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Method for preparing voriconazole racemate by adopting micro-channel reactor

A technology of voriconazole racemate and microchannel reactor, which is applied in chemical instruments and methods, chemical/physical/physical-chemical reactors, chemical/physical/physical-chemical processes, etc., can solve the problem of low conversion rate of raw materials and poor product selectivity , long reaction time and other problems, to achieve the effect of high product yield, high safety, and precise control of reaction conditions

Inactive Publication Date: 2021-03-05
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is the problem of long reaction time, poor product selectivity, and low co

Method used

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  • Method for preparing voriconazole racemate by adopting micro-channel reactor
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  • Method for preparing voriconazole racemate by adopting micro-channel reactor

Examples

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Embodiment 1

[0033] Preparation of voriconazole racemate

[0034] (1) Preparation of mixed solution C: add water (720g) and dichloromethane (720g) to voriconazole condensate hydrochloride III (200g), stir well to obtain mixed solution A, add 40% sodium hydroxide solution to adjust the pH value of the mixed solution A, let stand to separate the liquid, collect the dichloromethane layer and concentrate to obtain the intermediate product II, add ethanol (580g) and palladium carbon catalyst (8g) to the intermediate product II, and stir evenly to obtain Mixed solution C, set aside;

[0035](2) Open the microchannel reactor, open the valve of the nitrogen storage tank to fill the reactor channel with nitrogen, then pass in the solvent, adjust the temperature of the heat exchanger to 100 ° C, wait until the first reactor module, the second reactor module When the reaction pressure of the third reactor module reaches 8kg and the reaction temperature reaches 100°C, close the valve of the nitrogen ...

Embodiment 2

[0037] Preparation of voriconazole racemate

[0038] (1) Preparation of mixed solution C: add water (720g) and dichloromethane (720g) to voriconazole condensate hydrochloride (Ⅲ) (200g), stir well to obtain mixed solution A, add dropwise to mixed solution A 40% sodium hydroxide solution to adjust the pH value of the mixed solution A, let stand to separate the liquid, collect the dichloromethane layer and concentrate to obtain the intermediate product II, add ethanol (580g) and palladium carbon catalyst (8g) to the intermediate product II, stir Obtain the mixed solution C evenly and set aside;

[0039] (2) Open the microchannel reactor, open the valve of the nitrogen storage tank to fill the reactor channel with nitrogen, then pass in the solvent, adjust the temperature of the heat exchanger to 120 ° C, wait until the first reactor module, the second reactor module When the reaction pressure of the third reactor module reaches 10kg and the reaction temperature reaches 120°C, c...

Embodiment 3

[0041] Preparation of voriconazole racemate

[0042] (1) Preparation of mixed solution C: add water (720g) and dichloromethane (720g) to voriconazole condensate hydrochloride (Ⅲ) (200g), stir well to obtain mixed solution A, add dropwise to mixed solution A 40% sodium hydroxide solution to adjust the pH value of the mixed solution A, let stand to separate the liquid, collect the dichloromethane layer and concentrate to obtain the intermediate product II, add ethanol (580g) and palladium carbon catalyst (8g) to the intermediate product II, stir Obtain the mixed solution C evenly and set aside;

[0043] (2) Open the microchannel reactor, open the valve of the nitrogen storage tank to fill the reactor channel with nitrogen, then pass in the solvent, adjust the temperature of the heat exchanger to 130 ° C, wait until the first reactor module, the second reactor module And the reaction pressure of the third reactor module reaches 12kg and the reaction temperature reaches 130°C, cl...

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Abstract

The invention discloses a method for preparing voriconazole racemate by using a micro-channel reactor. The method comprises the following steps: using voriconazole condensate hydrochloride as a raw material, adding water and dichloromethane, stirring, dropwisely adding a sodium hydroxide solution to regulate the pH value, performing standing for liquid separation, collecting the dichloromethane layer, concentrating, adding ethanol and a palladium-carbon catalyst into the material, performing uniform stirring for later use, starting a micro-channel reactor, opening the valve of the nitrogen storage tank to adjust the pressure of the reactor, adjusting the temperature of a heat exchanger, adjusting a feeding pump for reaction, and performing sampling detection after material feeding is stable. The raw material conversion rate is high. The preparation method disclosed by the invention is short in reaction time, can effectively avoid safety risks caused by large-scale use of hydrogen and use of a high-pressure reaction kettle, and is high in safety, accurate in reaction condition control, high in product yield and good in purity.

Description

technical field [0001] The invention relates to the field of medicine preparation methods, in particular to a method for preparing voriconazole racemate by using a microchannel reactor. Background technique [0002] Voriconazole (Voriconazole) is a broad-spectrum triazole antifungal drug approved by the FDA in 2002 for the treatment of invasive aspergillosis, severe invasive infections caused by fluconazole-resistant Candida (including Candida krusei) , Serious infections caused by Actinomycetes sp. and Fusarium sp. Its mechanism of action is to inhibit the activity of CYP450-dependent 14α-lanosterol demethylase, thereby inhibiting the formation of functional fungal membranes and the biosynthesis of sterols that maintain fungal growth, hindering the synthesis of cell membranes and causing cell rupture and death. The Infectious Diseases Society of America (IDSA) recommends voriconazole as the first-line treatment for invasive Aspergillus infections and an alternative treatme...

Claims

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Application Information

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IPC IPC(8): C07D403/06B01J19/00
CPCB01J19/0093C07D403/06
Inventor 董雪林覃志俊蔡强胡双龙王晴晴
Owner 珠海润都制药股份有限公司