CN111518041A - Preparation method of 2'4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone - Google Patents
Preparation method of 2'4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone Download PDFInfo
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- CN111518041A CN111518041A CN202010335499.7A CN202010335499A CN111518041A CN 111518041 A CN111518041 A CN 111518041A CN 202010335499 A CN202010335499 A CN 202010335499A CN 111518041 A CN111518041 A CN 111518041A
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- 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 provides a preparation method of 2'4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, which comprises the steps of taking 2-chloro-2 '4' -difluoroacetophenone as a raw material, reacting with 3-chloro-1, 2, 4-triazolyl to obtain 2- (3-chloro-1H-1, 2, 4-triazolyl-1-) -1- (2, 4-difluorophenyl) acetophenone, carrying out hydrogenation and dehalogenation on palladium carbon to obtain a final product 2'4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, preparing 2'4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, simple steps, convenient operation, low economic cost, suitability for industrial production, good social benefit and economic benefit and great economic value potential.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis, in particular to a preparation method of voriconazole intermediate 2'4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone.
Background
Voriconazole is a broad-spectrum triazole antifungal drug developed by the american pfeiffer company, and its indications include the following: 1. treatment of invasive aspergillosis; 2. treatment of severe invasive infections caused by fluconazole-resistant candida species (including candida krusei); 3. treating severe infections caused by actinomycete and fusarium. The traditional Chinese medicine composition is mainly used for treating progressive and possibly life-threatening infection in immunodeficiency patients and the like, and brings good news to patients who are deeply infected by fungi.
Voriconazole (Voriconazole) is named as (2R,3S) -2- (2, 4-difluorophenyl) -3- (5-fluoropyrimidin-4-yl) -1- (1H-1,2, 4-triazol-1-yl) -2-butanol and has the molecular formula of C16H14F3N5O, CAS number 137234-62-9, having the following structural formula:
the voriconazole has strong bactericidal activity on aspergillus, has obvious curative effect when being used for treating invasive aspergillosis, and has obvious curative effect superior to amphotericin, itraconazole and echinocandin through clinical verification; meanwhile, the therapeutic efficacy of voriconazole on cryptococcus neoformans, candida gluconate, candida krusei and the like is better than that of itraconazole, and the voriconazole has the advantages of small side effect and high curative effect compared with other antifungal drugs.
One of the important intermediates in the synthesis of voriconazole is 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, and the preparation method thereof is disclosed in the related literature.
Disclosure of Invention
In view of the above problems in the prior art, the present invention provides a preparation method of 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, which solves the technical problems: provides a preparation method of 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, which has convenient operation and high yield of final products and is suitable for large-scale industrialization.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone comprises the following steps:
the synthesis path is as follows:
the preparation method comprises the following steps:
q1, selecting 2-chloro-2 ', 4' -difluoroacetophenone as a raw material at a reaction temperature, reacting with 3-chloro-1, 2, 4-triazole under a reaction solvent condition, and introducing potassium carbonate as an alkali into a reaction mixture during reaction, wherein the reaction temperature is 10-40 ℃, and the reaction time is 5-7 hours;
q2 and 2- (3-chloro-1H-1, 2, 4-triazole-1-) -1- (2, 4-difluorophenyl) ethanone are subjected to dehalogenation reaction in an alcohol solvent under the catalysis of palladium carbon in a hydrogen environment to obtain a final product, namely 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the reaction temperature is 40-75 ℃, and the reaction time is 2-5 hours.
In the above technical scheme, in Q1, the reaction solvent is one of anhydrous tetrahydrofuran, anhydrous diethyl ether, benzene, toluene, ethyl acetate, and acetonitrile, and is preferably anhydrous tetrahydrofuran.
In the above technical scheme, in Q1, after the reaction is completed, the mixture needs to be filtered, the filter cake is washed with the reaction solvent, and concentrated at room temperature, a proper amount of purified water is added for pulping and filtering, the filtered crystal is repulped in isopropanol and filtered again, the filter cake is washed with the reaction solvent, and the pressure reduction drying is performed.
In the technical scheme, in the Q1, the molar ratio of the 2-chloro-2 ', 4' -difluoroacetophenone to the 3-chloro-1, 2, 4-triazole is 1: 1-2.
In the above technical solution, the amount of the base used in Q1 is 1.5 times equivalent.
In the technical scheme, in Q2, after the reaction is finished, the temperature needs to be reduced to room temperature, hydrogen is discharged, the catalyst is filtered, and the mother liquor is concentrated under reduced pressure until the mother liquor is dry.
In the above technical solution, in Q2, the alcohol solvent may be methanol or ethanol or a mixture of the two, preferably ethanol.
In the above-described embodiment, in Q2, the mass fraction of palladium on carbon is 5% or 10%, preferably 10%.
In the above technical solution, in Q2, the mass ratio of palladium on carbon to 2- (3-chloro-1H-1, 2, 4-triazole-1-) -1- (2, 4-difluorophenyl) ethanone is 0.005-0.05: 1, preferably 0.01-0.03: 1.
In the above technical solution, in Q2, the hydrogen pressure range of the hydrogen environment is 0.2 to 1.5Mpa, preferably 1 Mpa.
The invention takes 2-chloro-2 ', 4' -difluoroacetophenone as a raw material, reacts with 3-chloro-1, 2, 4-triazole to obtain 2- (3-chloro-1H-1, 2, 4-triazole-1-) -1- (2, 4-difluorophenyl) acetophenone, then palladium carbon is hydrogenated and dehalogenated to obtain a final product 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, and the method is used for preparing the 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, has simple steps, convenient operation and low economic cost, is suitable for industrial production, and can bring good social benefit and economic benefit, the economic value potential is large.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
A process for the preparation of 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone as shown in the examples:
the synthesis path is as follows:
the preparation method comprises the following steps:
q1, selecting 2-chloro-2 ', 4' -difluoroacetophenone as a raw material at a reaction temperature, reacting with 3-chloro-1, 2, 4-triazole under a reaction solvent condition, and introducing potassium carbonate as an alkali into a reaction mixture during reaction, wherein the reaction temperature is 10-40 ℃, and the reaction time is 5-7 hours;
q2 and 2- (3-chloro-1H-1, 2, 4-triazole-1-) -1- (2, 4-difluorophenyl) ethanone are subjected to dehalogenation reaction under the catalysis of palladium carbon in an alcohol solvent and a hydrogen environment to obtain a final product, namely 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the reaction temperature is 40-75 ℃, and the reaction time is 2-5 hours.
The technical solution of the present invention is illustrated by the following specific examples:
step one, synthesizing 2- (3-chloro-1H-1, 2, 4-triazole-1-) -1- (2, 4-difluorophenyl) ethanone.
Firstly, adding 800mL of tetrahydrofuran into a 2L reaction bottle, adding 103.5g of 3-chloro-1, 2, 4-triazole into the reaction bottle, stirring the obtained mixture, and slowly adding 190.5g of 2-chloro-2 ', 4' -difluoroacetophenone into the mixture; next, 207g of potassium carbonate was introduced into the reaction mixture, and the resulting mixture was stirred at 25 ℃ for 7 hours; after completion of the reaction, the mixture was filtered, and the filter cake was washed with 300mL of tetrahydrofuran and concentrated at room temperature. Then, 800mL of purified water was added and the mixture was slurried and filtered, and the filtered crystals were repulped with isopropanol and filtered again, and the filter cake was washed and dried under reduced pressure to obtain 225.7g of 2- (3-chloro-1H-1, 2, 4-triazol-1-) -1- (2, 4-difluorophenyl) ethanone in a yield of 87.8%.
Step two, synthesizing 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone.
257.5g of 2- (3-chloro-1H-1, 2, 4-triazole-1-) -1- (2, 4-difluorophenyl) ethanone, 5.15g of 10% Pd/C catalyst and 1000ml of ethanol were added to a 2000ml three-neck reaction flask under the protection of nitrogen, nitrogen was replaced with hydrogen, the mixture was slowly heated to 50 ℃ under a pressure of 1MPa, the reaction was carried out for 5 hours under stirring, and the progress of the reaction was monitored by TLC. After the reaction was completed, the temperature was reduced to room temperature, hydrogen was discharged, the catalyst was filtered off, and the mother liquor was concentrated under reduced pressure to dryness to obtain 198.7g of a final product, 2'4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, in a yield of 89.1%.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. A preparation method of 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone is characterized in that:
the synthesis path is as follows:
the preparation method comprises the following steps:
q1, selecting 2-chloro-2 ', 4' -difluoroacetophenone as a raw material at a reaction temperature, reacting with 3-chloro-1, 2, 4-triazole under a reaction solvent condition, and introducing potassium carbonate as an alkali into a reaction mixture during reaction, wherein the reaction temperature is 10-40 ℃, and the reaction time is 5-7 hours;
q2 and 2- (3-chloro-1H-1, 2, 4-triazole-1-) -1- (2, 4-difluorophenyl) ethanone are subjected to dehalogenation reaction in an alcohol solvent under the catalysis of palladium carbon in a hydrogen environment to obtain a final product, namely 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone, wherein the reaction temperature is 40-75 ℃, and the reaction time is 2-5 hours.
2. The process for preparing 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone according to claim 1, characterized in that: in the Q1, after the reaction is finished, the mixture is filtered, the filter cake is washed by the reaction solvent, concentrated at room temperature, added with a proper amount of purified water, pulped and filtered, the filtered crystal is pulped again in isopropanol and filtered again, the filter cake is washed by the reaction solvent, and the pressure is reduced and the crystal is dried.
3. The process for producing 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone according to claim 1 or 2, characterized in that: in the Q1, the reaction solvent is one of anhydrous tetrahydrofuran, anhydrous ether, benzene, toluene, ethyl acetate and acetonitrile.
4. The process for preparing 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone according to claim 3, characterized in that: in the Q1, the molar ratio of the 2-chloro-2 ', 4' -difluoroacetophenone to the 3-chloro-1, 2, 4-triazole is 1: 1-2. .
5. The process for preparing 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone according to claim 4, wherein: in the Q1, the amount of the base used was 1.5 times equivalent.
6. The process for preparing 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone according to claim 5, wherein: in Q2, after the reaction is finished, cooling to room temperature, discharging hydrogen, filtering out the catalyst, and concentrating the mother liquor under reduced pressure until the mother liquor is dry.
7. The process for preparing 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone according to claim 6, wherein: in the Q2, the alcohol solvent can be methanol or ethanol or a mixture of the two.
8. The process for preparing 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone according to claim 7, wherein: in the Q2, the palladium on carbon is contained in an amount of either 5% or 10% by mass.
9. The process for preparing 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone according to claim 8, wherein: in the Q2, the mass ratio of the palladium carbon to the 2- (3-chloro-1H-1, 2, 4-triazole-1-) -1- (2, 4-difluorophenyl) ethanone is 0.005-0.05: 1.
10. The process for preparing 2', 4' -difluoro-2- [1- (1H-1,2, 4-triazolyl) ] acetophenone according to claim 9, wherein: in the Q2, the hydrogen pressure range of the hydrogen environment is 0.2-1.5 Mpa.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4404216A (en) * | 1981-06-06 | 1983-09-13 | Pfizer Inc. | Antifungal 1,3-bis-triazolyl-2-propanol derivative |
| CN1473825A (en) * | 2002-08-07 | 2004-02-11 | 张文祥 | Process for preparing voriconazole |
| CN1488629A (en) * | 2002-10-08 | 2004-04-14 | 张文更 | Method for preparing triazole antifungal agent |
| CN106957306A (en) * | 2016-01-11 | 2017-07-18 | 武汉诺安药业有限公司 | A kind of synthetic method for the fluconazole intermediate that ends |
-
2020
- 2020-04-24 CN CN202010335499.7A patent/CN111518041A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4404216A (en) * | 1981-06-06 | 1983-09-13 | Pfizer Inc. | Antifungal 1,3-bis-triazolyl-2-propanol derivative |
| CN1473825A (en) * | 2002-08-07 | 2004-02-11 | 张文祥 | Process for preparing voriconazole |
| CN1488629A (en) * | 2002-10-08 | 2004-04-14 | 张文更 | Method for preparing triazole antifungal agent |
| CN106957306A (en) * | 2016-01-11 | 2017-07-18 | 武汉诺安药业有限公司 | A kind of synthetic method for the fluconazole intermediate that ends |
Non-Patent Citations (1)
| Title |
|---|
| 楚勇 等: "新型三氮唑醇类抗真菌药物合成（Ⅰ）", 《中国药物化学杂志》, vol. 11, no. 2, pages 80 - 84 * |
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