Preparation method of Cidofovir and intermediate thereof

A compound, selected technology, applied in the direction of chemical instruments and methods, compounds of group 5/15 elements of the periodic table, organic chemistry, etc., can solve the problem of low synthesis yield, synthetic process, unsuitable for industrialization, multiple side reactions product and other issues

Inactive Publication Date: 2009-09-09
苏州凯达生物医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The main purpose of the present invention is to provide a kind of preparation method of cidofovir and its intermediate, which solves the problem that the synthesis yield of cidofovir and its intermediate in the prior art is relatively low or the synthesis process produces relatively low Many side reaction products are difficult to separate or the synthesis process is not economical and unsuitable for industrialization.

Method used

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  • Preparation method of Cidofovir and intermediate thereof
  • Preparation method of Cidofovir and intermediate thereof
  • Preparation method of Cidofovir and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Embodiment 1: the preparation of cidofovir

[0084] Preparation of (S)-1-benzyloxy-2,3-epoxypropane

[0085] Add 21.6g (0.2mol) of benzyl alcohol into 120mL of 50% sodium hydroxide, cool down to 0°C, add 74g (0.8mol) (R)-epichlorohydrin dropwise over 30min, and then react below 10°C 20h, gas spectrum tracking reaction ended. The reactant was poured into 70 mL of ice water. They were extracted with dichloroethane (2×70 mL), combined, washed once with 50 mL of water, once with 50 mL of saturated NaCl solution, and dried over anhydrous magnesium sulfate. Precipitation gave 26.7 g of anhydrous liquid. The yield is 83.5%, and the content is greater than 97%.

[0086] N 4 - Preparation of Benzoylcytosine

[0087]3.0 g of cytosine was added to 300 mL of pyridine, and 37.5 mL of benzoyl chloride was added dropwise. Stir at room temperature and add dropwise for half an hour. Stir for another hour. 2N hydrochloric acid solution was added dropwise and stirred at room temp...

Embodiment 2

[0099] Example 2(S)-N 1 -[(3-Hydroxy-2-phosphodiethylmethoxy)glycerol]-N 4 - Preparation of cytosine

[0100] Preparation of (S)-trityloxy-2,3-epoxypropane

[0101] Add 42.3g (0.2mol) of trityl alcohol into 150mL of 50% sodium hydroxide, cool down to 0°C, add 74g (0.8mol) (R)-epibromohydrin dropwise over 30min, and then lower the temperature below 30°C After 20 hours of reaction, the gas spectrum tracking reaction ended. The reactant was poured into 70 mL of ice water. They were extracted with dichloroethane (2×70 mL), combined, washed once with 50 mL of water, once with 50 mL of saturated NaCl solution, and dried over anhydrous magnesium sulfate. Precipitation gave 32.6 g of anhydrous liquid. The yield is 76.5%, and the content is greater than 92%.

[0102] N 4 - Preparation of Benzoylcytosine

[0103] 5.0 g of cytosine was added to 300 mL of toluene, and 37.5 mL of benzoyl bromide was added dropwise. Stir at room temperature, add dropwise for half an hour, and the r...

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Abstract

The invention discloses a preparation method of Cidofovir of a structural formula (I) and an intermediate thereof. The preparation method comprises the following steps: (1) a compound of a formula (II) reacts with epoxy halogenopropane in the presence of a catalyst in an alkaline environment to obtain a compound of a formula (III); (2) cytosine reacts with a compound of a formula (IV) in the presence of a proper solvent to obtain a compound of a formula (V); (3) compounds obtained in the two steps are condensed in the presence of the proper solvent to obtain a compound of a formula (VI); (4) the compound of the formula (VI) reacts with p-benzenesulfonyloxymethyl phosphoric acid diethylester in the presence of the proper solvent to obtain a compound of formula (VII); and (5) the compound of the formula (VII) is treated at proper pressure to obtain a compound of a formula (VIII). The preparation method shortens synthetic route and lowers synthesis cost, is simple and practical, has the advantages of higher yield and less pollution, and is applicable to industrialized production.

Description

technical field [0001] The invention belongs to the field of antiviral chemical drugs, and in particular relates to a preparation method of an anti-cytomegalovirus drug cidofovir and an intermediate thereof. Background technique [0002] Cytomegalovirus (Cytomegaoviyns, CMV) is a herpes virus group DNA virus. It is widely distributed and can be infected with other animals, causing various systemic infections mainly in the genitourinary system, central nervous system and liver diseases, ranging from mild asymptomatic infection to severe defects or death. People of all ages can be infected, especially newborns, organ transplant recipients, and immunocompromised persons. CMV infection is very widespread in the population. The infection rate of adults in my country is over 95%. It is usually a recessive infection. Most infected people have no clinical symptoms, but under certain conditions, it can invade multiple organs and systems and cause serious diseases. The virus can inv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6512A61P31/22
Inventor 沈宗旋张燕飞马海军郭丽琴张孟茅冬燕
Owner 苏州凯达生物医药技术有限公司
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