CN108997460A - The fluoro- 2`-C- methyluridine phosphoramidite monomer of 2`- deoxidation -2`- and its synthetic method - Google Patents
The fluoro- 2`-C- methyluridine phosphoramidite monomer of 2`- deoxidation -2`- and its synthetic method Download PDFInfo
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- CN108997460A CN108997460A CN201810738979.0A CN201810738979A CN108997460A CN 108997460 A CN108997460 A CN 108997460A CN 201810738979 A CN201810738979 A CN 201810738979A CN 108997460 A CN108997460 A CN 108997460A
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- deoxidation
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- methyluridine
- phosphoramidite monomer
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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
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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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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- 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
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/11—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- 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 fluoro- 2'-C- methyluridine phosphoramidite monomer of 2'- deoxidation -2'- and its synthetic methods.The general structure of the compound are as follows:The synthetic method includes the following steps: that the fluoro- 2'-C- methyluridine 5'-OH protection of 2'- deoxidation -2'- and 3'-OH are phosphorus acylated.The synthesising method reacting condition is mild, and post-processing is simple, easy to operate, is suitble to industrialized production.Raw material of the gained compound of the invention as DNA nucleotide synthesis in solid state, the fluoro- 2'-C- methyluridine phosphoramidite monomer of one or more 2'- deoxidation -2'-, the oligonucleotide sequence and its probe of synthesizing new are introduced in oligonucleotide fragment with can be convenient.It has broad application prospects in the medicament research and development of siDNA (small interference DNA, small interfering DNA), the research of gene function and the screening in full genome library etc..
Description
Technical field
The invention belongs to the chemosynthesis technical fields of nucleotide, more particularly to a kind of fluoro- 2'-C- of 2'- deoxidation -2'-
Methyluridine phosphoramidite monomer and its synthetic method.
Background technique
Oligonucleotides is general name (including the DNA DNA of a kind of short nucleotide for there was only 20 or less bases
Or the nucleotide in Ribonucleic RNA), because it is easily docked with their complementary strand, it is often used as probe and determines DNA or RNA
Structure.The DNA of oligonucleotide synthesis can be used for chain polymerization reaction, can amplify the segment for determining nearly all DNA, at this
Oligonucleotides is to be made the duplicate of DNA as the complementary fragment combination of target in introduction and DNA in the process.Wherein regulation is few
Nucleotide prevents it from translating into albumen, has positive meaning in the lysises such as treating cancer for inhibiting RNA segment.
Since the oligonucleotides of chemical modification is demonstrated by the property better than crude oligonucleotides, be at present biochemistry and
The big research hotspot of the one of molecular biosciences.The superiority of the oligonucleotides of chemical modification mainly has: in terms of can be used for basic research
Genetic analysis；It can be used for protein structure and its active research without making genetic mutation；It can be used for furtheing investigate the hair of cancer
Exhibition process；It may further be used to inhibit some important gene products, such as enzyme, ion channel, receptor, immune modulatory molecules and other tune
Save the generation of albumen.In short, the research in terms of research albumen and its with the interaction of nucleic acid, the oligonucleotides of chemical modification
Provide a kind of important research means.
It is this connected by many nucleotide by 3 ' -5 ' di-phosphate ester chain links that nineteen fifty-two, which illustrates nucleic acid molecule,
After basic structure, chemists, which are initiated as soon, attempts the artificial synthesized of nucleic acid.The laboratory univ cambridge uk Todd in
Nineteen fifty-five has synthesized TpT and pTpTt(A.M.Michelson with 3 ' -5 ' di-phosphate ester bond structures, Alexander first
R.Todd.Nucleotides part XXXII.Synthesis of a dithymidine dinucleotide
Containing a 3 ': 5 ' internucleotidic linkage [J] .J.Am.Chem.Soc., 1955,2632-2638).
Therefore nineteen fifty-seven, Alexander R.Todd also win Nobel chemistry Prize.Hereafter, Khorana et al. is to the artificial of gene
Synthesis is made that epoch-making contribution, not only creates the approach of gene chemical synthesis, but also developed a series of related cores
Hydroxyl, the separation of the protecting group of the amino of base and phosphate and condensing agent and synthetic product, purification process on the sugar of thuja acid, and
It was put forward for the first time in year in 1967 and chemically synthesizes gene.1970, Khorana etc. reported method for synthesizing gene for the first time
(Itakura, K., T.Hirose, R.Crea, et a1.Expression in Escherichia coli of a
Chemically Synthesized Gene for the Hormone Somatostatin [J] .Science, 1 977,198
(4321): 1056-1063).After 2 years, they have synthesized the DNA double chain of Yeast Alanine tRNA structural gene；Hereafter they
The gene of the Escherichia coli tyrosine tRNA with 126 nucleotide pairs has been synthesized again.Complete within 1979 including promoter and
Adjust sequence including, share 207bp Escherichia coli tyrosine suppression tRNA gene (Goeddel Dr, Kleid DG,
Bolivar F.Expression in Escherichia coli of chemically synthesized genes for
Human insulin [J] .Proc.Natl.Acad.Sci.USA., 1979,76 (1): 106-1 10).
In terms of chemically synthesized method, in addition to the reaction condition of approach that Khorana et al. is established and point
Continue other than improvement from method and the selection of protecting group etc., since 1966, be first Letsinger then
It is Reese, Narang, Itakara, Van Boon, Ohtsuka and Caruthers et al., is built for the deficiency of approach
Found and developed phosphotriester method and tris phosphite method.And on this basis, and phosphotriester method and the Asia of solid phase have been developed
Phosphotriester method.Hereafter develop solid phase synthesis technique again, provided new method for the artificial synthesized of DNA, realize DNA synthesis
Automation.
By exploration and research in more than 20 years, the chemical synthesis that deoxidation core wards off oligonucleotides be have developed rapidly, especially most
In recent years, due to the promotion and application of solid phase synthesis technique, reached the chemical synthesis of DNA fragmentation accurately, efficiently and certainly
The degree of dynamicization provides brand-new means (Itakura.K., Rossi.J.J., Wallace.R.B. for genetic engineering
Synthesis and Use of Synthetic Oligonucleotides [J]. Annual Review of
Biochemistry, 1984,53,323-356).Artificial synthesized just play in many fields such as biology and medicine of DNA is got over
Carry out more effects.
Synthesis in solid state typically refer to the active function groups being connected on solid phase carrier (such as resin) be dissolved in it is organic molten
The reaction between reagent in agent.Its main feature is that simplifying and speeding up the synthesis of multi-step；Because reacting in a simple reaction vessel
In can carry out, can avoid the loss because manual operations and material repetitive displacement due to generate；The peptide chain that solid phase carrier is covalently connected
In suitable physical state, intermediate purifying can not be completed by quickly filtering, washing, avoided superfluous in liquid phase peptide synthesis
Long recrystallization divides column step, and avoidable intermediate largely loses when isolating and purifying；Using excess reactant, force individual
Fully reacting, so that final product obtains high yield.These advantages of synthesis in solid state are that the artificial synthesized of oligonucleotide provides
New thinking.
The chemical synthesis research of DNA starts from the fifties in last century.Gene is by the nucleic acid with specific nucleotide sequence
The functional unit of composition, it carries specific hereditary information, arranges in sequence on chromosome.Nucleic acid it is artificial synthesized
Refer to and connect nucleotide monomer in a manner of 3 ' -5 ' phosphodiester bond, the whole for making it have native nucleic acid molecule is raw
Object is active and specifically puts in order.When synthesis in solid state nucleotide, the 3 '-OH and solid phase carrier of terminal nucleotide are formed covalently
Key, every to extend a nucleotide needs 4 steps chemical reaction, successively by deprotection, coupling, is closed and four steps of oxidation are mainly anti-
It answers.
In recent years, the research of the synthesis to the oligonucleotides of chemical modification and its property and application is carried out more and more extensive
With deeply.Chemical modification is related to each structure position of oligonucleotides, and such as to base, ribosyl is phosphate-based to have carried out respectively
Kind structure of modification；Link chimeric base, reactive group, chromophore and enzyme on oligonucleotide chain.To their property, such as hybrid stability
The research of property, the substrate properties of nuclease, the sequence specificity of inhibition of gene expression and the mechanism of action etc. also has a large amount of reports.Change
Learn the structural research that should can be not only used for nucleic acid of the oligonucleotides of modification, it is also possible to make the antiviral medicament (Eugen of anticancer
Uhlmann, Anusch Peyman.Antisense oligonucleotides:a new therapeutic principle
[J] .Chem.Rev., 1990,90 (4): 543-584.).
It can be realized gene high expression after synthesizing and be transformed by chemical method, and eliminate the good side of the multiple point mutation of gene
Method.The development of chemical method synthetic DNA in recent years to synthesize compared with length dna sequence on a large scale.With chemical synthesis
Oligonucleotide chain is widely used in the fields such as all kinds of primers, total gene synthesis, DNA chip, realizes and synthesizes few core former times acid chain
Miniaturization, automation and high pass quantization.
Due to the development of modern science and technology, automatic dna synthesizer has been widely used in DNA synthesis, only a small number of special feelings
Using artificial synthesized under condition.Currently, mainly having ABI (Applied Biosystem Inc.), Pharmacia, Backman etc. several
Company produces DNA/RNA synthesizer, wherein accounting for the 80%-90% of China and world market with the instrument of ABI company.Due to closing
At the modernization of technology, the man power and material of synthesis process is greatly reduced, Scientific Research Workers need to only input the DNA of synthesizer
Sequence, entire synthesis process can be completed in 1~2h.Synthesis column is finally removed to carry out DNA again and cut to fall and deprotecting base and pure
Required nucleotide just can be obtained in change.
Suo Feibuwei (and being translated into rope fluorine cloth Wei, English name Sofosbuvir, trade name Sovaldi) is that lucky Leadd B.V opens
Hair is ratified in 6 Nikkei U.S. Food and Drug Administration (FDA) December in 2013 in beauty in the new drug for the treatment of chronic hepatitis C
State's listing, the approval of 16 Nikkei Europe drug administration (EMEA) January in 2014 are listed in EU countries.2'- deoxidation -2'- is fluoro-
2'-C- methyluracil is the important intermediate for synthesizing Suo Feibuwei.
The present invention synthesizes a kind of 2'- deoxidation -2'- using the fluoro- 2'-C- methyluracil of 2'- deoxidation -2'- as starting material
Fluoro- 2'-C- methyluridine phosphoramidite monomer, can be used as the raw material of DNA nucleotide synthesis in solid state, can be convenient ground
The fluoro- 2'-C- methyluridine phosphoramidite monomer of one or more 2'- deoxidation -2'- is introduced in oligonucleotide fragment,
The oligonucleotide sequence and its probe of synthesizing new.In the drug of siDNA (small interference DNA, small interfering DNA)
Research and development, the research of gene function and the screening in full genome library etc. have broad application prospects.
Summary of the invention
The invention mainly solves the technical problem of providing a kind of fluoro- 2'-C- methyluridine of 2'- deoxidation -2'- is sub-
Phosphinylidyne amine monomers and its synthetic method, the synthesising method reacting condition is mild, and post-processing is simple, easy to operate, is suitble to industrialization
Production.Raw material can be provided to synthesize new DNA nucleotide sequences, be new siDNA medicament research and development and novel nucleic acids gene sequence analysis
Low cost, high speed and high throughput lay the foundation.
In order to solve the above technical problems, one technical scheme adopted by the invention is that: it is fluoro- to synthesize a kind of 2'- deoxidation -2'-
2'-C- methyluridine phosphoramidite monomer, it is characterised in that structure are as follows:
Wherein R1It is selected from:
R2It is selected from:
R3It is selected from:
。
Specific synthesis step are as follows:
。
(1) starting material is the fluoro- 2'-C- methyluracil of 2'- deoxidation -2'-, in the effect of alkaline condition and catalyst
Under, selective protection 5'-OH synthesizes 1 compound of formula, and protecting group preferably 4,4- dimethoxytrityl, catalyst is preferred
DMAP。
(2) 1 compound of formula, under the action of alkaline condition and catalyst, choosing protection 3'-OH synthesizes 2 compound of formula, protection
Preferred 2- cyanoethyl N, N- the diisopropyl chloro phosphoramidite of reagent, the preferred DMAP of catalyst.
Raw material of the gained compound of the invention as DNA nucleotide synthesis in solid state, can be convenient in oligonucleotide fragment
The fluoro- 2'-C- methyluridine phosphoramidite monomer of middle introducing one or more 2'- deoxidation -2'-, the few core of synthesizing new
Nucleotide sequence and its probe.Medicament research and development, gene function in siDNA (small interference DNA, small interfering DNA)
Research and the screening in full genome library etc. have broad application prospects.
The fluoro- 2'-C- methyluridine phosphoramidite monomer of following two 2'- deoxidation -2'- is preferredization of the invention
Close object:
。
The beneficial effects of the present invention are: the present invention is compared with the prior art, have the advantages that
1. great advantage of the invention is the fluoro- 2'-C- methyluridine phosphoramidite monomer of 2'- deoxidation -2'- as DNA
It is fluoro- to introduce one or more 2'- deoxidation -2'- with can be convenient in oligonucleotide fragment for the raw material of nucleotide synthesis in solid state
2'-C- methyluridine phosphoramidite monomer, 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 to have the important intermediate of synthesis Suo Feibuwei: the fluoro- 2'-C- methyluridine of 2'- deoxidation -2'- is made
For starting material, after thering is the structure of such characteristic to introduce oligonucleotide fragment, in Related Research Domain (especially siDNA drug
Research and development field) it is expected to making a breakthrough property achievement；
4. the fluoro- 2'-C- methyluridine of starting important source material 2'- deoxidation -2'- of the invention, has been commercialized at present, at
Originally cheap to be easy to get.
Detailed description of the invention
Fig. 1 is the synthetic route of the fluoro- 2'-C- methyluridine phosphoramidite monomer of 2'- deoxidation -2'- of the present invention.
Specific embodiment
The preferred embodiments of the present invention will be described in detail with reference to the accompanying drawing, 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 the fluoro- 2'-C- methyluridine of 5'-O- (4,4- dimethoxytrityl) -2'- deoxidation -2'-:
In 250ml two-mouth bottle, it is separately added into 100ml ethyl acetate, the fluoro- 2'-C- first of 2.6g (10mmol) 2'- deoxidation -2'-
4.4g is added under the conditions of nitrogen protection in base uridine, 2.0g (20mmol) triethylamine and 0.2g (2mmol) DMAP
Then (13mmol) 4,4'- dimethoxytrityl chloride solid is stirred to react 3 hours for 50 °C.After TLC detects fully reacting,
Water washing three times (50mlx3), after anhydrous sodium sulfate drying, is spin-dried for solvent, column chromatographs (methylene chloride/methanol=30:1), obtains
To 5.0g 5'-O- (4,4- dimethoxytrityl) -2'-C- methyluridine, yield 88.9%.
Embodiment 2
5'-O- (4,4- dimethoxytrityl) -3'- (2- cyano ethyl-N, N- diisopropyl) -2'- deoxidation -2'-
The synthesis of fluoro- 2'-C- methyluridine phosphoramidite:
In 250ml two-mouth bottle, by 0.84g (1.5mmol) 5'-O- (4,4- dimethoxytrityl) -2'- deoxidation -2'-
Fluoro- 2'-C- methyluridine is dissolved in l00ml anhydrous methylene chloride, then sequentially adds 0.7g (6mmol) diisopropyl ethyl amine
0.7g (3mmol) 2- cyanoethyl is slowly added dropwise under the conditions of ice bath nitrogen protection with the DMAP solid of 0.03g (0.3mmol)
N, N- diisopropyl chloro phosphoramidite (being dissolved in 30ml methylene chloride) continue stirring after five minutes, restore room temperature, and stirring 8 is small
When.After TLC detects fully reacting, after being spin-dried for solvent, direct column chromatographs (petrol ether/ethyl acetate=8:1), obtains 0.87g 5'-
O- (4,4- dimethoxytrityl) -3'- (2- cyano ethyl-N, N- diisopropyl) -2'-O- [(tert-butyl) dimethyl
Silicon substrate] the fluoro- 2'-C- methyluridine phosphoramidite of -2'- deoxidation -2'-, yield 76%.
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all 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 (5)
1. a kind of fluoro- 2'-C- methyluridine phosphoramidite monomer of 2'- deoxidation -2'-, it is characterised in that structure are as follows:
Wherein R1It is selected from:
R2It is selected from:
R3It is selected from:
。
2. a kind of fluoro- 2'-C- methyluridine phosphoramidite monomer of 2'- deoxidation -2'- according to claim 1 and
Its synthetic method, it is characterised in that specific synthesis step are as follows:
。
3. starting material is the fluoro- 2'-C- methyluracil of 2'- deoxidation -2'-, under the action of alkaline condition and catalyst, selection
Property protection 5'-OH synthesize 1 compound of formula, protecting group preferably 4,4- dimethoxytrityl, the preferred DMAP of catalyst.
4. 1 compound of formula, under the action of alkaline condition and catalyst, choosing protection 3'-OH synthesizes 2 compound of formula, reagent is protected
It is preferred that 2- cyanoethyl N, N- diisopropyl chloro phosphoramidite, the preferred DMAP of catalyst.
5. a kind of fluoro- 2'-C- methyluridine phosphoramidite monomer of 2'- deoxidation -2'- according to claim 1 and
Its synthetic method, it is characterised in that: the fluoro- 2'-C- methyluridine phosphoramidite monomer of 2'- deoxidation -2'- is as DNA core
The raw material of thuja acid synthesis in solid state, medicament research and development, gene function in siDNA (small interference DNA, small interfering DNA)
Can research and full genome library screening etc. application.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111961108A (en) * | 2019-05-20 | 2020-11-20 | 湖南大学 | Aptamer drug conjugate and preparation method and application 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 |
-
2018
- 2018-07-06 CN CN201810738979.0A patent/CN108997460A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111961108A (en) * | 2019-05-20 | 2020-11-20 | 湖南大学 | Aptamer drug conjugate and preparation method and application thereof |
| CN111961108B (en) * | 2019-05-20 | 2022-09-09 | 湖南大学 | Aptamer drug conjugate and preparation method and application 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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