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Preparation method of voriconazole intermediate

A technology for voriconazole and intermediates, which is applied in the field of drug synthesis, can solve the problems of difficult realization, many reaction impurities and a large amount, and achieves the effects of low production equipment requirements, simple synthesis conditions and high total yield

Active Publication Date: 2018-03-02
JIANGSU HANSYN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the step of preparing compound 7, this route needs to be reacted under strong basic conditions. Under this condition, methyl bromoacetate is easily hydrolyzed into bromoacetic acid, which produces a large amount of bromoacetic acid impurities, resulting in a lot of reaction impurities, and Compound 7 and compound 8 require rectification, which is not easy to achieve in industrial production, therefore, the development of a new synthetic method is of great significance for the industrial production of this intermediate

Method used

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  • Preparation method of voriconazole intermediate
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  • Preparation method of voriconazole intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Example 1 Preparation of 2'-chloro-2,4-difluoroacetophenone (compound 5)

[0028] Prepare a dry and clean 1000mL glass four-neck bottle, equipped with a suitable mechanical stirrer, condenser tube and thermometer, pay attention to check the airtightness before adding materials, N 2 Add 96.5g of 2,4-difluorobromobenzene (0.5mol, 1.0eq), 25.5g (0.525mol, 1.05eq) of magnesium strips, 500mL of tetrahydrofuran into the reaction flask under protection, start stirring, and raise the temperature of the reaction solution to 30 ~35°C, stirred and reacted for 2h. After the reaction was completed, the reaction solution was slowly added dropwise to 90.0g (0.55mol, 1.1eq.) of 4-(2-chloroacetyl)morpholine (compound 4) tetrahydrofuran solution (90.0 g dissolved in 360ml of tetrahydrofuran), the temperature was controlled at 0°C during the dropping process, and added dropwise (about 0.05mL per drop, the same below). After the reaction finished, the reaction system was dripped with 100m...

Embodiment 2

[0029] Example 2 Preparation of 2'-chloro-2,4-difluoroacetophenone (compound 5)

[0030] Prepare a dry and clean 1000mL glass four-neck bottle, equipped with a suitable mechanical stirrer, condenser tube and thermometer, pay attention to check the airtightness before adding materials, N 2 Add 96.5g of 2,4-difluorobromobenzene (0.5mol, 1.0eq), 25.5g (0.525mol, 1.05eq) of magnesium strips, 500mL of tetrahydrofuran into the reaction flask under protection, start stirring, and raise the temperature of the reaction solution to 30 ~35°C, stirred and reacted for 2h. After the reaction was completed, the reaction solution was slowly added dropwise to 90.0g (0.55mol, 1.1eq.) of 4-(2-chloroacetyl)morpholine (compound 4) tetrahydrofuran solution (90.0 g was dissolved in 360ml of tetrahydrofuran), the temperature was controlled at 20°C during the dropwise addition, and after the dropwise addition was completed, the temperature was kept at 20°C and stirred for 4 hours. After the reaction ...

Embodiment 3

[0031] Example 3 Preparation of 2'-chloro-2,4-difluoroacetophenone (compound 5)

[0032] Prepare a dry and clean 1000mL glass four-neck bottle, equipped with a suitable mechanical stirrer, condenser tube and thermometer, pay attention to check the airtightness before adding materials, N 2 Add 96.5g of 2,4-difluorobromobenzene (0.5mol, 1.0eq), 25.5g (0.525mol, 1.05eq) of magnesium strips, 500mL of tetrahydrofuran into the reaction flask under protection, start stirring, and raise the temperature of the reaction solution to 30 ~35°C, stirred and reacted for 2h. After the reaction was completed, the reaction solution was slowly added dropwise to 90.0g (0.55mol, 1.1eq.) of 4-(2-chloroacetyl)morpholine (compound 4) tetrahydrofuran solution (90.0 g was dissolved in 360ml of tetrahydrofuran), the temperature was controlled at 40°C during the dropwise addition, and after the dropwise addition was completed, the temperature was kept at 40°C and stirred for 2 hours. After the reaction ...

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Abstract

The invention discloses a preparation method of a voriconazole intermediate. The preparation method comprises the following steps of firstly, preparing 2,4-difluoro brmorobenzene (compound 2) into a format reagent; then reacting with 4-(2-chloracetyl)morpholine (compound 4), so as to obtain a compound, namely 2'-chloro-2,4-difluoroacetophenone (compound 5); finally, enabling the compound 5 to react with 1,2,4-sodium triazole, so as to obtain the voriconazole intermediate (compound 1). The preparation method has the advantages that the cost of the raw materials is low, and the obtaining is easy; the reaction conditions are moderate, the requirement on a reaction kettle is low, and the good industrialization prospect is realized.

Description

technical field [0001] The invention relates to a preparation method of a voriconazole intermediate, which belongs to the technical field of drug synthesis. Background technique [0002] Voriconazole ((2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazole-1- Base)-2-butanol) is a new type of broad-spectrum antifungal drug developed by Pfizer (Pfizer) in the early 21st century, which has a wider antibacterial spectrum than similar triazole antifungal drugs. [0003] Most of the currently reported methods for the synthesis of voriconazole are through the key intermediate 2'4'-difluoro [0004] -2-[1-(1H-1,2,4-triazolyl)]acetophenone with 4-chloro-6-ethyl-5-fluoropyrimidine or 4-(1-bromoethyl)-5 -Fluoro-6-chloropyrimidine reacts to form voriconazole racemate, and then uses chiral resolution to obtain voriconazole. [0005] (US5567817, US5278175, WO06065726, WO07013096). [0006] The traditional synthetic route of voriconazole intermediate 2'4'-difluo...

Claims

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Application Information

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IPC IPC(8): C07D249/08
CPCC07D249/08
Inventor 王希林余园园
Owner JIANGSU HANSYN PHARMA
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