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Preparation method of heptamethine benzoindocyanine dye

A technology for benzindocyanine and benzindole derivatives, which is applied in the field of preparation of polymethine benzindocyanine dyes, can solve the problems of high price, high consumption of organic solvents, low purity and the like, and achieves The effect of improving preparation efficiency, large single reaction volume and simple purification method

Pending Publication Date: 2019-05-24
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 benzindole cyanine sold in the market is only the new indocyanine green (IR-820), and the purity is low (80%), and the price is high (1324 yuan / 1g)
At the same time, the production and purification process of its different derivatives needs to screen a large number of conditions and consume a large amount of organic solvents. Therefore, it is necessary to develop a new heptamethine cyanine benzindole dye suitable for industrialization and its preparation and purification method.

Method used

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  • Preparation method of heptamethine benzoindocyanine dye
  • Preparation method of heptamethine benzoindocyanine dye
  • Preparation method of heptamethine benzoindocyanine dye

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Embodiment 1 synthetic compound 1

[0093] This embodiment synthesizes compound 1 according to the following route:

[0094]

[0095] (1) Synthesis of 2,3,3-trimethyl-1-(ethyl butyrate)-4,5-benzindole

[0096] Add 2,3,3-trimethyl-4,5-benzindole and ethyl 4-bromobutyrate at a molar ratio of 1:1.5 into the reactor, and heat to 120°C in a closed environment to melt Stir for 10 hours and cool to room temperature. It was recrystallized four times with acetone and dried under vacuum. The yield was 85.9%. It was used in the next reaction without further purification.

[0097] (2) Synthesis and purification of compound 1

[0098]Add 2-chloro-1-formyl-3-hydroxymethylenecyclohexene, 2,3,3-trimethyl-1-(butyric acid ethyl ester at a molar ratio of 1:2.5:2 to the reactor )-4,5-benzindole and anhydrous sodium acetate, and add ethanol to dissolve completely, then react under reflux in a closed environment (react at 75°C for 24 hours) until the ethanol is completely volatilized,...

Embodiment 2

[0099] Embodiment 2 synthetic compound 7

[0100] This embodiment synthesizes compound 7 according to the following route:

[0101]

[0102] (1) Synthesis of 2,3,3-trimethyl-1-(butanesulfonic acid)-4,5-benzindole

[0103] Add 2,3,3-trimethyl-4,5-benzindole and 1,4-butane sultone in a molar ratio of 1:1.5 into the reactor, and heat to 120°C in a closed environment to melt After melting, stir for 10 hours and cool to room temperature. It was recrystallized four times with acetone and dried in vacuo. The yield was 83.7%. It was used in the next reaction without further purification.

[0104] (2) Synthesis and purification of compound 7

[0105] Add 2-chloro-1-formyl-3-hydroxymethylenecyclohexene, 2,3,3-trimethyl-1-(butanesulfonic acid) in a molar ratio of 1:2.5:2 to the reactor -4,5-benzindole and anhydrous sodium acetate, and add ethanol to dissolve completely, then react in a closed environment under reflux (react at 75°C for 24 hours) until the ethanol is completely vol...

Embodiment 3

[0106] Embodiment 3 synthetic compound C1

[0107] This embodiment synthesizes compound C1 according to the following route:

[0108]

[0109] (1) Synthesis of 2,3,3-trimethyl-1-(butyramide)-4,5-benzindole

[0110] Add 2,3,3-trimethyl-4,5-benzindole and 4-bromobutyramide in a molar ratio of 1:1.5 into the reactor, heat to 120°C in a closed environment and stir for 10 hours after melting, Cool to room temperature. It was recrystallized four times with acetone and dried in vacuo. The yield was 85.7%. It was used in the next reaction without further purification.

[0111] (2) Synthesis and purification of compound C1

[0112] Add 2-chloro-1-formyl-3-hydroxymethylenecyclohexene, 2,3,3-trimethyl-1-(butanamide)- 4,5-benzindole and anhydrous sodium acetate, and add ethanol to dissolve completely, then react in a closed environment under reflux (75°C for 24 hours) to completely evaporate the ethanol, add methanol to dissolve and then mix with Petroleum ether was extracted and ...

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Abstract

The invention discloses a preparation method of a heptamethine benzoindocyanine dye. The method at least comprises the following steps that a 2,3,3-trimethyl-4,5-benzindole derivative reacts with a nucleophilic substitution compound and re-crystallized to obtain organic ammonium salt; the organic ammonium salt, a cyclohexene derivative and a sodium acetate solution react with one another, the product is mixed with alcohol and ether, the mixture is extracted many times, and the heptamethine benzoindocyanine dye is obtained. The method is short in synthetic route, simple in process, free of catalysis of precious metal and high in yield, the extraction method is simple, chromatographic column separation is not needed, the solvent consumption is low, the preparation efficiency of the dye is greatly improved, and low-cost batch production can be achieved. The method has great significance in the aspects of production and application research of heptamethine benzoindocyanine. The prepared heptamethine benzoindocyanine dye contains an aliphatic chain substituted N structure, and has or independently has near-infrared light absorption and fluorescent development functions.

Description

technical field [0001] The application relates to a preparation method of heptamethenebenzoindole cyanine dye, which belongs to the field of preparation of polymethinebenzoindole cyanine dye. 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. Its derivative, neo-indocyanine green, belongs to one of the heptamethine benzoindole cyanine dyes. This type of dye has a strong absorption effect in the near-infrared 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 or tomography) Imaging technology, also used as a photosensitizer for photothermal therapy, has important research and application value in life science and biomedical research. [0003] Heptamethylbenzindole cyanine dyes have multiple modifiable sites...

Claims

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Application Information

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IPC IPC(8): C09B23/08C09K11/06G01N21/64A61K49/00
Inventor 吴爱国蒋振奇袁博李娟王胤杰
Owner NINGBO INST OF MATERIALS TECH & ENG CHINESE ACADEMY OF SCI
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