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Voriconazole derivate and preparation process thereof

A technology of voriconazole and compounds, applied in the field of voriconazole derivatives and its preparation, can solve the problems of long steps and low yield, and achieve the effect of short route and high yield

Inactive Publication Date: 2007-07-18
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This compound was once disclosed in EP440372, US5278175, and its synthetic method has also been reported in CN1810806A, but the common problem that these synthetic methods exist is that the steps are lengthy and the yield is too low

Method used

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  • Voriconazole derivate and preparation process thereof
  • Voriconazole derivate and preparation process thereof
  • Voriconazole derivate and preparation process thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The preparation of embodiment 1 compound 2-(5-fluoro-4-yl) ethyl acetate (II):

[0040] Into a 100ml three-necked flask, add 25ml of absolute ethanol, 5g of 2-(5-fluoro-4-yl)acetic acid, carefully dropwise add 2ml of concentrated sulfuric acid, slowly heat up to reflux state after adding, keep warm for half an hour, cool to room temperature, slowly Pour into cold sodium carbonate solution, stir while pouring, keep the solution alkaline, precipitate solid, filter, wash the filter cake with a small amount of cold water, discard the filtrate, and air-dry the filter cake naturally to obtain 7.2g of white powder, melting point 77-78 °C, yield 94%.

[0041] 1 H NMR (CDCl 3 )δ: 8.90(d, J=3Hz, 1H), 8.50(d, J=3Hz, 1H), 3.50(s, 2H), 4.10(f, J=8Hz, 2H), 1.30(t, J=8Hz , 3H).

Embodiment 2

[0042] Preparation of Example 2 Compound 2-(5-fluoro-4-yl) ethyl propionate (III):

[0043] In a 100ml three-necked flask, add 25ml of anhydrous acetonitrile, 10g of anhydrous potassium carbonate, 5g of ethyl 2-(5-fluoro-4-yl)acetate, heat to reflux, add 3.8g of dimethyl sulfate dropwise, after the dropwise addition, Reflux for 6 hours, TLC detects the end point, recover the solvent, pour the residue into water, precipitate a light yellow solid, filter, wash the filter cake with a small amount of water, discard the filtrate, and recrystallize the filter cake with 95% ethanol to obtain 4.60 g of a white solid, melting point 69.5-71.5°C, yield 86%. 1 H NMR (CDCl 3)δ: 8.89(d, J=3Hz, 1H), 8.48(d, J=3Hz, 1H), 3.62(f, J=7.6Hz, 1H), 4.10(f, J=8Hz, 2H), 1.30( t, J=8Hz, 3H), 1.20 (d, J=7.5Hz, 3H).

Embodiment 3

[0044] Preparation of Example 3 Compound S-2-(5-fluoro-4-yl)propionic acid (IV):

[0045] Add the solid obtained in the second step to 25ml of dilute hydrochloric acid, heat to reflux for 2 hours, evaporate most of the water, adjust the pH to 8 with sodium bicarbonate solution, and precipitate a white solid, filter, add the filter cake to 10ml of water, add equimolar -(2-phenylethylamine), heated to dissolve, cooled to room temperature to obtain granular colorless transparent crystals, filtered, heated and dissolved the crystals in 5ml of water, adjusted the pH value to 8, cooled to precipitate 1.8g of white solid, separated After the mother liquor was racemized and resolved, another 1.6g was obtained with a melting point of 189-190°C and a yield of 86.1%. 1 H NMR (CDCl 3 )δ: 11.05(s, 1H), 8.88(d, J=2.8Hz, 1H), 8.30(d, J=2.8Hz, 1H), 3.85(q, J=7.6Hz, 1H), 1.39(d, J=7.6Hz, 3H).

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Abstract

This invention involves Voriconazole derivatives. The invention also involves Voriconazole derivatives preparation methods, including the following steps : 2 - (5-fluoro-4-yl) acetate and ethanol for esterification, generate 2 -(5-fluoro-4-yl) ethyl acetate, in alkaline conditions takes reaction with methylation agent, generate 2 - (5-fluoro-4-yl) ethyl propionate; hydrolysis of 2 - (5-fluoro-4-yl) propionic acid, through split gain S-2 - (5-fluoro-4-yl) propionic acid; for chlorination to gain S-2 - (5-fluoro-4-yl) propionyl chloride; occurred Friedel-Crafts reaction, generating S-1 - 2, 4-difluoro-2 - (5-fluoro-4-yl) acetone; with 1-methyl - 1-H-1 ,2,4 - triazol under alkali conditions to take reaction to gain voriconazole and the series of voriconazole derivatives. The methods described in this invention has short routes, only use of a pair of enantiomers separation, the overall yield has been greatly improved, is a simple and easy method for synthesis of voriconazole and its derivatives.

Description

technical field [0001] The invention relates to the field of medicine, in particular to voriconazole derivatives and a preparation method thereof. Background technique [0002] Voriconazole [2R,3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1-hydrogen-,1,2,4-triazole-1 -Base)-2-propanol] is an antifungal drug for clinical use. Voriconazole was researched and developed by Pfizer. It began Phase III clinical trials in 1996, ended clinical trials in 2000, and passed FDA expert review in October 2001. Tablets and injections were launched in the United States in 2002. Suppositories and ointments have not yet been marketed abroad, so the domestic declaration category is "Chemical Drug Class 2". It is highly sensitive and effective to the common deep fungal infection bacteria in clinical practice. The drug concentration in plasma and tissue can inhibit the vast majority of Candida strains (>90%), Aspergillus strains (>90%) and Cryptococcus neoformans (>99%) %) ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06C07D405/14A61K31/506A61P31/10
Inventor 王玉成辜顺林
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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