CN112625049A - Azido group modified fluorescein compound and preparation method and application thereof - Google Patents
Azido group modified fluorescein compound and preparation method and application thereof Download PDFInfo
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- CN112625049A CN112625049A CN202011230441.2A CN202011230441A CN112625049A CN 112625049 A CN112625049 A CN 112625049A CN 202011230441 A CN202011230441 A CN 202011230441A CN 112625049 A CN112625049 A CN 112625049A
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- -1 Azido group modified fluorescein compound Chemical class 0.000 title claims abstract description 88
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 13
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 13
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 9
- 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 3
- 238000012650 click reaction Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 9
- 125000003003 spiro group Chemical group 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
- JTYUIAOHIYZBPB-UHFFFAOYSA-N 1-bromo-6-chlorohexane Chemical compound ClCCCCCCBr JTYUIAOHIYZBPB-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 239000012535 impurity Substances 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000003745 diagnosis Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 abstract description 7
- 230000001093 anti-cancer Effects 0.000 abstract description 3
- 230000000857 drug effect Effects 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000009826 distribution Methods 0.000 abstract description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000005303 weighing Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- HGXJWXJFIVPEHZ-UHFFFAOYSA-N 3'-hydroxy-6'-(methoxymethoxy)spiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(OCOC)=CC=C21 HGXJWXJFIVPEHZ-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- CVDGHGWEHQIJTE-UHFFFAOYSA-N bromo(bromomethoxy)methane Chemical compound BrCOCBr CVDGHGWEHQIJTE-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007850 fluorescent dye Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 2
- 125000006012 2-chloroethoxy group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- AMJBCNIDVLQCBR-UHFFFAOYSA-N 1-bromo-10-chlorodecane Chemical compound ClCCCCCCCCCCBr AMJBCNIDVLQCBR-UHFFFAOYSA-N 0.000 description 1
- UJZMGXCPUXWIRM-UHFFFAOYSA-N 1-bromo-20-chloroicosane Chemical compound ClCCCCCCCCCCCCCCCCCCCCBr UJZMGXCPUXWIRM-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/555—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
- A61K49/0043—Fluorescein, used in vivo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- 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
- C09K2211/1018—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 invention relates to an azide group modified fluorescein compound and a preparation method and application thereof, wherein the general structural formula of the compound (I) is as follows:
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to an azide group modified fluorescein compound and a preparation method and application thereof.
Background
The fluorescein compound has good positioning and distributing effect characteristics on cancer cells, strong affinity, strong storage capacity in cancer tissues and slow excretion speed, and can increase blood concentration and improve curative effect. Fluorescein has been reported to be used for diagnosing cancers abroad, and the fluorescein itself has a certain anticancer effect.
The azide organic compound is a novel energetic material with azide groups (-N3), is mainly used as an energetic binder and an energetic plasticizer, and is a promising new energetic component due to the introduction of the azide groups, namely the introduction of the azide groups, the energy and the burning rate of the propellant can be improved, and the flame temperature and the smoke signal of the propellant can be reduced. The azide can be converted into various functional groups, and plays an important role in the fields of chemical biology and fluorescence labeling in recent years.
Therefore, there is a need for: how to combine the azide group with the fluorescent compound and how to endow the fluorescent compound with the ability of combining with other anti-cancer drugs so as to enhance the effect of the drugs and effectively track the drugs.
Disclosure of Invention
The invention aims to solve the problems and provide an azide group modified fluorescein compound and a preparation method and application thereof.
The purpose of the invention is realized by the following technical scheme:
the structural general formula of the azide group modified fluorescein compound is as follows:
wherein: m is an integer of 2 to 20, R1Is C1-C10Alkyl radical, C1-C10One of alkoxy or halogen.
The preparation method of the azide group modified fluorescein compound comprises the following steps:
s1: adding fluorescein (a) into a THF solution of NaH, adding bromomethyl methyl ether, stirring, extracting with water, extracting with diethyl ether, and washing with NaOH and NaCl solution to obtain fluorescein-MOM (b);
s2: the fluorescein-MOM (b) obtained in S1 and
adding the raw material into a reactor filled with ethanol solution, adding NaOH, adding 1-bromo-6-chloro-hexane, and reacting to obtain 3' - (6-chlorohexyloxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthic acid]-3-ketone (c);
s3: 3'- ((6-azidohexyl) oxy-6' - (methoxymethoxy) -3H spiro [ isobenzofuran-1, 9 '-xanthic acid ] -3-ketone) prepared in S2 and sodium azide are used as raw materials to react to prepare 3' - ((6-azidohexyl) oxy-6 '- (methoxymethoxy) -3H spiro [ isobenzofuran-1, 9' -xanthic acid ] -3-ketone (d);
s4: and (3) ((6-azidohexyl) oxy-6 '- (methoxymethoxy) -3H spiro [ isobenzofuran-1, 9' -xanthane ] -3-ketone (d) prepared in S3 is added into a trifluoroacetic acid and dichloromethane mixed solution to react at normal temperature, TLC monitors the reaction to be complete, and the impurities are removed and purified to obtain the compound (I).
Further, in S1, the molar ratio of fluorescein (a), bromomethyl methyl ether, NaH was 1: (1-2): (1-2).
Further, in the step (1),
wherein m is an integer of 2 to 20.
Further, in S2, the molar ratio of fluorescein-mom (b), 1-bromo-6-chloro-hexane, and NaOH is 1: 2: (1-2).
Further, in S4, the molar ratio of 3' - (6-chlorohexyloxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthic acid ] -3-one (c) to sodium azide was 1: (1-3).
In S4, the molar ratio of 3' - ((6-azidohexyl) oxy-6 ' - (methoxymethoxy) -3H spiro [ isobenzofuran-1, 9' -xanth ] -3-one (d), trifluoroacetic acid and dichloromethane is 1 (1-5) to (1-3).
Further, the step of purifying and removing impurities in the step S4 is as follows: and (3) after spin-drying the reaction product, adding water and dichloromethane for pre-extraction, sequentially drying and concentrating the organic phase combined by the pre-extraction by using anhydrous sodium sulfate, and carrying out column chromatography separation to obtain the compound (I).
Preferably, in step (2), the formula (b) fluorescein-MOM, the 1-bromo-6-chloro-hexane, and the molar ratio of the sodium hydroxide is 1: 2: 1.
preferably, in step (3), the molar ratio of the sodium azide in the 3' - (6-chlorohexyloxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthic acid ] -3-one of formula (c) is 1: 2-3.
When the azide group modified fluorescein compound prepared by the technical scheme is applied to anticancer drugs, the prepared azide group modified fluorescein compound can be combined with the alkyne-containing anticancer drugs through click reaction, so that the drug effect of the anticancer drugs and the drug tracking capability are enhanced.
Compared with the prior art, the azide group is combined with the fluorescein according to a specific mixing ratio through a plurality of steps to generate the azide group modified fluorescein compound, the compound has the original positioning distribution action characteristic and affinity of the fluorescein, the combination of the azide group improves the combination ability of the compound and a specific anti-cancer drug, and the action of the anti-cancer drug and the ability of effectively tracking the drug are further enhanced. The overall preparation process has high yield, few byproducts and mild reaction environment, and can realize industrialized popularization.
Detailed Description
The present invention is described in detail below with reference to specific examples, but the present invention is not limited thereto in any way.
Several structural formulae are referred to in this example as follows:
in this embodiment, the synthesis of the azide group-modified fluorescein compound comprises the following steps:
wherein R1 is H, and m is 6.
(1) Slowly adding fluorescein shown in formula (a) into a THF solution of NaH at 0 ℃, dropwise adding bromomethyl methyl ether after 30min, and stirring for 30 min; extracting with water, and extracting with diethyl ether; washing with NaOH and NaCl solution; to obtain 3' -hydroxy-6 ' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthic acid ] -3-ketone, namely fluorescein-MOM;
(2) adding the fluorescein-MOM (b) obtained in the step (1) into a reaction tube filled with an ethanol solution, then adding NaOH, adding 1-bromo-6-chloro-hexane, and standing overnight at 80 ℃ to obtain 3' - (6-chlorohexyloxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthic acid ] -3-ketone;
(3) adding the 3'- (6-chlorohexyloxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9 '-xanthic acid ] -3-ketone with the structural formula shown in the formula (c) obtained in the step (2) into an N, N-dimethylformamide solvent, adding sodium azide, and reacting at 80 ℃ for 12H to obtain 3' - ((6-azidohexyl) oxy-6 '- (methoxymethoxy) -3H spiro [ isobenzofuran-1, 9' -xanthic acid ] -3-ketone;
(4) adding the 3' - ((6-azidohexyl) oxy-6 ' - (methoxymethoxy) -3H spiro [ isobenzofuran-1, 9' -xanthane ] -3-ketone with the structural formula shown in the formula (d) obtained in the step (3) into a mixed solution of trifluoroacetic acid and dichloromethane in a ratio of 1: 2, wherein the volume of the solution is about 4-5 times of that of the raw materials, reacting for one hour at normal temperature, TLC monitoring reaction, spin-drying, extracting with dichloromethane and water, combining organic phase, drying with anhydrous sodium sulfate, concentrating to obtain 3' - ((6-azidohexyl) oxy) -6' -hydroxy-3H-spiro [ isobenzofuran-1, 9' -xanthene ] -3-ketone with the structural formula shown in formula (d).
Common procedures such as extraction, quenching, chromatography, etc., are well known in the art, and reagents employed are generally obtained from commercial sources or readily prepared using methods well known to those skilled in the art. The implementation of other structures is detailed by the following embodiments.
Example 1
The embodiment is a preparation method of 3' - (2-azidoethoxy) -6' -hydroxy-3H-spiro [ isobenzofuran-1, 9' -xanthane ] -3-ketone, namely, the fluorescein compound (f) modified by the azido group in the structural formula is prepared by the following method, and the preparation route is as follows:
(1) fluorescein (4.72g,14.2mmol) was weighed out and slowly added to a solution of NaH (600mg,25mmol) in THF (3.5g,49.23mmol) at 0 deg.C, after 30min bromomethyl ether (3.06g,24.71mmol) was added dropwise and stirred for 30 min; extracting with water, and extracting with diethyl ether; washing with NaOH and NaCl solution; 8.03g (yield 60%) of 3' -hydroxy-6 ' - (methoxymethyloxy) -3H-spiro [ isobenzofuran-1, 9' -xanthen ] -3-one, fluorescein-MOM, were obtained;
(2) weighing (360mg,956.52 mu mol) the fluorescein-MOM obtained in the step (1) and adding the weighed fluorescein-MOM into a reaction tube filled with an ethanol solution, then adding NaOH (80mg,2mmol), then adding 1-bromo-2-chloro-ethane (287mg,2mmol), and standing overnight at 80 ℃ to obtain 580mg (yield 80%) of 3' - (2-chloroethoxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthane ] -3-one;
(3) weighing (320mg,729.16 mu mol) of the 3'- (2-chloroethoxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9 '-xanthic acid ] -3-ketone obtained in the step (2), adding into an N, N-dimethylformamide solvent, adding sodium azide (111mg, 1.7mmol) and reacting at 80 ℃ for 12H to obtain 366mg (yield is 85%) of 3' - (2-azidooxy) -6'- (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthic acid ] -3-ketone;
(4) weighing (300mg, 675.3. mu. mol) 3' - (2-azidooxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthen ] -3-one obtained in the step (3) into trifluoroacetic acid and dichloromethane 1: 2, reacting at room temperature for one hour, monitoring by TLC (thin layer chromatography) after the reaction is completed, performing extraction by using dichloromethane and water, combining organic phases, drying by using anhydrous sodium sulfate, and concentrating to obtain 240mg (yield is 80%) of 3' - (2-azidoethoxy) -6' -hydroxy-3H-spiro [ isobenzofuran-1, 9' -xanthen ] -3-one of which the structural formula is shown as a formula (f).
Example 2
This example illustrates the preparation of 3' - ((10-azidododecyl) oxy) -6' -hydroxy-3H-spiro [ isobenzofuran-1, 9' -xanthen ] -3-one, an azido group-modified fluorescein compound of formula (g), using the following procedure:
(1) fluorescein (4.72g,14.2mmol) was weighed out and slowly added to a solution of NaH (600mg,25mmol) in THF (3.5g,49.23mmol) at 0 deg.C, after 30min bromomethyl ether (3.06g,24.71mmol) was added dropwise and stirred for 30 min; extracting with water, and extracting with diethyl ether; washing with NaOH and NaCl solution; 8.03g (yield 60%) of 3' -hydroxy-6 ' - (methoxymethyloxy) -3H-spiro [ isobenzofuran-1, 9' -xanthen ] -3-one, fluorescein-MOM, were obtained;
(2) weighing the fluorescein-MOM obtained in the step (1) (360mg,956.52 mu mol) into a reaction tube filled with an ethanol solution, adding NaOH (40mg,1mmol), adding 1-bromo-10-chlorodecane (510mg,2mmol), and standing overnight at 80 ℃ to obtain 728mg (yield 80%) of 3' - ((10-chlorodecyl) oxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthane ] -3-one;
(3) weighing (320mg,580 mu mol) of 3'- ((10-chlorodecyl) oxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9 '-xanth ] -3-one obtained in the step (2), adding the weighed material into an N, N-dimethylformamide solvent, adding sodium azide (90mg, 1.4mmol) and reacting at 80 ℃ for 12H to obtain 328mg (yield is 85%) of 3' - ((10-azidododecyl) oxy) -6'- (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanth ] -3-one;
(4) weighing 3' - ((10-azidododecyl) oxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthen ] -3-one obtained in the step (3) (300mg, 538. mu. mol) to trifluoroacetic acid and dichloromethane 1: 2, reacting at room temperature for one hour, monitoring by TLC (thin layer chromatography) after the reaction is completed, performing extraction by using dichloromethane and water, combining organic phases, drying by using anhydrous sodium sulfate, and concentrating to obtain 240.2mg (yield 80%) of 3' - ((10-azidododecyl) oxy) -6' -hydroxy-3H-spiro [ isobenzofuran-1, 9' -xanthen ] -3-one with a structural formula shown in a formula (g).
Example 3
This example illustrates the preparation of 3' - ((20-azido heterocycle) oxy) -6' -hydroxy-3H-spiro [ isobenzofuran-1, 9' -xanthen ] -3-one, an azido group-modified fluorescein compound of formula (H), using the following method, the preparation route is shown below:
(1) fluorescein (4.72g,14.2mmol) was weighed out and slowly added to a solution of NaH (600mg,25mmol) in THF (3.5g,49.23mmol) at 0 deg.C, after 30min bromomethyl ether (3.06g,24.71mmol) was added dropwise and stirred for 30 min; extracting with water, and extracting with diethyl ether; washing with NaOH and NaCl solution; 8.03g (yield 60%) of 3' -hydroxy-6 ' - (methoxymethyloxy) -3H-spiro [ isobenzofuran-1, 9' -xanthen ] -3-one, fluorescein-MOM, were obtained;
(2) weighing the fluorescein-MOM obtained in the step (1) (360mg,956.52 mu mol), adding the weighed fluorescein-MOM into a reaction tube filled with an ethanol solution, adding NaOH (40mg,1mmol), adding 1-bromo-20-chloroeicosane (757mg,1.9mmol), and standing overnight at 80 ℃ to obtain 925.6mg (yield 80%) of 3' - (20-chloroethoxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthane ] -3-one;
(3) weighing (320mg,463 mu mol) of the 3'- (20-chloroethoxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9 '-xanthane ] -3-ketone obtained in the step (2), adding the weighed material into an N, N-dimethylformamide solvent, and then adding sodium azide (65mg, 1mmol) to react at the temperature of 80 ℃ for 12 hours to obtain 327.5mg of 3' - ((20-azidoheterocycle) oxy) -6'- (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthane ] -3-ketone (yield is 85%);
(4) weighing 3' - ((20-azidoheterocycle) oxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthen ] -3-one obtained in the step (3) (300mg, 430. mu. mol) to trifluoroacetic acid and dichloromethane 1: 2, reacting at room temperature for one hour, monitoring by TLC (thin layer chromatography) after the reaction is completed, performing extraction by using dichloromethane and water, combining organic phases, drying by using anhydrous sodium sulfate, and concentrating to obtain 243mg (yield is 81%) of 3' - ((20-azido heterocyclic) oxy) -6' -hydroxy-3H-spiro [ isobenzofuran-1, 9' -xanthene ] -3-ketone with a structural formula shown in formula (H).
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. An azide group modified fluorescein compound is characterized in that the structural general formula of the compound (I) is as follows:
wherein: m is an integer of 2 to 20, R1Is C1-C10Alkyl radical, C1-C10One of alkoxy or halogen.
2. The preparation method of the azide group modified fluorescein compound in the claim 1 is characterized by comprising the following steps:
s1: adding fluorescein (a) into a THF solution of NaH, adding bromomethyl methyl ether, stirring, extracting with water, extracting with diethyl ether, and washing with NaOH and NaCl solution to obtain fluorescein-MOM (b);
s2: the fluorescence obtained in S1photoprotein-MOM (b) and
adding the raw material into a reactor filled with ethanol solution, adding NaOH, adding 1-bromo-6-chloro-hexane, and reacting to obtain 3' - (6-chlorohexyloxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthic acid]-3-ketone (c);
s3: 3'- ((6-azidohexyl) oxy-6' - (methoxymethoxy) -3H spiro [ isobenzofuran-1, 9 '-xanthic acid ] -3-ketone) prepared in S2 and sodium azide are used as raw materials to react to prepare 3' - ((6-azidohexyl) oxy-6 '- (methoxymethoxy) -3H spiro [ isobenzofuran-1, 9' -xanthic acid ] -3-ketone (d);
s4: and (3) ((6-azidohexyl) oxy-6 '- (methoxymethoxy) -3H spiro [ isobenzofuran-1, 9' -xanthane ] -3-ketone (d) prepared in S3 is added into a trifluoroacetic acid and dichloromethane mixed solution to react at normal temperature, TLC monitors the reaction to be complete, and the impurities are removed and purified to obtain the compound (I).
3. The azide group-modified fluorescein compound and the preparation method thereof as claimed in claim 2, wherein the azide group-modified fluorescein compound comprises the following components: in S1, the molar ratio of fluorescein (a), bromomethyl methyl ether, and NaH is 1: (1-2): (1-2).
4. The azide group-modified fluorescein compound and the preparation method thereof as claimed in claim 2, wherein the azide group-modified fluorescein compound comprises the following components: in the step (1), the step (c),
wherein m is an integer of 2 to 20.
5. The azide group-modified fluorescein compound and the preparation method thereof as claimed in claim 2, wherein the azide group-modified fluorescein compound comprises the following components: in S2, the molar ratio of fluorescein-MOM (b), 1-bromo-6-chloro-hexane and NaOH is 1: 2: (1-2).
6. The azide group-modified fluorescein compound and the preparation method thereof as claimed in claim 2, wherein the azide group-modified fluorescein compound comprises the following components: in S4, the molar ratio of 3' - (6-chlorohexyloxy) -6' - (methoxymethoxy) -3H-spiro [ isobenzofuran-1, 9' -xanthogenic ] -3-one (c) to sodium azide was 1: (1-3).
7. The azide group-modified fluorescein compound and the preparation method thereof as claimed in claim 2, wherein the azide group-modified fluorescein compound comprises the following components: in S4, the molar ratio of 3' - ((6-azidohexyl) oxy-6 ' - (methoxymethoxy) -3H spiro [ isobenzofuran-1, 9' -xanthene ] -3-ketone (d), trifluoroacetic acid and dichloromethane is 1 (1-5) to (1-3).
8. The azide group-modified fluorescein compound and the preparation method thereof as claimed in claim 2, wherein the azide group-modified fluorescein compound comprises the following components: the purification and impurity removal steps in S4 are as follows: and (3) after spin-drying the reaction product, adding water and dichloromethane for pre-extraction, sequentially drying and concentrating the organic phase combined by the pre-extraction by using anhydrous sodium sulfate, and carrying out column chromatography separation to obtain the compound (I).
9. The application of the azide group modified fluorescein compound in the anti-cancer drugs as claimed in claim 1, which is characterized in that the azide group modified fluorescein compound is applied in the preparation of the anti-cancer drugs for diagnosis and/or treatment.
10. The application of the azide group-modified fluorescein compound as described in claim 1 in anticancer drugs, wherein the azide group-modified fluorescein compound can be combined with an alkyne-containing anticancer drug through a click reaction, so that the efficacy of the anticancer drug and the drug tracking ability are enhanced.
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