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A kind of synthetic method of valganciclovir hydrochloride

The technology of a kind of valganciclovir hydrochloride and synthetic method is applied in the field of synthesis of valganciclovir hydrochloride, which can solve problems such as unfavorable industrial production, cumbersome separation process, and influence on process yield, and achieves mild conditions and simple process operation , The effect of simplifying the process steps

Active Publication Date: 2022-07-22
河北合佳医药科技集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the synthetic process of intermediate triacetyl ganciclovir, there are separation and conversion problems of N-7 and N-9 isomers in this process route, and the separation process is loaded down with trivial details, which seriously affects the process yield; in the preparation of ganciclovir In the valganciclovir hydrochloride process, a large number of residues of ganciclovir in the orthoester protection process will lead to the production of diesters in the subsequent process, which is also difficult to separate, and often requires additional purification steps to obtain a product with higher purity. The steps are cumbersome and seriously affect the process yield
At present, the existing production technology of valganciclovir hydrochloride has problems such as long process route, complicated industry, low yield, and unfavorable industrialized production.

Method used

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  • A kind of synthetic method of valganciclovir hydrochloride
  • A kind of synthetic method of valganciclovir hydrochloride
  • A kind of synthetic method of valganciclovir hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1. Preparation of compound 11

[0033] 120g of 1,3-dichloro-2-acetoxymethoxypropane, 300ml of N,N-dimethylformamide, 70g of anhydrous potassium acetate, 5g of benzyltriethylammonium chloride were added to the reaction flask, and the temperature was controlled. The reaction was stirred at 20-30 °C for 4 hours. After the reaction was completed, N,N-dimethylformamide was evaporated under reduced pressure, 100 ml of dichloromethane and 100 ml of purified water were added for stirring and washing, the organic phase was separated, and the solvent was distilled off to obtain a residue. Compound 103g, namely compound 11.

Embodiment 2

[0034] Example 2. Preparation of compound 11

[0035] 120g of 1,3-dichloro-2-acetoxymethoxypropane, 200ml of N,N-dimethylformamide, 54g of anhydrous sodium acetate, 4g of tetrabutylammonium bromide were added to the reaction flask, and the temperature was controlled to 30- The reaction was stirred at 40 °C for 4 hours. After the reaction was over, N,N-dimethylformamide was evaporated under reduced pressure, 100 ml of dichloromethane and 100 ml of purified water were added for stirring and washing, the organic phase was separated, and the solvent was distilled off to obtain 108 g of residue. , namely compound 11.

Embodiment 3

[0036] Example 3. Preparation of compound 13

[0037] Add 75g diacetylguanine, 4g p-toluenesulfonic acid, 200ml N,N-dimethylformamide to the reaction flask, heat up to 115-120°C, slowly add a total of 100g of compound 11 prepared in Example 1, continue The reaction was carried out at this temperature for 24 hours. After the reaction was completed, the system was cooled to 50 °C, 100 ml of 40% methyl ammonia solution was slowly added, and the reaction was stirred at 50-60 °C for 4 hours. At 10°C, the solid was filtered off, and the filter cake was recrystallized with 1200 ml of purified water to obtain 56.5 g of compound 13.

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Abstract

The invention discloses a method for synthesizing valganciclovir hydrochloride. Using 1,3-dichloro-2-acetoxymethoxypropane as a starting material, monochloroganciclovir is prepared by esterification. , hydrolysis, deprotection into salt and finally obtain valganciclovir hydrochloride. The invention provides a method for synthesizing cganciclovir hydrochloride, which avoids the problem of separation and conversion of N-7 and N-9 isomers in the condensation process of diacetylguanine, and directly synthesizes monochlorovir without ganciclovir. Genanciclovir replaces the synthesis of monoacetyl ganciclovir in the prior art, and avoids the difficult problem of separation of diesters caused by residual ganciclovir. The method has short process steps, simple operation, easy purification and low cost. , conducive to industrial production, suitable for the synthesis of valganciclovir hydrochloride.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing valganciclovir hydrochloride. Background technique [0002] Valganciclovir hydrochloride is a cytomegalovirus (CMV) nucleoside analog DNA polymerase inhibitor, it is a prodrug of the antiviral drug ganciclovir, and its bioavailability is the same as that of the traditional drug ganciclovir. 10 times, while the toxicity is greatly reduced. It is clinically used for the treatment of acute retinitis caused by CMV infection in patients with acquired immunodeficiency syndrome (AIDS), and the prevention and treatment of secondary CMV infection in organ transplant recipients. Valganciclovir has become the best new drug for the treatment of CMV infection due to its safer, more convenient administration and higher bioavailability. Its structural formula is: [0003] [0004] For the synthesis of valganciclovir hydrochloride, the current production...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/18
Inventor 刘振强刘新元梁丙辰王宇栋
Owner 河北合佳医药科技集团股份有限公司
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