CN107973831A - A kind of extended pattern fluorescence cytidine analog and preparation method thereof - Google Patents
A kind of extended pattern fluorescence cytidine analog and preparation method thereof Download PDFInfo
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- CN107973831A CN107973831A CN201711245577.9A CN201711245577A CN107973831A CN 107973831 A CN107973831 A CN 107973831A CN 201711245577 A CN201711245577 A CN 201711245577A CN 107973831 A CN107973831 A CN 107973831A
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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
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
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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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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1011—Condensed systems
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
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Abstract
The object of the present invention is to provide a kind of method for preparing extended pattern cytidine derivatives.It is characterized in that, carry out as follows：(1) it is reaction raw materials by alkali, 3 butine, 1 alcohol and 1 bromomethyl naphthalene of NaH in the case of nitrogen, temperature control when reaction 2~4 is small, obtains the sterling of 2 (3 butine oxygen methyl) naphthalenes between 0 10 DEG C.(2) upper step product, 5 ioduria glycosides and a certain amount of palladium catalyst and cuprous iodide are dissolved in N, in N dimethylformamides, reacted at 65~70 DEG C 7~10 it is small when, separating-purifying obtains target product.Resulting product structure of the present invention is similar to natural nucleus glycoside, and has good fluorescent characteristic, can be used as fluorescence Nucleotide probes, has good application prospect in biochemistry and medicine and other fields.
Description
Technical field
The present invention is a kind of extended pattern cytidine derivatives and preparation method thereof.Cytidine derivatives can be used as fluorescence probe,
The multiple fields such as biology, medicine suffer from important application prospect, such as can be as DNA fluorescence probes, the process based on RNA
Research and anticarcinogen etc..
Technical background
The research work of nucleic acid, depends on the technologies such as fluorescence spectrum, electrophoresis, nuclear magnetic resonance and X-ray single crystal diffraction
Means.Wherein, fluorescence spectrum with its easy to operate, high sensitivity, selectivity it is strong the features such as, favored be subject to numerous researchers,
It is widely used in the conformation transition process of nucleic acid and its research of Conformational dynamics.Fluorescence nucleoside analog, its optical physics
Matter can the change of Development pattern with the change of microenvironment condition, thus be widely used in the structure and function of nucleic acid
Research in.Isomorphism fluorescence nucleoside analog, because its structure is similar with natural nucleus glycoside, after nucleotide sequence is inserted into, to parent
26S Proteasome Structure and Function influences smaller, it is thus possible to substitutes the cell function that natural nucleus glycoside is brought into normal play.According to desirable fluorescent nucleosides
It is required that design has synthesized this kind of isomorphism fluorescence nucleoside analog herein, by inquiring into the synthetic method of cytidine analog, obtain
This base analog and its nucleoside precursor synthesis condition.
Because natural nucleus glycoside is almost without emissivity, therefore, synthesis possesses the nucleoside analog of fluorescent characteristic, passes through its light
Signal is learned to study the change of cell micro-environment, becomes the hot spot that biochemists study.The external research to fluorescence nucleosides
Compare actively, developed a series of derivatives, in polymorphism (SNP) detection and the research of nucleic acid structure and function of monokaryon glycosides
Etc. be widely used, and domestic development is then relatively slow.Preferable fluorescence nucleoside analog, passes through enzymatic or chemical synthesis
Method carries out base modification preparation, similar with natural nucleus glycoside in structure.
The content of the invention
The present invention is prepared corresponding nucleosides with the coupling reaction of 5- iodine cytidines and is spread out by 2- (3- butine oxygen methyl) naphthalene
Biology.The present invention directly acts on generation target product by base and cytidine, avoids the synthetic reaction such as glycosylation, hydrolysis.Have
The features such as reaction condition is relatively easy controllable, no coupling product generation and yield is high.
Specific method：The first step is 3- butyne-1-ols and benzyl bromine reaction；Second step is 2- (3- butine oxygen methyl) naphthalenes and 5-
Iodine cytidine reacts, and obtains nucleoside derivates.
The technical solution adopted by the present invention is as follows：
Nucleoside derivates containing alkynyl and naphthalene nucleus and preparation method thereof, comprise the following steps：
1) using 3- butyne-1-ols and 1- bromomethyls naphthalene as raw material, in the case of nitrogen, temperature control between 0-10 DEG C,
When reaction 2~4 is small, filter, wash, extraction, the sterling of 2- (3- butine oxygen methyl) naphthalene is obtained through column chromatography chromatogram.
2) product and cuprous iodide, the palladium chloride catalyst obtained above-mentioned steps is added in reaction tube, adds solvent
DMF and triethylamine, under nitrogen protection, react two hours, add 2- (3- butine oxygen methyl) naphthalene, in 65-70 DEG C of reaction
For a period of time, filter, wash, extraction, through the isolated nucleoside derivates of column chromatography chromatogram.
In the above method, when 3- butyne-1-ols and 1- bromomethyl naphthalene reaction time are 2~4 small, light yellow solid is obtained.
In the above method, when the reaction time of 2- (3- butine oxygen methyl) naphthalenes and 5- iodine cytidines is 7~10 small, yellow is obtained
Solid.
The present invention is a kind of preparation method of new nucleoside derivates, which has excellent photoluminescent property, can make
For fluorescence probe, it is widely used in the field such as biochemistry and medicine and pharmacology.
Brief description of the drawings
The preparation of Fig. 1 2- (3- butine oxygen methyl) naphthalene.
The preparation of Fig. 2 fluorescence nucleoside analogs.
Embodiment
It is divided into two steps below for the embodiment of the present invention, specific synthetic route.
The first step, prepares 2- (3- butine oxygen methyl) naphthalene.Using tetrahydrofuran as solvent, 3- butyne-1-ols and 1- bromomethyls
Naphthalene is raw material, it reacts expression formula and sees Fig. 1.
Second step, prepares nucleoside analog.By the first step react made from 5- iodine cytidines and 2- (3- butine oxygen methyl) naphthalene
Add in reaction tube, add palladium chloride catalyst etc., in 70-80 DEG C of reaction a period of time, when the reaction time is 7-10 small,
It reacts expression formula and sees Fig. 2.
Example one：The preparation of 2- (3- butine oxygen methyl) naphthalene
70mg (1mol) 3- butyne-1-ols, 221mg (1mol) 1- bromomethyls naphthalene and 20ml are separately added into round-bottomed flask
Tetrahydrofuran, when reaction 2-4 is small at 0-10 DEG C.It is cooled to room temperature, filters, it is faint yellow through the isolated 84mg of column chromatography chromatogram
Solid-state 2- (3- butine oxygen methyl) naphthalene, yield 40%.
Example two：The preparation of nucleoside derivates
Under nitrogen protection, 486mg (2mol) 5- iodine born of the same parents that upper step is reacted are separately added into 100ml reaction tubes
Glycosides, 630mg (3mol) 2- (3- butine oxygen methyl) naphthalene, 76mg (0.55mmol) bi triphenyl phosphorus palladium chloride, 51mg
(0.45mmol) cuprous iodide, 40ml (21mmol) triethylamines and 10ml n,N-Dimethylformamide, in 65~70 DEG C of reactions
When 7-10 is small.Solvent is removed in vacuum, adds the dissolving of 30ml methanol, insoluble solids is filtered to remove, through ethanol/methylene system
The isolated 298mg yellow solids nucleoside derivates of column chromatography chromatogram, yield 66%.
Claims (6)
1. one kind obtains the method for target nucleotide derivative products using 3- butyne-1-ols as raw material through nucleophilic displacement of fluorine, coupling reaction,
Including following synthesis step：
(1) preparation of 2- (3- butine oxygen methyl) naphthalene
Using 3- butyne-1-ols and 1- bromomethyls naphthalene as raw material, in the case of nitrogen, temperature control between 0-10 DEG C, reaction 2~
4 it is small when, filter, wash, extraction, the sterling through the isolated 2- of column chromatography chromatogram (3- butine oxygen methyl) naphthalene.
(2) preparation of nucleoside derivates
Product, cuprous iodide and the palladium chloride that above-mentioned steps are obtained are added in reaction tube, add solvent DMF and three second
Amine, under nitrogen protection, reacts two hours, adds 2- (3- butine oxygen methyl) naphthalene, in 65-70 DEG C of reaction a period of time, filtering,
Washing, extraction, through the isolated nucleoside derivates of column chromatography chromatogram.
2. one kind as claimed in claim 1 obtains the side of nucleoside derivates using 3- butyne-1-ols as raw material through two-step reaction
Method, its synthetic route are as follows.
①
②
。
3. one kind as claimed in claim 1 obtains the method for target product using 3- butyne-1-ols as raw material through two-step reaction,
It is characterized in that：The solvent THF；Second step is triethylamine and N,N-dimethylformamide.
4. one kind as claimed in claim 1 obtains the method for target product using 3- butyne-1-ols as raw material through two-step reaction,
It is characterized in that：Described two kinds of reaction raw materials rate of charges of the first step are 1:1~1:1.4, second step reaction rate of charge is 1:1~1:
1.3。
5. one kind as claimed in claim 1 obtains the method for target product using 3- butyne-1-ols as raw material through two-step reaction,
It is characterized in that：The reaction temperature is 0-10 DEG C before this of the first step, and second step is 65-70 DEG C.
6. one kind as claimed in claim 1 obtains the method for target product using 3- butyne-1-ols as raw material through two-step reaction,
It is characterized in that：When the reaction time first step is 2~4 small, when second step is 7~10 small.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711245577.9A CN107973831A (en) | 2017-12-01 | 2017-12-01 | A kind of extended pattern fluorescence cytidine analog and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711245577.9A CN107973831A (en) | 2017-12-01 | 2017-12-01 | A kind of extended pattern fluorescence cytidine analog and preparation method thereof |
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| CN107973831A true CN107973831A (en) | 2018-05-01 |
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| CN201711245577.9A Pending CN107973831A (en) | 2017-12-01 | 2017-12-01 | A kind of extended pattern fluorescence cytidine analog and preparation method thereof |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060142311A1 (en) * | 2004-11-18 | 2006-06-29 | Kyoto University | Prodan-containing nucleotide and use thereof |
| CN101268200A (en) * | 2005-07-20 | 2008-09-17 | Lgc有限公司 | Oligonucleotides |
| CN102030792A (en) * | 2009-09-29 | 2011-04-27 | 韩国科学技术研究院 | 3'-o-fluorescently modified nucleotides and uses thereof |
| CN104650170A (en) * | 2013-11-20 | 2015-05-27 | 上海毕欧桥生物科技有限公司 | Solid phase synthesis method of fluorescent dye modified nucleotides and analogues |
| CN106674316A (en) * | 2016-12-20 | 2017-05-17 | 江南大学 | Preparation method of novel nucleoside derivatives |
| CN106699827A (en) * | 2016-12-21 | 2017-05-24 | 江南大学 | Extended type fluorescent nucleoside analog and preparing method thereof |
-
2017
- 2017-12-01 CN CN201711245577.9A patent/CN107973831A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060142311A1 (en) * | 2004-11-18 | 2006-06-29 | Kyoto University | Prodan-containing nucleotide and use thereof |
| CN101268200A (en) * | 2005-07-20 | 2008-09-17 | Lgc有限公司 | Oligonucleotides |
| CN102030792A (en) * | 2009-09-29 | 2011-04-27 | 韩国科学技术研究院 | 3'-o-fluorescently modified nucleotides and uses thereof |
| CN104650170A (en) * | 2013-11-20 | 2015-05-27 | 上海毕欧桥生物科技有限公司 | Solid phase synthesis method of fluorescent dye modified nucleotides and analogues |
| CN106674316A (en) * | 2016-12-20 | 2017-05-17 | 江南大学 | Preparation method of novel nucleoside derivatives |
| CN106699827A (en) * | 2016-12-21 | 2017-05-24 | 江南大学 | Extended type fluorescent nucleoside analog and preparing method thereof |
Non-Patent Citations (1)
| Title |
|---|
| VINCENT N. G. LINDSAY，ET AL.: ""Stereodivergent Intramolecular C(sp3)-H Functionalization of Azavinyl Carbenes: Synthesis of Saturated Heterocycles and Fused N-Heterotricycles"", 《J. AM. CHEM. SOC.》 * |
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