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Preparation method of famciclovir

A technology of famciclovir and amino, which is applied in the field of medicine, can solve the problems of poor selectivity of N-alkylation reaction, potential safety hazards in the use of diazonium salts, and high production costs, and achieve low prices, improved atom economy, and low production costs. Effect

Active Publication Date: 2019-03-12
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] The technical problem to be solved in the present invention is: based on the problems existing in the above-mentioned route, a preparation method of famciclovir is provided to solve the poor selectivity of the N-alkylation reaction in the above-mentioned route, the need for additional purification of reaction intermediates, and the complicated process operation , intermediates are unstable, the use of diazonium salts has potential safety hazards and high production costs

Method used

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  • Preparation method of famciclovir

Examples

Experimental program
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Embodiment 1

[0054] The first step, the synthesis of 2-amino-4,6-pyrimidinediol

[0055] Control the temperature at 5°C, put 30.52g (0.25mol) of guanidine nitrate and 100ml of methanol into a 500ml four-necked bottle, start stirring, and slowly drop in 250ml of 2.5M sodium methoxide methanol solution after all the solids are dissolved, and keep stirring for 0.5h; Subsequently, 41.64 g (0.26 mol) of diethyl malonate was slowly dropped into the above-mentioned reaction flask, and after the drop was completed, the temperature was raised to reflux for 6 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain an off-white solid. Add 60ml of drinking water to the reaction bottle to dissolve the solid, then adjust the pH value of the system to 6 with 10% dilute hydrochloric acid solution, at this time a large amount of solid precipitates; ℃ blast drying to constant weight to obtain 29.74 g of off-white product, the yield of this step is 93.6%, and the HPLC p...

Embodiment 2

[0057] The first step, the synthesis of 2-amino-4,6-pyrimidinediol

[0058] Control the temperature at 5°C, put 30.52g (0.25mol) of guanidine nitrate and 100ml of absolute ethanol into a 500ml four-necked bottle, start stirring, and slowly drop in 250ml of 2.5M sodium methoxide ethanol solution after all the solids are dissolved, keep stirring for 0.5 h; then slowly drop 41.64 g (0.26 mol) of diethyl malonate into the above-mentioned reaction flask, after the drop is complete, raise the temperature to 65° C. for 6 h. After the reaction was completed, it was concentrated under reduced pressure to obtain an off-white solid. Add 60ml of drinking water to the reaction bottle to dissolve the solid, then adjust the pH value of the system to 6 with 10% dilute hydrochloric acid solution, at this time a large amount of solid precipitates; ℃ blast drying to constant weight, to obtain 30.56 g of off-white product, the yield of this step is 96.10%, and the HPLC purity is 99.7%.

Embodiment 3

[0060] The first step, the synthesis of 2-amino-4,6-pyrimidinediol

[0061] Control the temperature at 5°C, put 30.52g (0.25mol) of guanidine nitrate and 100ml of absolute ethanol into a 500ml four-neck bottle, start stirring, and slowly drop in 250ml of 2.5M sodium ethoxide ethanol solution after all the solids are dissolved, keep stirring for 0.5 h; then slowly drop 41.64 g (0.26 mol) of diethyl malonate into the above reaction flask, after the drop is complete, heat up to reflux for 4 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain an off-white solid. Add 60ml of drinking water to the reaction bottle to dissolve the solid, then adjust the pH value of the system to 6 with 10% dilute hydrochloric acid solution, at this time a large amount of solid precipitates; ℃ blast drying to constant weight to obtain 28.78 g of off-white product, the yield of this step is 90.59%, and the HPLC purity is 99.7%.

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Abstract

The invention relates to a preparation method of famciclovir. The preparation method comprises the following steps of: adopting guanidine nitrate and diethyl malonate as raw materials, carrying out ring-closing reaction under an alkaline condition to obtain 2-amino-4,6-pyrimidinediol, then obtaining 2-amino-4,6-dichloropyrimidine by hydroxyl chlorination, reacting with 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl-1-amine to generate 6-chloro-N(i)4( / i)-(2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl)pyrimidine-2,4-diamine, then reacting with sodium nitrite under the acidic condition to obtain 2-(2-((2-amino-6-chloro-5-nitrosopyrimidin-4-yl)amino)ethyl)propane-1,3-diol, and finally carrying out reduction / dechloridation, ring-closing and esterification reaction to obtain the famciclovir. The preparation method has the beneficial effects that the problems of poor N-alkylation reaction selectivity and need of additional purification of reaction intermediates and the like in the current process are solved.

Description

technical field [0001] The invention relates to a preparation method of famciclovir, belonging to the technical field of medicine. Background technique [0002] Famciclovir (Famciclovir, 1), developed by SmithKline Beecham in the 1990s, is a new nucleoside broad-spectrum antiviral drug that is widely used for severe herpes zoster and primary genital herpes. Its chemical name is: 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol-diethyl ester, and its chemical structure is as follows: [0003] . [0004] The existing famciclovir synthetic method patents mainly include: EP 182024, EP 0302644, US 5138057, CN 108314685A, CN 101195622A, CN 100455583C; WO2004 / 110343, US5917041, CN101555249B, CN 102924455A, etc. [0005] According to the structural characteristics of famciclovir, its synthetic method mainly contains two categories: [0006] The first type is to use 2-amino-6-chloropurine as a starting material, which is respectively connected with different alkane side chains...

Claims

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Application Information

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IPC IPC(8): C07D473/32
CPCC07D473/32
Inventor 刘超葛执信李廷义苗华明蔡亚辉
Owner 迪嘉药业集团股份有限公司
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