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2'-C-methyl adenosine phosphoramidite monomer and synthesis method thereof

A technology of methyl adenine nucleoside phosphoramidite and synthesis method, which is applied in the field of 2'-C-methyl adenine nucleoside phosphoramidite monomer and its synthesis, and can solve the cost limitation of chemically modified RNA technology development, The phosphoramidite monomer needs to be developed to achieve the effect of simple operation, simple post-treatment, low cost and easy availability

Inactive Publication Date: 2018-10-16
南京百芙利科技有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the high difficulty and cost of chemical synthesis limit the development of chemically modified RNA technology, and more and more complex phosphoramidite monomers need to be developed

Method used

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  • 2'-C-methyl adenosine phosphoramidite monomer and synthesis method thereof
  • 2'-C-methyl adenosine phosphoramidite monomer and synthesis method thereof
  • 2'-C-methyl adenosine phosphoramidite monomer and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Synthesis of 3',5'-O-(di-tert-butylsilylbis)-2'-O-tert-butyldimethylsilane-2'-C-methyladenosine:

[0035]

[0036] In a 250ml two-necked bottle, add 100ml DMF and 2.8g (10mmol) 2'-C-methyladenosine (this compound has been industrialized by our company) respectively, and slowly drop 4.8g (11mmol) under the condition of nitrogen protection and 0°C ) di-tert-butylsilylbis(trifluoromethanesulfonic acid), and then stirred at 0°C for 30 minutes. Then add 3.4g (50mmol) imidazole in batches, then 25 DEG C of stirring reaction 30 minutes. 1.9 g (12 mmol) of tert-butyldimethylchlorosilane was slowly added dropwise, and then reacted with stirring at 80° C. for 3 hours. Cool to 0°C to crystallize, filter and wash with cold acetonitrile, and finally dry to obtain 4.7g 3',5'-O-(di-tert-butylsilylbis)-2'-O-tert-butyldimethylsilane- 2'-C-methyladenosine, yield 88%.

Embodiment 2

[0038] Synthesis of 3',5'-O-(di-tert-butylsilylbis)-2'-O-tert-butyldimethylsilane-N6-benzoyl-2'-C-methyladenosine:

[0039]

[0040] In a 250ml two-necked bottle, add 100ml of dichloromethane, 2.7g (5mmol) 3',5'-O-(di-tert-butylsilylbis)-2'-O-tert-butyldimethylsilane-2 '-C-methyladenosine, 1.0g (10mmol) triethylamine and 0.1g (1mmol) DMAP, under the condition of nitrogen protection and 0°C, 1.1g (7.5mmol) benzoyl chloride was added dropwise, then 25° C stirred the reaction for 3 hours. After the completion of the reaction detected by TLC, washed with water three times (50mlx3), dried with anhydrous magnesium sulfate, spin-dried the solvent, and then recrystallized with 20ml of acetonitrile to obtain 2.4g of 3',5'-O-(di-tert-butylsilylbis )-2'-O-tert-butyldimethylsilane-N6-benzoyl-2'-C-methyladenosine, the yield was 75%.

Embodiment 3

[0042] 5'-O-(4,4-dimethoxytrityl)-2'-O-[(tert-butyl)dimethylsilyl]-N6-benzoyl-2'-C-methyl Synthesis of base adenosine:

[0043]

[0044] In a 250ml two-necked bottle, 1.3g (2mmol) 3',5'-O-(di-tert-butylsilylbis)-2'-O-tert-butyldimethylsilane-N6-benzoyl-2 '-C-methyladenosine was dissolved in 5Oml of anhydrous dichloromethane. Under the conditions of ice bath and nitrogen protection, slowly add 1.0g (10mmol) pyridine hydrogen fluoride (dissolved in 6ml pyridine) dropwise, continue to stir at 0°C for 1 hour, after TLC detection reaction is complete, 50ml water and 50ml saturated sodium bicarbonate The aqueous solutions were washed once, dried with anhydrous magnesium sulfate, and the solvent was spin-dried. Then add 50ml of dichloromethane, 0.5g (5mmol) triethylamine and 0.03g (0.3mmol) DMAP respectively, and add 0.7g (2.2mmol) 4,4'-bismethyl in batches under the conditions of ice bath and nitrogen protection Oxytrityl chloride solid, then stirred at 25°C for 6 hours. Afte...

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Abstract

The invention discloses a 2'-C-methyl adenosine phosphoramidite monomer and a synthesis method thereof. The compound has a structural formula as shown in the specification. The synthesis method of the2'-C-methyl adenosine phosphoramidite monomer comprises reaction steps as shown in the specification. The synthesis method is gentle in reaction condition, simple in aftertreatment and simple and convenient to operate, and conditions are provided for large-scale synthesis of the compounds. The compound disclosed by the invention is a raw material for solid-phase synthesis of RNA (Ribose Nucleic Acid) nucleotide, one or more 2'-C-methyl adenosine phosphoramidite monomers are introduced into an oligonucleotide segment conveniently, and a novel oligonucleotide sequence and a probe thereof can besynthesized. The compound has wide application prospects in research and development of siRNA (small interfering RNA) medicines, study on gene functions, screening of all gene pools, and the like.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis of nucleotides, in particular to a 2'-C-methyladenosine phosphoramidite monomer and a synthesis method thereof. Background technique [0002] RNA interference technology (RNA interference, RNAi) won the Nobel Prize in Physiology and Medicine in 2006. RNA interference is a gene silencing phenomenon triggered by double-stranded RNA in molecular biology, and its mechanism is to inhibit gene expression by hindering the translation or transcription of specific genes. Small interfering RNA (siRNA) is not only an excellent tool for molecular biology research, but more importantly, it is a potential biomolecule with pharmaceutical application prospects. In recent years, the drug application of siRNA has become a research hotspot in scientific research institutions and enterprises. Among them, the method of chemical modification is a very important method. Although short double-stranded RNA mo...

Claims

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Application Information

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IPC IPC(8): C07H19/207C07H1/00
CPCC07H1/00C07H19/207Y02P20/55
Inventor 高元和
Owner 南京百芙利科技有限责任公司
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