A kind of method of synthesizing cytidine nucleoside

A technology of cytidine nucleoside and tetraacetyl ribose, which is applied in chemical instruments and methods, sugar derivatives, organic chemistry, etc., can solve the problems of inability to industrialized production, cytosine is easy to deliquesce, and is not easy to obtain, and achieves novel design routes, The effect of simple process operation and stable yield

Active Publication Date: 2022-03-08
TUOXIN GROUP +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In this method, silicon etherified cytosine is easy to deliquescence, the raw material 1-acetyl-2,3,5-tribenzoyl ribose is not easy to obtain, and the yield of this method is low, so it cannot be produced industrially

Method used

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  • A kind of method of synthesizing cytidine nucleoside
  • A kind of method of synthesizing cytidine nucleoside
  • A kind of method of synthesizing cytidine nucleoside

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027]

[0028] The first step: add cyanoacetaldehyde urea 1 (22g, 0.2mol) and dichloroethane 300mL into the three-necked flask and mix well, then add hexamethyldisilazane (19.4g, 0.12mol), 5 % Catalyst ammonium sulfate (1.32g, 0.01mol), heat up to reflux for 5h, the reaction liquid dissolves, and the raw materials can be directly put into the next reaction after the reaction is complete.

[0029] The second step: add tetraacetyl ribose 3 (66.84g, 0.21mol) to the reaction solution of the previous step, after stirring and dissolving, the reaction solution is cooled to -5°C, and tin tetrachloride (26g, 0.1mol) is slowly added dropwise to keep The temperature of the reaction solution was below 5°C. After the dropwise addition, the temperature was raised to 35°C and reacted for 3 hours. TLC tracked until the raw materials disappeared, and then the reaction solution was cooled to -5°C, and saturated sodium bicarbonate was slowly added dropwise to quench the reaction. Then extrac...

Embodiment 2

[0032]

[0033] The first step: add cyanoacetaldehyde urea 1 (22g, 0.2mol) and hexamethyldisilazane (84g, 0.52mol) in the there-necked flask and mix well, then add 5% catalyst ammonium sulfate (1.32g , 0.01mol), the temperature was raised to reflux for 5 hours, the reaction solution was dissolved and the raw materials were completely reacted. The reaction solution was concentrated under reduced pressure to obtain hexamethyldisilazane, and 300 mL of methylene chloride was added.

[0034] The second step: add tetraacetylribose 3 (67.4g, 0.21mol) to the solution of the previous step, after stirring and dissolving, the reaction solution is cooled to -5°C, and tin tetrachloride (28.6g, 0.11mol) is slowly added dropwise to keep The temperature of the reaction solution was below 5°C. After the dropwise addition, the temperature was raised to 35°C and reacted for 3 hours. TLC tracked until the raw materials disappeared, and then the reaction solution was cooled to -5°C, and saturate...

Embodiment 3

[0037]

[0038] The first step: add cyanoacetaldehyde urea 1 (22g, 0.2mol) and dichloroethane 300mL in the there-necked flask and stir and mix evenly, trimethylchlorosilane (33.2g, 0.22mol), triethylamine ( 22.3g, 0.22mol), heated to reflux for 5h. The temperature of the reaction solution was lowered to 0°C, and triethylamine hydrochloride was removed by filtration, and the filtrate could be directly put into the next reaction.

[0039] The second step: add tetraacetyl ribose 3 (76.39g, 0.24mol) to the filtrate of the previous step, stir and dissolve, then cool the reaction solution to -5°C, and slowly drop tin tetrachloride (26g, 0.1mol) to maintain the reaction The temperature of the liquid is below 5°C. After the dropwise addition, the temperature is raised to 35°C and reacted for 3 hours. TLC traces until the raw materials disappear, and then the reaction liquid is cooled to -5°C, and saturated sodium bicarbonate is slowly added dropwise to quench the reaction. Extract...

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Abstract

The invention discloses a method for synthesizing cytidine nucleoside, which belongs to the field of nucleoside synthesis in organic chemistry. Using cyanoacetaldehyde urea as raw material, after silicon etherification, it condenses with tetraacetyl ribose under the catalysis of Lewis acid to obtain an intermediate, and then completes cyclization and deprotection under the action of sodium alkoxide to obtain cytosine nucleus Glycosides. The method of the present invention has convenient sources of raw materials, simple operation, continuous process in the three-step reaction process, and only needs to carry out recrystallization and purification for the final product; compared with the traditional process, the process operation is simple, the yield is stable, and the final alkaline hydrolysis and condensation process The one-pot method facilitates industrial scale-up production.

Description

technical field [0001] The invention belongs to the field of organic chemistry and relates to the synthesis of pyrimidine nucleoside, in particular to a method for synthesizing cytidine nucleoside. Background technique [0002] Cytosine, CAS: 65-46-3, molecular formula C 9 h 13 N 3 o 5 , is the main base component in nucleic acid RNA, as a very important pharmaceutical intermediate, it can be used to prepare antiviral, antitumor cytarabine and citicoline and other drugs. The methods currently reported in the literature are as follows: [0003] 1) Nishimara et al. proposed a new method of chemically synthesizing cytidine nucleoside as early as 1964, that is, using silyl ether-protected N4-acetylcytosine and 1-chlorotriphenylformyl ribose (α and β-mixture) under heating and reflux conditions to generate mixed-configuration cytidine nucleoside (α-configuration and β-configuration), and then use recrystallization and column chromatography to separate the two isomers to obta...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/067C07H1/00
CPCC07H19/067C07H1/00
Inventor 李涛杨西宁王德地卫涛赵娜李淑恒
Owner TUOXIN GROUP
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