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Preparation method of CBZ-valganciclovir

A technology of ganciclovir and ganciclovir condensate, which is applied in the field of preparation of CBZ-valganciclovir to achieve the effects of simplifying synthetic process steps, reducing environmental pollution and reducing residual raw materials

Active Publication Date: 2016-06-22
ANHUI HAIKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The remaining disadvantage is that ganciclovir needs to be taken out separately, and then used as a starting material for CBZ-valganciclovir synthesis

Method used

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  • Preparation method of CBZ-valganciclovir
  • Preparation method of CBZ-valganciclovir
  • Preparation method of CBZ-valganciclovir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] A kind of CBZ-valganciclovir preparation method, it comprises the steps:

[0081] (1) 40kg ganciclovir condensate 7-position isomer, 3.0kg p-toluenesulfonic acid, 400kg solvent-DMF, 77kg1,3-diacetoxy-2-(acetoxymethoxy)propane, 60kg Put diacetylguanine into a 1000L reaction kettle, add 40kg of acetic anhydride, keep warm at 80-140°C for 3-5 hours and stir, then distill the acetic anhydride, continue to keep warm at 120-130°C for 18 hours, and distill 2- 3 times of acetic anhydride, so that the chemical balance reacts to the ganciclovir condensate;

[0082] (2) After the reaction in the step (1) ends, concentrate under reduced pressure and evaporate acetic anhydride and solvent-DMF until there is basically no evaporation to obtain a residue;

[0083](3) Add 500L of ethyl acetate to the residue obtained in step (2), then heat up to reflux, cool down to 0-5°C, and keep warm for 1-24 hours for crystallization;

[0084] (4) The product obtained in the step (3) is centrifuge...

Embodiment 2

[0104] A kind of CBZ-valganciclovir preparation method, it comprises the steps:

[0105] (1) Put 100kg 7-position isomer of ganciclovir condensate, 3.0kg p-toluenesulfonic acid, 300kg solvent-DMF, 15kg1,3-diacetoxy-2-(acetoxymethoxy)propane into 1000L Add 100kg of acetic anhydride to the reaction kettle, keep it warm at 80-140°C for 3-5 hours and stir it, then distill the acetic anhydride, and continue to keep warm at 120-130°C for 18 hours, distilling the acetic anhydride 2-3 times during the period, so that Chemical equilibrium reaction to ganciclovir condensate;

[0106] (2) After the reaction in the step (1) ends, concentrate under reduced pressure and evaporate acetic anhydride and solvent-DMF until there is basically no evaporation to obtain a residue;

[0107] (3) Add 500L of ethyl acetate to the residue obtained in step (2), then heat up to reflux, cool down to 0-5°C, and keep warm for 1-24 hours for crystallization;

[0108] (4) The product obtained in the step (3) ...

Embodiment 3

[0118] A kind of CBZ-valganciclovir preparation method, it comprises the steps:

[0119](1) 30kg ganciclovir condensate 7-isomer, 30kg ganciclovir 7-isomer, 2.3kg p-toluenesulfonic acid, 330kg solvent-DMF, 60kg1,3-diacetoxy-2- (Acetoxymethoxy) propane, 45kg diacetylguanine into a 1000L reactor, add 140kg acetic anhydride, keep warm at 80~140℃ for 3~5h and stir, then distill acetic anhydride, continue at 120-130 Keep warm for 18 hours under high temperature conditions, distill acetic anhydride 2-3 times during this period, so that the chemical equilibrium will react to the ganciclovir condensate;

[0120] (2) After the reaction in the step (1) ends, concentrate under reduced pressure and evaporate acetic anhydride and solvent-DMF until there is basically no evaporation to obtain a residue;

[0121] (3) Add 500L of ethyl acetate to the residue obtained in step (2), then heat up to reflux, cool down to 0-5°C, and keep warm for 1-24 hours for crystallization;

[0122] (4) The pr...

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Abstract

The invention discloses a preparation method of CBZ-valganciclovir, and belongs to the field of preparation of valganciclovir. The preparation method includes the following steps: feeding a starting material in a reactor and carrying out condensation reaction; evaporating to remove a catalyst and a first solvent; adding a second solvent and carrying out hydrolysis; evaporating to remove the second solvent, adding water for making a solution to be clear, decolorizing and filtering, crystallizing, and centrifugally drying to obtain a crude product of ganciclovir; and placing the crude product of the ganciclovir and a third solvent in a reactor and heating and stirring, cooling and filter-pressing to obtain a first filter cake and first filtrate, and directly synthesizing the valganciclovir by using the first filtrate. By the preparation method of the CBZ-valganciclovir, ganciclovir condensation compound isomer is treated effectively, furthermore, the CBZ valganciclovir is synthesized directly in the filtrate synthesized by the 9-bit ganciclovir, a 'one-pot' type preparation technology is adopted, steps of a synthesis technology of the CBZ valganciclovir are simplified, residual raw materials are reduced, production cost is reduced, synthesis quality of the CBZ valganciclovir is improved, production efficiency is high, and the CBZ-valganciclovir is suitable for being industrially produced in a large scale.

Description

technical field [0001] The invention belongs to the field of preparation of valganciclovir, more specifically, relates to a preparation method of CBZ-valganciclovir. Background technique [0002] Valganciclovir is the L-valyl ester (prodrug) of ganciclovir, which is rapidly converted into ganciclovir by acylases in the small intestine and liver after oral administration, and is used for acquired immunodeficiency syndrome (AIDS). ) patients with cytomegalovirus (CMV) retinitis, and cytomegalovirus (CMV) infection after organ transplantation, it is the first choice for the prevention of CMV infection in the world. Cytomegalovirus (CMV) belongs to the herpesviridae family. The virus is in a dormant state in individuals with normal immune function, but when the immune function is impaired, such as AIDS patients, patients receiving immunosuppressants after organ transplantation, etc., The virus can cause illness. The most common condition of CMV in HIV / AIDS patients is CMV reti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
CPCC07D473/18
Inventor 张小顺
Owner ANHUI HAIKANG PHARMA
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