2H), 6.72-6.88(m, 2H), 7.47-7.53(m, 1H), 7.89(s, 2H) , 8.02(s, 2H)。FAB-MS(m/z)：307(M+H)。
Embodiment 12
Other steps are identical with embodiment 1, and just the preparation method of the fluconazole of D step is as follows:
In reactor, add 3,5-difluoro bromobenzene (222g, 1.15mol), anhydrous tetrahydro furan (650g), magnesium chips (27.6g, 1.15mol) and iodine (9.6g), being heated to backflow, (iodine color fade) regulated heating unit and made mixture maintenance slight boiling condition after the initiation reaction, until the magnesium chips primitive reaction is complete, about 4 hours, prepare 3,5-difluoro bromobenzene grignard reagent is stand-by.
In another reactor, add 1,3-two (1H-1,2,4-triazole-1-yl) acetone (192g, 1mol), anhydrous tetrahydro furan (450g), the rear dropping that stirs is above-mentioned prepare 3,5-difluoro bromobenzene grignard reagent, the dropping process keeps mixture temperature to be no more than 50 ℃, dropwise rear continuation stirring at room reaction 9 hours, reaction finishes, and adds saturated aqueous ammonium chloride cancellation reaction, separatory, water extracts 2 times with ethyl acetate (576g), merge organic phase, the rear anhydrous sodium sulfate drying of using, remove by filter the siccative anhydrous sodium sulphate after, filtrate is warming up to 80 ℃ of desolventizings, obtain the fluconazole crude product, crude product obtains white crystalline powder with 75% isopropanol water solution (576g) recrystallization after the oven dry, be elaboration fluconazole (256.3g), yield 83.8%.M.P.138-141℃。1H-NMR (CDCl3，500MHz) δ：4.41(d, 2H), 4.78(d, 2H), 6.72-6.88(m, 2H), 7.47-7.53(m, 1H), 7.89(s, 2H) , 8.02(s, 2H)。FAB-MS(m/z)：307(M+H)。
Although the contriver has done comparatively detailed elaboration to technical scheme of the present invention and has enumerated, be to be understood that, for the those skilled in the art in this area, above-described embodiment is modified and/or flexible or to adopt the replacement scheme that is equal to be obvious, the essence that all can not break away from spirit of the present invention, the term that occurs among the present invention is used for elaboration and the understanding to technical solution of the present invention, can not be construed as limiting the invention.
Claims (1)
1. the preparation method of a fluconazole, it is characterized in that: the fluconazole that represents with formula I obtains in accordance with the following steps:
(Ⅳ) (Ⅰ)
A.2,2-dibromo methyl isophthalic acid, the preparation of 3-dioxolane (II)
In reactor, add 1,1 times of 3-dibromoacetone, toluene 4-8 is (weight ratio) doubly, ethylene glycol 0.31-0.38 is (weight ratio) and catalyzer p-methyl benzenesulfonic acid 0.01-0.03 times (weight ratio) doubly, is warming up to 100 ℃ of stirring reactions, then reflux water-dividing under this temperature, until distillate is clear liquid, about 6 hours, then be cooled to room temperature, remove by filter insolubles, filtrate is warming up to 120 ℃ of distillations and removes toluene, the resistates that obtains is 2,2-dibromo methyl isophthalic acid, 3-dioxolane crude product, 121-124 ℃/10mmHg cut is collected in underpressure distillation, namely 2,2-dibromo methyl isophthalic acid, 3-dioxolane (II);
B.1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1, the preparation of 3-dioxolane (III)
In reactor, add methylene dichloride 3-6 doubly (weight ratio), under agitation condition, add 1H-1,2,4-triazole 0.53-0.59 is (weight ratio) doubly, ionic liquid 0.1 times (weight ratio) and yellow soda ash 0.81-0.90 are doubly or salt of wormwood 1.06-1.17 doubly (weight ratio), stirring at room 1 hour, then drip 2,2-dibromo methyl isophthalic acid, 1 times of 3-dioxolane (II), reaction mixture constantly stirs in the dropping process, be warming up to 35 ℃ after dropwising and continued stirring reaction 10-20 hour, then be cooled to room temperature, remove by filter insolubles, organic layer is used anhydrous sodium sulfate drying after using the saturated common salt water washing, after removing by filter the siccative anhydrous sodium sulphate, filtrate is warming up to 50 ℃ of desolventizings, and the resistates that obtains is 1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1,3-dioxolane (III) crude product, this step product do not need to be further purified and can be directly used in next step reaction; The ionic liquid that relates in this step refers to 3-methyl isophthalic acid-ethyl imidazol(e) hydrosulfate, a kind of in the middle of 1,3-diethyl imidazole bisulfate and the 3-butyl-1-ethyl imidazol(e) hydrosulfate;
C.1, the preparation of 3-two (1H-1,2,4-triazole-1-yl) acetone (IV)
In reactor, add 1,1'-(2,2-dimethylene-two 1H-1,2,4-triazole)-1,1 times of 3-dioxolane (III), concentration be 20% or concentration be 25% hydrochloric acid soln 4-6 doubly (weight ratio), post-heating to 100 ℃ reaction 24-36 hour that stirs, reaction finishes the afterreaction mixture and is cooled to room temperature, remove by filter insolubles, filtrate is regulated pH to 12 with 5% aqueous sodium hydroxide solution, and then mixed solution is used anhydrous sodium sulfate drying with 5 times of (weight ratio) extractions of methylene dichloride 2 times behind the merging organic layer, after removing by filter the siccative anhydrous sodium sulphate, filtrate is warming up to 50 ℃ of desolventizings, obtains 1,3-, two (1H-1,2,4-triazole-1-yl) acetone (IV) crude product obtains elaboration 1,3-two (1H-1 behind 3 times of (weight ratio) recrystallizations of ethanol, 2,4-triazole-1-yl) acetone (IV);
D. the preparation of fluconazole (I)
In reactor, add 3,5-difluoro bromobenzene 1.10-1.21 is (weight ratio) doubly, anhydrous tetrahydro furan 3-4 is (weight ratio) doubly, magnesium chips 0.13-0.15 is (weight ratio) and 0.05 times of iodine (weight ratio) doubly, is heated to backflow, regulates heating unit after the initiation reaction and makes mixture keep slight boiling condition, until the magnesium chips primitive reaction is complete, about 4 hours, prepare 3,5-difluoro bromobenzene grignard reagent is stand-by;
In another reactor, add 1,3-two (1H-1,2,4-triazole-1-yl) acetone (IV) is 1 times, anhydrous tetrahydro furan 2-3 is (weight ratio) doubly, the rear dropping that stirs is above-mentioned prepare 3,5-difluoro bromobenzene grignard reagent, the dropping process keeps mixture temperature to be no more than 50 ℃, dropwise rear continuation stirring at room reaction 8-10 hour, reaction finishes, and adds saturated aqueous ammonium chloride cancellation reaction, separatory, water extracts 2 times with ethyl acetate 3 times (weight ratios), merge organic phase, the rear anhydrous sodium sulfate drying of using, remove by filter the siccative anhydrous sodium sulphate after, filtrate is warming up to 80 ℃ of desolventizings, obtain fluconazole (I) crude product, crude product obtains elaboration fluconazole (I) with 3 times of (weight ratio) recrystallizations of isopropanol water solution of 75%.
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| CN106749055A (en) * | 2016-12-19 | 2017-05-31 | 苏州天马精细化学品股份有限公司 | A kind of preparation method of Fluconazole |
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| CN111362853A (en) * | 2020-04-27 | 2020-07-03 | 安徽大学 | Preparation method of 3-oxazetidine-1-carboxylic acid tert-butyl ester |
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| ES8604938A1 (en) * | 1985-11-19 | 1986-03-01 | Inke Sa | 2-(Difluorophenyl)-1,3-bis(triazolyl) propan-2-ol prepn. |
| ES2020785A6 (en) * | 1990-07-19 | 1991-09-16 | Inke Sa | Process for obtaining 1,3-bis(1H-1,2,4-triazol-1-yl)- propan-2-one |
| CN1353108A (en) * | 2000-11-02 | 2002-06-12 | 中国人民解放军第二军医大学 | Process for preparing fluconazole as antifungal medicine |
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| ES8604938A1 (en) * | 1985-11-19 | 1986-03-01 | Inke Sa | 2-(Difluorophenyl)-1,3-bis(triazolyl) propan-2-ol prepn. |
| ES2020785A6 (en) * | 1990-07-19 | 1991-09-16 | Inke Sa | Process for obtaining 1,3-bis(1H-1,2,4-triazol-1-yl)- propan-2-one |
| CN1353108A (en) * | 2000-11-02 | 2002-06-12 | 中国人民解放军第二军医大学 | Process for preparing fluconazole as antifungal medicine |
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