Method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate

A technology of ethyl oxyvalerate and voriconazole, applied in the separation/purification of carboxylic acid esters, preparation of carboxylic acid esters, chemical instruments and methods, etc., can solve the problem that the purity of ethyl 2-fluoro-3-oxovaleric acid is difficult to further improve Improvements, technical difficulties, etc.

Active Publication Date: 2020-03-24
南京恒道医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the boiling point of 2-fluoro-3-oxopentanoic acid is close to that of the main product ethyl 2-fluoro-3-oxopentanoate, so it is difficult to separate the impurity from the main product by general rectification operation
This makes it difficult to further improve the purity of ethyl 2-fluoro-3-oxopentanoate, and finally brings certain technical difficulties to the subsequent synthesis of high-purity voriconazole

Method used

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  • Method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate
  • Method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate
  • Method for continuously preparing voriconazole intermediate ethyl 2-fluoro-3-oxopentanoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The reaction product is qualitatively and quantitatively detected by high-performance liquid chromatography: octadecylsilane bonded silica gel is used as a filler (4.6mm×150mm, 3μm or a chromatographic column with equivalent performance), and 0.03mol / L disodium hydrogen phosphate solution (Adjust the pH value to 6.5 with phosphoric acid)-acetonitrile (55:45) as the mobile phase; the detection wavelength is 230nm, and the injection volume is 20 μl.

[0025] Using tetrahydrofuran as the reaction solvent, propionyl chloride and 2-fluoro-ethyl acetate are pumped into the reaction kettle at a molar ratio of 5:1; sodium hydrogen and 2-fluoro-ethyl acetate are pumped into the reaction kettle at a molar ratio of 1:1. Heat to the reaction temperature of 35°C, stir vigorously for 10 h, add boric acid and acetic anhydride, so that the molar ratio of boric acid, acetic anhydride and 2-fluoro-ethyl acetate is 1:1:5. The reaction solution is pumped from the bottom of the reaction ket...

Embodiment 2

[0027] Reaction product qualitative and quantitative detection method and operation are all the same as in Example 1, and the implementation steps of changing the reactant molar proportion and each operating parameter are as follows:

[0028] With tetrahydrofuran as the reaction solvent, propionyl chloride and 2-fluoro-ethyl acetate are pumped into the reaction kettle in a molar ratio of 4:1; sodium hydrogen and 2-fluoro-ethyl acetate are pumped into the reaction kettle in a molar ratio of 3:1. Heat to the reaction temperature of 60°C, stir vigorously for 3 hours, add boric acid and acetic anhydride, so that the molar ratio of boric acid, acetic anhydride and 2-fluoro-ethyl acetate is 1:1:8. The reaction solution is pumped from the bottom of the reaction kettle into a centrifuge to remove the generated sodium chloride. The filtrate is continuously pumped into the middle of the rectification tower, heated and rectified to 85°C, and the product is separated, the light component ...

Embodiment 3

[0030] Reaction product qualitative and quantitative detection method and operation are all the same as in Example 1, and the implementation steps of changing the reactant molar proportion and each operating parameter are as follows:

[0031] With tetrahydrofuran as the reaction solvent, propionyl chloride and 2-fluoro-ethyl acetate are pumped into the reaction kettle at a molar ratio of 3:1; sodium hydrogen and 2-fluoro-ethyl acetate are pumped into the reaction kettle at a molar ratio of 6:1. Heat to the reaction temperature of 20°C, stir vigorously for 1 h, add boric acid and acetic anhydride, so that the molar ratio of boric acid, acetic anhydride and 2-fluoro-ethyl acetate is 1:1:13. The reaction solution is pumped from the bottom of the reaction kettle into a centrifuge to remove the generated sodium chloride. The filtrate is continuously pumped into the middle of the rectification tower, heated and rectified to 100°C, and the product is separated, the light component pr...

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Abstract

The invention discloses a method for continuously preparing a voriconazole intermediate, namely ethyl 2-fluoro-3-oxopentanoate. The method comprises the following steps: feeding a reaction solvent, ethyl 2-fluoro-acetate, propionyl chloride and sodium hydrogen into a reaction kettle for a reaction, then adding boric acid and acid anhydride, feeding a reaction liquid into a centrifugal machine, continuously feeding a supernatant into the middle part of a rectifying tower for heating and rectifying, condensing light components at the top of the tower, allowing the condensed light components to flow back to the reaction kettle, and collecting a heavy component product from the bottom of the tower so as to obtain the voriconazole intermediate. According to the invention, boric acid and acid anhydride are added after the reaction is finished, so a reaction byproduct, namely 2-fluoro-3-oxopentanoic acid is converted into 2-fluoro-3-oxopentanoic acid-O3,O4-borodiacetate which can be easily separated from a main product, so the purity of the product is further improved; low-energy-consumption, simple, rapid and continuous production is realized; and the yield of the obtained reaction product ethyl 2-fluoro-3-oxopentanoate is greater than 90%, and the purity of the product is 98% or above.

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to a method for producing ethyl 2-fluoro-3-oxopentanoate by using 2-fluoro-ethyl acetate and propionyl chloride, and relates to the important intermediate 2-fluoro-3 of voriconazole in the field of pharmacy - Preparation technology of ethyl oxyvalerate. Background technique [0002] Voriconazole (Voriconazole) is a broad-spectrum antifungal drug developed by Pfizer Inc (Pifzer.Inc) of the United States. Its trade name is Vfend. As a derivative of fluconazole, voriconazole increases its affinity to the target enzyme after adding a methyl group to the propyl structure of fluconazole; the pyrimidine ring also increases the antifungal activity; the fluorine at the 5-position can enhance Active in vitro and primarily indicated for the treatment of progressive, potentially life-threatening infections in immunocompromised patients. Like other azole drugs, its mechanism of action is by inhibiting ...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): C07C67/60C07C67/343C07C67/48C07C67/54C07C69/716
CPCC07C67/60C07C67/343C07C67/48C07C67/54C07C69/716
Inventor陶义华凌岫泉穆加兵
Owner南京恒道医药科技股份有限公司