CN109456341B - Sulfonamide rhodamine compounds with alkynyl or azido derivative sites, and preparation method and application thereof - Google Patents

Sulfonamide rhodamine compounds with alkynyl or azido derivative sites, and preparation method and application thereof Download PDF

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CN109456341B
CN109456341B CN201811218269.1A CN201811218269A CN109456341B CN 109456341 B CN109456341 B CN 109456341B CN 201811218269 A CN201811218269 A CN 201811218269A CN 109456341 B CN109456341 B CN 109456341B
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rhodamine
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alkynyl
sulfonamide
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肖义
郑莹
张新富
陈令成
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Dalian University of Technology
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Abstract

A sulfonamide rhodamine compound with alkynyl or azido derivative sites, a preparation method and application thereof belong to the field of fine chemical engineering. The sulfamide rhodamine compound with alkynyl or azido derivative sites is prepared through amidation reaction of common sulforhodamine, and the defect that the common sulforhodamine cannot be applied because of no derivative sites is overcome. By utilizing the characteristic that alkynyl and azido can be connected through Click reaction under mild conditions, the sulfonamide rhodamine compound with alkynyl or azido groups can perform Click reaction with biological macromolecules such as nucleic acid, polypeptide, phospholipid and the like, drug micromolecules or bioactive molecules and the like to synthesize novel molecules with specific functions, which can be applied to the field of life science.

Description

Sulfonamide rhodamine compounds with alkynyl or azido derivative sites, and preparation method and application thereof
Technical Field
The invention relates to a sulfonamide rhodamine compound with alkynyl or azido derivative sites, a preparation method and application thereof, and belongs to the field of fine chemical engineering.
Background
Fluorescence imaging technology is widely used in various fields, and has notably developed particularly in the field of life sciences, in which super-resolution fluorescence microscopy images are frequently acquired for the nobel chemical prize. The development of fluorescent probes has led to an increase in fluorescence imaging technology. Fluorescent probes have been regarded as treasure by scientists due to their unique characteristics such as high sensitivity. Among them, rhodamine fluorescent dyes have become one of the most widely used fluorescent probes due to their excellent photophysical and photochemical properties, such as good photostability, high fluorescence quantum yield, long absorption and emission wavelength, etc. Scientists have carried out a great deal of structural modification by taking rhodamine as a parent, wherein silicon-based rhodamine is the most successful (oxygen atoms in rhodamine are replaced by silicon atoms), the wavelength of rhodamine dyes is prolonged to a near infrared region, and the rhodamine dyes are successfully applied to cell microscopic imaging. The sulforhodamine has similar spectral properties with common oxido rhodamine and also has excellent photophysical properties, but has not been widely noticed and applied due to the lack of derivatization sites capable of being derivatized.
Click chemistry (click reaction) has attracted great attention in the field of chemical synthesis after being proposed by Barry sharp in 2001 due to its advantages of mild reaction conditions and high reaction rate. The Click reaction realizes connection between chemical molecules through generating a triazole structure by an alkynyl group and an azide group under the catalysis of metallic copper, and is used for increasing the variability of chemical structures.
Disclosure of Invention
In order to solve the technical problem that sulforhodamine lacks derivative sites, the invention provides a sulfonamide rhodamine compound with alkynyl or azido derivative sites, wherein alkynyl or azido groups are connected to sulforhodamine through amidation reaction, and the alkynyl or azido groups are used as the derivative sites of sulforhodamine. By utilizing the advantage that alkynyl can carry out Click reaction with azide groups under mild conditions, the compound can generate novel molecules with specific functions applied to the field of life science through Click reaction.
A sulfonamide rhodamine compound with alkynyl or azido derivative sites has the following structural general formula:
Figure GDA0002971282970000021
in the general formula, R1And
Figure GDA0002971282970000022
Figure GDA0002971282970000023
wherein: n is an integer of 0 to 18, m is an integer of 0 to 18, X-Is an anion, the anion being BF4 -、Cl-、Br-、I-、NO3 -、SO4 2-、ClO4 -、CH3COO-、CH3SO3 -Or CF3SO3 -。
The above-mentioned
Figure GDA0002971282970000024
The total number of positive charges equals the total number of negative charges of the anion, R1And R2May be different groups.
R3And
Figure GDA0002971282970000025
wherein: r3And R4May be different groups.
Figure GDA0002971282970000026
Wherein: n is1N is an integer of 0 to 1120 to 5, m1N is an integer of 0 to 1130 to 11, m2N is an integer of 0 to 1140 to 5, m30-11.
Figure GDA0002971282970000027
Or N3。
A preparation method of sulfonamide rhodamine compounds with alkynyl or azido derivative sites comprises the following steps:
first of all, synthesizing
Figure GDA0002971282970000028
Figure GDA0002971282970000029
When it is an alkynylamine
Figure GDA00029712829700000210
A3＝N3When it is azidoamine
Figure GDA00029712829700000211
Carrying out amidation reaction with sulfoacid rhodamine to obtain a sulfonamide rhodamine compound with alkynyl or azido derivative sites, wherein the preparation method comprises the following steps:
Figure GDA0002971282970000031
wherein: r1，R2，R3，R4，R5，X-，n，m，n1，n2，n3，n4，m1，m2，m3，A3The definition of (A) is the same as that in the general structural formula.
Application of sulfonamide rhodamine compounds with alkynyl or azido derivative sites, alkynyl derivatives of the compounds and compounds with azido groups
Figure GDA0002971282970000032
Or an azido derivative and an alkynyl group of the compound
Figure GDA0002971282970000033
Ligation by Click reaction to give novel compounds with specific functions, said compounds having azido groups
Figure GDA0002971282970000034
Being a biological macromolecule, a drug small molecule or a biological active molecule with azide group, the alkynyl group
Figure GDA0002971282970000035
Is a biological macromolecule, a drug micromolecule or a biological active molecule with alkynyl, and has the following reaction general formula:
Figure GDA0002971282970000041
wherein R is1，R2，R3，R4，R5，X-，n，m，n1，n2，n3，n4，m1，m2，m3The definition of (A) is the same as that in the general structural formula.
The invention has the beneficial effects that: a sulfonamide rhodamine compound with alkynyl or azido derivative sites is prepared by common sulfoacid rhodamine. The preparation method is simple, and simultaneously overcomes the defect that common sulfoacid rhodamine can not be applied because of no derivative sites. By utilizing the characteristic that alkynyl and azido can be connected through click reaction under mild conditions, the sulfonamide rhodamine compound with alkynyl or azido groups can perform specific fluorescent labeling with biological macromolecules such as nucleic acid, polypeptide, phospholipid and the like, and can also perform click reaction with drug micromolecules, bioactive molecules and the like to synthesize novel molecules with specific functions, which can be applied to the field of life science.
Detailed Description
The invention is illustrated but not limited by the following examples in which all parts and percentages are by weight unless otherwise indicated.
The following describes specific embodiments of the present invention in detail with reference to the technical solutions.
Example 1
Figure GDA0002971282970000051
Weighing 3-chloropropylamine (10.69mmol) in a reaction bottle, adding a solvent DMSO, fully stirring, adding sodium azide (32mmol), reacting at room temperature, adding a NaOH aqueous solution into a reaction solution until the reaction is complete, extracting with diethyl ether for 3-5 times, combining organic phases, washing with saturated saline water for 3-5 times, and carrying out decompression and spin-drying on the organic phases to obtain the product. The product structure was identified by HRMS.
Example 2
Figure GDA0002971282970000052
Dissolving 3, 3' -diamino dipropylamine with one end amino group protected by Boc group in DMF solvent, adding K2CO3Stirring, adding azido chloropropane, reacting at room temperature, extracting with diethyl ether for 3-5 times after the reaction is completed, combining organic phases, washing with saturated salt water for 3-5 times, and performing reduced pressure spin drying on the organic phases. Adding the product obtained by spin drying into a solution of DCM and TFA, reacting for 12h at room temperature, washing with water for three times, and spin drying the organic phase under reduced pressure to obtain the target product. The product structure was identified by HRMS.
Example 3
Figure GDA0002971282970000053
Synthetic method referring to example 2, ethylene glycol di (3-aminopropyl) ether was used instead of 3, 3' -diaminodipropylamine.
Example 4
Figure GDA0002971282970000061
Dissolving 2,2' -oxybis (ethylamine) in DMF solvent, adding K2CO3Stirring, adding bromopropyne, reacting at room temperature, extracting with diethyl ether for 3-5 times after reaction, mixing organic phases, washing with saturated salt water for 3-5 times, mixing organic phases, and spin-drying under reduced pressure. Adding the product obtained by spin drying into a solution of DCM and TFA, reacting for 12h at room temperature, washing with water for three times, and spin drying the organic phase under reduced pressure to obtain the target product. The product structure was identified by HRMS.
Example 5
Figure GDA0002971282970000062
Synthetic procedure 2,2 '-oxybis (ethylamine) was replaced by 3, 3' -diaminodipropylamine, in accordance with example 4.
Example 6
Figure GDA0002971282970000063
Weighing rhodamine sulfonate (1.83mmol) in a reaction bottle, adding 1, 2-dichloroethane, stirring thoroughly, slowly dropwise adding phosphorus oxychloride, carrying out reflux reaction at 95 ℃, detecting the reaction progress by thin-layer chromatography, and after the rhodamine sulfonate is reacted completely, cooling, decompressing and distilling out the solvent to obtain rhodamine sulfonyl chloride for later use; adding azidoamine (3.66mmol), triethylamine and acetonitrile into a reaction bottle, stirring at room temperature, dissolving rhodamine sulfonyl chloride into acetonitrile, slowly adding reaction liquid, reacting at room temperature, and detecting the reaction progress by thin-layer chromatography. Washing and extracting the product, decompressing and evaporating the solvent, separating and purifying by column chromatography, and identifying the product structure by HRMS.
Example 7
Figure GDA0002971282970000071
The synthesis method is referred to example 6.
Example 8
Figure GDA0002971282970000072
The synthesis method is referred to example 6.
Example 9
Figure GDA0002971282970000073
The synthesis method is referred to example 6.
Example 10
Figure GDA0002971282970000081
The synthesis method is referred to example 6.
Example 11
Figure GDA0002971282970000082
The synthesis method is referred to example 6.
Example 12
Figure GDA0002971282970000083
The synthesis method is referred to example 6.
Example 13
Figure GDA0002971282970000084
Weighing rhodamine sulfonate (1.83mmol) in a reaction bottle, adding 1, 2-dichloroethane, fully stirring, adding phosphorus oxychloride, carrying out reflux reaction at 95 ℃, detecting the reaction progress by thin-layer chromatography, cooling the reaction liquid, reducing pressure and evaporating the solvent to obtain rhodamine sulfonyl chloride for later use when the rhodamine sulfonate is completely reacted; adding azidoamine (3.66mmol), triethylamine and acetonitrile into a reaction bottle, stirring at room temperature, dissolving rhodamine sulfonyl chloride into acetonitrile, slowly adding into a reaction solution, reacting at room temperature, and detecting the reaction progress by thin-layer chromatography. Washing and extracting the product, decompressing and evaporating the solvent, separating and purifying by column chromatography, and identifying the product structure by HRMS.
Example 14
Figure GDA0002971282970000091
Synthetic methods refer to example 13.
Example 15
Figure GDA0002971282970000092
Synthetic methods refer to example 13.
Example 16
Figure GDA0002971282970000093
Synthetic methods refer to example 13.
Example 17
Figure GDA0002971282970000094
Synthetic methods refer to example 13.
Example 18
Figure GDA0002971282970000101
Synthetic methods refer to example 13.
Example 19
Figure GDA0002971282970000102
Synthetic methods refer to example 13.
Example 20
Figure GDA0002971282970000103
Weighing rhodamine sulfonate (1.83mmol) in a reaction bottle, adding 1, 2-dichloroethane, fully stirring, adding phosphorus oxychloride, carrying out reflux reaction at 95 ℃, detecting the reaction progress by thin-layer chromatography, cooling the reaction liquid, reducing pressure and evaporating the solvent to obtain rhodamine sulfonyl chloride for later use when the rhodamine sulfonate is completely reacted; adding azido amine (3.66mmol), triethylamine and acetonitrile into a reaction bottle, stirring at room temperature, dissolving rhodamine sulfonyl chloride in acetonitrile, slowly adding into the reaction solution, reacting at room temperature, and detecting the reaction progress by thin-layer chromatography. Washing and extracting the product, decompressing and evaporating the solvent, separating and purifying by column chromatography, and identifying the product structure by HRMS.
Example 21
Figure GDA0002971282970000111
The synthesis method is referred to example 20.
Example 22
Figure GDA0002971282970000112
The synthesis method is referred to example 20.
Example 23
Figure GDA0002971282970000113
The synthesis method is referred to example 20.
Example 24
Figure GDA0002971282970000114
The synthesis method is referred to example 20.
Example 25
Figure GDA0002971282970000121
The synthesis method is referred to example 20.
Example 26
Figure GDA0002971282970000122
The synthesis method is referred to example 20.
Example 27
Figure GDA0002971282970000123
Weighing rhodamine sulfonate (1.83mmol) in a reaction bottle, adding 1, 2-dichloroethane, fully stirring, adding phosphorus oxychloride, carrying out reflux reaction at 95 ℃, detecting the reaction progress by thin-layer chromatography, cooling the reaction liquid, reducing pressure and evaporating the solvent to obtain rhodamine sulfonyl chloride for later use when the rhodamine sulfonate is completely reacted; adding azido amine (3.66mmol), triethylamine and acetonitrile into a reaction bottle, stirring at room temperature, dissolving rhodamine sulfonyl chloride in acetonitrile, slowly adding into the reaction solution, reacting at room temperature, and detecting the reaction progress by thin-layer chromatography. Washing and extracting the product, decompressing and evaporating the solvent, separating and purifying by column chromatography, and identifying the product structure by HRMS.
Example 28
Figure GDA0002971282970000131
The synthesis method is referred to example 27.
Example 29
Figure GDA0002971282970000132
The synthesis method is referred to example 27.
Example 30
Figure GDA0002971282970000133
The synthesis method is referred to example 27.
Example 31
Figure GDA0002971282970000134
The synthesis method is referred to example 27.
Example 32
Figure GDA0002971282970000141
The synthesis method is referred to example 27.
Example 33
Figure GDA0002971282970000142
The synthesis method is referred to example 27.
Example 34
Figure GDA0002971282970000143
Weighing rhodamine sulfonate (1.83mmol) in a reaction bottle, adding 1, 2-dichloroethane, fully stirring, adding phosphorus oxychloride, carrying out reflux reaction at 95 ℃, detecting the reaction progress by thin-layer chromatography, cooling the reaction liquid, reducing pressure and evaporating the solvent to obtain rhodamine sulfonyl chloride for later use when the rhodamine sulfonate is completely reacted; adding alkynylamine (3.66mmol), triethylamine and acetonitrile into a reaction bottle, stirring at room temperature, dissolving rhodamine sulfonyl chloride in acetonitrile, slowly adding the solution into the reaction solution, reacting at room temperature, and detecting the reaction progress by thin-layer chromatography. Washing and extracting the product, decompressing and evaporating the solvent, and identifying the structure of the product by HRMS.
Example 35
Figure GDA0002971282970000151
The synthesis method is referred to example 34.
Example 36
Figure GDA0002971282970000152
Weighing rhodamine sulfonate (1.83mmol) in a reaction bottle, adding 1, 2-dichloroethane, fully stirring, adding phosphorus oxychloride, carrying out reflux reaction at 95 ℃, detecting the reaction progress by thin-layer chromatography, cooling the reaction liquid, reducing pressure and evaporating the solvent to obtain rhodamine sulfonyl chloride for later use when the rhodamine sulfonate is completely reacted; adding alkynylamine (3.66mmol), triethylamine and acetonitrile into a reaction bottle, stirring at room temperature, dissolving rhodamine sulfonyl chloride in acetonitrile, slowly adding the solution into the reaction solution, reacting at room temperature, and detecting the reaction progress by thin-layer chromatography. Washing and extracting the product, decompressing and evaporating the solvent, and identifying the structure of the product by HRMS.
Example 37
Figure GDA0002971282970000153
The synthesis method is referred to example 36.
Example 38
Figure GDA0002971282970000161
The synthesis method is referred to example 36.
Example 39
Figure GDA0002971282970000162
The synthesis method is referred to example 36.
Example 40
Figure GDA0002971282970000163
The synthesis method is referred to example 36.
EXAMPLE 41
The synthesis method is referred to example 36.
Figure GDA0002971282970000164
Example 42
Figure GDA0002971282970000171
Weighing rhodamine sulfonate (1.83mmol) in a reaction bottle, adding 1, 2-dichloroethane, fully stirring, adding phosphorus oxychloride, carrying out reflux reaction at 95 ℃, detecting the reaction progress by thin-layer chromatography, cooling the reaction liquid, reducing pressure and evaporating the solvent to obtain rhodamine sulfonyl chloride for later use when the rhodamine sulfonate is completely reacted; adding alkynylamine (3.66mmol), triethylamine and acetonitrile into a reaction bottle, stirring at room temperature, dissolving rhodamine sulfonyl chloride in acetonitrile, slowly adding the solution into the reaction solution, reacting at room temperature, and detecting the reaction progress by thin-layer chromatography. Washing and extracting the product, decompressing and evaporating the solvent, and identifying the structure of the product by HRMS.
Example 43
Figure GDA0002971282970000172
The synthesis method is referred to example 42.
Example 44
Figure GDA0002971282970000173
The synthesis method is referred to example 42.
Example 45
Figure GDA0002971282970000181
The synthesis method is referred to example 42.
Example 46
Figure GDA0002971282970000182
Weighing rhodamine sulfonate (1.83mmol) in a reaction bottle, adding 1, 2-dichloroethane, fully stirring, adding phosphorus oxychloride, carrying out reflux reaction at 95 ℃, detecting the reaction progress by thin-layer chromatography, cooling the reaction liquid, reducing pressure and evaporating the solvent to obtain rhodamine sulfonyl chloride for later use when the rhodamine sulfonate is completely reacted; adding alkynylamine (3.66mmol), triethylamine and acetonitrile into a reaction bottle, stirring at room temperature, dissolving rhodamine sulfonyl chloride in acetonitrile, slowly adding the solution into the reaction solution, reacting at room temperature, and detecting the reaction progress by thin-layer chromatography. Washing and extracting the product, decompressing and evaporating the solvent, and identifying the structure of the product by HRMS.
Example 47
Figure GDA0002971282970000183
The synthesis method is referred to example 46.
Example 48
Figure GDA0002971282970000191
The synthesis method is referred to example 46.
Example 49
Figure GDA0002971282970000192
Adding the azido sulfonamide rhodamine compound into a reaction bottle, adding DMF under the protection of argon, fully stirring at room temperature until the azido sulfonamide rhodamine compound is completely dissolved, adding butyne, and fully stirring. Respectively dissolving copper sulfate pentahydrate and sodium ascorbate in water, sequentially adding into a reaction flask, reacting at room temperature, and detecting the reaction progress by a thin-layer chromatography plate. The product was washed with water and extracted, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product is separated and purified by column chromatography, and the structure of the product is identified by HRMS.
Example 50
Figure GDA0002971282970000193
The synthesis was as in example 49.
Example 51
Figure GDA0002971282970000201
The synthesis was as in example 49.
Example 52
Figure GDA0002971282970000202
Adding the alkynyl sulfonamide rhodamine compound into a reaction bottle, adding DMF (dimethyl formamide) under the protection of argon, fully stirring at room temperature to completely dissolve, adding azidopropane into the reaction bottle, and fully stirring. Respectively dissolving copper sulfate pentahydrate and sodium ascorbate in water, sequentially adding into a reaction flask, reacting at room temperature, and detecting the reaction progress by thin layer chromatography. The product was washed with water and extracted, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product is separated and purified by column chromatography, and the structure of the product is identified by HRMS.
Example 53
The synthesis method is referred to example 52.
Figure GDA0002971282970000203
Example 54
Figure GDA0002971282970000204
The synthesis method is referred to example 52.
Example 55
Figure GDA0002971282970000211
Adding the alkynyl sulfonamide rhodamine compound into a reaction bottle, adding DMF (dimethyl formamide) under the protection of argon, fully stirring at room temperature to completely dissolve, adding azide polypeptide chain into the reaction bottle, and fully stirring. Respectively dissolving copper sulfate pentahydrate and sodium ascorbate in water, sequentially adding into a reaction flask, reacting at room temperature, and detecting the reaction progress by thin layer chromatography. The product was washed with water and extracted, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product is separated and purified by column chromatography, and the structure of the product is identified by HRMS.
Example 56
Figure GDA0002971282970000212
The synthesis was as in example 55.
Example 57
Figure GDA0002971282970000213
The synthesis was as in example 55.
Example 58
Figure GDA0002971282970000221
Adding an alkynyl sulfonamide rhodamine compound into a reaction bottle, adding DMF (dimethyl formamide) under the protection of argon, fully stirring at room temperature to completely dissolve, adding an azide nucleic acid chain into the reaction bottle, and fully stirring. Respectively dissolving copper sulfate pentahydrate and sodium ascorbate in water, sequentially adding into a reaction flask, reacting at room temperature, and detecting the reaction progress by thin layer chromatography. The product was washed with water and extracted, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product is separated and purified by column chromatography, and the structure of the product is identified by HRMS.
Example 59
Figure GDA0002971282970000222
The synthesis was performed as described in example 58.
Example 60
Figure GDA0002971282970000231
Adding the azido sulfonamide rhodamine compound into a reaction bottle, adding DMF under the protection of argon, fully stirring at room temperature to completely dissolve, adding the alkynyl nucleic acid chain into the reaction bottle, and fully stirring. Respectively dissolving copper sulfate pentahydrate and sodium ascorbate in water, sequentially adding into a reaction flask, reacting at room temperature, and detecting the reaction progress by thin layer chromatography. The product was washed with water and extracted, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product is separated and purified by column chromatography, and the structure of the product is identified by HRMS.
Example 61
Figure GDA0002971282970000232
Adding the alkynyl sulfonamide rhodamine compound into a reaction bottle, adding DMF (dimethyl formamide) under the protection of argon, fully stirring at room temperature to completely dissolve, adding azide into the reaction bottle, and fully stirring. Respectively dissolving copper sulfate pentahydrate and sodium ascorbate in water, sequentially adding into a reaction flask, reacting at room temperature, and detecting the reaction progress by thin layer chromatography. The product was washed with water and extracted, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product is separated and purified by column chromatography, and the structure of the product is identified by HRMS.

Claims (3)

1. A sulfonamide rhodamine compound with azido derivative sites is characterized in that the compound has the following structural general formula:
Figure FDA0002971282960000011
in the general formula, R1And
Figure FDA0002971282960000012
Figure FDA0002971282960000013
wherein: n is an integer of 0 to 18, and m is 0An integer of-18, X-Is an anion, the anion being BF4 -、Cl-、Br-、I-、NO3 -、SO4 2-、ClO4 -、CH3COO-、CH3SO3 -Or CF3SO3 -Said
Figure FDA0002971282960000014
The total number of positive charges equals the total number of negative charges of the anion, R1，R2Are independent of each other;
R3，R4each independently is
Figure FDA0002971282960000015
Figure FDA0002971282960000016
Wherein: n is20 to 5, m1N is an integer of 0 to 1130 to 11, m2N is an integer of 0 to 1140 to 5, m30-11.
2. The method for preparing sulfonamide rhodamine compounds with azido derivative sites as claimed in claim 1, wherein the method for preparing sulfonamide rhodamine compounds with azido derivative sites comprises the following steps:
first of all, synthesizing
Figure FDA0002971282960000017
Carrying out amidation reaction with sulfoacid rhodamine to obtain a sulfonamide rhodamine compound with azido derivative sites, wherein the preparation method comprises the following steps:
Figure FDA0002971282960000021
wherein: r1，R2，R3，R4，R5Is as defined in the general formula of claim 1.
3. The use of the sulfonamide rhodamine compounds having azido derivative sites as defined in claim 1, wherein the azido derivative sites of the compounds are conjugated with alkynyl groups
Figure FDA0002971282960000022
The compounds with the alkynyl group are connected by a Click reaction to generate compounds with specific functions
Figure FDA0002971282960000023
Is a polypeptide chain with an alkynyl group.
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