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Voriconazole derivate and preparation process thereof

A technology for voriconazole and compounds is applied in the field of voriconazole derivatives and their preparation, which can solve the problems of low yield, long steps and the like, and achieve the effects of short route and improved yield

Inactive Publication Date: 2009-04-15
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-fluoropyrimidin-4-yl) ethyl acetate (II):

[0040] In a 100ml three-necked flask, add 25ml of absolute ethanol, 5g of 2-(5-fluoropyrimidin-4-yl) acetic acid, carefully dropwise add 2ml of concentrated sulfuric acid, slowly heat up to reflux 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 solids, filter, wash the filter cake with a small amount of cold water, discard the filtrate, and naturally air-dry the filter cake to obtain 7.2 g 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-fluoropyrimidin-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-fluoropyrimidin-4-yl)acetate, heat to reflux, add dropwise 3.8g of dimethyl sulfate, after the dropwise addition , refluxed for 6 hours, TLC detected the end point, recovered the solvent, poured the residue into water, precipitated a light yellow solid, filtered, washed the filter cake with a small amount of water, discarded the filtrate, and recrystallized the filter cake with 95% ethanol to obtain 4.60 g of a white solid. The melting point is 69.5-71.5°C, and the yield is 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] The preparation of embodiment 3 compound S-2-(5-fluoropyrimidin-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 (S)-(-)-1-phenylethylamine, heated to dissolve, cooled to room temperature, granular colorless transparent crystals were obtained, filtered, the crystals were heated and dissolved in 5ml of water, adjusted to pH 8, cooled to precipitate a white solid 1.8g, the resolved mother liquor was racemized again, resolved to obtain another 1.6g, melting point 189-190°C, yield 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-butanol] 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%) %) g...

Claims

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Application Information

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Patent Type & Authority Patents(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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