CN106397342A - A method of preparing 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone - Google Patents
A method of preparing 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone Download PDFInfo
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- CN106397342A CN106397342A CN201610597108.2A CN201610597108A CN106397342A CN 106397342 A CN106397342 A CN 106397342A CN 201610597108 A CN201610597108 A CN 201610597108A CN 106397342 A CN106397342 A CN 106397342A
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- phenylethanone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
The invention relates to the technical field of medicine intermediates, particularly a preparing method of 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone. The method includes steps of (1) adding m-difluorobenzene and anhydrous aluminium chloride into a reaction container, adding dropwise chloroacetyl chloride at 10-15 DEG C under stirring, reacting at 40-50 DEG C for 5 h after the addition is finished while maintaining the temperature, hydrolyzing after the reaction is finished, and removing water to obtain a water-washed product, (2) adding isopropanol and 4-aminotriazole into the water-washed product, heating and refluxing for 10 h, cooling to 5 DEG C or below after the reaction is finished, discharging, filtering and drying after filtration to obtain an intermediate condensate, and (3) adding the intermediate condensate and diluted hydrochloric acid into a reaction container, adding dropwise an aqueous solution of sodium nitrite with the temperature being controlled to be 5-10 DEG C, determining the end point by utilizing starch-potassium iodide test paper, reacting at 15 DEG C for 1 h while maintaining the temperature, neutralizing with liquid caustic soda at 10 DEG C below until the pH is 7-8, filtering, and performing air blast drying to obtain a product. The 4 position of the 4-aminotriazole is provided with amino protection, and therefore a 4-site isomer is not generated, a high-purity product can be obtained after amino removal, and the reaction yield is increased.
Description
Technical field
The present invention relates to medicine intermediate technical field, especially a kind of 2'4'- bis- fluoro- 2- [1- (1H-1,2,4- triazoles
Base)] preparation method of 1-Phenylethanone..
Background technology
The fluoro- 2- of 2'4'- bis- [1- (1H-1,2,4- triazolyls)] 1-Phenylethanone. is the key intermediate for preparing fluconazol,
Fluconazol is a kind of new antifungal drug in triazole class, is characterized in that bacterium spectrum processed is wide, can be administered orally, absorb completely, organizer
In official, concentration is high, in addition, goes back the advantages of toxic side effect is little, clinical effectiveness is good, is deep antifungal choice drug.But
The price of fluconazol is all very high always, and one of its reason is exactly the fluoro- 2- of intermediate 2'4'- bis- [1- (1H-1,2,4- triazolyls)]
1-Phenylethanone. price and quality.
Documents and materials Bioorganic and Medicinal Chemistry Letters, 2009, vol.19, (20)
P.5965-5969, the preparation method of the disclosure fluoro- 2- of 2'4'- bis- [1- (1H-1,2,4- triazolyls)] 1-Phenylethanone. is：With a difluoro
Benzene is initiation material, occurs Fu Ke acylation reaction to generate after 2'- chloro- 2.4- difluoro acetophenone with chloracetyl chloride and lewis acid,
Then with 1,2,4 one triazoles are condensed, and generate target product.This preparation method is classical method, thus extensive always
Using, but this method unavoidably produces isomer in the condensation process, refines and is very difficult to remove.
Content of the invention
The technical problem to be solved is：Overcome deficiency of the prior art, provide a kind of reaction conversion ratio high,
The method preparing the fluoro- 2- of 2'4'- bis- [1- (1H-1,2,4- triazolyl)] 1-Phenylethanone. of superior product quality.
For solving above-mentioned technical problem, the technical solution used in the present invention is as follows：
A kind of preparation method of 2'4'- bis- fluoro- 2- [1- (1H-1,2,4- triazolyls)] 1-Phenylethanone., described preparation method bag
Include following steps：
(1) m-difluorobenzene and aluminum trichloride (anhydrous) are put in reaction vessel, in 10-15 DEG C of Deca chloracetyl under stirring
Chlorine, drip off in 40-50 DEG C of insulation reaction 5h, reaction terminates, control below 25 DEG C of interior temperature Deca water to be hydrolyzed, hydrolysis end is stirred
Mix 1 hour, pump water, and wash with water twice, obtain washing thing；
(2) the washing thing being obtained in step (1) is added isopropanol, add 4- amino triazole, heating reflux reaction
10h, reaction end is cooled to 5 DEG C and is filtered with bottom discharge, and the solidss forced air drying obtaining after filtration obtains intermediate condensation
Thing；
(3) intermediate condensate being obtained in step (2) and dilute hydrochloric acid are put in reaction vessel, control temperature in 5-10
DEG C Deca sodium nitrite in aqueous solution, determines terminal with starch-kalium iodide reagent paper, makes interior temperature rise to 15 DEG C of insulation reaction to after terminal
1h, is then cooled to less than 10 DEG C and is neutralized to pH7-8 filtration with liquid caustic soda, wash three times, forced air drying obtains product.
Further, in described step (1), the mol ratio of m-difluorobenzene and aluminum trichloride (anhydrous) is 1:1-1.2, described between
Difluorobenzene is 1 with the mol ratio of chloracetyl chloride:1-1.5.
Further, in described step (1), the mol ratio of m-difluorobenzene and aluminum trichloride (anhydrous) is 1:1.16, described between two
Fluorobenzene is 1 with the mol ratio of chloracetyl chloride:2.
Further, in described step (2), the mol ratio of m-difluorobenzene and 4- amino triazole is 1:1-1.5.
Further, in described step (2), the mol ratio of m-difluorobenzene and 4- amino triazole is 1:1.34.
Further, described intermediate condensate and the mol ratio of dilute hydrochloric acid are 1:2, the mass fraction of dilute hydrochloric acid is
6.3%.
Further, also include before pH regulator being carried out to filtrate in described step (3) plus activated carbon stirring 0.5h, then
Filter the operation removing breeze.
Concrete reaction scheme is as follows：
Beneficial effect using technical scheme is：
The synthetic method of the fluoro- 2- of this 2'4'- two [1- (1H-1,2,4- triazolyl)] 1-Phenylethanone. has the advantages that：
2'- chloro- 2.4- difluoro acetophenone and 4- amino -1,2,4- triazole condensations, due to 4- amino -1, on 4 of 2,4- triazoles
There is amido protecting, so not having 4 position isomers to produce, after removing amino group, obtaining high purity product, improve reaction simultaneously and receiving
Rate.
Specific embodiment
With reference to specific embodiment, the present invention will be further described.
Embodiment 1
1L four-hole boiling flask puts into 50g m-difluorobenzene and the stirring homoiothermic of 58.6g aluminum trichloride (anhydrous) to 15 DEG C in 15～
25 DEG C of Deca 49.7g chloracetyl chlorides drip off and are slowly heated to 40 DEG C and in 40～50 DEG C of insulation reaction 5h, and reaction terminates cooling and rises
To 25 DEG C, Deca water 400g below 25 DEG C, drip off stirring 1 hour, standing filter stick pumps water, add cold water 400g stirring half
Hour, standing filter stick pumps water, repeats and washes secondary, drains water, in bottle, solid is intermediate 2'- chloro- 2.4- difluorobenzene second
Ketone；
Isopropanol 300g is added, stirring is lower to be added in the above-mentioned reaction bulb containing intermediate 2'- chloro- 2.4- difluoro acetophenone
4- amino -1,2,4- triazole 49.6g, it is cooled to 5 DEG C after being heated to reflux 10h, sucking filtration, a small amount of isopropyl alcohol of filter cake,
Drain, solidss forced air drying obtains condensation substance 100g；
In 1L four-hole boiling flask, put into water 400g, 36% concentrated hydrochloric acid 85g, stirring is lower to add condensation substance 100g, drops after dissolving
Temperature, to 5 DEG C, is controlled temperature in 5～10 DEG C of Deca 20% sodium nitrite in aqueous solution about 135g, is determined eventually with starch-kalium iodide reagent paper
Point, makes interior temperature rise to 15 DEG C of insulation reaction 1h to after terminal, adds 5g activated carbon to stir 0.5 hour, is filtered to remove carbon slag, clear liquid
Put in clean 1L four-hole boiling flask, be cooled to 10 DEG C of Deca 30% liquid caustic soda about 140g, make liquid pH7～8, filter, water floats
Filter wash cake, a small amount of isopropyl alcohol, drain, forced air drying, obtain product 55g, purity 99.8%.
Embodiment 2
In 1L four-hole boiling flask, put into 50g m-difluorobenzene and 67.5g aluminum trichloride (anhydrous), stir homoiothermic to 15 DEG C, in 15
～25 DEG C of Deca 60g chloracetyl chlorides, drip off and are slowly heated to 40 DEG C, and in 40～50 DEG C of insulation reaction 5h, reaction terminates cooling
Rise to 25 DEG C, Deca water 400g below 25 DEG C, drip off stirring 1 hour, standing, pump water with filter stick, add cold water 400g, stir
Mix half an hour, standing, pump water with filter stick, repeat and wash secondary, drain water, in bottle, solid is intermediate 2'- chloro- 2.4- difluoro
1-Phenylethanone.；
In the above-mentioned reaction bulb containing intermediate 2'- chloro- 2.4- difluoro acetophenone, add isopropanol 300g, stirring is lower to be added
Enter 4- amino -1,2,4- triazole 50g, after being heated to reflux 10h, be cooled to 5 DEG C, sucking filtration, a small amount of isopropyl alcohol of filter cake,
Drain, solidss forced air drying obtains condensation substance 105g；
Put into water 400g, 36% concentrated hydrochloric acid 85g in 1L four-hole boiling flask, stirring is lower to add condensation substance 100g, drops after dissolving
Temperature, to 5 DEG C, is controlled temperature in 5～10 DEG C of Deca 20% sodium nitrite in aqueous solution about 135g, is determined eventually with starch-kalium iodide reagent paper
Point, makes interior temperature rise to 15 DEG C of insulation reaction 1h to after terminal, adds 5g activated carbon, stir 0.5 hour, be filtered to remove carbon slag, clearly
Liquid is put in clean 1L four-hole boiling flask, is cooled to 10 DEG C, Deca 30% liquid caustic soda about 140g, makes liquid pH7～8, filters, water
Rinsing filter cake, a small amount of isopropyl alcohol, drain forced air drying, obtain product 55g, purity 99.8%.
Embodiment 3
In 1L four-hole boiling flask, put into 50g m-difluorobenzene and 70.3g aluminum trichloride (anhydrous), stir homoiothermic to 15 DEG C, in 15
～25 DEG C of Deca 74.5g chloracetyl chlorides, drip off and are slowly heated to 40 DEG C, and in 40～50 DEG C of insulation reaction 5h, reaction terminates fall
Temperature rise to 25 DEG C, Deca water 400g below 25 DEG C, drip off stirring 1 hour, standing, pump water with filter stick, add cold water 400g,
Stirring half an hour, standing, pump water with filter stick, repeat and wash secondary, drain water, in bottle, solid is the chloro- 2.4- of intermediate 2'- bis-
Fluoro acetophenone；
Isopropanol 300g is added, stirring is lower to be added in the above-mentioned reaction bulb containing intermediate 2'- chloro- 2.4- difluoro acetophenone
4- amino -1,2,4- triazole 55.5g, it is cooled to 5 DEG C after being heated to reflux 10h, sucking filtration, a small amount of isopropyl alcohol of filter cake,
Drain, solidss forced air drying, obtain condensation substance 106g；
Put into water 400g, 36% concentrated hydrochloric acid 85g in 1L four-hole boiling flask, stirring is lower to add condensation substance 100g, drops after dissolving
Temperature, to 5 DEG C, controls temperature at 5～10 DEG C, and Deca 20% sodium nitrite in aqueous solution about 135g is determined with starch-kalium iodide reagent paper
Terminal, makes interior temperature rise to 15 DEG C of insulation reaction 1h to after terminal, adds 5g activated carbon, stir 0.5 hour, be filtered to remove carbon slag,
Clear liquid is put in clean 1L four-hole boiling flask, is cooled to 10 DEG C, Deca 30% liquid caustic soda about 140g, makes liquid pH7～8, filters,
Water rinses filter cake, a small amount of isopropyl alcohol, drains, forced air drying, obtains product 55g, purity 99.8%.
Embodiment 2 is preferred implementation.
Although above-described embodiment is described in detail to technical scheme, the technical side of the present invention
Case is not limited to above example, in the case of the thought without departing from the present invention and objective, to technical scheme institute
Any change done falls within claims of the present invention limited range.
Claims (7)
1. a kind of preparation method of 2'4'- bis- fluoro- 2- [1- (1H-1,2,4- triazolyls)] 1-Phenylethanone. is it is characterised in that described system
Preparation Method comprises the following steps：
(1) m-difluorobenzene and aluminum trichloride (anhydrous) are put in reaction vessel, under stirring in 10-15 DEG C of Deca chloracetyl chloride, drip
Complete in 40-50 DEG C of insulation reaction 5h, reaction terminates, and controls below 25 DEG C of interior temperature Deca water to be hydrolyzed, hydrolysis stirs 1 after terminating
Hour, pump water, and wash with water twice, obtain washing thing；
(2) washing thing in add isopropanol, 4- amino triazole, heating reflux reaction 10h, reaction end be cooled to 5 DEG C with
Under, discharging is filtered, and the solidss forced air drying obtaining after filtration obtains intermediate condensate；
(3) intermediate condensate being obtained in step (2) and dilute hydrochloric acid are put in reaction vessel, control temperature at 5-10 DEG C,
Deca sodium nitrite in aqueous solution, determines terminal with starch-kalium iodide reagent paper, makes interior temperature rise to 15 DEG C of insulation reaction to after terminal
1h, is then cooled to less than 10 DEG C and is neutralized to pH7-8 filtration with liquid caustic soda, wash three times, forced air drying obtains product.
2. the preparation side of a kind of 2'4'- bis- according to claim 1 fluoro- 2- [1- (1H-1,2,4- triazolyl)] 1-Phenylethanone.
Method it is characterised in that：In described step (1), the mol ratio of m-difluorobenzene and aluminum trichloride (anhydrous) is 1:1-1.2, described between difluoro
Benzene is 1 with the mol ratio of chloracetyl chloride:1-1.5.
3. the preparation side of a kind of 2'4'- bis- according to claim 2 fluoro- 2- [1- (1H-1,2,4- triazolyl)] 1-Phenylethanone.
Method it is characterised in that：In described step (1), the mol ratio of m-difluorobenzene and aluminum trichloride (anhydrous) is 1:1.16, described between difluoro
Benzene is 1 with the mol ratio of chloracetyl chloride:2.
4. the preparation side of a kind of 2'4'- bis- according to claim 1 fluoro- 2- [1- (1H-1,2,4- triazolyl)] 1-Phenylethanone.
Method it is characterised in that：In described step (2), the mol ratio of m-difluorobenzene and 4- amino triazole is 1:1-1.5.
5. the preparation side of a kind of 2'4'- bis- according to claim 4 fluoro- 2- [1- (1H-1,2,4- triazolyl)] 1-Phenylethanone.
Method it is characterised in that：In described step (2), the mol ratio of m-difluorobenzene and 4- amino triazole is 1:1.34.
6. the preparation side of a kind of 2'4'- bis- according to claim 1 fluoro- 2- [1- (1H-1,2,4- triazolyl)] 1-Phenylethanone.
Method it is characterised in that：Described intermediate condensate is 1 with the mol ratio of dilute hydrochloric acid：2, the mass fraction of dilute hydrochloric acid is 6.3%.
7. the preparation side of a kind of 2'4'- bis- according to claim 1 fluoro- 2- [1- (1H-1,2,4- triazolyl)] 1-Phenylethanone.
Method it is characterised in that：Also include before pH regulator being carried out to filtrate in described step (3) plus activated carbon stirring 0.5h, then mistake
Filter off the operation except breeze.
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| CN201610597108.2A CN106397342A (en) | 2016-07-26 | 2016-07-26 | A method of preparing 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone |
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| CN201610597108.2A CN106397342A (en) | 2016-07-26 | 2016-07-26 | A method of preparing 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110028458A (en) * | 2019-05-09 | 2019-07-19 | 广东广康生化科技股份有限公司 | A kind of new method preparing metconazole |
| CN113336715B (en) * | 2021-08-04 | 2021-11-23 | 山东海利尔化工有限公司 | Preparation method of triazole compound containing dioxolane and intermediate thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5710280A (en) * | 1996-07-09 | 1998-01-20 | Development Center For Biotechnology | Preparation of fluconazole and pharmaceutically acceptable salts thereof |
| HRP20000680B1 (en) * | 2000-10-13 | 2004-06-30 | Belupo Lijekovi I Kozmetika D | Process for the preparation of fluconazole |
-
2016
- 2016-07-26 CN CN201610597108.2A patent/CN106397342A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5710280A (en) * | 1996-07-09 | 1998-01-20 | Development Center For Biotechnology | Preparation of fluconazole and pharmaceutically acceptable salts thereof |
| HRP20000680B1 (en) * | 2000-10-13 | 2004-06-30 | Belupo Lijekovi I Kozmetika D | Process for the preparation of fluconazole |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110028458A (en) * | 2019-05-09 | 2019-07-19 | 广东广康生化科技股份有限公司 | A kind of new method preparing metconazole |
| CN110028458B (en) * | 2019-05-09 | 2022-10-11 | 广东广康生化科技股份有限公司 | Novel method for preparing metconazole |
| CN113336715B (en) * | 2021-08-04 | 2021-11-23 | 山东海利尔化工有限公司 | Preparation method of triazole compound containing dioxolane and intermediate thereof |
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Application publication date: 20170215 |