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Method for synthesizing 5'-chloro-nucleoside

A technology for chlorinated nucleosides and synthesis methods, applied in the directions of sugar derivatives, organic chemistry, etc., can solve the problems of high cost, complicated processing, low yield, etc., and achieves the development and application, mild reaction conditions and high yield. Effect

Inactive Publication Date: 2008-08-27
ZHENGZHOU UNIV
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Problems solved by technology

[0006] As an important drug intermediate, there are many synthetic methods of 5'-chlorinated nucleosides. Generally, the hydroxyl groups at the 2' and 3' positions need to be protected, and the amino groups on the bases also need to be protected, resulting in complex reactions and low yields. Low
For example, relevant literature (Synlett, (5), 671-673; 2000) has reported that the use of i-Pr 2 NCl and PPh 3 Reagents are used to chlorinate the 5' position of nucleosides, and the disadvantage is that the cost is high; there are also documents (Canadian Journal of Chemistry, 69(9), 1468-74; 1991) reporting the use of SOCl 2 The disadvantage of preparing 5'-chlorinated nucleosides by reaction in pyridine is serious pollution. When synthesizing 5'-chlorinated nucleosides from nucleosides with amino groups, the amino groups need to be protected and deprotected separately, and the treatment is complicated. low yield

Method used

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  • Method for synthesizing 5'-chloro-nucleoside
  • Method for synthesizing 5'-chloro-nucleoside

Examples

Experimental program
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Effect test

Embodiment 1

[0016] Embodiment 1 uses adenosine as raw material to prepare 5'-chlorinated nucleosides

[0017] 1g of adenosine (3.7mmol) and 3.33g of triphenylphosphine (12.7mmol) were dissolved in 25ml of dichloromethane, protected by argon, and 3.01g of hexachloroethane (12.7mmol) was added dropwise under reflux. After stirring under reflux at 40°C for 10 hours, cool to room temperature at 15°C, add acetic acid corresponding to 50% of the volume of the reaction solution, stir at 70°C for 3 hours, and evaporate the solvent to dryness under reduced pressure. Wash with dichloromethane until TLC shows that the washing liquid no longer contains triphenoxyphosphine. After column chromatography using 3% methanol / dichloromethane as eluent, white powdery crystals are obtained with a yield of 83.8%.

[0018] 1 H NMR ((CD 3 ) 2 SO, 400MHz): δ8.36(s, 1H, 2-H), 8.16(s, 1H, 8-H), 7.32(s, 1H, -NH 2 ), 5.93 (d, J=5.6Hz, 1H, 1′-H), 5.62 (d, J=6.0Hz, 1H, 2′-OH), 5.45 (d, J=5.4Hz, 1H, 3′- OH), 4.75(m,...

Embodiment 2

[0019] Example 2 Preparation of 5'-chloronucleosides with guanosine as raw material

[0020] 1 g of guanosine (3.5 mmol) and 3.24 g of triphenylphosphine (12.3 mmol) were dissolved in 25 ml of dichloromethane, protected by argon, and 2.91 g of hexachloroethane (12.3 mmol) was added dropwise under reflux. After stirring under reflux at 50°C for 10 hours, cool to room temperature 25°C, add acetic acid corresponding to 50% of the volume of the reaction solution, stir at 70°C for 3 hours, and evaporate the solvent to dryness under reduced pressure. Wash with dichloromethane until TLC shows that the washing liquid no longer contains triphenoxyphosphine. After column chromatography using 15% methanol / dichloromethane as eluent, white powdery crystals are obtained with a yield of 86.1%.

[0021] 1 H NMR (D 2 O, 400MHz) δ7.93(s, 1H, 8-H), 5.80(d, J=4.8Hz, 1H, 1'-H), 4.70(m, 1H, 2'-H), 4.37(m, 1H, 3′-H), 4.28 (m, 1H, 4′-H), 3.80 (m, 2H, 5′-2H); ESIMS (C 10 h 12 ClN 5 o 4 ): 302.1...

Embodiment 3

[0022] Example 3 Preparation of 5'-chloronucleosides with cytidine as raw material

[0023] 1 g of cytidine (4.1 mmol) and 3.78 g of triphenylphosphine (14.4 mmol) were dissolved in 25 ml of cyclohexane, protected by argon, and 3.41 g of hexachloroethane (14.4 mmol) was added dropwise under reflux. After stirring under reflux at 30°C for 10 hours, cool to room temperature at 20°C, add 50% acetic acid corresponding to the volume of the reaction solution, stir at 70°C for 3 hours, and evaporate the solvent to dryness under reduced pressure. Wash with dichloromethane until TLC shows that the washing liquid no longer contains triphenoxyphosphine. After column chromatography using 15% methanol / dichloromethane as eluent, white powdery crystals are obtained with a yield of 89.6%.

[0024] 1 H NMR ((CD 3 ) 2 SO, 400MHz): δ7.60 (d, J=7.4Hz, 1H, 6-H), 7.26 (br, 2H, -NH 2 ), 5.82 (d, J=4.6Hz, 1H, 1′-H), 5.75 (d, J=7.4Hz, 1H, 5-H), 5.43 (d, J=5.6Hz, 1H, 2′-OH ), 5.30(d, J=5.6Hz, 1H, ...

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Abstract

The invention discloses a preparation method of 5'-chlorine nucleoside belonging to medicinal chemistry technical field, which uses adenosine, guanosine, cytidine or uridine as raw material, adds triphenyl phosphine and hexachloroethane while the mol ratio of nucleoside / triphenyl phosphine / exachloroethane is 1:3-3.5:3-3.5, in one reactor to synthesize 5'-chlorine nucleoside. The preparation method has high yield, selective synthesis, simple operation, mild conditions, non pollution and support for industrial production. The 5'-chlorine nucleoside derivative is important intermediate of organic synthesis or drug synthesis, and the invention provides a synthesis method for 5'-chlorine nucleoside with high industrial value, which can accelerate the development and application of 5'-chlorine nucleoside.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a method for preparing a class of nucleosides, that is, a method for preparing 5'-chlorinated nucleosides. Background technique [0002] As an important synthetic intermediate, halogenated nucleosides are often used in the synthesis of cyclic nucleotides, nucleotides, thionucleoside derivatives, phosphonic acid derivatives, deoxyribonucleosides, unsaturated nucleoside derivatives and Nucleoside derivatives such as amino sugars, and many chlorinated nucleosides themselves have antiviral activity and other biological activities. Therefore, it is of great application value to study the synthesis method of chlorinated nucleosides. [0003] The structure of 5-chloronucleoside is shown in the figure: [0004] [0005] Formula 1 5'-Chlorinated Nucleosides [0006] As an important drug intermediate, there are many synthetic methods of 5'-chlorinated nucleosid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/167C07H19/067
Inventor 赵玉芬张红雨刘向前陈晓岚屈凌波
Owner ZHENGZHOU UNIV
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