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 PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- rhodamine
- reaction
- alkynyl
- sulfonamide
- azido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 Sulfonamide rhodamine compounds Chemical class 0.000 title claims abstract description 27
- 125000000304 alkynyl group Chemical group 0.000 title claims abstract description 26
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 title claims abstract description 26
- 229940124530 sulfonamide Drugs 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000012650 click reaction Methods 0.000 claims abstract description 10
- 238000007112 amidation reaction Methods 0.000 claims abstract description 4
- 229920001184 polypeptide Polymers 0.000 claims abstract description 4
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 4
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 9
- 150000001450 anions Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 3
- 229910001914 chlorine tetroxide Inorganic materials 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 229920002521 macromolecule Polymers 0.000 abstract description 4
- 230000000975 bioactive effect Effects 0.000 abstract description 2
- 238000003889 chemical engineering Methods 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract description 2
- 239000012847 fine chemical Substances 0.000 abstract description 2
- 150000007523 nucleic acids Chemical class 0.000 abstract description 2
- 102000039446 nucleic acids Human genes 0.000 abstract description 2
- 108020004707 nucleic acids Proteins 0.000 abstract description 2
- 150000003904 phospholipids Chemical class 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 78
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- 238000003756 stirring Methods 0.000 description 31
- 238000001308 synthesis method Methods 0.000 description 31
- 239000002904 solvent Substances 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000004809 thin layer chromatography Methods 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 16
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 16
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 16
- 238000001704 evaporation Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 14
- 238000005406 washing Methods 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 238000005303 weighing Methods 0.000 description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 238000010189 synthetic method Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- OTBHHUPVCYLGQO-UHFFFAOYSA-N bis(3-aminopropyl)amine Chemical compound NCCCNCCCN OTBHHUPVCYLGQO-UHFFFAOYSA-N 0.000 description 6
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 6
- 235000010378 sodium ascorbate Nutrition 0.000 description 6
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 6
- 229960005055 sodium ascorbate Drugs 0.000 description 6
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- ICCBZGUDUOMNOF-UHFFFAOYSA-N azidoamine Chemical group NN=[N+]=[N-] ICCBZGUDUOMNOF-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000007850 fluorescent dye Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- GXVUZYLYWKWJIM-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanamine Chemical compound NCCOCCN GXVUZYLYWKWJIM-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical compound CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000001022 rhodamine dye Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- QTVXTQKATDYOSY-UHFFFAOYSA-N 1-azido-1-chloropropane Chemical compound CCC(Cl)N=[N+]=[N-] QTVXTQKATDYOSY-UHFFFAOYSA-N 0.000 description 1
- XXFUZSHTIOFGNV-UHFFFAOYSA-N 1-bromoprop-1-yne Chemical compound CC#CBr XXFUZSHTIOFGNV-UHFFFAOYSA-N 0.000 description 1
- POTQBGGWSWSMCX-UHFFFAOYSA-N 3-[2-(3-aminopropoxy)ethoxy]propan-1-amine Chemical compound NCCCOCCOCCCN POTQBGGWSWSMCX-UHFFFAOYSA-N 0.000 description 1
- BZFKSWOGZQMOMO-UHFFFAOYSA-N 3-chloropropan-1-amine Chemical compound NCCCCl BZFKSWOGZQMOMO-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- TVPPZASKIXGUJQ-UHFFFAOYSA-N n-propyl azide Chemical compound CCCN=[N+]=[N-] TVPPZASKIXGUJQ-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010857 super resolution fluorescence microscopy Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- 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
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- 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
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
-
- 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
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
- C09K2211/1037—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom with sulfur
-
- 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
-
- 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
- C09K2211/1059—Heterocyclic compounds characterised by ligands containing three nitrogen atoms as heteroatoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Health & Medical Sciences (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
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
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:
in the general formula, R1And 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-mentionedThe total number of positive charges equals the total number of negative charges of the anion, R1And R2May be different groups.
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.
A preparation method of sulfonamide rhodamine compounds with alkynyl or azido derivative sites comprises the following steps:
first of all, synthesizing When it is an alkynylamineA3=N3When it is azidoamineCarrying 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:
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 groupsOr an azido derivative and an alkynyl group of the compoundLigation by Click reaction to give novel compounds with specific functions, said compounds having azido groupsBeing a biological macromolecule, a drug small molecule or a biological active molecule with azide group, the alkynyl groupIs a biological macromolecule, a drug micromolecule or a biological active molecule with alkynyl, and has the following reaction general formula:
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
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
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
Synthetic method referring to example 2, ethylene glycol di (3-aminopropyl) ether was used instead of 3, 3' -diaminodipropylamine.
Example 4
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
Synthetic procedure 2,2 '-oxybis (ethylamine) was replaced by 3, 3' -diaminodipropylamine, in accordance with example 4.
Example 6
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
The synthesis method is referred to example 6.
Example 8
The synthesis method is referred to example 6.
Example 9
The synthesis method is referred to example 6.
Example 10
The synthesis method is referred to example 6.
Example 11
The synthesis method is referred to example 6.
Example 12
The synthesis method is referred to example 6.
Example 13
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
Synthetic methods refer to example 13.
Example 15
Synthetic methods refer to example 13.
Example 16
Synthetic methods refer to example 13.
Example 17
Synthetic methods refer to example 13.
Example 18
Synthetic methods refer to example 13.
Example 19
Synthetic methods refer to example 13.
Example 20
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
The synthesis method is referred to example 20.
Example 22
The synthesis method is referred to example 20.
Example 23
The synthesis method is referred to example 20.
Example 24
The synthesis method is referred to example 20.
Example 25
The synthesis method is referred to example 20.
Example 26
The synthesis method is referred to example 20.
Example 27
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
The synthesis method is referred to example 27.
Example 29
The synthesis method is referred to example 27.
Example 30
The synthesis method is referred to example 27.
Example 31
The synthesis method is referred to example 27.
Example 32
The synthesis method is referred to example 27.
Example 33
The synthesis method is referred to example 27.
Example 34
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
The synthesis method is referred to example 34.
Example 36
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
The synthesis method is referred to example 36.
Example 38
The synthesis method is referred to example 36.
Example 39
The synthesis method is referred to example 36.
Example 40
The synthesis method is referred to example 36.
EXAMPLE 41
The synthesis method is referred to example 36.
Example 42
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
The synthesis method is referred to example 42.
Example 44
The synthesis method is referred to example 42.
Example 45
The synthesis method is referred to example 42.
Example 46
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
The synthesis method is referred to example 46.
Example 48
The synthesis method is referred to example 46.
Example 49
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
The synthesis was as in example 49.
Example 51
The synthesis was as in example 49.
Example 52
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.
Example 54
The synthesis method is referred to example 52.
Example 55
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
The synthesis was as in example 55.
Example 57
The synthesis was as in example 55.
Example 58
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
The synthesis was performed as described in example 58.
Example 60
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
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:
in the general formula, R1And 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 -SaidThe total number of positive charges equals the total number of negative charges of the anion, R1,R2Are independent of each other;
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, synthesizingCarrying out amidation reaction with sulfoacid rhodamine to obtain a sulfonamide rhodamine compound with azido derivative sites, wherein the preparation method comprises the following steps:
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 groupsThe compounds with the alkynyl group are connected by a Click reaction to generate compounds with specific functionsIs a polypeptide chain with an alkynyl group.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811218269.1A CN109456341B (en) | 2018-10-19 | 2018-10-19 | Sulfonamide rhodamine compounds with alkynyl or azido derivative sites, and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811218269.1A CN109456341B (en) | 2018-10-19 | 2018-10-19 | Sulfonamide rhodamine compounds with alkynyl or azido derivative sites, and preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109456341A CN109456341A (en) | 2019-03-12 |
CN109456341B true CN109456341B (en) | 2021-06-15 |
Family
ID=65607826
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811218269.1A Active CN109456341B (en) | 2018-10-19 | 2018-10-19 | Sulfonamide rhodamine compounds with alkynyl or azido derivative sites, and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109456341B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110229231A (en) * | 2019-07-17 | 2019-09-13 | 大连理工大学 | A kind of fluorescent labeled antibody and application |
CN110283189A (en) * | 2019-07-17 | 2019-09-27 | 大连理工大学 | A kind of fluorescent chemicals of tracer Ofloxacin antibiotic and application |
CN110204562A (en) * | 2019-07-17 | 2019-09-06 | 大连理工大学 | One kind has fluorescent chemicals and the application of protein labeling function |
CN111533761B (en) * | 2020-05-24 | 2021-09-21 | 大连理工大学 | Ratio type pH probe with organelle or protein targeting function and application thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108191884A (en) * | 2017-12-28 | 2018-06-22 | 湖北工业大学 | A kind of synthetic method of more unit and fluorescence unit compound molecules and its application |
CN108640948A (en) * | 2018-04-26 | 2018-10-12 | 福建师范大学泉港石化研究院 | A kind of detection Cr3+Rhodamine base fluorescent probe and preparation method thereof |
CN108659189A (en) * | 2018-03-22 | 2018-10-16 | 黔南民族师范学院 | One metal ion species and pH response fluorescence chain extenders and its preparation method and application |
-
2018
- 2018-10-19 CN CN201811218269.1A patent/CN109456341B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108191884A (en) * | 2017-12-28 | 2018-06-22 | 湖北工业大学 | A kind of synthetic method of more unit and fluorescence unit compound molecules and its application |
CN108659189A (en) * | 2018-03-22 | 2018-10-16 | 黔南民族师范学院 | One metal ion species and pH response fluorescence chain extenders and its preparation method and application |
CN108640948A (en) * | 2018-04-26 | 2018-10-12 | 福建师范大学泉港石化研究院 | A kind of detection Cr3+Rhodamine base fluorescent probe and preparation method thereof |
Non-Patent Citations (3)
Title |
---|
An inexpensive fluorescent labeling protocol for bioactive natural products utilizing Cu(I)-catalyzed Huisgen reaction;Yan-Hong Zhang,等;《Tetrahedron》;20070425;第63卷;第6813-6821页 * |
One-Step Click Engineering Considerably Ameliorates the Practicality of an Unqualified Rhodamine Probe;Kai-Bin Li,等;《ACS Appl. Mater. Interfaces》;20141107;第6卷;第19600-19605页 * |
Synthesis of triazole-linked fluorescent saccharides and glycosyl amino esters;Hua Yi,等;《Synthesis》;20120905;第44卷(第11期);第1647-1656页,尤其参见第1647页右栏第2段-第1648页左栏第1段,方案1,方案2,第1652页右栏第3-7段 * |
Also Published As
Publication number | Publication date |
---|---|
CN109456341A (en) | 2019-03-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109456341B (en) | Sulfonamide rhodamine compounds with alkynyl or azido derivative sites, and preparation method and application thereof | |
KR20180132501A (en) | Ultra bright dimeric or polymeric dyes | |
US9815764B2 (en) | Homochiral metal-organic framework with enantiopure pillar[5]arene active domains | |
JPS6157546A (en) | Sulfurization of compound containing hydroxyethyl group | |
CN105367687A (en) | Chitosan amphiphilic polymer surfactant, and synthetic method thereof | |
CN102167673A (en) | Surfactant containing adamantane and preparation method thereof | |
Hu et al. | Sulfonamide and urea-based anions chemosensors | |
CN109851530B (en) | N, N, N ', N' -dodecyl tetra-substituted diphenyl ether sulfonate anionic gemini surfactant and synthesis thereof | |
CN113061111A (en) | Method for preparing amino acid compound with photocrosslinking activity | |
CN113402576B (en) | Cystine cholesterol gelator and preparation method thereof | |
CN112125823B (en) | Organic gel compound with AIE effect and preparation method and application thereof | |
US6884882B1 (en) | 2′-deoxyuridine derivatives and hydrogels formed therewith | |
CN110156641B (en) | Synthesis method of substituted guanidine | |
CN104744293B (en) | Cholinomimetic and its preparation method and application, by tetrazine probe of dye molecule labelling and its preparation method and application | |
CN107674036B (en) | Asymmetric bis-1, 2, 3-triazole compound as well as preparation method and application thereof | |
CN115160253A (en) | NBD fluorophore-based fluorescent dye probe for latent fingerprint detection and preparation method and application thereof | |
Liu et al. | Chemoselective desulfurization-fluorination/bromination of carbonofluoridothioates for the O-trifluoromethylation and O-bromodifluoromethylation of alcohols | |
CN105566206B (en) | The preparation and the application in terms of Heavy Metal Pollution Control of a kind of renewable fluorescence display material | |
CN111217842B (en) | Spiro-dipyrromethene boron complex/dipyrromethene boron complex and preparation method and application thereof | |
CN110372577B (en) | Pyridinium fluorescent probe and preparation method and application thereof | |
CN109456219B (en) | Method for stably and efficiently preparing N-acrylamide compound | |
CN108409635B (en) | Carbazole fluorescent thymine drug labeling reagent, synthesis and application | |
DE10308941A1 (en) | Monofunctionalized perylene tetracarboxylic acid bisimides | |
CN103773360A (en) | Schiff base fluorescent polymer and preparation method thereof | |
CN115160292B (en) | Synthesis method of 3-perfluoroalkyl thioflavone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
CB03 | Change of inventor or designer information |
Inventor after: Xiao Yi Inventor after: Zheng Ying Inventor after: Zhang Xinfu Inventor after: Chen Lingcheng Inventor before: Xiao Yi Inventor before: Zheng Ying Inventor before: Zhang Xinfu |
|
CB03 | Change of inventor or designer information | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |