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Method for preparing ganciclovir

A technology of ganciclovir and acetoxymethoxypropane, applied in the field of preparation of ganciclovir, can solve problems such as needs, and achieve the effects of reducing reaction steps, high product yield and cost saving

Inactive Publication Date: 2012-10-03
HUBEI GEDIAN HUMANWELL PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method requires column chromatographic separation of intermediates and expensive noble metal catalysts

Method used

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  • Method for preparing ganciclovir
  • Method for preparing ganciclovir
  • Method for preparing ganciclovir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of 1,3-Dichloro-2-acetoxymethoxypropane [4]

[0034] Add 100g of 1,3-dichloroglycerin, 24g of paraformaldehyde and 1g of methanesulfonic acid in turn, stir and heat to 85 oC . After 6 hours of reaction, cool to 10 oC , 158g of acetic anhydride was started to be dripped, and after the dripping, the stirring was continued for 6 hours, and the mixture was allowed to stand overnight. Liquid separation, drying, and distillation to obtain the product 1,3-dichloro-2-acetoxymethoxypropane [4] 65g. The weight yield is 65%, and the content is 97%.

[0035] Preparation of 1,3-Diacetoxy-2-acetoxymethoxypropane [5]

[0036] Add 10g of 1,3-dichloro-2-acetoxymethoxypropane, 25ml of N,N-dimethylacetamide, and 4ml of acetic anhydride to the reaction flask, and add 25g of anhydrous potassium acetate under stirring. , Warming to 80 oC Add 0.2g of tetrabutylammonium bromide, adjust the temperature to 140°C, start timing, and keep the reaction for 24 hours. Cool down, filter by s...

Embodiment 2

[0043] Preparation of 1,3-Dichloro-2-acetoxymethoxypropane [4]

[0044] Add 100g of 1,3-dichloroglycerin, 28g of paraformaldehyde and 1g of p-toluenesulfonic acid in sequence, stir and heat to 105 oC . After 2 hours of reaction, cool to 40 oC , Start dripping 80g of acetic anhydride, continue to stir for 4 hours after dripping, and let stand overnight. Liquid separation, drying, and distillation to obtain product 1,3-dichloro-2-acetoxymethoxypropane [4] 68g. The weight yield is 68%, and the content is 97%.

[0045] Preparation of 1,3-Diacetoxy-2-acetoxymethoxypropane [5]

[0046] Add 10g of 1,3-dichloro-2-acetoxymethoxypropane, 30ml of N,N-dimethylformamide, and 8ml of acetic anhydride to the reaction flask, and add anhydrous sodium acetate 11.3 under stirring. g, increase the temperature, add 0.4g of tetramethylammonium bromide, then continue to adjust the temperature to 100°C, start timing, and keep the reaction for 30 hours. Cool down, filter by suction, and wash the filter c...

Embodiment 3

[0058] Preparation of 1,3-Dichloro-2-acetoxymethoxypropane [4]

[0059] Add 100g of 1,3-dichloroglycerin, 100g of paraformaldehyde and 3g of concentrated sulfuric acid in turn, stir and heat to 110 oC . After 4 hours of reaction, cool to 20 oC Begin to add 380g of acetic anhydride, and continue to stir for 8 hours after the addition, and let it stand overnight. Liquid separation, drying, and distillation to obtain the product 1,3-dichloro-2-acetoxymethoxypropane [4] 70g. The weight yield is 70%, and the content is 98%.

[0060] Preparation of 1,3-Diacetoxy-2-acetoxymethoxypropane [5]

[0061] Add 10g of 1,3-dichloro-2-acetoxymethoxypropane, dimethyl sulfoxide solvent, and 2.35ml of acetic anhydride into the reaction flask accordingly, add 8g of anhydrous sodium acetate under stirring, increase the temperature, and add Tetramethylammonium bromide 7g, then adjust the temperature to 120°C, start timing, and keep the reaction for 18 hours. Cool down, filter by suction, and wash the ...

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Abstract

The invention relates to a method for preparing ganciclovir. The method comprises the following steps of: a, adding paraformaldehyde into 1,3-dichloro-2-propanol [2], reacting under the action of a catalyst to obtain hemiformal [3], and reacting with an acetic anhydride to obtain 1,3-dichloro-2-acetoxylmethoxylpropane [4]; b, making 1,3-dichloro-2-acetoxylmethoxylpropane [4] react with absolute postassium acetate or anhydrous sodium acetate in an organic solvent medium in the presence of a tetraalkyl ammonium bromide catalyst with 1-20 carbon atoms and an acetic anhydride serving as a dehydrating agent to obtain 1,3-diacetoxy-2-acetoxymethoxyl propane [5]; c, performing a condensation reaction on 1,3-diacetoxy-2-acetoxymethoxyl propane [5] and 2,9-diacetyl guanine [6] in an organic solvent medium in the presence of a catalyst and an acetic anhydride serving as a dehydrating agent to obtain triacetyl ganciclovir [7]; and d, hydrolyzing the triacetyl ganciclovir [7] to obtain ganciclovir [1]. The method has the advantages of easy and controllable preparation process, high utilization ratios of raw materials, low cost and high yield of a prepared ganciclovir product.

Description

Technical field [0001] The invention belongs to the technical field of medicine and relates to a preparation method of ganciclovir. Background technique [0002] Ganciclovir [chemical name 9-(1,3-dihydroxy-2-propoxymethyl)-guanine] is a derivative of nucleoside antiviral drug guanosine (the structural formula is shown in formula 1) It was synthesized by Julien Verheyden and John Martin of Syntex Research in 1980. It has a stronger and broader-spectrum antiviral effect than acyclovir. It is an antiviral chemotherapeutic agent with high efficiency, low toxicity and strong selectivity. It has been widely used in clinical practice. application. In 1986, Syntex Corporation of the United States obtained the exclusive production and management rights. It was first approved for listing in the United Kingdom in June 1988, and subsequently, France, the United States, Japan, West Germany, Italy, and Canada have also approved the use. In 1989, the US FDA officially approved it as a first-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
Inventor 赵静殷超袁观华
Owner HUBEI GEDIAN HUMANWELL PHARMACEUTICAL CO LTD
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