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Preparation method for ganciclovir valine ester derivative

A technology of lovir valine ester and ganciclovir, which is applied in the field of preparation of ganciclovir valine ester derivatives, can solve the problems of high irritation, complicated extraction process, influence on yield and final product quality, etc.

Active Publication Date: 2011-05-25
ZHEJIANG CHARIOTEER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of this method are: the extraction process is complicated, and the monoester, diester and ganciclovir need to be extracted and separated separately with various solvent systems; and although the trifluoroacetic acid used is an excellent solvent, it is more corrosive
[0008] This synthetic method route is brief, but there is following defect in the process of synthesizing monoester: use organic amine substance as catalyzer irritation bigger, can cause bad influence to environment; The ester content is not high, only about 60-70%; and there is no post-treatment process such as refining, which will definitely affect the yield of the entire reaction and the quality of the final product, and is not suitable for industrial production

Method used

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  • Preparation method for ganciclovir valine ester derivative
  • Preparation method for ganciclovir valine ester derivative
  • Preparation method for ganciclovir valine ester derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Put 10 g of ganciclovir, 30 g of CBZ-L-valine, 1.92 g of DMAP, and 100 ml of DMF into the reaction pot, and stir for 0.5 hours. Add 25 g of DCC dissolved in 20 ml of DMF dropwise at room temperature to the above solution system, and the dropwise addition is completed within 2 hours, then stir the reaction at room temperature, and monitor the progress of the reaction with TLC. The mixed solution of methane and methanol is developed as a developer, and basically no ganciclovir spots can be seen as the reaction end point. After the reaction was finished, filter and wash the filter cake with 20ml DMF. Combine the washing liquid and filtrate, concentrate in vacuo at no higher than 100°C until almost no liquid drops, cool to room temperature, add 120ml CH 2 Cl 2 Stir to dissolve, then fully wash with 120ml of 5wt% sodium bicarbonate aqueous solution, and then wash the organic phase with 120ml×2 water (that is, wash twice with water, each time with a volume of 120ml). The s...

Embodiment 2

[0072] Other operations are the same as in Example 1, except that the solvent in step a is changed to 100 ml of acetone, the DMF of 5 times of amount in step g is changed to 8 times of acetonitrile, the temperature of water is changed to 30 ° C, other reaction conditions and The operation was the same as in Example 1, and 11.8 g of the crude product of Ganciclovir-CBZ-L-monovaline ester was obtained, the mass yield was 118%, and the content was 96.1%, and 9.6 g of the pure product was obtained after purification, and the content was 99.3%. The molar yield is 50.2%, and the mass yield is 96.0%.

Embodiment 3

[0074]Other operations are the same as in Example 1, the difference is that the solid sodium hydroxide in step a is changed to 3.3g, and the aqueous phase C in step d is adjusted to 7 with saturated sodium carbonate solution at 0°C, and 20 times in step g The amount of methyl alcohol was changed to 20 times the amount of acetone, and other reaction conditions and operations were the same as in Example 1 to obtain 12.9 g of Ganciclovir-CBZ-L-monovaline ester crude product, with a mass yield of 129% and a content of 95.8%. , 10.3g of pure product was obtained after purification, with a content of 99.25%, a molar yield of 53.8%, and a mass yield of 103.0%.

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Abstract

The invention discloses a preparation method for a ganciclovir valine ester derivative. The method comprises the following steps of: dissolving ganciclovir-CBZ-L-dual-valine ester shown as a formula II in a reaction solvent B at the temperature of 0 to 60 DEG C; adding a basic catalyst; keeping the temperature and reacting; tracking and monitoring the reaction solution until the reaction is finished; and obtaining a dissolving ganciclovir-CBZ-L-single-valine ester pure product by operations such as extracting, leaching, purifying and the like. The method has the advantages that: the route is simple and short; used auxiliary materials have no pollution to the environment basically; high-purity ganciclovir-CBZ-L-single-valine ester can be obtained; the molar yield of a refined product can reach over 50 percent and the content is easy to reach over 99.0 percent; complicated means such as column or column chromatography and the like are not needed; therefore, the method is very beneficialfor industrial production.

Description

(1) Technical field [0001] The invention relates to a preparation method of ganciclovir valine ester derivatives, in particular to a method for preparing ganciclovir-CBZ-L-monovalinate from ganciclovir-CBZ-L-double valine ester Amino acid ester method. (2) Background technology [0002] Valganciclovir (VGVC) is a new antiviral drug, mainly used to treat acute retinitis caused by cytomegalovirus infection in HIV-infected patients (AIDS patients); its indication was expanded in May 2003 , for the prevention and treatment of secondary cytomegalovirus infection in organ transplant recipients. This product was originally researched and developed by Roche, and was approved by the US FDA in March 2001, and was first launched in the US in May 2001. The drug is the prodrug of ganciclovir (ganciclovir), which is an active ganciclovir valine ester, which can be rapidly hydrolyzed into ganciclovir by phosphatase in intestinal and liver cells after oral administration. Its antiviral s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
Inventor 蒲通王家洪李东兴王乃星范一陈恬杨振
Owner ZHEJIANG CHARIOTEER PHARMA
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