CN106699827A - Extended type fluorescent nucleoside analog and preparing method thereof - Google Patents
Extended type fluorescent nucleoside analog and preparing method thereof Download PDFInfo
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- CN106699827A CN106699827A CN201611189408.3A CN201611189408A CN106699827A CN 106699827 A CN106699827 A CN 106699827A CN 201611189408 A CN201611189408 A CN 201611189408A CN 106699827 A CN106699827 A CN 106699827A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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- C09K2211/1092—Heterocyclic compounds characterised by ligands containing sulfur as the only heteroatom
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Abstract
The invention aims at providing a synthesis method of obtaining a fluorescent nucleoside analog by adopting 2, 2'-bithiophene and 5-iodouridine as raw materials and through a reaction with a palladium catalyst. The method is characterized by comprising the steps of 1, stirring 2, 2'-bithiophene and N-iodosuccinimide for seven hours at the temperature of 20-50 DEG C, and obtaining an intermediate product through treatment; 2, stirring the product in the last step and the catalyst for 4-6 hours at the temperature of 50-70 DEG C, reducing the temperature to the room temperature, adding a certain amount of potash, stirring for 3 hours again, and obtaining 2, 2'-bithiophene acetylide; 3, dissolving the product in the last step, 5-iodouridine, a certain amount of palladium catalyst and cuprous iodide into N, N-dimethylformamide to be subjected to a reaction for 2-5 hours at the temperature of 65-70 DEG C, and obtaining a final product through separation and purification. The fluorescent nucleoside analog is similar to natural nucleoside in structure, has good fluorescence characteristics, can be applied as a fluorescent nucleoside probe, and has a good application prospect in the fields of biochemistry, medicine and the like.
Description
Technical field
The present invention is a kind of extended pattern fluorescence nucleoside analog and preparation method thereof, and two thiophene pass through acetylene bond and pyrimidine ring
Conjugated structure is formed, natural nucleus glycoside is shown good fluorescent characteristic, can be as fluorescence Nucleotide probes, in biochemistry and doctor
There is good application prospect in the fields such as medicine.
Technical background
Nucleic acid is the important inhereditary material of life entity, in a series of great biological phenomenas such as growth, heredity, variation, is played the part of
Vital role is drilled, its research turns into the focus of each research field such as molecular biology, biochemistry already.Nucleosides
Class compound occupies an important position in antitumor, antiviral and anti-AIDS drug, is that there have been antiviral potential at present
A class medicine.
At present, the research work of nucleic acid, depends on fluorescence spectrum, electrophoresis, nuclear magnetic resonance and X-ray single crystal diffraction
Etc. technological means.Wherein, fluorescence spectrum with its simple to operate, sensitivity it is high, selectivity is strong the features such as, by numerous researchers'
Favor, is widely used in the research of the conformation transition process of nucleic acid and its Conformational dynamics.
Common fluorescent probe structure is larger, and has certain influence on bioactivity, and the application in fields such as biological detections is received
To limitation.And fluorescence nucleoside analog is due to its special structure so that it has more preferable in cell than other fluorescence probes
Bio-compatibility.Therefore, increasing chemist starts to carry out natural nucleus glycoside structural modification to increase its fluorescence
Intensity.It is external more active to the research of fluorescence nucleosides, a series of derivatives are had been developed for, in the polymorphism (SNP) of monokaryon glycosides
The aspect such as detection and the research of nucleic acid structure and function is widely used, and domestic development is then relatively slow.The conjunction of nucleoside analog
Long into there are reactions steps, condition is harsh, the shortcomings of post-process cumbersome and product low yield.
The content of the invention
The present invention is obtained with fluorescence by from 2,2'- Dithiophenes and 5- ioduria glycosides through Sonogashira coupling reactions
The nucleoside analog of characteristic.It is of the invention compared with first synthetic modification base carries out glycosylation synthetic method again, with reaction condition
Gently, the features such as easy to control and yield high.
Specific method is the first step first by 2,2'- Dithiophene iodate；Second step is by the iodo- 2,2'- Dithiophenes of 5- and trimethyl
Silico acetylene etc. carries out alkynylation reaction；3rd step is then in palladium catalyst by 2,2'- Dithiophenes alkynylation products and 5- ioduria glycosides
Under, Sonogashira coupling reactions are carried out, obtain fluorescence nucleoside analog.
The technical solution adopted by the present invention is as follows：
A kind of novel fluorescence nucleoside analog and preparation method thereof, comprises the following steps：
1) 5- iodo- 2 is reacted to obtain under the conditions of 20~50 DEG C for raw material with 2,2'- Dithiophenes and N- N-iodosuccinimides,
2'- Dithiophenes.
2) iodo- 2, the 2'- Dithiophenes of 5- and trimethylsilyl acetylene are raw material, in palladium catalyst, cuprous iodide, triethylamine effect
Under, after stirring a period of time at 50~70 DEG C, trimethyl silyl is sloughed with carbonic acid nak response, obtain 2,2'- Dithiophene alkynes
Compound, without purification, directly carries out next step reaction.
3) product and 5- ioduria glycosides for obtaining above-mentioned steps are added in the round-bottomed flask containing DMF,
Be separately added into a certain amount of palladium catalyst and cuprous iodide again, at 65~70 DEG C react a period of time, filtering, washing, extraction and
Column chromatography chromatogram obtains final product.
In the above method, 2,2'- Dithiophenes are 5~8 hours with the reaction time of N- N-iodosuccinimides, obtain white
Solid.
In the above method, the reaction time of 2,2'- Dithiophene alkynyls is 7~10 hours, obtains brown solid.
In the above method, 2,2'- Dithiophene alkynylation products and 5- ioduria glycosides reaction time are 2~5 hours, filter, wash
Wash, extract and column chromatography chromatogram obtains faint yellow solid.
The present invention is a kind of preparation method of new fluorescence nucleoside analog, and the product has excellent photoluminescent property,
Can be widely used in the field such as biochemistry and medicine and pharmacology as fluorescence probe.
Brief description of the drawings
The preparation of the iodo- 2,2'- Dithiophenes of Fig. 1 5-
The preparation of Fig. 2 2,2'- Dithiophene acetylides
The preparation of Fig. 3 fluorescence nucleoside analogs
Specific embodiment
It is below specific embodiment of the invention, specific synthetic route is divided into three steps.
The first step, prepares iodo- 2, the 2'- Dithiophenes of 5-.With chloroform as solvent, 2,2'- Dithiophenes and N- iodos succinyl are sub-
Amine reacts 5~8 hours at 20~50 DEG C, and its reaction expression formula is shown in Fig. 1.
Second step, prepares 2,2'- Dithiophene acetylides.The product and trimethylsilyl acetylene that the first step is obtained are added and contained
In the round-bottomed flask of DMF, a certain amount of palladium catalyst, cuprous iodide and triethylamine are added, at 50~70 DEG C
Lower reaction 4~6 hours, potassium carbonate is added after being down to room temperature, continues to react 3~5 hours, and its reaction expression formula is shown in Fig. 2.
3rd step, prepares nucleoside analog, and 2,2'- Dithiophenes acetylide and 5- ioduria glycosides are dissolved in into N, N- dimethyl formyls
Amine, adds a certain amount of palladium catalyst, cuprous iodide and triethylamine, is reacted 2~5 hours at 65~70 DEG C, filter, wash,
Extraction and column chromatography chromatogram obtain final product, and its reaction expression formula is shown in Fig. 3.
Example one：The synthesis of the iodo- 2,2'- Dithiophenes of 5-
0.499g (3mmol) 2,2'- Dithiophenes, 0.810g (3.6mmol) N- iodo fourths are separately added into round-bottomed flask
Imidodicarbonic diamide and 30ml chloroforms, then stirring are warming up to 20~50 DEG C and react 7 hours.Room temperature is cooled to, 5ml deionized waters are added
Impurity is separated out, then is extracted with ethyl acetate (3 × 5ml), white solid 0.75g is obtained after rotary evaporation, yield is 86%.
Example two：The synthesis of 2,2'- Dithiophene acetylides
Nitrogen protection under, be separately added into reaction tube walk reaction iodo- 2, the 2'- Dithiophenes crude products of product 5-,
25ml N,N-dimethylformamides, 0.46ml (3.6mmol) trimethylsilyl acetylene, 0.08g (0.12mmol) bi triphenyls phosphorus two
Palladium bichloride, 0.11g (0.57mmol) cuprous iodides and 1,7ml (12mmol) triethylamine, are warming up to 50~70 DEG C and react 4 hours.
Temperature adds 1g (4.5mmol) potassium carbonate, stirring at normal temperature 3 hours after being down to room temperature, and solution is in light brown.After filtering, revolving, plus
Enter 10ml deionized waters, be extracted with ethyl acetate (3 × 5ml), after merging organic phase rotary evaporation, obtain brown solid 0.39g,
Yield is 83%.
Example three：The synthesis of fluorescence nucleoside analog
Under nitrogen protection, to being separately added into 2,2'- Dithiophenes acetylide, 0.37g that the reaction of upper step is obtained in reaction tube
(1mmol) 5- ioduria glycosides, 0.06g (0.05mmol) bi triphenyl phosphorus palladium chloride, 0.01g (0.07mmol) cuprous iodide,
0.7ml (5.3mmol) triethylamines and 20ml DMFs, react 4 hours at 65~70 DEG C.It is filtered to remove solid
Body, 10ml dchloromethanes are added after filtrate concentration, are washed three times with saturated common salt, organic phase anhydrous sodium sulfate drying mistake
Night.After filtering, revolving, cross post with ethanol/methylene mixed solvent and obtain nucleoside derivates 0.60g (faint yellow solid), yield
It is 70%.
Claims (8)
1. a kind of 2,2'- Dithiophenes and 5- ioduria glycosides of passing through obtains fluorescence under palladium catalyst through Sonogashira coupling reactions
The synthetic method of nucleoside analog, including following synthesis step：
(1) preparation of the iodo- 2,2'- Dithiophenes of 5-
By 2,2'- Dithiophenes and N- N-iodosuccinimides according to mol ratio 1:1.2 are added in reaction vessel, at 20~50 DEG C
Lower stirring 7 hours, intermediate product is obtained through washing, extraction and revolving.
(2) preparation of 2,2'- Dithiophenes acetylide
By in the addition reaction tube such as upper step product, catalyst and solvent, stirred 4-6 hours at 50~70 DEG C, be down to room temperature and add
Enter a certain amount of potassium carbonate, continue to stir 3 hours, washing, extraction and revolving obtain intermediate product.
(3) preparation of fluorescence nucleoside analog
2,2'- Dithiophenes acetylide and 5- ioduria glycosides are dissolved in DMF, a certain amount of palladium catalyst is added
And cuprous iodide etc., being reacted 2~5 hours at 65~70 DEG C, separating-purifying obtains final product.
2. a kind of reaction with 5- ioduria glycosides by 2,2'- Dithiophenes as claimed in claim 1 is obtained with fluorescent characteristic nucleosides
The synthetic method of analog, its synthetic route is as follows：
①
②
③
3. a kind of reaction with 5- ioduria glycosides by 2,2'- Dithiophenes as claimed in claim 1 is obtained with fluorescent characteristic nucleosides
The synthetic method of analog, it is characterized in that：Described solvent is chloroform, N,N-dimethylformamide.
4. a kind of reaction with 5- ioduria glycosides by 2,2'- Dithiophenes as claimed in claim 1 is obtained with fluorescent characteristic nucleosides
The synthetic method of analog, it is characterized in that：Described two kinds of reaction raw materials rate of charges of the first step are 1:1.0~1:1.5, second step
Reaction raw materials are 1 with ethynylation reagent rate of charge:1.1~1.5, the 3rd step 2,2'- Dithiophenes acetylide and 5- ioduria glycosides rate of charges
It is 0.5:1~2:1.
5. a kind of reaction with 5- ioduria glycosides by 2,2'- Dithiophenes as claimed in claim 1 is obtained with fluorescent characteristic nucleosides
The synthetic method of analog, it is characterized in that：Described reaction temperature is 20~50 DEG C before this of the first step, and second step is 50~70
DEG C, the 3rd step is 65~70 DEG C.
6. a kind of reaction with 5- ioduria glycosides by 2,2'- Dithiophenes as claimed in claim 1 is obtained with fluorescent characteristic nucleosides
The synthetic method of analog, it is characterized in that：The described reaction time first step is 5~8 hours, and second step is 7~10 hours, the
Three steps are 2~5 hours.
7. a kind of reaction with 5- ioduria glycosides by 2,2'- Dithiophenes as claimed in claim 1 is obtained with fluorescent characteristic nucleosides
The synthetic method of analog, it is characterized in that：Second step used catalyst is bi triphenyl phosphorus palladium chloride, cuprous iodide, three second
Amine, rate of charge is respectively 1:0.02~0.06,1:0.1~0.4,1:1~5.Three-step reaction used catalyst ratio and first
Step is identical.
8. a kind of reaction with 5- ioduria glycosides by 2,2'- Dithiophenes as claimed in claim 1 is obtained with fluorescent characteristic nucleosides
The synthetic method of analog, it is characterized in that：Second step sloughs alkali used by trimethyl silyl for potassium carbonate, with raw material rate of charge
It is 1:2~6.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973831A (en) * | 2017-12-01 | 2018-05-01 | 江南大学 | A kind of extended pattern fluorescence cytidine analog and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070099222A1 (en) * | 2005-10-27 | 2007-05-03 | Gee Kyle R | Methods and compositions for labeling nucleic acids |
| CN102884071A (en) * | 2009-10-06 | 2013-01-16 | 塔古西库斯生物株式会社 | Novel artificial fluorescent bases |
| CN103467549A (en) * | 2013-08-26 | 2013-12-25 | 大连大学 | Sulfur-bearing uridine anticancer drug, intermediate and synthesis method |
-
2016
- 2016-12-21 CN CN201611189408.3A patent/CN106699827A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070099222A1 (en) * | 2005-10-27 | 2007-05-03 | Gee Kyle R | Methods and compositions for labeling nucleic acids |
| CN102884071A (en) * | 2009-10-06 | 2013-01-16 | 塔古西库斯生物株式会社 | Novel artificial fluorescent bases |
| CN103467549A (en) * | 2013-08-26 | 2013-12-25 | 大连大学 | Sulfur-bearing uridine anticancer drug, intermediate and synthesis method |
Non-Patent Citations (2)
| Title |
|---|
| MASSIMO L. CAPOBIANCO ET AL.: "Oligothiophene-5-Labeled Deoxyuridines for the Detection of Single Nucleotide Polymorphisms", 《BIOCONJUGATE CHEM.》 * |
| N. P. F. BARTHES ET AL.: "Development of environmentally sensitive fluorescent and dual emissive deoxyuridine analogues", 《RSC ADV.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973831A (en) * | 2017-12-01 | 2018-05-01 | 江南大学 | A kind of extended pattern fluorescence cytidine analog and preparation method thereof |
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