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Preparation method of carbamazepine (CBZ)-valaciclovir

A CBZ-L-, solvent technology, applied in the direction of organic chemistry, can solve the problem of DCU affecting the product content, and achieve the effect of benefiting the utilization rate of palladium carbon

Active Publication Date: 2013-01-02
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is to provide a preparation method of CBZ-valaciclovir for the problem that DCU affects the content of the product in the existing CBZ-valaciclovir production process

Method used

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  • Preparation method of carbamazepine (CBZ)-valaciclovir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Dissolve 25.1g of CBZ-L-valine in 150ml of dichloromethane, control the reaction temperature at 5°C, slowly add 12.8g of oxalyl chloride dropwise, control the dropping time for 1h, after the dropping is completed, keep warm for 2h, stop the reaction, and depressurize Concentrate, distill off dichloromethane and excess oxalyl chloride, and prepare the acid chloride for use in the next step;

[0024] Add 20g of acyclovir to 300ml of N,N-dimethylformamide, control the reaction temperature at 20°C, add 13.8g of potassium carbonate, then slowly add the acid chloride prepared in the previous step dropwise, control the dropping time for 1h, and then raise the temperature To 40°C, continue to react for 4h, through liquid-phase central control reaction, after aciclovir remaining less than 1%, carry out vacuum concentration, add 600ml methanol to recrystallize the crude product after concentration, obtain 34g CBZ-valaciclovir, product yield 85% %, its purity measured by liquid ch...

Embodiment 2

[0026] Dissolve 25.1g of CBZ-L-valine in 150ml of benzene, control the temperature at 10°C, slowly add 13g of thionyl chloride dropwise, control the dropping time for 5h, after the dropwise addition is completed, keep warm for 2h, stop the reaction, concentrate under reduced pressure, Evaporate excess thionyl chloride, and prepare the acid chloride for use in the next step;

[0027] Add 20g of acyclovir to 300ml of benzene, control the temperature at 20°C, add 13.8g of potassium carbonate, then slowly drop in the acid chloride prepared in the previous step, control the drop time for 1h, then raise the temperature to 40°C, and continue the reaction for 4h, Through the liquid-phase control reaction, the remaining acyclovir was less than 1%, and then concentrated under reduced pressure. After concentration, the crude product was recrystallized by adding 600ml of methanol to obtain 31.6g of CBZ-valaciclovir. The product yield was 79%. The purity is 99.0%.

Embodiment 3

[0029] Dissolve 25.1g of CBZ-L-valine in 150ml of benzene, control the reaction temperature at 40°C, slowly add 13g of thionyl chloride dropwise, control the dropping time for 1h, after the dropping is completed, keep warm for 2h, stop the reaction, and concentrate under reduced pressure , distill off benzene and excess thionyl chloride, and prepare the acid chloride for use in the next step;

[0030] Add 20g of acyclovir to 300ml of N,N-dimethylformamide, control the reaction temperature at 20°C, add 12g of triethylamine, then slowly add the acid chloride prepared in the previous step, control the dropping time for 1h, and then raise the temperature To 60°C, continue to react for 4 hours, through the liquid phase control reaction, the remaining acyclovir is less than 1%, then concentrate under reduced pressure, after concentration, the crude product is recrystallized by adding 600ml of ethanol to obtain 35.6g of CBZ-valaciclovir, the product yield 89%, its purity measured by ...

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Abstract

The invention relates to the field of a medicine synthesis technology, and in particular relates to a preparation method of carbamazepine (CBZ)-valaciclovir. The preparation method comprises the steps of: reacting CBZ-L-valine with an acyl chlorination reagent to obtain acyl chloride; then, reacting acyl chloride with a mixed system of acyclovir and an acid-binding agent; and finally, filtering and refining to obtain the CBZ-valaciclovir. According to the method, acyl chloride is utilized to prepare ester, dicyclohexylcarbodiimide (DCC) is not used in the reaction process and does not generate dicyclohexylurea (DCU) is not remianed in the product, thus being beneficial to improvement of the palladium-carbon utilization rate; and the preparation method disclosed by the invention is an effective method for preparing the high-purity CBZ-valaciclovir.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of CBZ-valaciclovir. Background technique [0002] Acyclovir is a synthetic purine nucleoside analog, mainly used for various infections caused by herpes simplex virus, and can be used for initial or recurrent skin, mucous membrane, external genital infection and HSV infection in immunocompromised patients ; EP99493 first announced the glycine and alanine esters of acyclovir, which can significantly improve its solubility and bioavailability. EP0308065 and US495792 announced that the valine and isoleucine esters of acyclovir have better solubility and bioavailability problems, especially the L configuration. Glaxo company marketed Acyclovir-L-valine ester as the prodrug of Acyclovir, and its chemical name was L-valine-2-[(6-oxoaminodihydro-9H-purine- 9-yl)methoxy]ethyl ester hydrochloride, the Chinese name is valaciclovir hydrochloride. [0003] Val...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
Inventor 赵攀峰郑庚修马崇雷
Owner SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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