CN108659080A - A kind of 2`-C- methyl adenines nucleoside phosphoramidites monomer and its synthetic method - Google Patents
A kind of 2`-C- methyl adenines nucleoside phosphoramidites monomer and its synthetic method Download PDFInfo
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- CN108659080A CN108659080A CN201810535394.9A CN201810535394A CN108659080A CN 108659080 A CN108659080 A CN 108659080A CN 201810535394 A CN201810535394 A CN 201810535394A CN 108659080 A CN108659080 A CN 108659080A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a kind of 2'C methyl adenines nucleoside phosphoramidites monomer and its synthetic methods.The general structure of the compound is：The reaction step of the synthetic method of the 2'C methyl adenines nucleoside phosphoramidites monomer is as follows：
Description
Technical field
The invention belongs to the chemosynthesis technical fields of nucleotide, more particularly to a kind of 2'-C- methyl adenines nucleosides
Phosphoramidite monomer and its synthetic method.
Background technology
RNA perturbation techniques (RNA interference, RNAi) obtained Nobel's physiology and Medicine in 2006.
RNA interference is the gene silencing phenomenon caused by double-stranded RNA on molecular biology, and mechanism is by hindering specific gene
Translation or transcription carry out inhibition of gene expression.SiRNA (siRNA) is not only a kind of outstanding molecular biology research hand
Section, it is often more important that, it is a kind of potential biomolecule with medicinal application foreground.In recent years, the medicinal application of siRNA
As the research hotspot of scientific research institution and enterprise.The method of wherein chemical modification is a kind of very important means, although short
Double stranded rna molecule can be used in gene silencing, and have higher activity and stability on a cellular level, but either
It is all very necessary that an introducing modification or two chains, which all introduce modification, wherein.For medical application, into one
It is highly important that step, which improves thermodynamic stability and the resistance of ribozyme,.Second, chemical modification can improve double-strand siRNA in body
Internal half-life period.Third, chemical modification can also improve distribution and the pharmacokinetic properties of double-strand siRNA, and can allow
SiRNA targets specific cell.4th, the affinity with target gene can be changed by suitable chemical modification, to carry
The interference effect of high siRNA reduces the undershooting-effect of siRNA.2 '-O-Me and 2 '-F modifications are the siRNA modifications carried out earliest
It explores, 2 '-O-Me and 2 '-F modifications are used interchangeably to modify natural siRNA can be to significantly improving its serum stable
Property, and may can improve RNAi activity (Allerson, C. R. to a certain extent in partial sequence；Sioufi, N.；
James, R., et al.J. Med. Chem, 2005,48,901.).SiRNA Synesis Company can provide both quotient at present
The modification service of product.But it is chemical synthesis the development that highly difficult and cost limits chemical modification RNA technologies, more, more
Complicated phosphoramidite monomer has to be developed.The selection of abundant chemical modification siRNA monomers will be promoted siRNA by the present invention
The research and development of drug.
In recent years studies have shown that 2'-C- methyl adenine nucleosides shows up-and-coming anticancer drug, antiviral work
Property and interested biochemical characteristic.（Ronald C. G.; Lillian Lou; Christopher D. R.; Uli
Schmitz. Annual reports in medicinal chemistry, 2004, vol. 39, p. 223-237；
Franchetti, P.; Cappellacci, L.; Marchetti, S.; Trincavelli, L.; Martini, C.;
Mazzoni, M. R.; Lucacchini, A.; Grifantini, M.. J. Med. Chem., 1998, 41,
1708-1715; Matsuda, A.; Takenuki, K.; Sasaki,T.; Ueda, T. J. Med. Chem. 1991,
34, 234; Harry-O’Kuru, R. E.; Smith, J. M.; Wolfe, M. S. J. Org. Chem. 1997,
62, 1754; Awano, H.; Shuto, S.; Baba, M.; Kira, T.; Shigeta, S.; Matsuda, A.
Bioorg. Med. Chem. Lett. 1994, 4, 367; Matsuda, A.; Azuma, A. Nucleosides
Nucleotides 1995, 14, 461; Baker, C. H.; Banzon, J.; Bollinger, J. M.;
Stubbe, J.; Samano,V.; Robin, M. J.; Lippert, B.; Jarvi, E.; Resvick, R. J.
Med. Chem. 1991,34, 1879.）.
The present invention using the 2'-C- methyl adenines nucleosides with good anticancer and antiviral activity as starting material,
A kind of 2'-C- methyl adenines nucleoside phosphoramidites monomer is synthesized, can be as the raw material of RNA nucleotide synthesis in solid state, it can be with
One or more 2'-C- methyl adenine nucleoside phosphoramidites monomers, synthesizing new are easily introduced in oligonucleotide fragment
Oligonucleotide sequence and its probe.Medicament research and development, base in siRNA (siRNA, small interfering RNA)
Because the research of function and the screening etc. in full genome library have broad application prospects.
Invention content
The invention mainly solves the technical problem of providing a kind of 2'-C- methyl adenines nucleoside phosphoramidites monomer and its
Synthetic method, the synthesising method reacting condition is mild, and post-processing is simple, easy to operate, is suitble to industrialized production, for a large amount of synthesis
Such compound provides condition.Raw material can be provided to synthesize new RNA nucleotide sequences, for novel siRNA medicament research and development and newly
Low cost, high speed and the high throughput of nucleic acid sequence analysis technology lay the foundation.
In order to solve the above technical problems, one aspect of the present invention is：Synthesize a kind of 2'-C- methyl adenines
Nucleoside phosphoramidites monomer, it is characterised in that structure is：
Wherein R1It is selected from：
R2It is selected from：
R3It is selected from：
R4It is selected from：
。
Specifically synthesis step is：
（1）Starting material is 2'-C- methyladenosines（2'-C- methyl adenine nucleosides）, under alkaline condition, first use two tertiary fourths
Base silicon substrate bis- (trifluoromethayl sulfonic acids) protects 5'-OH and 3'-OH to synthesize 1 compound of formula.It then proceedes to that fert-butyidimethylsilyl is added
Chlorosilane protects 2'-OH, directly obtains 2 compound of formula；
（2）2 compound of formula, under the action of alkaline condition and catalyst, protection-NH23 compound of synthesis formula, catalyst are preferred
DMAP；
（3）3 compound of formula, under the action of alkaline condition and catalyst hydrogen fluoride pyridine, the de- 5'-OH and 3'-OH of selectivity is protected
Protect 4 compound of synthesis formula.Then after simple post-processing, directly under the action of alkaline condition and catalyst, selective protection
5'-OH synthesizes 5 compound of formula, protecting group preferably 4,4- dimethoxytrityls, the preferred DMAP of catalyst；
（4）5 compound of formula, under the action of alkaline condition and catalyst, selective protection 3'-OH synthesizes 6 compound of formula.Protection
Preferred 2- cyanoethyls N, N- the diisopropyl chloro phosphoramidite of reagent, the preferred DMAP of catalyst.
Raw material of the gained compound of the invention as RNA nucleotide synthesis in solid state, can be easily in oligonucleotide fragment
Middle introducing one or more 2'-C- methyl adenine nucleoside phosphoramidites monomers, the oligonucleotide sequence of synthesizing new and its spy
Needle.In the medicament research and development of siRNA (siRNA, small interfering RNA), the research of gene function and full genome
The screening in library etc. has broad application prospects.
Three kinds of 2'-C- methyl adenine nucleoside phosphoramidites monomers are the priority compounds of the present invention below：
。
The beneficial effects of the invention are as follows：The present invention is compared with the prior art, have the following advantages that：
1. the great advantage of the present invention is 2'-C- methyl adenine nucleoside phosphoramidites monomers as RNA nucleotide synthesis in solid state
Raw material, can easily in oligonucleotide fragment introduce one or more 2'-C- methyl adenine nucleoside phosphoramidites lists
Body, the oligonucleotide sequence and its probe of synthesizing new.
2. the synthesising method reacting condition is mild, post-processing is simple, easy to operate, is suitble to industrialized production.
3. the present invention is former using the 2'-C- methyl adenines nucleosides with good anticancer and antiviral activity as starting
Material, after thering is the structure of such characteristic to introduce oligonucleotide fragment, in Related Research Domain（Especially siRNA Field of Drug Discovery）
It is expected to making a breakthrough property achievement.
4. the starting important source material 2'-C- methyl adenine nucleosides of the present invention, our company has industrialized, of low cost to be easy to get.
Description of the drawings
Fig. 1 is the synthetic route of 2'-C- methyl adenines nucleoside phosphoramidites monomer of the present invention.
Specific implementation mode
The preferred embodiments of the present invention will be described in detail below in conjunction with the accompanying drawings, so that advantages and features of the invention energy
It is easier to be readily appreciated by one skilled in the art, so as to make a clearer definition of the protection scope of the present invention.
Referring to Fig. 1, the embodiment of the present invention includes：
Embodiment 1
The synthesis of 3', 5'-O- (di-t-butyl silicon substrate is double) -2'-O- t-butyldimethyl silane -2'-C- methyladenosines：
In 250ml two-mouth bottles, it is separately added into 100mlDMF and 2.8g (10mmol) 2'-C- methyladenosines（This compound our company
It has industrialized）, under the conditions of nitrogen protection and 0 °C, it is slowly dropped into the bis- (fluoroforms of 4.8g (11mmol) di-t-butyl silicon substrate
Sulfonic acid), then it is stirred to react 30 minutes for 0 °C.Then 3.4g (50mmol) imidazoles is added portionwise, is then stirred to react 30 points for 25 °C
Clock.1.9g (12mmol) tert-butyl chloro-silicane is slowly added dropwise, is then stirred to react 3 hours for 80 °C.It is cooled to 0 °C of analysis
Crystalline substance is filtered and is washed with cold acetonitrile, is finally dried to obtain 4.7g 3', 5'-O- (di-t-butyl silicon substrate is double) -2'-O- tertiary butyls
Dimethylsilane -2'-C- methyladenosines, yield 88%.
Embodiment 2
3', 5'-O- (di-t-butyl silicon substrate is double) -2'-O- t-butyldimethyl silane-N6- benzoyl -2'-C- methyladenosines
Synthesis：
In 250ml two-mouth bottles, it is separately added into 100ml dichloromethane, 2.7g (5mmol) 3', 5'-O- (di-t-butyl silicon substrate
It is double) -2'-O- t-butyldimethyl silane -2'-C- methyladenosines, 1.0g (10mmol) triethylamines and 0.1g (1mmol)
DMAP is added dropwise 1.1g (7.5mmol) chlorobenzoyl chloride, is then stirred to react 3 hours for 25 °C under the conditions of nitrogen protection and 0 °C.
TLC detections are after the reaction was complete, and water washing is three times（50mlx3）, after being dried with anhydrous magnesium sulfate, it is spin-dried for solvent, then uses 20ml second
Nitrile is recrystallized to give 2.4g 3', 5'-O- (di-t-butyl silicon substrate is double) -2'-O- t-butyldimethyl silane-N6- benzoyls -
2'-C- methyladenosines, yield 75%.
Embodiment 3
5'-O- (4,4- dimethoxytrityls) -2'-O- [(tertiary butyl) dimethyl silicon substrate]-N6- benzoyl -2'-C- first
The synthesis of base adenosine：
In 250ml two-mouth bottles, by 1.3g (2mmol) 3', 5'-O- (di-t-butyl silicon substrate is double) -2'-O- tertiary butyl diformazans
Base silane-N6- benzoyl -2'-C- methyladenosines are dissolved in 5Oml anhydrous methylene chlorides.In ice bath and nitrogen protection condition
Under, 1.0g (10mmol) hydrogen fluoride pyridine (being dissolved in 6ml pyridines) is slowly added dropwise, after 0 °C of continuation stirring 1 hour, TLC detections
After the reaction was complete, 50ml water and 50ml saturated sodium bicarbonate aqueous solutions respectively washed once, and after being dried with anhydrous magnesium sulfate, be spin-dried for molten
Agent.Be then respectively adding 50ml dichloromethane, 0.5g (5mmol) triethylamines and 0.03g (0.3mmol) DMAP, in ice bath and
Under the conditions of nitrogen protection, 0.7g (2.2mmol) 4,4'- dimethoxytrityl chloride solids are added portionwise, then stir for 25 °C
Mix reaction 6 hours.TLC detections are after the reaction was complete, and water washing is three times（50mlx3）, after being dried with anhydrous sodium sulfate, it is spin-dried for solvent,
Column chromatography (petrol ether/ethyl acetate=3：1) 1.5g 5'-O- (4,4- dimethoxytrityl) -2'-O- [(tertiary fourths, are obtained
Base) dimethyl silicon substrate]-N6- benzoyl -2'-C- methyladenosines, yield 93%.
Embodiment 4
5'-O- (4,4- dimethoxytrityls) -2'-O- [(tertiary butyl) dimethyl silicon substrate]-N6- benzoyl -2'-C- first
The synthesis of base adenosine -3'- (2- cyano ethyls-N, N- diisopropyl) phosphoramidite：
In 250ml two-mouth bottles, by 1.2g (1.5mmol) 5'-O- (4,4- dimethoxytrityl) -2'-O- [(tertiary fourths
Base) dimethyl silicon substrate]-N6- benzoyl -2'-C- methyladenosines are dissolved in 8Oml anhydrous methylene chlorides, then sequentially add
The DMAP solids of 0.7g (6mmol) diisopropyl ethyl amines and 0.03g (O.3mmol), under the conditions of ice bath nitrogen protection, slowly
0.7g (3mmol) 2- cyanoethyls N, N- diisopropyl chloro phosphoramidite (being dissolved in 30ml dichloromethane) is added dropwise, continues to stir
It mixes after five minutes, restores room temperature, stir 8 hours.TLC detections are after the reaction was complete, after being spin-dried for solvent, direct column chromatography (petroleum ether/
Ethyl acetate=8：1) 1.3g 5'-O- (4,4- dimethoxytrityl) -2'-O- [(tertiary butyl) dimethyl silicon substrate] -, is obtained
N6- benzoyl -2'-C- methyladenosines -3'- (2- cyano ethyls-N, N- diisopropyl) phosphoramidite, yield 86%.
Example the above is only the implementation of the present invention is not intended to limit the scope of the invention, every to utilize this hair
Equivalent structure or equivalent flow shift made by bright specification and accompanying drawing content is applied directly or indirectly in other relevant skills
Art field, is included within the scope of the present invention.
Claims (3)
1. a kind of 2'-C- methyl adenines nucleoside phosphoramidites monomer, it is characterised in that structure is：
Wherein R1It is selected from：
R2It is selected from：
R3It is selected from：
R4It is selected from：
。
2. a kind of 2'-C- methyl adenines nucleoside phosphoramidites monomer according to claim 1 and its synthetic method, special
Sign is that specific synthesis step is：
（1）Starting material is 2'-C- methyladenosines（2'-C- methyl adenine nucleosides）, under alkaline condition, first use two tertiary fourths
Base silicon substrate bis- (trifluoromethayl sulfonic acids) protects 5'-OH and 3'-OH to synthesize 1 compound of formula；
It then proceedes to that tert-butyl chloro-silicane protection 2'-OH is added, directly obtains 2 compound of formula；
（2）2 compound of formula, under the action of alkaline condition and catalyst, protection-NH23 compound of synthesis formula, catalyst are preferred
DMAP；
（3）3 compound of formula, under the action of alkaline condition and catalyst hydrogen fluoride pyridine, the de- 5'-OH and 3'-OH of selectivity is protected
4 compound of synthesis formula is protected, then after simple post-processing, directly under the action of alkaline condition and catalyst, selective protection
5'-OH synthesizes 5 compound of formula, protecting group preferably 4,4- dimethoxytrityls, the preferred DMAP of catalyst；
（4）5 compound of formula, under the action of alkaline condition and catalyst, selective protection 3'-OH synthesizes 6 compound of formula；
Protect preferred 2- cyanoethyls N, N- the diisopropyl chloro phosphoramidite of reagent, the preferred DMAP of catalyst.
3. a kind of 2'-C- methyl adenines nucleoside phosphoramidites monomer according to claim 1 and its synthetic method, special
Sign is：Raw material of the 2'-C- methyl adenine nucleoside phosphoramidites monomers as RNA nucleotide synthesis in solid state is (small in siRNA
RNA interfering, small interfering RNA) medicament research and development, the research of gene function and the screening etc. in full genome library
Application.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109970832A (en) * | 2019-04-09 | 2019-07-05 | 沈阳药科大学 | A kind of alkynyl-modified desoxyadenosine phosphoramidite monomer and preparation method thereof |
| CN114685560A (en) * | 2020-12-31 | 2022-07-01 | 沈阳药科大学 | Synthesis and application of phosphoramidite monomer containing piperidine skeleton and oligonucleotide |
-
2018
- 2018-05-30 CN CN201810535394.9A patent/CN108659080A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109970832A (en) * | 2019-04-09 | 2019-07-05 | 沈阳药科大学 | A kind of alkynyl-modified desoxyadenosine phosphoramidite monomer and preparation method thereof |
| CN109970832B (en) * | 2019-04-09 | 2022-06-03 | 沈阳药科大学 | Alkynyl-modified deoxyadenosine phosphoramidite monomer and preparation method thereof |
| CN114685560A (en) * | 2020-12-31 | 2022-07-01 | 沈阳药科大学 | Synthesis and application of phosphoramidite monomer containing piperidine skeleton and oligonucleotide |
| CN114685560B (en) * | 2020-12-31 | 2024-05-14 | 沈阳药科大学 | Synthesis and application of phosphoramidite monomer containing piperidine skeleton and oligonucleotide |
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