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Nucleoside phosphoramidite used in RNA oligo-nucleotide synthesis and its synthesizing method

A nucleoside phosphoramidite and nucleoside technology, which is applied in the field of chemical synthesis of oligonucleotides, can solve problems such as poor compatibility, and achieve the effect of mild conditions

Inactive Publication Date: 2007-01-24
张必良
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The main disadvantage of acetals is poor compatibility with acid-labile DMTr

Method used

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  • Nucleoside phosphoramidite used in RNA oligo-nucleotide synthesis and its synthesizing method
  • Nucleoside phosphoramidite used in RNA oligo-nucleotide synthesis and its synthesizing method
  • Nucleoside phosphoramidite used in RNA oligo-nucleotide synthesis and its synthesizing method

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Experimental program
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Effect test

Embodiment 1

[0047] The synthesis of embodiment 1 adenosine phosphoramidite

[0048] Synthesis of 6-N-benzoyladenosine (compound 1): adenosine (10.68g, 39.96mmol) was dissolved in 200mL pyridine to form a suspension, trimethylchlorosilane (38.1mL, 300mmol) was added therein, at room temperature Under the protection of argon flow, the mixture was fully mixed and reacted for 45 min, then benzoyl chloride (23.1 mL, 200 mmol) was added and mixed for 4 h, the mixture was cooled in an ice bath and 40 mL of water was added, and after 20 min, 29% ammonium hydroxide was slowly added. Aqueous solution (96mL, 713.3mmol), mixed at room temperature for 45min, centrifuged and vacuumed to dry powder, added 320mL of water to dissolve. The solution was washed once with ethyl acetate (100 mL) and crystals formed immediately. After filtration, it was washed successively with 30 mL EtOAc, 40 mL ice water, and 40 mL acetone (twice) to obtain a white solid 6-N-benzoyladenosine (Compound 1) (14.17 g...

Embodiment 2

[0053] The synthesis of embodiment 2 cytidine phosphoramidites

[0054] Synthesis of 4-N-benzoylcytidine (Compound 7): Cytidine (9.72 g, 39.96 mmol) was added to 200 mL of pyrimidine to form a suspension, and then trimethylchlorosilane (38.1 mL, 300 mmol) was added thereto. Mix well at room temperature under the protection of argon flow for 1 h, then add benzoyl chloride (23.0 mL, 200 mmol) at room temperature and mix for 4 h, add 40 mL of water after the mixture is cooled in an ice bath, and add 29% ammonium hydroxide after 20 min Solution (60mL, 445.8mmol), mixed at room temperature for 25min, centrifuged and evacuated to dry powder, added 400mL of water to dissolve. Crystallization occurred after adding 150 mL of EtOAc. After filtration, it was washed successively with 30 mL of ethyl acetate, 30 mL of ice water, and 30 mL of acetone (twice) to obtain 4-N-benzoylcytidine (Compound 7) (13.1 g, 94.4%) as a white solid. R f =0.55 (20% methanol-ethyl acetyl ester)...

Embodiment 3

[0057] The synthesis of embodiment 3 guanosine phosphoramidites

[0058] 6-N-benzoyl-2'-O-DNPA-5'-O-(4,4'-dimethoxytrityl)guanosine-3 was prepared according to the corresponding method in Example 1 '-O-(2-ethylcyano-N,N-diisopropylphosphoramidite.

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Abstract

The present invention discloses a kind of nucleoside phosphoramidite for synthesizing RNA oligonucleotide and its synthesis. The present invention adopts [2, 2-dimethyl-2-(o-nitrophenyl) acetylmethoxy] ether (DNPA) as the 2'-hydroxy protecting radical. The protecting radical DNPA is compatible with convenient 5'-hydroxy protecting radical, and may be eliminated under mild condition, so that it can ensure the RNA integrality and is suitable for synthesis of RNA oligonucleotide. The present invention provides one new path for synthesizing RNA oligonucleotide and may be used for the RNA molecule synthesis of various kinds of natural nucleoside, non-natural nucleoside, labeling nucleoside or their derivatives.

Description

technical field [0001] The present invention relates to a kind of chemical synthesis method of oligonucleotide, more specifically, the present invention relates to a kind of nucleoside phosphoramidite (or claim RNA oligonucleotide derivative) in RNA oligonucleotide synthesis and its synthesis method. Background technique [0002] The research on RNA interference (RNAi) is developing at an unprecedented speed, and its application scope is becoming wider and wider. , high-efficiency siRNA synthesis and chemically improved siRNA molecule derivatives. At present, most successful strategies for synthesizing RNA are based on the previous DNA synthesis method, except that the 2'-hydroxyl must be protected, and other chemical processes are very similar to the DNA synthesis process. That is, most strategies use tert-butyldimethylsilyl ether (TBDMS) to protect the 2'-hydroxyl of ribose. This protection method results in a longer coupling time per cycle, typically 10 min, because th...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H19/16
Inventor 张必良崔智勇
Owner 张必良
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