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Method for continuously preparing voriconazole intermediate 2-fluoro-3-oxopentanoic acid ethyl ester

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

Active Publication Date: 2022-02-25
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 2-fluoro-3-oxopentanoic acid ethyl ester
  • Method for continuously preparing voriconazole intermediate 2-fluoro-3-oxopentanoic acid ethyl ester
  • Method for continuously preparing voriconazole intermediate 2-fluoro-3-oxopentanoic acid ethyl ester

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 voriconazole intermediate 2-fluoro-3-oxyvaleric acid ethyl ester, comprising: feeding a reaction solvent, 2-fluoro-ethyl acetate, propionyl chloride and sodium hydrogen into a reaction kettle for reaction, Then add boric acid and acid anhydride, then send the reaction solution into the centrifuge, the supernatant is continuously sent to the middle of the rectification tower for heating and rectification, the light components are condensed at the top of the tower, and refluxed into the reaction kettle, and the heavy component products are extracted from the tower Bottom collection, that is. The invention realizes the continuous production process of the reaction of 2-fluoro-ethyl acetate and propionyl chloride and the separation of 2-fluoro-3-oxopentanoic acid ethyl ester through the reaction kettle coupling rectification tower. By adding boric acid and anhydride after the reaction, the reaction by-product 2-fluoro-3-oxopentanoic acid is converted into 2-fluoro-3-oxovaleric acid- which is easily separated from the main product O 3, O 4‑boryl diacetate improves the purity of the product, realizes low energy consumption, simple and rapid continuous production, the product yield is greater than 90%, and the purity is above 98%.

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 & Authority Patents(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
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