CN110903194A - Method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate - Google Patents
Method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate Download PDFInfo
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- CN110903194A CN110903194A CN201911263105.5A CN201911263105A CN110903194A CN 110903194 A CN110903194 A CN 110903194A CN 201911263105 A CN201911263105 A CN 201911263105A CN 110903194 A CN110903194 A CN 110903194A
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- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/60—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
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- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07C67/00—Preparation of carboxylic acid esters
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- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
- C07C67/54—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation
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Abstract
The invention discloses a method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate, which comprises the following steps: feeding a reaction solvent, 2-fluoro-ethyl acetate, propionyl chloride and sodium hydrogen into a reaction kettle for reaction, then adding boric acid and acid anhydride, then feeding a reaction solution into a centrifuge, continuously feeding a supernatant into the middle part of a rectifying tower for heating and rectifying, condensing a light component at the top of the tower, refluxing the light component into the reaction kettle, and collecting a heavy component product from the bottom of the tower. The reaction of 2-fluoro-ethyl acetate and propionyl chloride and the separation of 2-fluoro-3-oxopentanoic acid ethyl ester are realized by adopting a reaction kettle coupled rectifying towerThe continuous production process. By adding boric acid and acid anhydride after the reaction is finished, the reaction byproduct 2-fluoro-3-oxovaleric acid is converted into 2-fluoro-3-oxovaleric acid which is easy to separate from the main productO3,O4-boron diacetate further improves the purity of the product, realizes low energy consumption, simple and rapid continuous production, and obtains the reaction product 2-fluoro-3-oxopentanoic acid ethyl ester with the yield of more than 90 percent and the purity of more than 98 percent.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a method for producing 2-fluoro-3-oxopentanoic acid ethyl ester by using 2-fluoro-ethyl acetate and propionyl chloride, and relates to a preparation technology of voriconazole important intermediate 2-fluoro-3-oxopentanoic acid ethyl ester in the field of pharmacy.
Background
Voriconazole (Voriconazole), a broad-spectrum antifungal drug developed by pfend, inc, pfzer, inc, usa, and marketed for the first time in america and successively in english and de in 2002. The voriconazole is used as a derivative of the fluconazole, and after 1 methyl is added to a propyl structure of the fluconazole, the affinity of the voriconazole to a target enzyme is increased; the pyrimidine ring also increases antifungal activity; fluorine in position 5 enhances in vitro activity and is used primarily to treat progressive, potentially life-threatening infections in immunodeficient patients. Like other azole drugs, its mechanism of action is through inhibiting the function of cytochrome P450-dependent 14A sterol demethylase, thereby inhibiting the formation of functional fungal membranes and the key step of sterol biosynthesis that maintains fungal growth. Indications include: immunosuppressed patients had severe fungal infections, acute invasive aspergillosis (the most common pathogenic bacteria were aspergillus fumigatus, followed by aspergillus flavus, aspergillus niger and aspergillus terreus), severe invasive infections caused by fluconazole-resistant candida species (including candida krusei), severe infections caused by actinomycete species and fusarium species.
The ethyl 2-fluoro-3-oxopentanoate is an important intermediate in the process of voriconazole production. At present, the production method of 2-fluoro-3-oxopentanoic acid ethyl ester which is applied more in industry is mainly a route taking 2-fluoro-acetic acid ethyl ester and propionyl chloride as raw materials, and the reaction formula is as follows:
in the reaction process, the product ethyl 2-fluoro-3-oxopentanoate is easy to undergo hydrolysis reaction under acidic reaction conditions to generate a byproduct 2-fluoro-3-oxopentanoic acid. And the boiling point of the 2-fluoro-3-oxopentanoic acid is close to that of the main product ethyl 2-fluoro-3-oxopentanoate, and the impurities are difficult to separate from the main product by ordinary rectification. Therefore, the purity of the ethyl 2-fluoro-3-oxopentanoate is difficult to further improve, and certain technical difficulty is brought to the subsequent synthesis of high-purity voriconazole.
Disclosure of Invention
The technical purpose of the invention is to provide a method for producing 2-fluoro-3-oxopentanoic acid ethyl ester by using 2-fluoro-ethyl acetate and propionyl chloride, and the process realizes the continuous production process of the reaction of the 2-fluoro-ethyl acetate and the propionyl chloride and the separation of the 2-fluoro-3-oxopentanoic acid ethyl ester by adopting a reaction kettle coupling rectifying tower. And boric acid and acid anhydride are added after the reaction is finished, so that the reaction byproduct 2-fluoro-3-oxopentanoic acid is converted into 2-fluoro-3-oxopentanoic acid-O3, O4-boron diacetate, which has a relatively low boiling point and is easier to separate from the main product, the purity of the product 2-fluoro-3-oxopentanoic acid ethyl ester is further improved, low-energy consumption, simple and rapid continuous production is realized, the yield of the obtained reaction product 2-fluoro-3-oxopentanoic acid ethyl ester is more than 90%, and the purity is more than 98%.
The partial reaction formula of converting the byproduct 2-fluoro-3-oxovaleric acid into 2-fluoro-3-oxovaleric acid-O3, O4-boron diacetate is as follows:
in order to realize the technical purpose of the invention, the technical scheme of the invention is as follows:
a method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate comprises the following steps:
sending a reaction solvent, 2-fluoro-ethyl acetate, propionyl chloride and sodium hydrogen into a reaction kettle for reaction, adding boric acid and acid anhydride into reaction liquid after the reaction is completed, then sending the reaction liquid into a centrifuge from the bottom of the reaction kettle to remove generated sodium chloride, continuously sending supernate into the middle part of a rectifying tower, heating and rectifying, separating products, condensing a light component propionyl chloride and a generated byproduct derivative 2-fluoro-3-oxovaleric acid-O3, O4-boron diacetate at the tower top, refluxing into the reaction kettle, collecting a heavy component product from the tower bottom, and obtaining high-purity 2-fluoro-3-oxovaleric acid ethyl ester.
Preferably, the reaction solvent is tetrahydrofuran.
Preferably, the molar ratio of the propionyl chloride to the 2-fluoro-ethyl acetate is 1: 1-5: 1.
Preferably, the molar ratio of the sodium hydrogen to the 2-fluoro-ethyl acetate is 1: 1-10: 1.
Preferably, the reaction temperature is 10-60 ℃.
Preferably, the reaction time is 1-10 h.
Preferably, the molar ratio of the added boric acid and the added acid anhydride to the 2-fluoro-ethyl acetate is 1:1: 5-1: 1: 20.
Preferably, the acid anhydride is acetic anhydride or propionic anhydride.
Preferably, the operating temperature of the rectifying tower is 70-120 ℃.
Preferably, the reaction is carried out under vigorous stirring.
Drawings
FIG. 1 is a diagram of a process apparatus according to the present invention.
Wherein, 1 is a reaction kettle, 2 is a centrifuge, 3 is a rectifying tower, and 4 is a product collecting storage tank.
Detailed Description
Example 1
And (3) carrying out qualitative and quantitative detection on the reaction product by adopting a high performance liquid chromatography: octadecylsilane chemically bonded silica is used as a filler (4.6mm multiplied by 150mm, 3 mu m or a chromatographic column with equivalent efficiency), and 0.03mol/L disodium hydrogen phosphate solution (pH value is adjusted to 6.5 by phosphoric acid) -acetonitrile (55:45) is used as a mobile phase; the detection wavelength was 230nm and the amount of sample was 20. mu.l.
Taking tetrahydrofuran as a reaction solvent, and mixing propionyl chloride and 2-fluoro-ethyl acetate in a molar ratio of 5: 1; pumping sodium hydrogen and 2-fluoro-ethyl acetate into a reaction kettle according to the molar ratio of 1:1, heating to the reaction temperature of 35 ℃, reacting for 10 hours by strong stirring, and adding boric acid and acetic anhydride to ensure that the molar ratio of the boric acid to the acetic anhydride to the 2-fluoro-ethyl acetate is 1:1: 5. And pumping the reaction liquid from the bottom of the reaction kettle to a centrifuge to remove the generated sodium chloride. Continuously pumping the filtrate into the middle part of a rectifying tower, heating and rectifying to 120 ℃, separating products, condensing light components of propionyl chloride and byproduct derivatives of 2-fluoro-3-oxopentanoic acid-O3, O4-boron diacetate at the tower top, and refluxing to a reaction kettle. The heavy component product flows out from the bottom of the tower and enters a product collecting storage tank, so that the high-purity ethyl 2-fluoro-3-oxopentanoate can be obtained, the yield is 91.1%, and the purity is 98.7%.
Example 2
The qualitative and quantitative detection method and operation of the reaction product are the same as those in example 1, and the implementation steps for changing the molar ratio of the reactants and the operation parameters are as follows:
taking tetrahydrofuran as a reaction solvent, and carrying out reaction on propionyl chloride and 2-fluoro-ethyl acetate according to a molar ratio of 4: 1; pumping sodium hydrogen and 2-fluoro-ethyl acetate into a reaction kettle according to the molar ratio of 3:1, heating to the reaction temperature of 60 ℃, reacting for 3 hours by strong stirring, and adding boric acid and acetic anhydride to ensure that the molar ratio of the boric acid to the acetic anhydride to the 2-fluoro-ethyl acetate is 1:1: 8. And pumping the reaction liquid from the bottom of the reaction kettle to a centrifuge to remove the generated sodium chloride. Continuously pumping the filtrate into the middle part of a rectifying tower, heating and rectifying to 85 ℃, separating products, condensing light components of propionyl chloride and byproduct derivatives of 2-fluoro-3-oxopentanoic acid-O3, O4-boron diacetate at the tower top, and refluxing to a reaction kettle. The heavy component product flows out from the bottom of the tower and enters a product collecting storage tank, so that the high-purity ethyl 2-fluoro-3-oxopentanoate can be obtained, the yield is 90.7%, and the purity is 99.3%.
Example 3
The qualitative and quantitative detection method and operation of the reaction product are the same as those in example 1, and the implementation steps for changing the molar ratio of the reactants and the operation parameters are as follows:
taking tetrahydrofuran as a reaction solvent, and carrying out reaction on propionyl chloride and 2-fluoro-ethyl acetate according to a molar ratio of 3: 1; pumping sodium hydrogen and 2-fluoro-ethyl acetate into a reaction kettle according to the molar ratio of 6:1, heating to the reaction temperature of 20 ℃, reacting for 1 hour by strong stirring, and adding boric acid and acetic anhydride to ensure that the molar ratio of the boric acid to the acetic anhydride to the 2-fluoro-ethyl acetate is 1:1: 13. And pumping the reaction liquid from the bottom of the reaction kettle to a centrifuge to remove the generated sodium chloride. Continuously pumping the filtrate into the middle part of a rectifying tower, heating and rectifying to 100 ℃, separating products, condensing light components of propionyl chloride and byproduct derivatives of 2-fluoro-3-oxopentanoic acid-O3, O4-boron diacetate at the tower top, and refluxing to a reaction kettle. The heavy component product flows out from the bottom of the tower and enters a product collecting storage tank, so that the high-purity ethyl 2-fluoro-3-oxopentanoate can be obtained, the yield is 92.9%, and the purity is 98.5%.
Example 4
The qualitative and quantitative detection method and operation of the reaction product are the same as those in example 1, and the implementation steps for changing the molar ratio of the reactants and the operation parameters are as follows:
taking tetrahydrofuran as a reaction solvent, and mixing propionyl chloride and 2-fluoro-ethyl acetate in a molar ratio of 2: 1; pumping sodium hydrogen and 2-fluoro-ethyl acetate into a reaction kettle according to the molar ratio of 8:1, heating to the reaction temperature of 10 ℃, reacting for 7 hours by strong stirring, and adding boric acid and acetic anhydride to ensure that the molar ratio of the boric acid to the acetic anhydride to the 2-fluoro-ethyl acetate is 1:1: 16. And pumping the reaction liquid from the bottom of the reaction kettle to a centrifuge to remove the generated sodium chloride. Continuously pumping the filtrate into the middle part of a rectifying tower, heating and rectifying to 110 ℃, separating products, condensing light components of propionyl chloride and byproduct derivatives of 2-fluoro-3-oxopentanoic acid-O3, O4-boron diacetate at the tower top, and refluxing to a reaction kettle. The heavy component product flows out from the bottom of the tower and enters a product collecting storage tank, so that high-purity ethyl 2-fluoro-3-oxopentanoate can be obtained, the yield is 93.3%, and the purity is 99.2%.
Example 5
The qualitative and quantitative detection method and operation of the reaction product are the same as those in example 1, and the implementation steps for changing the molar ratio of the reactants and the operation parameters are as follows:
taking tetrahydrofuran as a reaction solvent, and mixing propionyl chloride and 2-fluoro-ethyl acetate in a molar ratio of 1: 1; pumping sodium hydrogen and 2-fluoro-ethyl acetate into a reaction kettle according to the molar ratio of 10:1, heating to the reaction temperature of 50 ℃, reacting for 5 hours by strong stirring, and adding boric acid and acetic anhydride to ensure that the molar ratio of the boric acid to the acetic anhydride to the 2-fluoro-ethyl acetate is 1:1: 20. And pumping the reaction liquid from the bottom of the reaction kettle to a centrifuge to remove the generated sodium chloride. Continuously pumping the filtrate into the middle part of a rectifying tower, heating and rectifying to 70 ℃, separating products, condensing light components of propionyl chloride and byproduct derivatives of 2-fluoro-3-oxopentanoic acid-O3, O4-boron diacetate at the tower top, and refluxing to a reaction kettle. The heavy component product flows out from the bottom of the tower and enters a product collecting storage tank, so that the high-purity ethyl 2-fluoro-3-oxopentanoate can be obtained, the yield is 94.6%, and the purity is 98.9%.
Claims (9)
1. A method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate is characterized by comprising the following steps:
sending a reaction solvent, 2-fluoro-ethyl acetate, propionyl chloride and sodium hydrogen into a reaction kettle for reaction, adding boric acid and acid anhydride into a reaction solution after the reaction is completed, then sending the reaction solution into a centrifuge from the bottom of the reaction kettle to remove the generated sodium chloride, continuously sending the supernatant into the middle part of a rectifying tower, heating and rectifying, separating a product, a light component propionyl chloride and a generated byproduct derivative 2-fluoro-3-oxypentanoic acid-O3,OAnd condensing the 4-boron diacetate at the tower top, refluxing to the reaction kettle, and collecting the heavy component product from the tower bottom to obtain the product.
2. The continuous preparation method of voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate according to claim 1, wherein said reaction solvent is tetrahydrofuran.
3. The method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate according to claim 1, wherein the molar ratio of propionyl chloride to the ethyl 2-fluoro-acetate is 1: 1-5: 1.
4. The method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate according to claim 1, wherein the molar ratio of sodium hydrogen to ethyl 2-fluoro-acetate is 1:1 to 10: 1.
5. The method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate according to claim 1, wherein the reaction temperature is 10-60 ℃.
6. The method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate according to claim 1, wherein the reaction time is 1-10 h.
7. The method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate according to claim 1, wherein the molar ratio of boric acid and anhydride to 2-fluoro-ethyl acetate is 1:1:5 to 1:1: 20.
8. The method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate according to claim 1, wherein said anhydride is acetic anhydride or propionic anhydride.
9. The method for continuously preparing ethyl 2-fluoro-3-oxopentanoate according to claim 1, wherein said distillation column is operated at a temperature of from 70 ℃ to 120 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013066629A1 (en) * | 2011-10-19 | 2013-05-10 | Bioformix, Llc | Methylene beta-ketoester monomers, methods for making methylene beta-ketoester monomers, polymerizable compositions and products formed therefrom |
| CN105085522A (en) * | 2015-10-12 | 2015-11-25 | 山东罗欣药业集团股份有限公司 | Method for preparing high-purity moxifloxacin hydrochloride |
| CN105859764A (en) * | 2016-05-04 | 2016-08-17 | 江苏苏南药业实业有限公司 | Preparation method of key intermediate of moxifloxacin |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013066629A1 (en) * | 2011-10-19 | 2013-05-10 | Bioformix, Llc | Methylene beta-ketoester monomers, methods for making methylene beta-ketoester monomers, polymerizable compositions and products formed therefrom |
| CN105085522A (en) * | 2015-10-12 | 2015-11-25 | 山东罗欣药业集团股份有限公司 | Method for preparing high-purity moxifloxacin hydrochloride |
| CN105859764A (en) * | 2016-05-04 | 2016-08-17 | 江苏苏南药业实业有限公司 | Preparation method of key intermediate of moxifloxacin |
Non-Patent Citations (1)
| Title |
|---|
| 吕微巍 等: "相转移法制备2-氟丙酰乙酸乙酯", 《中国医药工业杂志》 * |
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