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Heptamethine hydroxyl indocyanine dye, synthesis method and application thereof

A technology of heptamethylindole cyanine and methindole cyanine, which is applied in the field of polymethylindole cyanine dye and its preparation, and can solve the problems of large consumption of organic solvent, high price, low purity, etc.

Pending Publication Date: 2020-09-15
NINGBO INST OF MATERIALS TECH & ENG CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the heptamethine indole cyanine sold in the market is only a new indocyanine green (IR-820), and the purity is low (80%), and the price is high (1324 yuan / g)
At the same time, the production and purification process of its different derivatives requires a lot of condition screening and consumes a lot of organic solvents, and most of the selected solvents are highly toxic solvents, such as o-dichlorobenzene, toluene, benzene, etc.

Method used

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  • Heptamethine hydroxyl indocyanine dye, synthesis method and application thereof
  • Heptamethine hydroxyl indocyanine dye, synthesis method and application thereof
  • Heptamethine hydroxyl indocyanine dye, synthesis method and application thereof

Examples

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preparation example Construction

[0147] As mentioned above, this application relates to a preparation method of heptamethine oxindole cyanine dye, comprising the following steps: reacting 2,3,3-trimethyl-oxindole derivatives with nucleophilic substitution compounds to obtain organic Ammonium salt: Mix organic ammonium salt and cycloalkene derivatives in an environment-friendly organic solvent for reaction, add an organic precipitant to the product after cooling and let it stand overnight to obtain the heptamethine hydroxyindole cyanine dye. The method has wider applicability. This method can realize the synthesis of more structural types of products under the condition of adopting more environment-friendly solvents and milder reaction conditions.

[0148] In addition, the preparation method of the heptamethine hydroxyindole cyanine dye according to the present application has the advantages of short synthetic route, simple process, no catalyst, high yield, simple purification method, high atom utilization rat...

Embodiment 1

[0155] Example 1 Synthesis of 2,3,3-trimethyl-4-oxindole

[0156] Dissolve p-hydroxyphenylhydrazine, 3-methyl-2-butanone, and anhydrous sodium acetate at a molar ratio of 1:1.1:1.5 in acetic acid, and react under reflux and stirring for 8 hours. The reaction solvent was removed by rotary evaporation, and then a mixed solution of water and methanol with a volume ratio of 9:1 was added to dissolve the remaining substances. The resultant was filtered, and then exposed to crystallization at room temperature for 48 hours to obtain crystal 2,3,3-trimethyl-4-oxindole.

Embodiment 2

[0157] Example 2 Synthesis of Compound 53

[0158] Compound 53 was synthesized according to the following route:

[0159]

[0160] 1) Synthesis of 2,3,3-trimethyl-1-(butane)-oxindole

[0161] The 2,3,3-trimethyl-oxindole and 4-bromobutane obtained in Example 1 were added into the reactor at a molar ratio of 1:1.5, and the reactor was closed and then evacuated to 10 Pa. The reaction system was heated to 110° C. and stirred for 8 hours, then cooled to room temperature. The obtained product was filtered with suction and used directly for the next reaction.

[0162] 2) Synthesis and purification of compound 53

[0163] Add 2-chloro-1-formyl-3 to the reactor in a molar ratio of 1:2.5 to 2,3,3-trimethyl-1-(butane)-oxindole obtained in step 1) -Hydroxymethylenecyclopentene. After completely dissolving with methanol, the reaction system was heated to 75° C. for 24 hours under closed conditions, then cooled to room temperature, and placed in a 4° C. refrigerator for 24 hours. ...

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Abstract

The invention discloses a heptamethine hydroxyl indocyanine dye, a synthesis method and application thereof, and belongs to the field of polymethine indocyanine dyes and preparation thereof, wherein the structural formula of the heptamethine hydroxyl indocyanine dye is represented by a formula (I), and the dye has near-infrared light absorption and fluorescence development performances and can beused as a probe auxiliary agent. The preparation method of the dye comprises the following steps: 1) carrying out a heating reaction on raw materials containing a 2,3,3-trimethyl-hydroxyindole derivative and a nucleophilic substituted compound under a vacuum condition to obtain an organic ammonium salt; and 2) carrying out a heating reaction on a solution containing the organic ammonium salt obtained in the step (1) and a cycloalkene derivative under a closed condition. The method has the advantages of short synthesis route, environment-friendly solvent, simple process, avoidance of noble metal catalysis, high yield, high purity and the like, is high in applicability, and can be used for synthesizing products of various structure types.

Description

technical field [0001] The application relates to a heptamethylindole cyanine dye, its synthesis method and application, and belongs to the field of polymethylindole cyanine dye and its preparation. Background technique [0002] The indocyanine green in the heptamethine cyanine dye is the only near-infrared dye approved by the US Food and Drug Administration for clinical photothermal therapy, and its derivative new indocyanine green belongs to the heptamethine indocyanine dye kind of. This type of dye has a strong absorption effect in the near-infrared region around 808nm, which can be used as a complement to other medical diagnosis and treatment methods (such as MRI, PET, SPECT, ultrasound echo scanning technology, radiography and tomography) Imaging technology, also used as a photosensitizer for photothermal therapy, has important research and application value in life science and biomedical research. [0003] Heptamethine indole cyanine dyes have multiple modifiable sit...

Claims

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Application Information

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IPC IPC(8): C09B23/08C07D209/10C09K11/06G01N21/64A61K49/00
CPCA61K49/0032C07D209/10C09B23/0066C09B23/08C09K11/06C09K2211/1007C09K2211/1029G01N21/643
Inventor 李娟袁博蒋振奇吴爱国
Owner NINGBO INST OF MATERIALS TECH & ENG CHINESE ACADEMY OF SCI
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