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A kind of preparation method of 3'-oxygen-methoxyethyl nucleoside

A technology for methoxyethyl nucleoside and methylcytosine, which is applied in the field of nucleoside compound synthesis, can solve the problem of difficulty in large-scale production, no method suitable for industrialized preparation of 3'-oxy-methoxyethyl nucleoside, and low yield And other issues

Active Publication Date: 2021-04-23
SHANGHAI ZHAOWEI TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] So far, the synthetic methods reported in the literature are difficult to meet the market demand and the total yield of the whole route is low, and there is no suitable method for the industrial preparation of 3'-oxygen-methoxyethyl nucleosides
Even for laboratory-scale experiments, there are few reports in the literature at home and abroad. Usually, the way to obtain 3'-oxygen-methoxyethyl nucleosides is as a by-product in the process of preparing 2'-oxygen-methoxyethyl nucleosides. The product is obtained by separation, the yield is also low, and it is difficult to scale up

Method used

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  • A kind of preparation method of 3'-oxygen-methoxyethyl nucleoside
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  • A kind of preparation method of 3'-oxygen-methoxyethyl nucleoside

Examples

Experimental program
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Effect test

Embodiment 1

[0094] Preparation of 3'-Oxy-methoxyethyl-5-methyluridine

[0095] 1.1,2; 5,6-Diacetonylidene-3-methoxyethyl allose (IM1) preparation:

[0096]

[0097] Under the protection of argon, weigh 60.0g SM (1,2; 5,6-diacetonylidene allose), add 300mL DMSO to dissolve, stir 300mL 50% KOH aqueous solution for 5 minutes, add 43.6g 2- Chloroethyl methyl ether, heated to 55 ° C reaction. After reacting for 16 hours, sampling TLC detection showed that the raw material SM had all disappeared, and a new point was formed on the upper part of the raw material.

[0098] In the reaction process, the TLC detection condition is: after ethyl acetate / n-hexane=3 / 5 system develops, with the methanol solution of 5% sulfuric acid immerse plate, heat gun blows plate to show black spot after the methanol solution of 5% sulfuric acid, raw material Rf:0.25, product Rf: 0.3.

[0099] After the reaction was completed, 800 mL of dichloromethane was added to the reaction solution for dilution, poured into...

Embodiment 2

[0123] Preparation of 3'-oxo-methoxyethyl-5-methylcytidine (A-2)

[0124]

[0125] Weigh 22.5g of Compound B, suspend 6.5g of 5-methylcytosine in 250mL of acetonitrile, add 26.4g of BSA dropwise, and raise the temperature to 75°C to dissolve the system. After the reaction liquid was lowered to 5°C, 14.4 g of TMSOTf was added dropwise, and the reaction temperature returned to 75°C. After completion of the reaction as monitored by HPLC, the reaction was quenched. The reaction solution was diluted with ethyl acetate, washed with water, and the organic phase was dried and concentrated to obtain crude product C-2. The crude product was dissolved in 200 mL methanol / ammonia water, and stirred at 25°C overnight. After the reaction was completed, it was concentrated, and 100 mL of absolute ethanol was added for crystallization to obtain 10.5 g of the product 3'-oxy-methoxyethyl-5-methylcytidine (A-2), with a purity of 99.9% and a yield of 77.0%.

[0126] 1 H NMR (500MHz, DMSO-d ...

Embodiment 3

[0128] Preparation of 3'-Oxy-methoxyethyl adenosine (A-3)

[0129]

[0130] Weigh 26.0g of compound B, suspend 8.1g of adenine in 250mL of acetonitrile and 1,2-dichloroethane, cool down to 10°C, add 26.1g of tin tetrachloride dropwise, and stir at 25°C to react after the dropwise addition. After completion of the reaction as monitored by HPLC, it was quenched with water. The reaction solution was diluted with dichloromethane, washed with water, and the organic phase was dried and concentrated to obtain crude product C-3. The crude product was dissolved in 200 mL methanol / ammonia water, and stirred at 25°C overnight. After the reaction was completed, it was concentrated and chromatographically obtained 12.1 g of the product 3'-oxygen-methoxyethyladenosine (A-3), with a purity of 99.6% and a yield of 70%.

[0131] 1 H NMR (500MHz, DMSO-d 6 )δ (ppm): 8.35 (s.1H), 8.15 (s, 1H), 7.34 (s.2H), 5.89 (d, J = 8.5Hz, 1H), 5.48-5.45 (m, 1H), 5.41 ( d,J=8.5Hz,1H),4.77-4.73(m,1H),4....

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Abstract

The invention discloses a preparation method of 3'-oxy-methoxyethyl nucleoside. The method comprises the steps of: (1) condensing a compound with a structure shown in formula B and a silylated protected base to obtain a compound with a structure shown in formula C; the base is selected from thymine, 5-methyl Cytosine, adenine or 2,6-diaminopurine; and (2) the 3'-oxygen-methoxyethyl nucleoside whose structure is shown in formula A is obtained through alkaline hydrolysis reaction by the compound shown in formula C ;

Description

technical field [0001] The invention relates to the field of nucleoside compound synthesis, in particular to a preparation method of 3'-oxygen-methoxyethyl nucleoside. Background technique [0002] In recent years, with the development of genome-based drugs, antisense oligonucleotide drugs have been rapidly developed. The reason is that compared with traditional drugs, antisense oligonucleotide drugs have the following advantages, such as stronger specificity and greater information content. Because it acts on the upstream of the transmission of genetic information, the required dose is lower and the side effects are also less. [0003] 3'-Oxy-methoxyethyl nucleoside is an analogue of the second generation antisense oligonucleoside, which is the basic raw material for nucleoside synthesis. 3'-O-methoxyethyl nucleosides can be used in scientific research, especially functional genomics research, in addition to being used as a drug development tool. However, the existing lit...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/067C07H19/167C07H1/00
CPCC07H1/00C07H19/067C07H19/167Y02P20/55
Inventor 李喜群孙波
Owner SHANGHAI ZHAOWEI TECH DEV
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