Novel preparation method of nucleoside modified 5'-dmtr-2'-eoe-5-me-cytidine nucleoside

A nucleoside and compound technology, applied in the field of nucleoside compound synthesis

Active Publication Date: 2021-12-07
SHANGHAI ZHAOWEI TECH DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Even for laboratory-scale experiments, there are few literature reports at home and abroad

Method used

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  • Novel preparation method of nucleoside modified 5'-dmtr-2'-eoe-5-me-cytidine nucleoside
  • Novel preparation method of nucleoside modified 5'-dmtr-2'-eoe-5-me-cytidine nucleoside
  • Novel preparation method of nucleoside modified 5'-dmtr-2'-eoe-5-me-cytidine nucleoside

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preparation example Construction

[0061] In a specific embodiment of the present invention, a preparation method of a compound of formula A is provided, comprising the steps of:

[0062] In the first step, the compound D was dissolved in the dichloromethane / triethylamine system, cooled to about 0°C, and then the R1-Cl reagent was added dropwise to obtain the crude compound C;

[0063] In the second step, dissolve the triazole in the dichloromethane / triethylamine system, lower the temperature to about 0°C, and then add the chlorination reagent dropwise; then add the reaction solution of compound C obtained in the first step into the reaction kettle dropwise , to obtain the crude compound B reaction solution;

[0064] In the third step, the crude compound B reaction solution was washed with water, concentrated to dryness, and the crude compound B was obtained;

[0065] In the fourth step, the crude compound B is dissolved in the ammonia water / acetonitrile system, and after stirring and reacting, the crude compo...

Embodiment 1

[0084] Embodiment 1, the preparation of compound C

[0085]

[0086] Weigh 47.70 kg of 5'-DMTr-2'-EOE-thymidine, add 500 L of dichloromethane (DCM) to dissolve, cool the reaction solution to 0°C, add 22.89 kg of triethylamine (TEA), stir for 30 min, and pour into the system 16.38 kg of TMS-Cl was added dropwise, the temperature of the system was kept at 0°C during the dropwise addition, and the reaction was stirred at 0°C after the dropwise addition until the raw materials were completely reacted to obtain the crude compound C. This reaction solution was directly used in the next step without treatment.

Embodiment 2

[0087] Embodiment 2, the preparation of compound B

[0088]

[0089] In another reaction kettle, add 480 L of dichloromethane (DCM), 31.24 kg of triazole, and 61.03 kg of triethylamine, and stir for 30 min. Cool in an ice bath to 0°C, add POCl dropwise to the system 3 17.34kg, stirring for 30 minutes after dropping. Then, at 0°C, the crude product of the reaction solution of compound C was added dropwise into the reaction kettle; after the dropwise addition, the reaction was stirred at 25°C until the reaction of raw material C was complete. Then the reaction solution was quenched with water, washed with water, and the organic phase was concentrated to dryness to obtain a crude compound B. This crude product was directly used in the next reaction without further purification.

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Abstract

The invention relates to a preparation method of a novel nucleoside modifier 5'-DMTr-2'-ethoxyethyl (EOE)-5-Me-cytidine nucleoside. The method of the present invention uses the novel nucleoside modified substance 5'-DMTr-2'-EOE-thymidine as the starting material, and through processes such as reaction with chlorinating agent and triazole, ammonolysis treatment, etc., the yield is high. , to generate another novel nucleoside modification 5'-DMTr-2'-EOE-5-Me-cytidine nucleoside with high selectivity. The method of the invention can easily and economically synthesize the novel nucleoside modified 5'-DMTr-2'-EOE-5-Me-cytidine nucleoside in large quantities.

Description

technical field [0001] The invention belongs to the field of nucleoside compound synthesis, more specifically, the invention relates to a novel nucleoside modified 5'-DMTr-2'-EOE-5-Me-cytidine nucleoside and a preparation method thereof. Background technique [0002] In recent years, with the development of genomic medicines, antisense oligonucleotide drugs have been rapidly developed. The reason is that they have the following advantages over traditional drugs: 1) Stronger specificity. A 15-mer antisense oligonucleotide contains 30-45 hydrogen bonds, while low-molecular traditional drugs (200-600u) generally only form 1-4 bonds with the target; 2) The amount of information is large. Genetic information is from DNA-RNA-protein, and it is very accurate to block the synthesis of a certain protein with complementary oligonucleotides; 3) antisense drugs target nucleic acid, which is easier to rationally design new drugs than proteins . Since it acts on the upstream of the tran...

Claims

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Application Information

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