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Nucleotide and/or oligonucleotide and preparation method thereof

An oligonucleotide and nucleotide technology, applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., can solve the problems of high cost and small synthesis scale, and achieve the effect of saving raw materials and reducing costs

Active Publication Date: 2014-07-23
昆山市工业技术研究院小核酸生物技术研究所有限责任公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to provide a method for synthesizing RNA by the liquid-phase hydrogen phosphonic acid method, which overcomes the shortcomings of the current solid-phase oligonucleotide synthesis method, such as small synthesis scale and high cost, and provides a method capable of large-scale synthesis of oligonucleotides sour method

Method used

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  • Nucleotide and/or oligonucleotide and preparation method thereof
  • Nucleotide and/or oligonucleotide and preparation method thereof
  • Nucleotide and/or oligonucleotide and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0062] According to a preferred embodiment of the present invention, wherein, the method may also include the following steps:

[0063] In the second liquid reaction medium, the substance of formula (4) is contacted with the substance of formula (5) to obtain the substance of formula (6);

[0064] Formula (5)

[0065]

[0066] Formula (6)

[0067] Among them, in formula (5) and formula (6), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 The definition of is the same as that in formula (1).

[0068] Wherein, relative to 1 mole of the substance of the formula (4), the amount of the second liquid reaction medium can be 5-50 L, and the amount of the substance of the formula (5) can be 1-10 moles; the reaction temperature can be minus 50 ° C to 50°C; the reaction time can be 0.2-10 hours.

[0069] Wherein, the second liquid reaction medium may be pyridine or a mixed solution of pyridine and one or more of dichloromethane, acetonitrile, dioxane and tetrahydrofuran. ...

Embodiment 1

[0115] This embodiment synthesizes the substance of formula (1), wherein m and n are 0, R is trityl, R 5 and R 6 for -CH 2 CH 2 CN, R 7 is tert-butyldimethylsilyl, R 8 For uracil, the substance of the formula (1) is named as Tr[U]BH 3 .

[0116] PCl 3 (468mg, 3.4mmol) was dissolved in 20ml of the seventh liquid reaction medium (tetrahydrofuran), and at -78°C, added 2,6-lutidine (1.64g, 15.3mmol) and dissolved in 20ml of the seventh liquid reaction medium Formula (9) compound (wherein n is 0, R 1 is trityl, R 7 is tert-butyldimethylsilyl and R 8 Uracil, that is, 5'-O-Tr-2'O-TBDMS-rU, purchased from Shanghai Gemma Pharmaceutical Technology Co., Ltd., 1.0g, 1.7mmol), maintained for 5min.

[0117] Then, 3-hydroxypropionitrile (905 mg, 12.8 mmol) was added dropwise for 20 min.

[0118] Then, the temperature was raised to -20°C, and BH dissolved in the seventh liquid reaction medium (tetrahydrofuran, 7ml) was added dropwise. 3 (7 mmol), after maintaining at 0°C for 30 mi...

Embodiment 2

[0121] This embodiment synthesizes the substance of formula (3), wherein, y is 0, R 1 is trityl, R 7 is tert-butyldimethylsilyl, R 8 For uracil, the substance of the formula (1) is named Tr[U]PH, specifically through the above-mentioned Tr[U]BH 3 take off R 5 、BH 3 group and R 6 to fulfill.

[0122] At room temperature, in the third liquid reaction medium (CH 3 CN, 30ml), the Tr[U]BH 3 (784mg, 1mmol) was kept in contact with triethylamine (10ml) for 15min. Then concentrated under reduced pressure and sucked dry, promptly took off Tr[U]BH 3 R in 5 (-CH 2 CH 2 CN).

[0123] At 0°C, in the fourth liquid reaction medium (dichloromethane, 170ml), the dried solid product was kept in contact with dichloroacetic acid (5mmol) and methoxytrityl alcohol (735mg, 2.1mmol) for 10min . The reaction was quenched by adding 100 ml of saturated sodium bicarbonate solution. The reaction liquid was extracted twice with dichloromethane, 50 ml each time. Combine the extracted organic...

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Abstract

The invention discloses a nucleotide and / or oligonucleotide represented by the formula (1) and a preparation method thereof. In the preparation method, protected nucleotide and / or oligonucleotide is taken as the raw material, the synthesis reaction is carried out in a reaction bottle or a reactor, thus the synthesis reaction is not restricted by the solid carrier or synthesizer, so large-scale preparation of nucleotide and / or oligonucleotide is achieved.

Description

technical field [0001] The present invention relates to the field of chemical biology, in particular to a nucleotide and / or oligonucleotide and a preparation method of the nucleotide and / or oligonucleotide. Background technique [0002] Chemical synthesis of oligonucleotides refers to the process of linking multiple nucleotide units into an oligonucleotide chain by promoting the formation of 5'-3' phosphodiester bonds between nucleotide monomers, involving a protected core Synthesis of glycosides. [0003] The methods for synthesizing oligonucleotides include solid-phase synthesis and liquid-phase synthesis. The solid-phase synthesis usually uses the phosphoramidite condensation reaction, and the liquid-phase synthesis usually uses the phosphotriester condensation reaction or the hydrogen phosphonate condensation reaction. Compared with solid-phase synthesis, liquid-phase synthesis has the characteristics of easy identification of intermediates and easy scale of reaction. ...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H21/02C07H1/00
Inventor 席真黄金宇陆威
Owner 昆山市工业技术研究院小核酸生物技术研究所有限责任公司
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