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The preparation method of high-purity cbz-valacyclovir

A technology of valacyclovir and CBZ-L-, which is applied in the field of preparation of high-purity CBZ-valacyclovir, can solve the problem of high product impurity content, and achieve the effects of improving product purity, shortening reaction time and reducing energy consumption

Active Publication Date: 2011-12-14
LIVZON GROUP CHANGZHOU KONY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to overcome the above-mentioned defects, the technical problem to be solved in the present invention is: for the problem that the product impurity content that exists in the existing CBZ-valacyclovir production technology is high, a kind of preparation method of high-purity CBZ-valacyclovir is provided

Method used

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  • The preparation method of high-purity cbz-valacyclovir

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Experimental program
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Effect test

Embodiment 1

[0031] Put 800ml of N,N-dimethylformamide into the reaction flask, add 25g of acyclovir, 50g of N-benzyloxycarbonyl-L-valine and 0.5g of 4-dimethylaminopyridine under stirring, and cool to 10℃ Hereinafter, 40g of dicyclohexylcarbodiimide was added, and after the reaction was kept at 5-10°C for 2 hours, the temperature was raised to 20-25°C within 55-65 minutes, and the reaction was kept at temperature for 15 hours. The solid in the reaction system (dicyclohexylurea) was filtered off with suction, and the filtrate was concentrated under reduced pressure to obtain an oily substance. 300ml of ethanol was added to heat to dissolve the concentrate. After the solution was cleared, it was cooled to -5 to 0°C for crystallization for 10 hours. After suction filtration, the obtained solid was heated and dissolved with 250 ml of ethanol, and then cooled to -5 to 0°C for 10 hours to crystallize. Suction filtration, the obtained solid was dissolved by heating with 100ml of N,N-dimethylforma...

Embodiment 2

[0033] Put 800ml of N,N-dimethylformamide into the reaction flask, add 25g of acyclovir, 50g of N-benzyloxycarbonyl-L-valine and 0.5g of 4-dimethylaminopyridine under stirring, and cool to 10℃ Hereinafter, 40g of dicyclohexylcarbodiimide is added, and after the reaction is kept at 5-10°C for 1 hour, the temperature is raised to 20-25°C in 115-125 minutes, and the reaction is kept at temperature for 15 hours. The solid in the reaction system (dicyclohexylurea, a byproduct of the reaction) was filtered off with suction, the filtrate was concentrated under reduced pressure to obtain an oily substance, 300ml of ethanol was added to heat to dissolve the concentrate, dissolved and then cooled to -5°C for crystallization for 10 hours. Suction filtration, the obtained solid was dissolved by heating with 100ml of N,N-dimethylformamide, and then the obtained N,N-dimethylformamide solution was added to 600ml of hot water at a temperature of 55~65℃, and Stir at 55°C for 30 minutes, filter ...

Embodiment 3

[0035] Put 800ml of N,N-dimethylformamide into the reaction flask, add 25g of acyclovir, 50g of N-benzyloxycarbonyl-L-valine and 0.5g of 4-dimethylaminopyridine under stirring, and cool to 5℃ Hereinafter, 40g of dicyclohexylcarbodiimide is added, and after the reaction is kept at 0-5°C for 2 hours, the temperature is raised to 20-25°C in 55-65 minutes, and the reaction is kept at the temperature for 15 hours. The solid (dicyclohexylurea) in the reaction system was filtered off with suction, and the filtrate was concentrated under reduced pressure to obtain an oily substance. 300ml of ethanol was added to heat to dissolve the concentrate, dissolved and cooled to 0°C for crystallization for 10 hours. After suction filtration, the obtained solid was dissolved by heating with 250 ml of ethanol, and then cooled to 0°C to crystallize for 10 hours. Suction filtration, the obtained solid was dissolved by heating with 100ml of N,N-dimethylformamide, and then the obtained N,N-dimethylfor...

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Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of high-purity CBZ-valacyclovir. The preparation method of high-purity CBZ-valacyclovir is to suspend acyclovir in N,N-dimethylformamide, add CBZ-L-valine and 4-dimethylaminopyridine to obtain a cloudy solution, Cool the turbid liquid to 0-10°C, add dicyclohexylcarbodiimide, keep it warm for 1-5 hours, raise the temperature to 18-30°C, control the heating time at 1-2 hours, and keep it warm at 18-30°C for 10-20 hours Finally, filter out the solid in the reaction system, concentrate the filtrate under reduced pressure to obtain an oil, heat and dissolve the concentrate with ethanol, cool and crystallize after dissolving and filter, recrystallize and filter the obtained solid with ethanol, and use a dosed N,N-di Methylformamide is heated and dissolved to obtain a crude CBZ-valacyclovir solution. The solution is added to water between 50 and 80°C to precipitate solids, filtered, and the obtained filter cake is washed with water between 50 and 80°C and dried. Dry to obtain high-purity CBZ-valacyclovir.

Description

Technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a method for preparing high-purity CBZ-valaciclovir. Background technique [0002] Valacyclovir hydrochloride is a prodrug of acyclovir. It is quickly absorbed after oral administration and quickly converted into acyclovir in the body. Its antiviral effect is exerted by acyclovir and is used to treat type I and II Type herpes simplex and herpes zoster. This product has no effect on the central nervous system, respiratory and blood circulatory system, autonomic nervous system, digestive system and smooth muscle. Valaciclovir hydrochloride has good water solubility and can be quickly absorbed by the human body after oral administration. Compared with acyclovir, its oral bioavailability is 3 to 4 times that of acyclovir. In terms of safety, valacyclovir is similar to acyclovir. According to the website of the British "New Scientist" magazine, a small-scale experiment condu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/18
Inventor 陈敖李鸣海柏凤飞马立新
Owner LIVZON GROUP CHANGZHOU KONY PHARMA
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