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Preparation and purification of 2'-o-(2-methoxyethyl)-5-methyluridine and 2'-o-(2-methoxyethyl)-5-methylcytidine and their derivatives method

A technology of methyluridine and alkylating reagents, applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc.

Active Publication Date: 2016-02-10
SHANGHAI ZHAOWEI TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Preparation methods of 2'-O-(2-methoxyethyl)-5-methyluridine and 2'-O-(2-methoxyethyl)-5-methylcytidine and their derivatives at home and abroad rarely reported

Method used

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  • Preparation and purification of 2'-o-(2-methoxyethyl)-5-methyluridine and 2'-o-(2-methoxyethyl)-5-methylcytidine and their derivatives method
  • Preparation and purification of 2'-o-(2-methoxyethyl)-5-methyluridine and 2'-o-(2-methoxyethyl)-5-methylcytidine and their derivatives method
  • Preparation and purification of 2'-o-(2-methoxyethyl)-5-methyluridine and 2'-o-(2-methoxyethyl)-5-methylcytidine and their derivatives method

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preparation example Construction

[0031] Specifically, the present invention provides a method for preparing a compound as shown in formula I or formula II, comprising the steps of:

[0032] In the first step, 2,2'-anhydro-5-methyluridine or its derivatives, or 2,2'-anhydro-5-methylcytidine or its derivatives are dissolved in ethylene glycol methyl ether, Mixture 1 is obtained;

[0033] In the second step, mix the mixture 1, the alkylating agent and the carbonate of alkali or alkali metal, and react to obtain the compound shown in formula I or formula II;

[0034] In the third step, the alcohol or halogenated alkane solution containing the compound shown in formula I or formula II is loaded onto the silica gel chromatography column;

[0035] The fourth step is to make the eluent pass through the chromatographic column to obtain the collected solution;

[0036] In the fifth step, the collected solution is mixed with an organic solvent, and crystallized to obtain a high-purity compound represented by formula I...

Embodiment 1

[0098] Preparation of 2'-O-(2-methoxyethyl)-5-methyluridine

[0099] 1. Preparation of 2'-O-(2-methoxyethyl)-5-methyluridine

[0100] Add 10Kg of 2,2'-anhydro-5-methyluridine into 150L of anhydrous ethylene glycol methyl ether, then add 9.15Kg of bromomethoxyethane and 3.3Kg of solid sodium hydroxide and heat to 120°C, The system was kept warm at 110-120°C, stirred and sealed for reaction, monitored by HPLC until the main raw material was completely reacted, and then concentrated to dryness under reduced pressure at 80°C to obtain a brown oily substance called 2'-O-(2-methoxyethyl )-5-methyluridine (I)

[0101] 2. Purification of 2'-O-(2-methoxyethyl)-5-methyluridine

[0102] The above oil was dissolved in 5L of anhydrous methanol, and then loaded onto a 20L silica gel column. The aspect ratio of the silica gel column was 3:1, the silica gel particles were 100-200 mesh, and the temperature of the silica gel column was kept at 10-15°C. Then wash the column quickly with 30L o...

Embodiment 2

[0104] Preparation of 2'-O-(2-methoxyethyl)-5-methylcytidine (II)

[0105] 1. Preparation of 2'-O-(2-methoxyethyl)-5-methylcytidine (II)

[0106] Add 10Kg of 2,2'-anhydro-5-methylcytidine into 150L of anhydrous ethylene glycol methyl ether, then add 9.15Kg of bromomethoxyethane and 3.3Kg of solid sodium hydroxide and heat to 90°C, the system Insulate at 90-100°C, stir and seal the reaction, monitor by HPLC until the reaction of the main raw material is complete, then concentrate under reduced pressure at 80°C to dryness to obtain a brown oily substance called 2'-O-(2-methoxyethyl) -5-methylcytidine(II)

[0107] 2. Purification of 2'-O-(2-methoxyethyl)-5-methylcytidine (II)

[0108]Dissolve the above oil with 5L of anhydrous methanol, and then load it on a 20L silica gel column. The aspect ratio of the silica gel used for chromatography is 3:1, the silica gel particles are 100-200 mesh, and the temperature of the silica gel column is maintained at 10- 15°C. Then use 30L of ...

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Abstract

The invention discloses the preparation of 2'-O-(2-methyl ethyl)-5-methyl uridine and 2'-O-(2-methyl ethyl)-5-methyl cytidine and derivative and a purifying method thereof. The invention provides a preparation method of a compound shown in formula I or II. The method comprises the following steps: (1) dissolving 2,2'-dehydrated-5-methyl uridine or the derivative (III) or 2,2'-dehydrated-5-methyl cytidine or the derivative (IV) in a polar solvent to obtain a mixture 1; and mixing the mixture 1, an alkylating reagent and alkali, and reacting to obtain the compound shown as formula I or II, wherein R1 represents H, 4,4-dimethoxyl triphenyl methyl, R2 represents H, R3 represents H and benzoyl, the polar solvent is ethylene glycol methyl ether, the alkylating reagent is bromo methyl ethyl alkane, and the alkali is sodium hydroxide and anhydrous potassium carbonate.

Description

technical field [0001] The present invention relates to 2'-O-(2-methoxyethyl)-5-methyl-uridine and 2'-O-(2-methoxyethyl)-5-methyl-cytidine and derivatives thereof preparation and purification methods. Background technique [0002] In recent years, with the development of genomic medicines, antisense oligonucleotide drugs have been developed rapidly, especially recently, with the in-depth research of second-generation antisense drugs, it has been discovered that 2'-O- Alkyl nucleosides can enhance the affinity with RNA and enhance the resistance of oligonucleotides to nucleases, among which the effect of 2'-O-methoxyethyl is superior. Subsequently, the demand for oligonucleosides and their derivatives that constitute oligomer raw materials is increasing day by day, especially 2'-O-methoxyethyl nucleoside modifications, which have a greater market prospect. [0003] On the other hand, in pharmaceutical applications, it is necessary to use extremely high-purity oligonucleosid...

Claims

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Application Information

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