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Synthetic method of 7-denitrified-7-substituted guanosine

A technology of guanine nucleoside and guanine nucleotide, which is applied in the fields of chemical synthesis and biochemistry, can solve the problems of expensive synthesis methods, complexity, and high price of nucleosides containing substituents, and achieve easy-to-obtain and simple raw materials Effect

Inactive Publication Date: 2014-02-26
SHANGHAI JIAO TONG UNIV
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Problems solved by technology

[0005] The reversible terminal for sequencing generally selects nucleotides with four bases of U, C, A, and G. In actual work, we found that the starting materials for the synthesis of four different base nucleotides, namely four Substituent nucleosides with different bases (U, C, A, G) are expensive, especially 7-deaza-7-substituted guanosine (including guanosine dG-X and G-X) is not only very expensive but also synthetic The method is very complicated, causing many researchers to avoid using guanosine as much as possible (J.Org.Chem.2011, 76, 3457-3462), which makes the original perfect research work a bit regrettable

Method used

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  • Synthetic method of 7-denitrified-7-substituted guanosine

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Embodiment 1

[0042] One of the synthetic methods of embodiment 1,7-deaza-7-iodo-2'-deoxyguanosine dG-I

[0043] The synthesis schematic diagram of dG-I in this embodiment is as follows figure 1 As shown, the specific synthetic method comprises the following steps respectively:

[0044] step one,

[0045]

[0046] Compound dG 1 -A (0.20g; 0.714mmol) was dissolved in anhydrous pyridine, pivaloyl chloride (0.75mL; 7.14mmol) was slowly added dropwise at 0°C, stirred at 0°C for 1h, then 2ml of methanol was added, stirred for 10min, and the solvent was spun out , adding ethyl acetate (200ml) and saturated sodium bicarbonate solution (50ml) for extraction, separating the organic phase, adding saturated sodium bicarbonate solution and saturated brine successively for washing, drying over anhydrous sodium sulfate, spinning off the solvent, and silica gel column chromatography [V (ethyl acetate): V (petroleum ether) = 1: 1] to obtain 0.39 g of white solid, namely compound dG 1 -B, yield 92%...

Embodiment 2

[0056] Embodiment 2, the second synthetic method of 7-deaza-7-iodo-2'-deoxyguanosine dG-I

[0057] The synthesis schematic diagram of dG-I in this embodiment is as follows figure 2 As shown, the specific synthetic method comprises the following steps respectively:

[0058] step one,

[0059]

[0060] After Sm-1 (27.3g, 138mmol) was added to 70mL of water, 3.0mL of concentrated hydrochloric acid was added and stirred at 90°C for 0.5h. After cooling to room temperature, sodium acetate (13.6g, 165mmol) was added and stirred, and Sm-2 ( 20.0g, 159mmol) and sodium acetate (7.0g, 85.4mmol) were dissolved in 150mL water and added to the reaction, stirred at 80°C for 2h, then moved to zero°C and stirred for 1.5h, filtered, and washed with ice water and acetone, It was sucked dry to obtain 15.4 g, and the yield was 74%. 1 H NMR (400MHz, DMSO): δ=10.94(s, 1H), 10.35(s, 1H), 6.58(dd, J=3.4, 2.2Hz, 1H), 6.15(dd, J=3.4, 2.1Hz, 1H ), 6.09(s, 2H).

[0061] Step two,

[0062]

...

Embodiment 3

[0079] The synthetic method of embodiment 3,7-deaza-7-iodine-guanosine G-I

[0080] The synthesizing schematic diagram of G-I in the present embodiment is as image 3 As shown, the specific synthetic method comprises the following steps respectively:

[0081] step one,

[0082]

[0083] G008 (1.5g, 4.0mmol) and ammonium sulfate (15mg, 0.11mmol) were refluxed in hexamethyldisilazane (15mL, 72.76mmol) for 20h under the protection of argon, and 40mL of dichloro Ethane, add G-I-O (6.0mmol) and TMSOTf (1.25mL, 6.47mmol) and stir at room temperature until clarified, then stir at 50 degrees Celsius for 24h, add 60mL DCM, and wash with 30mL saturated sodium bicarbonate and saturated brine, spin After removing the organic phase, 1.6 g of compound G-I-B was obtained by column chromatography. 1H NMR (600MHz, DMSO): δ=10.29(s, 1H), 8.02(s, 1H), 7.91-7.85(m, 6H), 7.64-7.58(m, 3H), 7.46-7.39(m, 6H) , 6.48(d, J=3.9Hz, 1H), 6.41(t, J=6.1, 6.1Hz, 1H), 6.32(dd, J=6.0, 4.0Hz, 1H), 4.82(...

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Abstract

The invention discloses a synthetic method of 7-denitrified-7-substituted guanosine; the method comprise following steps: a compound with formula (IV 1) or (IV 2) is obtained from a compound with formula (III) by removing protective groups under a alkaline condition; further a compound with formula (I) is obtained by demethylation, that is the 7-denitrified-7-substituted guanosine; wherein, R1 is H or H, R2 is I, Br or Cl, R3 is H or OBz. The synthetic 7-denitrified-7-halogen substituted guanosine is a basic raw material which is widely applied to DNA sequencing, marking, extension and other biological fields, and is very expensive at market with complex synthetic method and difficult control; the synthetic method provided by the invention has the advantages that the raw materials are simple and easily available, and the synthetic process is a routine chemical reaction, and the method can be widely used in a large scale.

Description

technical field [0001] The invention relates to the fields of chemical synthesis and biochemistry, in particular to a synthesis method of 7-deaza-7-substituted guanosine (guanosine for short, including dG-X and G-X). Background technique [0002] DNA sequencing technology is one of the important means of modern life science and medical research. DNA sequencing started with Sanger sequencing technology (generation sequencing) in 1977, and has developed rapidly in the past thirty years. The throughput of sequencing has been greatly increased and the cost has dropped sharply. Some people even think that the speed of its development has broken the existing Moore's Law budget in the semiconductor industry. The emergence of the second-generation high-throughput parallel sequencing technology is a concentrated expression of the rapid development of sequencing technology. Using first-generation sequencing technology, the Human Genome Project (HGP) spent $3 billion to sequence the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/167C07H19/173C07H19/20C07H1/00C07H1/04C07H19/23
CPCY02P20/55
Inventor 沈玉梅龚兵刘亚智魏晓飞邵志峰汤道年赵小东李小卫伍新燕
Owner SHANGHAI JIAO TONG UNIV
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