WO2020181931A1 - 一种七甲川羧基吲哚花菁染料及其制备方法和应用 - Google Patents

一种七甲川羧基吲哚花菁染料及其制备方法和应用 Download PDF

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WO2020181931A1
WO2020181931A1 PCT/CN2020/073661 CN2020073661W WO2020181931A1 WO 2020181931 A1 WO2020181931 A1 WO 2020181931A1 CN 2020073661 W CN2020073661 W CN 2020073661W WO 2020181931 A1 WO2020181931 A1 WO 2020181931A1
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formula
heptamethine
iii
hours
carboxyindole
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French (fr)
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李娟�
吴爱国
袁博
蒋振奇
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中国科学院宁波工业技术研究院慈溪生物医学工程研究所
中国科学院宁波材料技术与工程研究所
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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/0066—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • 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
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
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    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
    • C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
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    • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
    • C09B23/10—The polymethine chain containing an even number of >CH- groups
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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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    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N21/643—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" non-biological material
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    • C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom

Definitions

  • the application relates to a heptamethine carboxy indolecyanine dye and a preparation method and application thereof, belonging to the field of polymethine indole cyanine dye and preparation thereof.
  • Indocyanine green in heptamethine cyanine dyes is the only near-infrared dye approved by the US Food and Drug Administration for clinical imaging photothermal therapy. Its derivative, new indocyanine green, belongs to heptamethine indocyanine dyes Kind of. This type of dye has a strong absorption effect in the near-infrared light region near 808nm, which can be used as a complement to other medical diagnosis and treatment methods (such as MRI, PET, SPECT, ultrasonic echo scanning technology, radiography and tomography) Imaging technology, which is also used as a photosensitizer for photothermal therapy, has important research value and application value in life science and biomedical research.
  • medical diagnosis and treatment methods such as MRI, PET, SPECT, ultrasonic echo scanning technology, radiography and tomography
  • Heptamethine indocyanine dyes have multiple modifiable sites, which can greatly expand the combined use of such dyes and small molecule drugs.
  • heptamethine indocyanine on the market is only the new indocyanine green (IR-820), with low purity (80%) and high selling price (1324 yuan/g).
  • IR-820 new indocyanine green
  • high selling price 1324 yuan/g
  • the production and purification process of its different derivatives requires a lot of screening conditions and consumes a lot of organic solvents, and most of the selected solvents are highly toxic solvents, such as o-dichlorobenzene, toluene, benzene, etc.
  • a heptamethine carboxyindolecyanine dye which has the properties of near-infrared light absorption and fluorescence development.
  • the heptamethine carboxyindolecyanine dye is characterized in that its structural formula is as shown in formula (I):
  • R is selected from one of R 1 and R 2 ;
  • R is R 1
  • R' is selected from hydrogen, methyl, methoxy, hydroxyl, carboxyl, amide, sulfonic acid, ester, alkynyl or amino
  • a is selected from an integer greater than 0 and less than or equal to 14.
  • R is R 2
  • R " is selected from hydrogen, methyl, methoxy, hydroxy, a carboxyl group, an amide group, a sulfonic acid group, an ester group, an alkynyl group or an amino group
  • b is an integer selected from 0 to 7
  • A is selected from ethylene, linear propylene or linear butylene; or
  • R" is selected from carboxylate or sulfonate
  • b is selected from an integer from 0 to 7
  • Y is selected from hydrogen, sodium or potassium
  • A is selected from ethylene, linear propylene or straight Butylene.
  • the structural formula of the heptamethine carboxyindolecyanine dye is as shown in formula (I-1), formula (I-2) or formula (I-3):
  • R in formula (I) is selected from one of R 1 and R 2 ; wherein,
  • R is when R 2
  • b is selected from 0,1,3 or 5
  • X is selected from bromine or iodine
  • A is selected from ethylene Or linear propylene; or
  • R" is selected from carboxylate or sulfonate
  • b is selected from 0, 1, 3 or 5
  • Y is selected from sodium
  • A is selected from ethylene or linear propylene.
  • This application relates to a kind of N-aliphatic acid, N-aliphatic ester, N-aliphatic amide, N-aliphatic chain hydrocarbon, N-aromatic acid, N-aromatic ester, N-aromatic amide or N -Heptamethine carboxyl indolecyanine dyes with side chains such as aromatic chain hydrocarbons and methods for their synthesis and purification.
  • the heptamethine carboxyindolecyanine dye has or alone has the properties of near-infrared light absorption and fluorescence development.
  • the method has the advantages of short synthetic route, environmentally friendly solvent, simple process, avoiding precious metal catalysis, high yield, and simple purification method (no need for chromatography column separation and less solvent consumption), which can greatly improve the preparation of such dyes Efficiency and low-cost mass production are of great significance in the production and application research of heptamethine carboxyindole cyanine.
  • the heptamethine carboxyindolecyanine dye in this application is selected from compounds having the structural formula shown below:
  • a method for preparing the heptamethine carboxyindolecyanine dye is provided.
  • the method has the advantages of short synthetic route, friendly solvent environment, simple process, avoiding noble metal catalysis, high yield and large single reaction volume, and can greatly improve the preparation efficiency of such dyes and realize low-cost mass production.
  • the method has strong applicability and can be used to prepare heptamethine carboxyindolecyanine dyes of various structural types.
  • the nucleophilic substitution compound is selected from at least one compound having a structural formula such as formula (III-2), formula (III-3) or formula (III-4):
  • R 1 is selected from hydrogen, methyl, methoxy, hydroxyl, carboxyl, amide, sulfonic acid, ester, alkynyl, or amino, and a is selected from those greater than 0 and less than or equal to 14.
  • X is selected from fluorine, chlorine, bromine, iodine or perchlorate; in formula (III-3), R 2 is selected from c is selected from an integer from 1 to 13; in formula (III-4), R 3 is selected from hydrogen, methyl, methoxy, hydroxy, carboxy, amide, sulfonic acid, ester, alkynyl or amino, b An integer selected from 0 to 7, and X is selected from fluorine, chlorine, bromine, iodine or perchlorate;
  • step 2) Reacting the solution containing the organic ammonium salt and cycloalkene derivative obtained in step 1) at 50-80° C. for 8 to 48 hours under closed conditions to obtain the heptamethine carboxyindole cyanine dye;
  • A is selected from ethylene, linear propylene, or linear butylene.
  • step 1) the molar ratio of the 2,3,3-trimethyl-carboxyindole derivative to the nucleophilic substitution compound is 1:1 to 1:12.
  • the upper limit of the molar ratio of the 2,3,3-trimethyl-carboxyindole derivative to the nucleophilic substitution compound is selected from 1:12, 1:11, and 1: 10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2
  • the lower limit is selected from 1:1, 1:1.5, 1:2, 1 :3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11.
  • the molar ratio of the 2,3,3-trimethyl-carboxyindole derivative to the nucleophilic substitution compound is 1:1 to 1:2.
  • step 1) the molar ratio of the 2,3,3-trimethyl-carboxyindole derivative to the nucleophilic substitution compound is 1:1.5.
  • the upper limit of the reaction temperature of the raw materials is selected from 130°C, 125°C, 120°C, 115°C, 110°C, 105°C, 100°C, 95°C, 90°C, and the lower limit is selected from 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C;
  • the upper limit of the reaction time of the raw material is selected from 24 hours, 23 hours, 22 hours, 20 hours, 18 hours, 16 hours, 15 hours, 14 hours, 12 hours, 10 hours, 5 hours
  • the lower limit is selected from 4 hours, 5 hours, 8 hours, 10 hours, 12 hours, 14 hours, 15 hours, 16 hours, 18 hours, 20 hours, 22 hours , 23 hours.
  • step 1) the raw material is reacted at 100-120°C for 8-16 hours.
  • step 1) the raw materials are reacted at 110 to 120°C for 10 to 14 hours.
  • step 1) the raw material is reacted at 120°C for 12 hours.
  • step 1) the raw materials are reacted under closed conditions.
  • step 1) the raw materials are reacted under a pressure of 2 to 200 Pa.
  • the upper limit of the pressure of the raw material reaction is selected from 200Pa, 175Pa, 150Pa, 125Pa, 100Pa, 75Pa, 50Pa, 40Pa, 30Pa, 20Pa, 10Pa, 9Pa, 8Pa, 7Pa, 6Pa, 5Pa, 4Pa, 3Pa
  • the lower limit is selected from 2Pa, 3Pa, 4Pa, 5Pa, 6Pa, 7Pa, 8Pa, 9Pa, 10Pa, 20Pa, 30Pa, 40Pa, 50Pa, 75Pa, 100Pa, 125Pa, 150Pa, 175Pa.
  • step 1) the raw materials are reacted under a pressure of 5-50Pa.
  • step 1) the raw materials are reacted under a pressure of 10 Pa.
  • step 1) there is no particular restriction on whether a reaction medium is used in addition to the reactants in step 1), as long as the reactants can complete the reaction of step 1). That is, under the reaction conditions of step 1) as described above, when a liquid phase exists in the reaction system (for example, when at least part of the reactants are liquid), no reaction medium is required, or the reaction medium can still be used.
  • the reaction medium is an alcohol-based reaction medium.
  • the reaction medium is selected from at least one of methanol, ethanol, propanol, ethylene glycol, glycerol, butanol and butanediol.
  • step 2) the molar ratio of the cycloalkene derivative to the organic ammonium salt is 1:2 to 1:6.
  • the upper limit of the molar ratio of the cycloalkene derivative to the organic ammonium salt is selected from 1:6, 1:5.5, 1:5, 1:4.5, 1:4, 1: 3.8, 1:3.5, 1:3.4, 1:3.2, 1:3, 1:2.8, 1:2.5, 1:2.4, 1:2.2, 1:2.1, the lower limit is selected from 1:2, 1:2.1, 1 :2.2, 1:2.4, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.4, 1:3.5, 1:3.8, 1:4, 1:4.5, 1:5, 1:5.5 .
  • the molar ratio of the cycloalkene derivative to the organic ammonium salt is 1:2 to 1:3.
  • step 2 the molar ratio of the cycloalkene derivative to the organic ammonium salt is 1:2.5.
  • the upper limit of the reaction temperature of the solution is selected from 80°C, 75°C, 70°C, 65°C, 60°C, and 55°C
  • the lower limit is selected from 50°C, 55°C, 60°C, 65°C, 70°C, 75°C
  • the upper limit of the reaction time of the solution is selected from 48 hours, 38 hours, 35 hours, 32 hours, 30 hours, 28 hours, 24 hours, 20 hours, 18 hours, 15 hours, 10 hours
  • the lower limit is selected from 8 hours, 10 hours, 15 hours, 18 hours, 20 hours, 24 hours, 28 hours, 30 hours, 32 hours, 35 hours, and 38 hours.
  • step 2) the solution is reacted at 60-80°C for 10-30 hours.
  • step 2 the solution is reacted at 70-80°C for 10-30 hours.
  • step 2 the solution is reacted at 70-80°C for 15-28 hours.
  • step 2 the solution is reacted at 75°C for 24 hours.
  • step 2) a precipitating agent is added after the reaction, maintained at 1-10°C for 12-48 hours and then suction filtered to obtain the heptamethine carboxyindolecyanine dye.
  • the upper limit of the temperature maintained after adding the precipitant is selected from 10°C, 9°C, 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, and the lower limit is selected from 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C;
  • the upper limit of the holding time is selected from 48 hours, 44 hours, 40 hours, 36 hours, 32 hours, 28 Hour, 24 hour, 20 hour, 16 hour
  • the lower limit is selected from 12 hour, 16 hour, 20 hour, 24 hour, 28 hour, 32 hour, 36 hour, 40 hour, 44 hour.
  • step 2) a precipitating agent is added after the reaction, maintained at 4° C. for 24 hours and then filtered with suction to obtain the heptamethine carboxyindole cyanine dye.
  • the precipitating agent is selected from at least one of petroleum ether, ethyl ether, methyl ether, propyl ether, and methyl ethyl ether.
  • the precipitating agent includes petroleum ether.
  • the solvent in the solution is selected from at least one of water, methanol, ethanol, propanol, ethylene glycol, glycerol, butanol and butanediol.
  • the solvent in the solution is selected from at least one of methanol, ethanol and propanol.
  • step 1) of the method according to the present application depending on the state of the reactants, a solvent may not be used, or a solvent may be used and selected from alcohols; in step 2), a solvent selected from Water and alcohol solvents.
  • solvents such as ortho-dichlorobenzene and acetic anhydride used in conventional methods, the solvents that can be used in this application are more environmentally friendly and safer, and have less damage to health.
  • the preparation method of 2,3,3-trimethyl-carboxyindole derivative includes the following steps:
  • step 1) the molar ratio of the p-carboxyphenylhydrazine, 3-methyl-2-butanone and anhydrous sodium acetate is 1:1 ⁇ 1.2:1.4 ⁇ 1.6, preferably 1:1.1: 1.5.
  • step 1) the reaction is carried out under reflux and stirring for 6-10 hours, preferably 8 hours.
  • the volume ratio of water to methanol is 8:1-10:1, preferably 9:1.
  • step 3 the crystallization is carried out at room temperature for 36-50 hours, preferably 48 hours.
  • the purity of the heptamethine carboxyindolecyanine dye prepared by the method described in this application is greater than 90%.
  • the purity of the heptamethine carboxyindolecyanine dye prepared by the method described in this application is 85-99.5 percent.
  • the purity of the heptamethine carboxyindolecyanine dye prepared by the method described in this application is 90-99.5 percent.
  • the yield of the heptamethine carboxyindolecyanine dye prepared by the method described in this application is not less than 83.5%.
  • the yield of the heptamethine carboxyindolecyanine dye prepared by the method described in the present application is 83.5 to 93.7%.
  • the preparation method of the heptamethine carboxyindolecyanine dye is carried out according to the following route:
  • X is selected from one of halogens, preferably bromine;
  • R is a group composed of a linear alkylene group having 1 to 14 carbon atoms and a terminal group, the terminal group is selected from hydrogen, methyl, and methoxy Group, hydroxyl group, carboxyl group, amide group, sulfonic acid group, ester group, alkynyl group or amino group;
  • the molar ratio of 2,3,3-trimethyl-carboxyindole to the bromine substituent (XR) as the nucleophilic substitution compound is 1:1 to 1:12, preferably 1:1.5; the heating temperature is 80 ⁇ 130°C, preferably 120°C; the molar ratio of 2-chloro-1-formyl-3-hydroxymethylenecyclohexene as a cycloalkene derivative to the N-substituent as an organic ammonium salt is 1:2 ⁇ 1:4, preferably 1:2.5; heating temperature is 50-80°C, preferably 75°C.
  • the method for preparing the heptamethine carboxyindolecyanine dye includes the following steps:
  • step 2) Add 2-chloro-1-formyl-3-hydroxymethylene cyclohexene as a cycloalkene derivative to the solution after step 1), and heat the reaction under closed conditions. After the reaction, the reaction solution Placed in a refrigerator overnight at 4°C, and then precipitated with a precipitation agent.
  • the molar ratio of 2-chloro-1-formyl-3-hydroxymethylenecyclohexene to the N-substitute as an organic ammonium salt is 1: 2 ⁇ 1:4, the heating temperature is 50 ⁇ 80°C, and the reaction time is 8 ⁇ 48 hours; preferably, the molar ratio of 2-chloro-1-formyl-3-hydroxymethylene cyclohexene and N-substitute The ratio is 1:2.5, the heating temperature is 75°C, and the reaction time is 24 hours.
  • an application of the heptamethine carboxyindolecyanine dye is provided.
  • the heptamethine carboxyindole cyanine dye is used in the preparation of a probe auxiliary agent, and the probe aid includes the heptamethine carboxyindole cyanine dye and the heptamethine carboxyindole cyanine dye prepared by the above method. At least one of cyanine dyes.
  • the heptamethine carboxyindolecyanine dye is used to prepare near-infrared fluorescent probes.
  • the near-infrared fluorescent probes include small molecule probes and nano probes.
  • the heptamethine carboxyindolecyanine dye is used in trademark anti-counterfeiting, biomedicine, environmental monitoring, national defense detection and related fields.
  • alkyl means a group formed by the loss of any hydrogen atom on the molecule of an alkane compound; the alkane compound includes cycloalkanes, straight-chain alkanes, and branched-chain alkanes.
  • ethylene means a group with the structural formula -CH 2 -CH 2 -
  • linear propylene means a group with the structural formula -CH 2 -CH 2 -CH 2 -
  • String-chain butylene means a group having the structural formula -CH 2 -CH 2 -CH 2 -CH 2 -.
  • the heptamethine carboxyindolecyanine dye provided by this application has the properties of near-infrared light absorption and fluorescence development.
  • the preparation method of heptamethine carboxyindolecyanine dye provided by the present application has the advantages of short synthetic route, environmentally friendly solvent, simple process, avoiding noble metal catalysis, high yield, and large single reaction volume. Greatly improve the preparation efficiency of such dyes, and realize low-cost mass production.
  • the heptamethine carboxyindolecyanine dye obtained by the preparation method provided in the application has high purity, which can be higher than 90%.
  • the method for preparing heptamethine carboxyindolecyanine dye provided by this application has strong applicability and can be used to realize the synthesis of products of various structural types.
  • Figure 1 is an infrared absorption spectrum of compound C1 prepared according to Example 5 of the present application.
  • Figure 2 is a diagram showing the in vivo imaging effect of compound C1 prepared according to Example 5 of the present application after intravenous injection of mice 48 hours.
  • this application relates to a method for preparing heptamethine carboxyindole cyanine dye, which includes the following steps: reacting 2,3,3-trimethyl-carboxyindole derivatives with nucleophilic substituted compounds to obtain organic Ammonium salt: mixing organic ammonium salt and cycloalkene derivatives in an environmentally friendly organic solvent to react, adding an organic precipitant to the product after the reaction, cooling and standing overnight to obtain the heptamethine carboxyindole cyanine dye.
  • the method has the advantages of short synthetic route, simple process, no catalyst, high yield, simple purification method, high atom utilization rate and low consumption of organic solvents, which can greatly improve the preparation efficiency of such dyes and realize low-cost mass production It is of great significance in the production and application of heptamethine carboxyindolecyanine dyes.
  • the method for preparing heptamethine carboxyindolecyanine dye according to the present application has wider applicability. This method can realize the synthesis of more structural types of products under the condition of adopting more environmentally friendly solvents and milder reaction conditions.
  • ThermoNciolet 6700 infrared spectrometer for infrared absorption spectrum analysis.
  • PerkinElmer Lanbda ultraviolet spectrophotometer was used for ultraviolet absorption spectrum analysis.
  • PerkinElmer IVIS Lumina LT small animal imager was used for in vitro fluorescence detection and analysis.
  • Compound 53 was synthesized according to the following route:
  • Example 2 The 2,3,3-trimethyl-carboxyindole and 4-bromobutane obtained in Example 1 with a molar ratio of 1:1.5 were added to the reactor, and the reactor was closed and evacuated to 10 Pa. The reaction system was heated to 110°C and stirred for 8 hours, and then cooled to room temperature. The product obtained was filtered with suction and used directly in the next reaction.
  • the purity of compound 53 obtained in this example is greater than 92%.
  • Compound 26 was synthesized according to the following route:
  • Example 2 The 2,3,3-trimethyl-carboxyindole and p-bromomethyl benzoic acid obtained in Example 1 with a molar ratio of 1:1.5 were added to the reactor, and the reactor was closed and evacuated to 15 Pa. The reaction system was heated to 110°C and stirred for 12 hours, and then cooled to room temperature. The product obtained was filtered with suction and used directly in the next reaction.
  • the purity of compound 26 obtained in this embodiment is greater than 95%.
  • Example 2 The 2,3,3-trimethyl-carboxyindole and 4-bromobutyric acid obtained in Example 1 with a molar ratio of 1:1.5 were added to the reactor, and the reactor was closed and evacuated to 10 Pa. The reaction system was heated to 110°C and stirred for 12 hours, and then cooled to room temperature. The product obtained by suction filtration was directly used in the next reaction.
  • Example 2 Add the 2,3,3-trimethyl-carboxyindole and 1,4-butane sultone obtained in Example 1 with a molar ratio of 1:1.5 to the reactor, and then vacuum the reactor after sealing To 10Pa.
  • the reaction system was heated to 110°C and stirred for 12 hours, and then cooled to room temperature.
  • the product obtained was filtered with suction and used directly in the next reaction.
  • the purity of compound C1 obtained in this example is greater than 91%.
  • Compound 12 was synthesized according to the following route:
  • Example 2 Add the 2,3,3-trimethyl-carboxyindole and ethyl 4-bromobutyrate obtained in Example 1 with a molar ratio of 1:1.5 to the reactor, and then evacuate the reactor to 15Pa after closing the reactor. .
  • the reaction system was heated to 110°C and stirred for 12 hours, and then cooled to room temperature.
  • the product obtained was filtered with suction and used directly in the next reaction.
  • the purity of compound 12 obtained in this example was greater than 91%.
  • Compound 36 was synthesized according to the following route:
  • Example 2 Add the 2,3,3-trimethyl-carboxyindole and methyl p-bromomethyl benzoate obtained in Example 1 with a molar ratio of 1:1.5 into the reactor, and seal the reactor and evacuate to 20Pa.
  • the reaction system was heated to 110°C and stirred for 12 hours, and then cooled to room temperature.
  • the product obtained was filtered with suction and used directly in the next reaction.
  • the purity of compound 36 obtained in this example was greater than 87%.
  • Compound 25 was synthesized according to the following route:
  • Example 2 The 2,3,3-trimethyl-carboxyindole and bromomethylbenzene obtained in Example 1 with a molar ratio of 1:1.5 were added to the reactor, and the reactor was closed and evacuated to 10 Pa. The reaction system was heated to 110°C and stirred for 12 hours, and then cooled to room temperature. The product obtained was filtered with suction and used directly in the next reaction.
  • the purity of compound 25 obtained in this example is greater than 92%.
  • Compound 55 was synthesized according to the following route:
  • Example 2 The 2,3,3-trimethyl-carboxyindole and 1-iodododecane obtained in Example 1 with a molar ratio of 1:1.5 were added to the reactor, and the reactor was closed and evacuated to 15 Pa. The reaction system was heated to 110°C, stirred for 12 hours, and then cooled to room temperature. The product obtained was filtered with suction and used directly in the next reaction.
  • the purity of compound 55 obtained in this example was greater than 92%.
  • Compound 40 was synthesized according to the following route:
  • Example 2 Add the 2,3,3-trimethyl-carboxyindole and p-iodomethyl anisole obtained in Example 1 with a molar ratio of 1:1.5 into the reactor, close the reactor and evacuate to 20 Pa .
  • the reaction system was heated to 110°C, stirred for 12 hours, and then cooled to room temperature.
  • the product obtained was filtered with suction and used directly in the next reaction.
  • the purity of compound 40 obtained in this embodiment is greater than 92%.
  • step 1) add 2,3,3-trimethyl-carboxyindole and methyl p-bromomethyl benzoate in a molar ratio of 1:1; in step 2 In step 2), water is used instead of methanol as the solvent; in step 2), ethyl ether is used instead of petroleum ether as the precipitant to obtain the product compound 36.
  • step 1) add 2,3,3-trimethyl-carboxyindole and methyl p-bromomethyl benzoate in a molar ratio of 1:12; in step 2 In step 2), ethanol is used instead of methanol as the solvent; in step 2), methyl ether is used instead of petroleum ether as the precipitating agent to obtain the product compound 36.
  • step 1) the reaction system is heated to 80°C and stirred for 24 hours; in step 2), propanol is used instead of methanol as the solvent; in step 2), propyl ether is used instead Petroleum ether was used as a precipitant to obtain the product compound 36.
  • step 1) the reaction system is heated to 130° C. and stirred for 4 hours; in step 2), ethylene glycol is used instead of methanol as the solvent; in step 2), methyl ethyl ether is used Instead of petroleum ether as the precipitant, the product compound 36 was obtained.
  • step 2) 2-chloro-1-formyl-3-hydroxymethylene cyclohexene and 2,3,3-trimethyl-1-(butyric acid
  • the molar ratio of ethyl ester)-carboxyindole is 1:2; in step 2), glycerol is used instead of methanol as the solvent to obtain the product compound 12.
  • step 2) 2-chloro-1-formyl-3-hydroxymethylene cyclohexene and 2,3,3-trimethyl-1-(butyric acid
  • the molar ratio of ethyl ester)-carboxyindole is 1:6; in step 2), butanol is used instead of methanol as the solvent to obtain the product compound 12.
  • step 2) the reaction system is heated to 50°C under closed conditions for 48 hours, then cooled to room temperature, and placed in a refrigerator at 10°C for 48 hours; 2) Using butanediol instead of methanol as the solvent to obtain the product compound 12.
  • step 2) the reaction system is heated to 80°C under closed conditions for 8 hours, then cooled to room temperature, and placed in a 1°C refrigerator to stand for 12 hours;
  • step 2) a methanol/ethanol mixture is used instead of methanol as the solvent to obtain the product compound 12.
  • Example 6 The preparation process of Example 6 was repeated, with the difference that: in step 1), the reactor was closed and evacuated to 2 Pa to obtain the product compound 12.
  • Example 6 The preparation process of Example 6 was repeated, with the difference that: in step 1), the reactor was closed and evacuated to 200 Pa to obtain the product compound 12.
  • Example 5 The compound C1 prepared in Example 5 was analyzed by infrared spectroscopy. The results are shown in Figure 1. Among them, 3438cm -1 , 1629cm -1 (-COOH) and 1396cm -1 , 1167cm -1 and 1042cm -1 (-SO 3 H) is the absorption peak of the corresponding functional group. The test results of the other examples are similar to those of Example 5, and corresponding products are obtained.
  • the compound C1 prepared in Example 5 was subjected to ultraviolet spectroscopy analysis.
  • the compound C1 prepared in Example 5 typically has the highest absorption peak at 795 nm, which belongs to the near-infrared absorption peak.
  • the test results of the remaining examples are similar to those of Example 5, and the maximum absorption wavelength of the obtained product is in the range of 760-850 nm.
  • the compound C1 prepared in Example 5 was dissolved in PBS solution, and the concentration was diluted with PBS solution to obtain 0.2 mg/mL near-infrared targeting probe preparation.
  • the above-mentioned near-infrared targeting probe preparation at a concentration of 0.2 mg/mL was injected into nude mice with breast cancer, and fluorescence detection was performed 48 hours later.
  • the results are shown in Figure 2.
  • the near-infrared fluorescence signal peak of the near-infrared fluorescent probe is well separated from the background signal peak of the nude mouse itself, and the contrast between the tumor area and the normal tissue around the tumor is greater than 10. In this way, the background interference is small, which can provide the surgeon with a clear tumor location and precise tumor boundary, thereby improving the detection rate and resection rate of the tumor.

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Abstract

本申请公开了一种七甲川羧基吲哚花菁染料及其制备方法和应用，属于多甲川吲哚花菁染料及其制备领域。所述七甲川羧基吲哚花菁染料的结构式如式(I)所示：该染料具有近红外光吸收和荧光显影性能，可用于探针助剂。所述染料的制备方法包括以下步骤：1)将含有2,3,3-三甲基-羧基吲哚衍生物和亲核取代化合物的原料在真空条件下升温反应，得到有机铵盐；2)将含有步骤1)中得到的有机铵盐和环烯衍生物的溶液在封闭条件下升温反应。该方法具有合成路线短、溶剂环境友好、工艺简单、避免贵金属催化、产率高以及纯度高等优点，且适用性强，可用于合成多种结构类型的产物。

Description

一种七甲川羧基吲哚花菁染料及其制备方法和应用 技术领域
本申请涉及一种七甲川羧基吲哚花菁染料及其制备方法和应用，属于多甲川吲哚花菁染料及其制备领域。
背景技术
七甲川花菁染料中的吲哚菁绿是唯一被美国食品药品监督管理局批准可用于临床显影光热治疗的近红外染料，其衍生物新吲哚菁绿属于七甲川吲哚花菁染料中的一种。这一类染料在808nm附近的近红外光区具有较强的吸收效果，其可作为其他医学诊疗方法(例如MRI、PET、SPECT、超声回波扫描技术、放射摄影术和断层摄影术)的互补成像技术，同时也用做光热治疗的光敏剂，在生命科学和生物医学研究中具有重要的研究价值和应用价值。
七甲川吲哚花菁染料具有多个可改性位点，可大大拓展此类染料与小分子药物等的联合使用。目前，市面所售的七甲川吲哚花菁仅新吲哚菁绿(IR-820)一种，且纯度低(80％)、售价高(1324元/g)。同时，其不同衍生物的生产纯化过程需要进行大量条件筛选且耗费大量有机溶剂，并且所选用的溶剂大多为高毒性溶剂，如邻二氯苯、甲苯、苯等。因此，本领域需要开发一种新的适用于工业化、低毒、绿色的七甲川羧基吲哚花菁染料的制备纯化方法，从而实现此类染料的高效、低成本、低毒性的制备。
发明内容
根据本申请的一个方面，提供了一种七甲川羧基吲哚花菁染料，该染料具有近红外光吸收、荧光显影的性能。
所述七甲川羧基吲哚花菁染料，其特征在于，其结构式如式(I)所示：
Figure PCTCN2020073661-appb-000001
其中，R选自R 1和R 2中的一种；
Figure PCTCN2020073661-appb-000002
当R为R 1时，R'选自氢、甲基、甲氧基、羟基、羧基、酰胺基、磺酸基、酯基、炔基或氨基，a选自大于0且小于等于14的整数，X选自氟、氯、溴、碘或高氯酸根，m＝1，p＝0，A选自亚乙基、直链亚丙基或直链亚丁基；或
R'选自羧酸根或磺酸根，a选自大于0且小于等于14的整数，Y选自氢、钠或钾，m＝0，p＝1，A选自亚乙基、直链亚丙基或直链亚丁基；
当R为R 2时，R"选自氢、甲基、甲氧基、羟基、羧基、酰胺基、磺酸基、酯基、炔基或氨基， b选自0至7的整数，X选自氟、氯、溴、碘或高氯酸根，m＝1，p＝0，A选自亚乙基、直链亚丙基或直链亚丁基；或
R"选自羧酸根或磺酸根，b选自0至7的整数，Y选自氢、钠或钾，m＝0，p＝1，A选自亚乙基、直链亚丙基或直链亚丁基。
可选地，所述七甲川羧基吲哚花菁染料的结构式如式(I-1)、式(I-2)或式(I-3)所示：
Figure PCTCN2020073661-appb-000003
可选地，式(I)中的R选自R 1和R 2中的一种；其中，
当R为R 1时，R'选自氢、羧基或酯基，a选自2、4、6或8，X选自溴或碘，m＝1，p＝0，A选自亚乙基或直链亚丙基；或
R'选自羧酸根或磺酸根，a选自3、5、7或9，Y选自钠，m＝0，p＝1，A选自亚乙基或直链亚丙基；
当R为R 2时，R"选自氢、羧基或酯基，b选自0、1、3或5，X选自溴或碘，m＝1，p＝0，A选自亚乙基或直链亚丙基；或
R"选自羧酸根或磺酸根，b选自0、1、3或5，Y选自钠，m＝0，p＝1，A选自亚乙基或直链亚丙基。
本申请涉及一种含N-脂族酸、N-脂族酯、N-脂族酰胺、N-脂族链烃、N-芳族酸、N-芳族酯、N-芳族酰胺或N-芳族链烃等侧链的七甲川羧基吲哚花菁染料及其合成和纯化方法。所述七甲川羧基吲哚花菁染料具有或单独具有近红外光吸收、荧光显影的性能。所述方法具有合成路线短、溶剂环境友好、工艺简单、避免贵金属催化、产率高以及提纯方法简单(无需层析柱分离且所耗溶剂少)的优点，可极大地提高此类染料的制备效率，实现低成本批量生产，在七甲川羧基吲哚花菁的生产及应用研究方面均具有重大意义。
作为具体的实施方式，本申请中的七甲川羧基吲哚花菁染料选自具有如下所示的结构式的化合物：
(1)当A为直链亚丙基，R选自R 1，R'选自氢，a＝2，3，4，6，12时，所述七甲川羧基吲哚花菁染料分别为具有结构式1～5的化合物；
(2)当A为直链亚丙基，R选自R 1，R'选自羧酸根，a＝1，2，3，5时，所述七甲川羧基吲哚花菁染料分别为具有结构式6～9的化合物；
(3)当A为直链亚丙基，R选自R 1，R'选自乙酯基，a＝1，2，3，5时，所述七甲川羧基吲哚花菁染料分别为具有结构式10～13的化合物；
(4)当A为直链亚丙基，R选自R 1，R'选自羟基，a＝2，3，4，6时，所述七甲川羧基吲哚花菁染料分别为具有结构式14～17的化合物；
(5)当A为直链亚丙基，R选自R 1，R'选自甲氧基，a＝2，4，6时，所述七甲川羧基吲哚花菁染料分别为具有结构式18～20的化合物；
(6)当A为直链亚丙基，R选自R 1，R'选自酰胺基，a＝1，2，3，5时，所述七甲川羧基吲哚花菁染料分别为具有结构式21～24的化合物；
(7)当A为直链亚丙基，R选自R 2，R"选自氢，b＝0时，所述七甲川羧基吲哚花菁染料为具有结构式25的化合物；
(8)当A为直链亚丙基，R选自R 2，R"选自羧基，b＝0，1，3时，所述七甲川羧基吲哚花菁染料分别为具有结构式26～28的化合物；
(9)当A为直链亚丙基，R选自R 2，R"选自磺酸基，b＝0，1，4时，所述七甲川羧基吲哚花菁染料分别为具有结构式29～31的化合物；
(10)当A为直链亚丙基，R选自R 2，R"选自甲基，b＝0，1，3，5时，所述七甲川羧基吲哚花菁染料分别为具有结构式32～35的化合物；
(11)当A为直链亚丙基，R选自R 2，R"选自甲酯基，b＝0，1，3，5时，所述七甲川羧基吲哚花菁染料分别为具有结构式36～39的化合物；
(12)当A为直链亚丙基，R选自R 2，R"选自甲氧基，b＝0，1，3，4时，所述七甲川羧基吲哚花菁染料分别为具有结构式40～43的化合物；
(13)当A为直链亚丙基，R选自R 2，R"选自酰胺基，b＝0，1，2，3时，所述七甲川羧基吲哚花菁染料分别为具有结构式44～47的化合物；
(14)当A为直链亚丙基，R选自R 1，R'选自乙炔基，a＝3时，所述七甲川羧基吲哚花菁染料为具有结构式48的化合物；
(15)当A为直链亚丙基，R选自R 2，R"选自氨基，b＝0时，所述七甲川羧基吲哚花菁染料为具有结构式49的化合物；
(16)当A为直链亚丙基，R选自R 2，R"选自羟基，b＝0时，所述七甲川羧基吲哚花菁染料为具有结构式50的化合物；
(17)当A为亚乙基，R选自R 1，R'选自氢，a＝2，3，4，6，12时，所述七甲川羧基吲哚花菁染料分别为具有结构式51～55的化合物；
(18)当A为亚乙基，R选自R 1，R'选自羧酸根，a＝1，2，3，5时，所述七甲川羧基吲哚花菁染料分别为具有结构式56～59的化合物；
(19)当A为亚乙基，R选自R 1，R'选自乙酯基，a＝1，2，3，5时，所述七甲川羧基吲哚花菁染料分别为具有结构式60～63的化合物；
(20)当A为亚乙基，R选自R 1，R'选自羟基，a＝2，3，4，6时，所述七甲川羧基吲哚花菁染料分别为具有结构式64～67的化合物；
(21)当A为亚乙基，R选自R 1，R'选自甲氧基，a＝2，4，6时，所述七甲川羧基吲哚花菁染料分别为具有结构式68～70的化合物；
(22)当A为亚乙基，R选自R 1，R'选自酰胺基，a＝1，2，3，5时，所述七甲川羧基吲哚花菁染料分别为具有结构式71～74的化合物；
(23)当A为亚乙基，R选自R 2，R"选自氢，b＝0时，所述七甲川羧基吲哚花菁染料为具有结构式75的化合物；
(24)当A为亚乙基，R选自R 2，R"选自羧基，b＝0，1，3时，所述七甲川羧基吲哚花菁染料分别为具有结构式76～78的化合物；
(25)当A为亚乙基，R选自R 2，R"选自磺酸基，b＝0，1，4时，所述七甲川羧基吲哚花菁染料分别为具有结构式79～81的化合物；
(26)当A为亚乙基，R选自R 2，R"选自甲基，b＝0，1，3，5时，所述七甲川羧基吲哚花菁染料分别为具有结构式82～85的化合物；
(27)当A为亚乙基，R选自R 2，R"选自甲酯基，b＝0，1，3，5时，所述七甲川羧基吲哚花菁染料分别为具有结构式86～89的化合物；
(28)当A为亚乙基，R选自R 2，R"选自甲氧基，b＝0，1，3，4时，所述七甲川羧基吲哚花菁染料分别为具有结构式90～93的化合物；
(29)当A为亚乙基，R选自R 2，R"选自酰胺基，b＝0，1，2，3时，所述七甲川羧基吲哚花菁染料分别为具有结构式94～97的化合物；
(30)当A为亚乙基，R选自R 1，R'选自乙炔基，a＝3时，所述七甲川羧基吲哚花菁染料为具有结构式98的化合物；
(31)当A为亚乙基，R选自R 2，R"选自氨基，b＝0时，所述七甲川羧基吲哚花菁染料为具有结构式99的化合物；
(32)当A为亚乙基，R选自R 2，R"选自羟基，b＝0时，所述七甲川羧基吲哚花菁染料为具有结构式100的化合物。
Figure PCTCN2020073661-appb-000004
Figure PCTCN2020073661-appb-000005
Figure PCTCN2020073661-appb-000006
Figure PCTCN2020073661-appb-000007
根据本申请的另一个方面，提供了所述七甲川羧基吲哚花菁染料的制备方法。该方法具有合成路线短、溶剂环境友好、工艺简单、避免贵金属催化、产率高以及单次反应量大的优点，可极大地提高此类染料的制备效率，实现低成本批量生产。并且，该方法的适用性强，可用于制备多种结构类型的七甲川羧基吲哚花菁染料。
所述七甲川羧基吲哚花菁染料的制备方法，其特征在于，包括以下步骤：
1)将含有2,3,3-三甲基-羧基吲哚衍生物和亲核取代化合物的原料在真空条件下，在80～130℃下反应4～24小时，得到有机铵盐；
其中，所述2,3,3-三甲基-羧基吲哚衍生物的结构式如式(III-1)所示：
Figure PCTCN2020073661-appb-000008
所述亲核取代化合物选自具有结构式如式(III-2)、式(III-3)或式(III-4)所示的化合物中的至少一种：
Figure PCTCN2020073661-appb-000009
式(III-2)中，R 1选自氢、甲基、甲氧基、羟基、羧基、酰胺基、磺酸基、酯基、炔基或氨基，a选自大于0且小于等于14的整数，X选自氟、氯、溴、碘或高氯酸根；式(III-3)中，R 2选自
Figure PCTCN2020073661-appb-000010
Figure PCTCN2020073661-appb-000011
c选自1至13的整数；式(III-4)中，R 3选自氢、甲基、甲氧基、羟基、羧基、酰胺基、磺酸基、酯基、炔基或氨基，b选自0至7的整数，X选自氟、氯、溴、碘或高氯酸根；
所述有机铵盐的结构式如式(III-5)、式(III-6)或式(III-7)所示：
Figure PCTCN2020073661-appb-000012
Figure PCTCN2020073661-appb-000013
式(III-5)中，R 1、a和X的定义与式(III-2)中所述相同，m＝1；式(III-6)中，R 2'选自羧酸根或磺酸根，c的定义与式(III-3)中所述相同；式(III-7)中，R 3、b和X的定义与式(III-4)中所述相同，m＝1；
2)将含有步骤1)中得到的有机铵盐和环烯衍生物的溶液在封闭条件下，在50～80℃下反应8～48小时，得到所述七甲川羧基吲哚花菁染料；
其中，所述环烯衍生物的结构式如式(III-8)所示：
Figure PCTCN2020073661-appb-000014
式(III-8)中，A选自亚乙基、直链亚丙基或直链亚丁基。
可选地，所述环烯衍生物的结构式如式(III-8-1)、式(III-8-2)或式(III-8-3)所示：
Figure PCTCN2020073661-appb-000015
可选地，步骤1)中，所述2,3,3-三甲基-羧基吲哚衍生物与所述亲核取代化合物的摩尔比为1:1～1:12。
可选地，步骤1)中，所述2,3,3-三甲基-羧基吲哚衍生物与所述亲核取代化合物的摩尔比的上限选自1:12、1:11、1:10、1:9、1:8、1:7、1:6、1:5、1:4、1:3、1:2，下限选自1:1、1:1.5、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:11。
优选地，步骤1)中，所述2,3,3-三甲基-羧基吲哚衍生物与所述亲核取代化合物的摩尔比为1:1～1:2。
更优选地，步骤1)中，所述2,3,3-三甲基-羧基吲哚衍生物与所述亲核取代化合物的摩尔比为1:1.5。
可选地，步骤1)中，将所述原料反应的温度的上限选自130℃、125℃、120℃、115℃、110℃、105℃、100℃、95℃、90℃，下限选自80℃、85℃、90℃、95℃、100℃、105℃、110℃；将所述原料反应的时间的上限选自24小时、23小时、22小时、20小时、18小时、16小时、15小时、14小时、12小时、10小时、5小时，下限选自4小时、5小时、8小时、10小时、12小时、14小时、15小时、16小时、18小时、20小时、22小时、23小时。
优选地，步骤1)中，将所述原料在100～120℃下反应8～16小时。
更优选地，步骤1)中，将所述原料在110～120℃下反应10～14小时。
特别优选地，步骤1)中，将所述原料在120℃下反应12小时。
可选地，步骤1)中，将所述原料在封闭条件下反应。
可选地，步骤1)中，将所述原料在2～200Pa的压力下反应。
可选地，步骤1)中，将所述原料反应的压力的上限选自200Pa、175Pa、150Pa、125Pa、100Pa、75Pa、50Pa、40Pa、30Pa、20Pa、10Pa、9Pa、8Pa、7Pa、6Pa、5Pa、4Pa、3Pa，下限选自2Pa、3Pa、4Pa、5Pa、6Pa、7Pa、8Pa、9Pa、10Pa、20Pa、30Pa、40Pa、50Pa、75Pa、100Pa、125Pa、150Pa、175Pa。
优选地，步骤1)中，将所述原料在5～50Pa的压力下反应。
更优选地，步骤1)中，将所述原料在10Pa的压力下反应。
在根据本申请的方法中，对于步骤1)中除反应物外是否还使用反应介质没有特别限制，只要所述反应物能够完成步骤1)的反应即可。即，在如上所述的步骤1)的反应条件下，当反应体系中存在液相时(例如，在至少部分反应物为液态的情况下)，无需使用反应介质，或者仍可使用反应介质。
可选地，出于例如环保和安全的目的，所述反应介质为基于醇的反应介质。
优选地，所述反应介质选自甲醇、乙醇、丙醇、乙二醇、丙三醇、丁醇和丁二醇中的至少一种。
可选地，步骤2)中，所述环烯衍生物与所述有机铵盐的摩尔比为1:2～1:6。
可选地，步骤2)中，所述环烯衍生物与所述有机铵盐的摩尔比的上限选自1:6、1:5.5、1:5、1:4.5、1:4、1:3.8、1:3.5、1:3.4、1:3.2、1:3、1:2.8、1:2.5、1:2.4、1:2.2、1:2.1，下限选自1:2、1:2.1、1:2.2、1:2.4、1:2.5、1:2.8、1:3、1:3.2、1:3.4、1:3.5、1:3.8、1:4、1:4.5、1:5、1:5.5。
优选地，步骤2)中，所述环烯衍生物与所述有机铵盐的摩尔比为1:2～1:3。
更优选地，步骤2)中，所述环烯衍生物与所述有机铵盐的摩尔比为1:2.5。
可选地，步骤2)中，将所述溶液反应的温度的上限选自80℃、75℃、70℃、65℃、60℃、55℃，下限选自50℃、55℃、60℃、65℃、70℃、75℃；将所述溶液反应的时间的上限选自48小时、38小时、35小时、32小时、30小时、28小时、24小时、20小时、18小时、15小时、10小时，下限选自8小时、10小时、15小时、18小时、20小时、24小时、28小时、30小时、32小时、35小时、38小时。
优选地，步骤2)中，将所述溶液在60～80℃下反应10～30小时。
更优选地，步骤2)中，将所述溶液在70～80℃下反应10～30小时。
更优选地，步骤2)中，将所述溶液在70～80℃下反应15～28小时。
特别优选地，步骤2)中，将所述溶液在75℃下反应24小时。
可选地，步骤2)中，在反应后加入沉淀剂，在1～10℃下保持12～48小时后抽滤，得到所述七甲川羧基吲哚花菁染料。
可选地，步骤2)中，加入沉淀剂后保持的温度的上限选自10℃、9℃、8℃、7℃、6℃、5℃、4℃、3℃、2℃，下限选自1℃、2℃、3℃、4℃、5℃、6℃、7℃、8℃、9℃；保持的时间的上限选自48小时、44小时、40小时、36小时、32小时、28小时、24小时、20小时、16小时，下限选自12小时、16小时、20小时、24小时、28小时、32小时、36小时、40小时、44小时。
优选地，步骤2)中，在反应后加入沉淀剂，在4℃下保持24小时后抽滤，得到所述七甲川羧基吲哚花菁染料。
可选地，所述沉淀剂选自石油醚、乙醚、甲醚、丙醚和甲乙醚中的至少一种。
优选地，所述沉淀剂包括石油醚。
可选地，步骤2)中，所述溶液中的溶剂选自水、甲醇、乙醇、丙醇、乙二醇、丙三醇、丁醇和丁二醇中的至少一种。
优选地，步骤2)中，所述溶液中的溶剂选自甲醇、乙醇和丙醇中的至少一种。
因此，就溶剂而言，在根据本申请的方法的步骤1)中，取决于反应物的状态，可不使用溶剂，或者可使用溶剂并且选自醇类；在步骤2)中，可使用选自水和醇类的溶剂。与常规方法中使用的诸如邻二氯苯、乙酸酐的溶剂相比，本申请中可使用的溶剂更加环境友好和安全，并且对健康的损害更小。
在一个实施方案中，2,3,3-三甲基-羧基吲哚衍生物的制备方法包括以下步骤：
1)将对羧基苯肼、3-甲基-2-丁酮和无水乙酸钠溶于乙酸中进行反应；
2)除去反应溶剂，加入水和甲醇的混合溶液溶解剩余物质；
3)将所得物过滤，结晶，得到晶体2,3,3-三甲基-羧基吲哚。
可选地，步骤1)中，所述对羧基苯肼、3-甲基-2-丁酮和无水乙酸钠的摩尔比为1:1～1.2:1.4～1.6，优选为1:1.1:1.5。
可选地，步骤1)中，所述反应在回流和搅拌下进行6～10小时，优选8小时。
可选地，步骤2)中，所述水和甲醇的体积比为8:1～10:1，优选为9:1。
可选地，步骤3)中，所述结晶在室温下敞口进行36～50小时，优选48小时。
在一个具体的实施方案中，2,3,3-三甲基-羧基吲哚衍生物的合成按照以下步骤进行：
将摩尔比为1:1.1:1.5的对羧基苯肼、3-甲基-2-丁酮和无水乙酸钠溶解在乙酸中，并在回流和搅拌下反应8小时。通过旋蒸去除反应溶剂，其后加入体积比为9:1的水和甲醇的混合溶液溶解剩余物质。将所得物过滤，然后置于室温下敞口结晶48小时，得到晶体2,3,3-三甲基-4-羧基吲哚。
可选地，通过本申请所述方法制备的七甲川羧基吲哚花菁染料的纯度大于90％。
可选地，通过本申请所述方法制备的七甲川羧基吲哚花菁染料的纯度为85～99.5％。
可选地，通过本申请所述方法制备的七甲川羧基吲哚花菁染料的纯度为90～99.5％。
可选地，通过本申请所述方法制备的七甲川羧基吲哚花菁染料的产率不小于83.5％。
可选地，通过本申请所述方法制备的七甲川羧基吲哚花菁染料的产率为83.5～93.7％。
作为一种具体的实施方式，所述七甲川羧基吲哚花菁染料的制备方法按照如下路线进行：
Figure PCTCN2020073661-appb-000016
X选自卤素中的一种，优选为溴；R为由具有1至14个碳原子的直链亚烷基和端基组成的基团，所述端基选自氢、甲基、甲氧基、羟基、羧基、酰胺基、磺酸基、酯基、炔基或氨基；
其中，2,3,3-三甲基-羧基吲哚与作为亲核取代化合物的溴取代物(X-R)的摩尔比为1:1～1:12，优选为1:1.5；加热温度为80～130℃，优选为120℃；作为环烯衍生物的2-氯-1-甲酰-3-羟基亚甲基环己烯与作为有机铵盐的N-取代物的摩尔比为1:2～1:4，优选为1:2.5；加热温度为50～80℃，优选为75℃。
作为一种具体的实施方式，所述七甲川羧基吲哚花菁染料的制备方法包括以下步骤：
1)将2,3,3-三甲基-羧基吲哚和作为亲核取代化合物的溴取代物(X-R)充分混合后，在抽真空条件下加热反应，其中，2,3,3-三甲基-羧基吲哚与溴取代物的摩尔比为1:1～1:12，加热温度为80～130℃，反应时间为4～24小时；优选地，2,3,3-三甲基-羧基吲哚与溴取代物的摩尔比为1:1.5，加热温度为120℃，反应时间为12小时。
2)将作为环烯衍生物的2-氯-1-甲酰-3-羟基亚甲基环己烯加入到步骤1)反应完的溶液中，在封闭条件下加热反应，反应后将反应液置于4℃冰箱中过夜后用沉淀剂进行沉淀，其中，2-氯-1-甲酰-3-羟基亚甲基环己烯与作为有机铵盐的N-取代物的摩尔比为1:2～1:4，加热温度为50～80℃，反应时间 为8～48小时；优选地，2-氯-1-甲酰-3-羟基亚甲基环己烯与N-取代物的摩尔比为1:2.5，加热温度为75℃，反应时间为24小时。
根据本申请的又一个方面，提供了所述七甲川羧基吲哚花菁染料的应用。
可选地，所述七甲川羧基吲哚花菁染料应用于制备探针助剂，所述探针助剂包含上述七甲川羧基吲哚花菁染料、通过上述方法制备的七甲川羧基吲哚花菁染料中的至少一种。
可选地，所述七甲川羧基吲哚花菁染料应用于制备近红外荧光探针。
可选地，所述近红外荧光探针包括小分子探针、纳米探针。
可选地，所述七甲川羧基吲哚花菁染料应用于商标防伪、生物医学、环境监测、国防探测及其相关领域。
除非另行定义，本申请中使用的所有专业与科学用语与本领域技术人员所熟悉的含义相同。
本申请中，术语“烷基”意指烷烃化合物分子上失去任意一个氢原子而形成的基团；所述烷烃化合物包括环烷烃、直链烷烃、支链烷烃。
本申请中，术语“亚乙基”意指结构式为-CH 2-CH 2-的基团，“直链亚丙基”意指结构式为-CH 2-CH 2-CH 2-的基团，“直链亚丁基”意指结构式为-CH 2-CH 2-CH 2-CH 2-的基团。
本申请中所有涉及数值范围的条件均可独立地选自所述数值范围内的任意点值。
本申请具有以下有益效果，其包括但不限于：
1)本申请所提供的七甲川羧基吲哚花菁染料，其具有近红外光吸收、荧光显影的性能。
2)本申请所提供的七甲川羧基吲哚花菁染料的制备方法，其具有合成路线短、溶剂环境友好、工艺简单、避免贵金属催化、产率高以及单次反应量大的优点，可极大地提高此类染料的制备效率，实现低成本批量生产。
3)通过本申请所提供的制备方法得到的七甲川羧基吲哚花菁染料的纯度高，纯度可高于90％。
4)本申请所提供的七甲川羧基吲哚花菁染料的制备方法，其适用性强，可用于实现多种结构类型的产物的合成。
附图说明
图1为根据本申请实施例5制备的化合物C1的红外吸收谱图。
图2为根据本申请实施例5制备的化合物C1对小鼠静脉注射48小时后的体内成像效果图。
具体实施方式
如前所述，本申请涉及一种七甲川羧基吲哚花菁染料的制备方法，包括以下步骤：将2,3,3-三甲基-羧基吲哚衍生物与亲核取代化合物反应得到有机铵盐；将有机铵盐、环烯衍生物混合于环境友好有机溶剂中反应，反应后在产物中加入有机沉淀剂冷却静置过夜，即得所述七甲川羧基吲哚花菁染料。所述方法具有合成路线短、工艺简单、无催化剂、产率高、提纯方法简单、原子利用率高以及消耗有机溶剂少的优点，可极大地提高此类染料的制备效率，实现低成本批量生产，在七甲川羧基吲哚花菁染料的生产及应用研究方面均具有重大意义。
另外，根据本申请的七甲川羧基吲哚花菁染料的制备方法具有更广泛的适用性。该方法在采用更环境友好的溶剂和更温和的反应条件的情况下，可实现对更多结构类型的产物的合成。
下面结合实施例详述本申请，但本申请并不局限于这些实施例。
如无特别说明，本申请的实施例中的原料和试剂均通过商业途径购买。
本申请的实施例中的分析方法如下：
利用Thermo Nciolet 6700型红外光谱仪进行红外吸收光谱分析。
利用PerkinElmer Lanbda型紫外分光光度计进行紫外吸收光谱分析。
利用PerkinElmer IVIS Lumina LT型小动物成像仪进行体外荧光检测分析。
实施例1合成2,3,3-三甲基-4-羧基吲哚
将摩尔比为1:1.1:1.5的对羧基苯肼、3-甲基-2-丁酮和无水乙酸钠溶解在乙酸中，并在回流和搅拌下反应8小时。通过旋蒸去除反应溶剂，其后加入体积比为9:1的水和甲醇的混合溶液溶解剩余物质。 将所得物过滤，然后置于室温下敞口结晶48小时，得到晶体2,3,3-三甲基-4-羧基吲哚。
实施例2合成化合物53
按照如下路线合成化合物53：
Figure PCTCN2020073661-appb-000017
1)2,3,3-三甲基-1-(丁烷)-羧基吲哚的合成
在反应器中加入摩尔比为1:1.5的实施例1中得到的2,3,3-三甲基-羧基吲哚和4-溴丁烷，并将反应器封闭后抽真空至10Pa。将反应体系加热至110℃并搅拌8小时，然后冷却至室温。抽滤所得产物，直接用于下一步反应。
2)化合物53的合成与提纯
在反应器中加入与步骤1)中得到的2,3,3-三甲基-1-(丁烷)-羧基吲哚的摩尔比为1:2.5的2-氯-1-甲酰-3-羟基亚甲基环戊烯。用甲醇完全溶解后，将反应体系在封闭条件下加热至75℃反应24小时，然后降温至室温，并放入4℃冰箱中静置24小时。加入石油醚，其后静置并抽滤。将所得固体真空干燥，得到产物化合物53，产率为94.3％。
本实施例中得到的化合物53的纯度大于92％。
实施例3合成化合物26
按照如下路线合成化合物26：
Figure PCTCN2020073661-appb-000018
1)2,3,3-三甲基-1-(对甲基苯甲酸)-羧基吲哚的合成
在反应器中加入摩尔比为1:1.5的实施例1中得到的2,3,3-三甲基-羧基吲哚和对溴甲基苯甲酸，并将反应器封闭后抽真空至15Pa。将反应体系加热至110℃并搅拌12小时，然后冷却至室温。抽滤所得产物，直接用于下一步反应。
2)化合物26的合成与提纯
在反应器中加入与步骤1)中所得到的2,3,3-三甲基-1-(对甲基苯甲酸)-羧基吲哚摩尔比为1:2.5的2-氯-1-甲酰-3-羟基亚甲基环己烯。用甲醇完全溶解后，将反应体系在封闭条件下加热至75℃反应24小时，然后降温至室温，并放入4℃冰箱中静置24小时。加入石油醚，其后静置并抽滤。将所得固体真空干燥，得到产物化合物26，产率为91.5％。
本实施例中得到的化合物26的纯度大于95％。
实施例4合成化合物8
按照如下路线合成化合物8：
Figure PCTCN2020073661-appb-000019
1)2,3,3-三甲基-1-(丁酸)-羧基吲哚的合成
在反应器中加入摩尔比为1:1.5的实施例1中得到的2,3,3-三甲基-羧基吲哚和4-溴丁酸，并将反应器封闭后抽真空至10Pa。将反应体系加热至110℃并搅拌12小时，然后冷却至室温。抽滤所得产 物，直接用于下一步反应。
2)化合物8的合成与提纯
在反应器中加入与步骤1)中得到的2,3,3-三甲基-1-(丁酸)-羧基吲哚的摩尔比为1:2.5的2-氯-1-甲酰-3-羟基亚甲基环己烯。用甲醇完全溶解后，将反应体系在封闭条件下加热至75℃反应24小时，然后降温至室温，并放入4℃冰箱中静置24小时。加入石油醚，其后静置并抽滤。将所得固体真空干燥，得到产物化合物8，产率为87.2％。
本实施例中得到的化合物8的纯度大于92％。
实施例5合成化合物C1
按照如下路线合成化合物C1：
Figure PCTCN2020073661-appb-000020
1)2,3,3-三甲基-1-(丁磺酸)-羧基吲哚的合成
在反应器中加入摩尔比为1:1.5的实施例1中得到的2,3,3-三甲基-羧基吲哚和1,4-丁磺酸内酯，并将反应器封闭后抽真空至10Pa。将反应体系加热至110℃并搅拌12小时，然后冷却至室温。抽滤所得产物，直接用于下一步反应。
2)化合物C1的合成与提纯
在反应器中加入与步骤1)中得到的2,3,3-三甲基-1-(丁磺酸)-羧基吲哚摩尔比为1:2.5的2-氯-1-甲酰-3-羟基亚甲基环己烯。用甲醇完全溶解后，将反应体系在封闭条件下加热至75℃反应24小时，然后降温至室温，并放入4℃冰箱中静置24小时。加入石油醚，其后静置并抽滤。将所得固体真空干燥，得到产物化合物C1，产率为87.2％。
本实施例中得到的化合物C1的纯度大于91％。
实施例6合成化合物12
按照如下路线合成化合物12：
Figure PCTCN2020073661-appb-000021
1)2,3,3-三甲基-1-(丁酸乙酯)-羧基吲哚的合成
在反应器中加入摩尔比为1:1.5的实施例1中得到的2,3,3-三甲基-羧基吲哚和4-溴丁酸乙酯，并将反应器封闭后抽真空至15Pa。将反应体系加热至110℃并搅拌12小时，然后冷却至室温。抽滤所得产物，直接用于下一步反应。
2)化合物12的合成与提纯
在反应器中加入与步骤1)中所得2,3,3-三甲基-1-(丁酸乙酯)-羧基吲哚摩尔比为1:2.5的2-氯-1-甲酰-3-羟基亚甲基环己烯。用甲醇完全溶解后，将反应体系在封闭条件下加热至75℃反应24小时，然后降温至室温，并放入4℃冰箱中静置24小时。加入石油醚，其后静置并抽滤。将所得固体真空干燥，得到产物化合物12，产率为87.2％。
本实施例中得到的化合物12的纯度大于91％。
实施例7合成化合物36
按照如下路线合成化合物36：
Figure PCTCN2020073661-appb-000022
1)2,3,3-三甲基-1-(对甲基苯甲酸甲酯)-羧基吲哚的合成
在反应器中加入摩尔比为1:1.5的实施例1中得到的2,3,3-三甲基-羧基吲哚和对溴甲基苯甲酸甲酯，并将反应器封闭后抽真空至20Pa。将反应体系加热至110℃并搅拌12小时，然后冷却至室温。抽滤所得产物，直接用于下一步反应。
2)化合物36的合成与提纯
在反应器中加入与步骤1)中所得2,3,3-三甲基-1-(对甲基苯甲酸甲酯)-羧基吲哚摩尔比为1:2.5的2-氯-1-甲酰-3-羟基亚甲基环己烯。用甲醇完全溶解后，将反应体系在封闭条件下加热至75℃反应24小时，然后降温至室温，并放入4℃冰箱中静置24小时。加入石油醚，其后静置并抽滤。将所得固体真空干燥，得到产物化合物36，产率为87.4％。
本实施例中得到的化合物36的纯度大于87％。
实施例8合成化合物25
按照如下路线合成化合物25：
Figure PCTCN2020073661-appb-000023
1)2,3,3-三甲基-1-(甲基苯)-羧基吲哚的合成
在反应器中加入摩尔比为1:1.5的实施例1中得到的2,3,3-三甲基-羧基吲哚和溴甲基苯，并将反应器封闭后抽真空至10Pa。将反应体系加热至110℃并搅拌12小时，然后冷却至室温。抽滤所得产物，直接用于下一步反应。
2)化合物25的合成与提纯
在反应器中加入与步骤1)中得到的2,3,3-三甲基-1-(甲基苯)-羧基吲哚摩尔比为1:2.5的2-氯-1-甲酰-3-羟基亚甲基环己烯。用甲醇完全溶解后，将反应体系在封闭条件下加热至75℃反应24小时，然后降温至室温，并放入4℃冰箱中静置24小时。加入石油醚，其后静置并抽滤。将所得固体真空干燥，得到产物化合物25，产率为87.1％。
本实施例中得到的化合物25的纯度大于92％。
实施例9合成化合物55
按照如下路线合成化合物55：
Figure PCTCN2020073661-appb-000024
1)2,3,3-三甲基-1-(十二烷)-羧基吲哚的合成
在反应器中加入摩尔比为1:1.5的实施例1中得到的2,3,3-三甲基-羧基吲哚和1-碘十二烷，并将反应器封闭后抽真空至15Pa。将反应体系加热至110℃后搅拌12小时，然后冷却至室温。抽滤所得产物，直接用于下一步反应。
2)化合物55的合成与提纯
在反应器中加入与步骤1)中得到的2,3,3-三甲基-1-(十二烷)-羧基吲哚摩尔比为1:2.5的2-氯-1-甲酰-3-羟基亚甲基环戊烯。用甲醇完全溶解后，将反应体系在封闭条件下加热至75℃反应24小时，然后降温至室温，并放入4℃冰箱中静置24小时。加入石油醚，其后静置并抽滤。将所得固体真空 干燥，得到产物化合物55，产率为81.4％。
本实施例中得到的化合物55的纯度大于92％。
实施例10合成化合物40
按照如下路线合成化合物40：
Figure PCTCN2020073661-appb-000025
1)2,3,3-三甲基-1-(甲基苯甲醚)-羧基吲哚的合成
在反应器中加入摩尔比为1:1.5的实施例1中得到的2,3,3-三甲基-羧基吲哚和对碘甲基苯甲醚，并将反应器封闭后抽真空至20Pa。将反应体系加热至110℃后搅拌12小时，然后冷却至室温。抽滤所得产物，直接用于下一步反应。
2)化合物40的合成与提纯
在反应器中加入与步骤1)中得到的2,3,3-三甲基-1-(甲基苯甲醚)-羧基吲哚摩尔比为1:2.5的2-氯-1-甲酰-3-羟基亚甲基环己烯。用甲醇完全溶解后，将反应体系在封闭条件下加热至75℃反应24小时，然后降温至室温，并放入4℃冰箱中静置24小时。加入石油醚，其后静置并抽滤。将所得固体真空干燥，得到产物化合物40，产率为89.4％。
本实施例中得到的化合物40的纯度大于92％。
实施例11合成化合物36
重复实施例7的制备过程，区别在于：在步骤1)中加入摩尔比为1:1的2,3,3-三甲基-羧基吲哚和对溴甲基苯甲酸甲酯；在步骤2)中使用水替代甲醇作为溶剂；在步骤2)中使用乙醚替代石油醚作为沉淀剂，得到产物化合物36。
实施例12合成化合物36
重复实施例7的制备过程，区别在于：在步骤1)中加入摩尔比为1:12的2,3,3-三甲基-羧基吲哚和对溴甲基苯甲酸甲酯；在步骤2)中使用乙醇替代甲醇作为溶剂；在步骤2)中使用甲醚替代石油醚作为沉淀剂，得到产物化合物36。
实施例13合成化合物36
重复实施例7的制备过程，区别在于：在步骤1)中将反应体系加热至80℃并搅拌24小时；在步骤2)中使用丙醇替代甲醇作为溶剂；在步骤2)中使用丙醚替代石油醚作为沉淀剂，得到产物化合物36。
实施例14合成化合物36
重复实施例7的制备过程，区别在于：在步骤1)中将反应体系加热至130℃并搅拌4小时；在步骤2)中使用乙二醇替代甲醇作为溶剂；在步骤2)中使用甲乙醚替代石油醚作为沉淀剂，得到产物化合物36。
实施例15合成化合物12
重复实施例6的制备过程，区别在于：在步骤2)中2-氯-1-甲酰-3-羟基亚甲基环己烯与2,3,3-三甲基-1-(丁酸乙酯)-羧基吲哚的摩尔比为1:2；在步骤2)中使用丙三醇替代甲醇作为溶剂，得到产物化合物12。
实施例16合成化合物12
重复实施例6的制备过程，区别在于：在步骤2)中2-氯-1-甲酰-3-羟基亚甲基环己烯与2,3,3-三甲基-1-(丁酸乙酯)-羧基吲哚的摩尔比为1:6；在步骤2)中使用丁醇替代甲醇作为溶剂，得到产物化合物12。
实施例17合成化合物12
重复实施例6的制备过程，区别在于：在步骤2)中将反应体系在封闭条件下加热至50℃反应48小时，然后降温至室温，并放入10℃冰箱中静置48小时；在步骤2)中使用丁二醇替代甲醇作为 溶剂，得到产物化合物12。
实施例18合成化合物12
重复实施例6的制备过程，区别在于：在步骤2)中将反应体系在封闭条件下加热至80℃反应8小时，然后降温至室温，并放入1℃冰箱中静置12小时；在步骤2)中使用甲醇/乙醇混合物替代甲醇作为溶剂，得到产物化合物12。
实施例19合成化合物12
重复实施例6的制备过程，区别在于：在步骤1)中将反应器封闭后抽真空至2Pa，得到产物化合物12。
实施例20合成化合物12
重复实施例6的制备过程，区别在于：在步骤1)中将反应器封闭后抽真空至200Pa，得到产物化合物12。
实施例21红外光谱分析
对实施例5制备得到的化合物C1进行红外光谱分析，其结果如图1所示，其中3438cm -1、1629cm -1(-COOH)及1396cm -1、1167cm -1和1042cm -1(-SO 3H)为所对应的相应官能团的吸收峰。其余实施例的测试结果与实施例5类似，均得到了对应的产物。
实施例22紫外光谱分析
对实施例5制备得到的化合物C1进行紫外光谱分析，典型的如实施例5制备得到的化合物C1其最高吸收峰位于795nm，属于近红外吸收峰。其余实施例的测试结果与实施例5类似，所得产物的最大吸收波长在760～850nm范围内。
实施例23荧光显影分析
将实施例5制备得到的化合物C1溶解于PBS液中，并用PBS溶液将浓度稀释，得到0.2mg/mL的近红外靶向探针制剂。
将浓度为0.2mg/mL的上述近红外靶向探针制剂注射入患有乳腺癌的裸鼠体内，48小时后进行荧光检测，结果如图2所示。该近红外荧光探针的近红外荧光信号峰与裸鼠自身的背景信号峰分离良好，肿瘤区域与肿瘤周围正常组织的对比度大于10。这样背景干扰小，可以为术者提供清晰的肿瘤位置和精确的肿瘤边界，从而提高肿瘤的检测率和切除率。
使用其余实施例制备得到的产物重复上述荧光检测，其均产生与化合物C1类似的荧光显影效果。
以上所述，仅是本申请的几个实施例，并非对本申请做任何形式的限制，虽然本申请以较佳实施例揭示如上，然而并非用以限制本申请，任何熟悉本专业的技术人员，在不脱离本申请技术方案的范围内，利用上述揭示的技术内容做出些许的变动或修饰均等同于等效实施案例，均属于技术方案范围内。

Claims (24)

  1. 一种七甲川羧基吲哚花菁染料，其特征在于，其结构式如式(I)所示：
    Figure PCTCN2020073661-appb-100001
    其中，R选自R 1和R 2中的一种；
    Figure PCTCN2020073661-appb-100002
    当R为R 1时，R'选自氢、甲基、甲氧基、羟基、羧基、酰胺基、磺酸基、酯基、炔基或氨基，a选自大于0且小于等于14的整数，X选自氟、氯、溴、碘或高氯酸根，m＝1，p＝0，A选自亚乙基、直链亚丙基或直链亚丁基；或
    R'选自羧酸根或磺酸根，a选自大于0且小于等于14的整数，Y选自氢、钠或钾，m＝0，p＝1，A选自亚乙基、直链亚丙基或直链亚丁基；
    当R为R 2时，R"选自氢、甲基、甲氧基、羟基、羧基、酰胺基、磺酸基、酯基、炔基或氨基，b选自0至7的整数，X选自氟、氯、溴、碘或高氯酸根，m＝1，p＝0，A选自亚乙基、直链亚丙基或直链亚丁基；或
    R"选自羧酸根或磺酸根，b选自0至7的整数，Y选自氢、钠或钾，m＝0，p＝1，A选自亚乙基、直链亚丙基或直链亚丁基。
  2. 根据权利要求1所述的七甲川羧基吲哚花菁染料，其特征在于，所述七甲川羧基吲哚花菁染料的结构式如式(I-1)、式(I-2)或式(I-3)所示：
    Figure PCTCN2020073661-appb-100003
    Figure PCTCN2020073661-appb-100004
  3. 根据权利要求1所述的七甲川羧基吲哚花菁染料，其特征在于，式(I)中的R选自R 1和R 2中的一种；其中，
    当R为R 1时，R'选自氢、羧基或酯基，a选自2、4、6或8，X选自溴或碘，m＝1，p＝0，A选自亚乙基或直链亚丙基；或
    R'选自羧酸根或磺酸根，a选自3、5、7或9，Y选自钠，m＝0，p＝1，A选自亚乙基或直链亚丙基；
    当R为R 2时，R"选自氢、羧基或酯基，b选自0、1、3或5，X选自溴或碘，m＝1，p＝0，A选自亚乙基或直链亚丙基；或
    R"选自羧酸根或磺酸根，b选自0、1、3或5，Y选自钠，m＝0，p＝1，A选自亚乙基或直链亚丙基。
  4. 权利要求1至3中任一项所述的七甲川羧基吲哚花菁染料的制备方法，其特征在于，包括以下步骤：
    1)将含有2,3,3-三甲基-羧基吲哚衍生物和亲核取代化合物的原料在真空条件下，在80～130℃下反应4～24小时，得到有机铵盐；
    其中，所述2,3,3-三甲基-羧基吲哚衍生物的结构式如式(III-1)所示：
    Figure PCTCN2020073661-appb-100005
    所述亲核取代化合物选自具有结构式如式(III-2)、式(III-3)或式(III-4)所示的化合物中的至少一种：
    Figure PCTCN2020073661-appb-100006
    式(III-2)中，R 1选自氢、甲基、甲氧基、羟基、羧基、酰胺基、磺酸基、酯基、炔基或氨基，a选自大于0且小于等于14的整数，X选自氟、氯、溴、碘或高氯酸根；式(III-3)中，R 2选自
    Figure PCTCN2020073661-appb-100007
    Figure PCTCN2020073661-appb-100008
    c选自1至13的整数；式(III-4)中，R 3选自氢、甲基、甲氧基、羟基、羧基、酰胺基、磺酸基、酯基、炔基或氨基，b选自0至7的整数，X选自氟、氯、溴、碘或高氯酸根；
    所述有机铵盐的结构式如式(III-5)、式(III-6)或式(III-7)所示：
    Figure PCTCN2020073661-appb-100009
    式(III-5)中，R 1、a和X的定义与式(III-2)中所述相同，m＝1；式(III-6)中，R 2'选自羧酸根或磺酸根，c的定义与式(III-3)中所述相同；式(III-7)中，R 3、b和X的定义与式(III-4)中所述相同，m＝1；
    2)将含有步骤1)中得到的有机铵盐和环烯衍生物的溶液在封闭条件下，在50～80℃下反应8～48小时，得到所述七甲川羧基吲哚花菁染料；
    其中，所述环烯衍生物的结构式如式(III-8)所示：
    Figure PCTCN2020073661-appb-100010
    式(III-8)中，A选自亚乙基、直链亚丙基或直链亚丁基。
  5. 根据权利要求4所述的方法，其特征在于，所述环烯衍生物的结构式如式(III-8-1)、式(III-8-2) 或式(III-8-3)所示：
    Figure PCTCN2020073661-appb-100011
  6. 根据权利要求4所述的方法，其特征在于，步骤1)中，所述2,3,3-三甲基-羧基吲哚衍生物与所述亲核取代化合物的摩尔比为1:1～1:12。
  7. 根据权利要求6所述的方法，其特征在于，步骤1)中，所述2,3,3-三甲基-羧基吲哚衍生物与所述亲核取代化合物的摩尔比为1:1～1:2。
  8. 根据权利要求7所述的方法，其特征在于，步骤1)中，所述2,3,3-三甲基-羧基吲哚衍生物与所述亲核取代化合物的摩尔比为1:1.5。
  9. 根据权利要求4所述的方法，其特征在于，步骤1)中，将所述原料在100～120℃下反应8～16小时。
  10. 根据权利要求9所述的方法，其特征在于，步骤1)中，将所述原料在110～120℃下反应10～14小时。
  11. 根据权利要求4所述的方法，其特征在于，步骤1)中，将所述原料在2～200Pa的压力下反应。
  12. 根据权利要求4所述的方法，其特征在于，步骤2)中，所述环烯衍生物与所述有机铵盐的摩尔比为1:2～1:6。
  13. 根据权利要求12所述的方法，其特征在于，步骤2)中，所述环烯衍生物与所述有机铵盐的摩尔比为1:2～1:3。
  14. 根据权利要求13所述的方法，其特征在于，步骤2)中，所述环烯衍生物与所述有机铵盐的摩尔比为1:2.5。
  15. 根据权利要求4所述的方法，其特征在于，步骤2)中，将所述溶液在60～80℃下反应10～30小时。
  16. 根据权利要求15所述的方法，其特征在于，步骤2)中，将所述溶液在70～80℃下反应15～28小时。
  17. 根据权利要求4所述的方法，其特征在于，步骤2)中，在反应后加入沉淀剂，在1～10℃下保持12～48小时后抽滤，得到所述七甲川羧基吲哚花菁染料。
  18. 根据权利要求17所述的方法，其特征在于，步骤2)中，在反应后加入沉淀剂，在4℃下保持24小时后抽滤，得到所述七甲川羧基吲哚花菁染料。
  19. 根据权利要求17所述的方法，其特征在于，所述沉淀剂选自石油醚、乙醚、甲醚、丙醚和甲乙醚中的至少一种。
  20. 根据权利要求4所述的方法，其特征在于，步骤2)中，所述溶液中的溶剂选自水、甲醇、乙醇、丙醇、乙二醇、丙三醇、丁醇和丁二醇中的至少一种。
  21. 根据权利要求20所述的方法，其特征在于，步骤2)中，所述溶液中的溶剂选自甲醇、乙醇和丙醇中的至少一种。
  22. 一种探针助剂，其特征在于，包含权利要求1至3中任一项所述的七甲川羧基吲哚花菁染料、通过权利要求4至21中任一项所述方法制备的七甲川羧基吲哚花菁染料中的至少一种。
  23. 根据权利要求22所述的探针助剂，其特征在于，所述七甲川羧基吲哚花菁染料应用于制备近红外荧光探针。
  24. 根据权利要求23所述的探针助剂，其特征在于，所述近红外荧光探针包括小分子探针、纳米探针。
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