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Preparation method of α-uridine nucleoside

A technology of uracil and compounds, applied in the field of nucleoside compound synthesis, which can solve problems such as industrialization resistance

Active Publication Date: 2021-04-20
SHANGHAI ZHAOWEI TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the configuration of the sugar used in this method must be a β-configuration, which is difficult to supply in the market, and the available ones are all mixtures of α / β isomers; secondly, it is confirmed in the literature that under this reaction condition there will be There is β-isomer generation, which is 10-50%. The generation of β-isomer cannot be avoided and the total yield is low, which is a major obstacle to industrialization

Method used

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  • Preparation method of α-uridine nucleoside
  • Preparation method of α-uridine nucleoside
  • Preparation method of α-uridine nucleoside

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Preparation of α-uridine nucleoside (method one, R=NO 2 , located in the para position of the benzoyl group)

[0087] 1. Preparation of 2,6-O-di-p-nitrobenzoyl-3,4-O-acetonylidene-D-ribose:

[0088]

[0089] Under the protection of argon, put 100g of D-ribose into a dry 1L three-necked reaction flask, add 500ml of acetone to stir and suspend; Cool the system down to 0±3°C, add 75.6g of 2,2-dimethoxypropane dropwise to the reaction solution, and control the temperature at 0±3°C; return the reaction solution to 15±3°C and stir for reaction, after 2 hours of reaction, TLC The plate showed essentially no starting material and the reaction was considered complete; then 4.8 g NaHCO was added 3 After stirring for half an hour, suction filtration was performed, and the filtrate was concentrated to dryness under reduced pressure at 40±5°C to obtain crude IM-1, which was directly used in the next step without purification. Add 800ml of dichloromethane to the concentrate to ...

Embodiment 2

[0099] Preparation of α-uridine nucleoside (R=CN, located in the para position of benzoyl)

[0100] 1. Preparation of 2,6-O-di-p-cyanobenzoyl-3,4-O-acetonylidene-D-ribose:

[0101]

[0102]The preparation of IM-1 was as described above, and 100 g of D-ribose was fed for reaction preparation to obtain the crude product of IM-1. This crude product was dissolved in 800ml of dichloromethane, and added under stirring, 201.8g of triethylamine, and 275.7g of p-cyanobenzoyl chloride were slowly added. After stirring and reacting at room temperature for 2.5 hours, sample TLC plate analysis, IM-1 is not obvious, and the reaction is considered to be complete; after the reaction is completed, as described above, after extraction and concentration to dryness, the crude product of compound B is obtained without purification, and the same compound B It is a mixture of α and β configurations.

[0103] 2. Preparation of 2'3'-O-acetonylidene-α-uridine:

[0104]

[0105] Add 50g of Urac...

Embodiment 3

[0111] Preparation of α-uridine nucleoside (R = F, located in the para position of benzoyl)

[0112] 1. Preparation of 2,6-O-di-p-fluorobenzoyl-3,4-O-acetonylidene-D-ribose:

[0113]

[0114] The preparation of IM-1 was as described above, and 100 g of D-ribose was fed for reaction preparation to obtain the crude product of IM-1. This crude product was dissolved in 800ml of dichloromethane, and added under stirring, 201.8g of triethylamine, and 264g of p-fluorobenzoyl chloride were slowly added. After stirring and reacting at room temperature for 1.5 hours, sample TLC plate analysis, IM-1 is not obvious, and the reaction is considered to be complete; after the reaction is completed, as described above, after extraction and concentration to dryness, the crude product of compound B is obtained without purification, and the same compound B It is a mixture of α and β configurations.

[0115] 2. Preparation of 2'3'-O-acetonylidene-α-uridine:

[0116]

[0117] Add 50g of Ur...

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Abstract

The invention discloses a preparation method of α-uridine nucleoside. The method comprises the steps of: after alkaline hydrolyzing the compound shown in formula C, acid treatment is carried out to obtain the compound shown in formula A; the preparation method of the compound shown in formula C comprises the steps of: making The silylated uracil is condensed with the di-esterified ribose sugar shown in formula B to obtain the compound shown in formula C.

Description

technical field [0001] The invention belongs to the field of nucleoside compound synthesis, and more specifically, the invention relates to a preparation method of α-uridine nucleoside. Background technique [0002] In recent years, with the development of genome-based drugs, antisense oligonucleotide drugs have been rapidly developed. α-Uridine is the most basic raw material for the synthesis of α-configuration antisense oligonucleotides. In addition to being used as a drug development tool, α-uridine can also be used in scientific research, especially functional genomics research. However, the existing literature reports that it is still difficult to industrialize in the key steps of synthesis, and the production of β-isomer cannot be avoided. In order to remove this isomer in industry, preparative chromatography or repeated crystallization are generally used. However, the preparation by preparative chromatography cannot meet the requirements of industrialization, and t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/06C07H19/067C07H1/00
CPCC07H1/00C07H19/06C07H19/067
Inventor 孙波
Owner SHANGHAI ZHAOWEI TECH DEV
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