A kind of nucleoside bisphosphoramidite and preparation method thereof

A compound and general formula technology, applied in the field of nucleoside compound synthesis, can solve problems affecting the synthesis efficiency, purification and quality control of oligonucleotide monomers

Active Publication Date: 2021-10-22
SHANGHAI ZHAOWEI TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the synthesis of oligonucleotide monomers, this impurity can cause the generation of another kind of impurity nucleoside bisphosphoramidite monomer, as shown in formula (I), thereby can affect the synthesis efficiency of oligonucleotide monomers , purification and quality control

Method used

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  • A kind of nucleoside bisphosphoramidite and preparation method thereof
  • A kind of nucleoside bisphosphoramidite and preparation method thereof
  • A kind of nucleoside bisphosphoramidite and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Embodiment 1, the synthesis of thymidine bisphosphoramidite

[0091] 1. Synthesis of Compound A

[0092] Weigh 100 g of DMTCl (295.8 mmol) in a dry three-necked flask, add 400 ml of dichloromethane (DCM) to dissolve, and then use argon gas bubbling to drive off the air in the system. After the temperature of the reaction solution was lowered to 0° C. with an ice-water bath, 444 ml of 1M boron tribromide (BBr) was gradually added dropwise to the above system. 3 , 443.7mmol) dichloromethane solution, the dropwise addition time is about 60min. After the dropwise addition, the reaction was stirred at 20±5°C for about 12 hours until the raw material was no longer converted. HPLC monitors the reaction, and if the raw material is <7%, the reaction is stopped; otherwise, the reaction is continued, and samples are taken for HPLC analysis every 50-60 minutes until the raw material is <7%. After the reaction was completed, the reaction solution was concentrated to dryness under...

Embodiment 2

[0105] Embodiment 2, the synthesis of uridine bisphosphoramidite

[0106] Compound 1 was prepared according to the corresponding method in Example 1.

[0107] Synthesis of compound C-2

[0108] Weigh 28.4g of 2-F-uridine (115.4mmol) and 44g of compound 1 (121.2mmol) into a 250ml three-neck flask and stir and dissolve them with 180ml of dry pyridine. After stirring at room temperature for 5 h, TLC (CH 2 Cl 2 : MeOH=95:5, v / v) and HPLC monitors the reaction until the raw material disappears substantially (conversion rate 90%), and stops the reaction. The system was quenched by adding 6 ml of methanol, and concentrated to remove all solvents to obtain a crude product as a pale yellow solid. The crude product was diluted with 600ml of dichloromethane, washed with 600ml of water, and the organic phase was separated and dried with 10g of anhydrous sodium sulfate to obtain 76g of the crude product. The crude product was directly used in the next reaction without purification.

...

Embodiment 3

[0114] Embodiment 3, the synthesis of cytidine bisphosphorimide

[0115] Compound 1 was prepared according to the corresponding method in Example 1.

[0116] Compound 1 was reacted with 4-acetyl-2'-fluoro-dC, and the structure shown in cytidine bisphosphorimide 2c was obtained by referring to the corresponding steps in Example 1. Mass Spectrum: MS (ESI) m / z 976.6 (M+H + ,100).

[0117]

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Abstract

The invention relates to a nucleoside bisphosphoramidite and a preparation method thereof. The method of the present invention is based on the preparation method of the nucleoside bisphosphoramidite starting from 4-methoxy-4'-acetoxytrityl chloride. The nucleoside bisphosphoramidite designed and prepared by the invention can be used for impurity calibration and analysis in oligonucleotide synthesis, thereby facilitating large-scale synthesis, purification and quality control of oligonucleotide drugs.

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 a novel nucleoside bisphosphoramidite. Background technique [0002] Antisense technology (Antisense Technology) is based on the principle of base complementarity, using artificially synthesized or biologically synthesized specific DNA or RNA fragments to inhibit or block gene expression, and is a new drug development method. Drugs developed using antisense technology become antisense nucleic acid drugs (abbreviated as antisense drugs), including antisense oligonucleotides (including antisense DNA and reactive RNA), ribozymes, antisense RNA and RNA interference. According to the principle of nucleic acid hybridization, antisense drugs can hybridize with specific genes and interfere with the production of disease-causing proteins at the genetic level. Protein is the main substance of the structure and function of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/10C07H19/207C07H21/04C07H1/00G01N33/00
Inventor 赵谦益姚峰边瑞芳
Owner SHANGHAI ZHAOWEI TECH DEV
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