阅读说明：本技术 一种近红外染料的制备方法 (Preparation method of near-infrared dye ) 是由 汪涛 曹雪 张云然 乔子原 秦海芳 周海平 于 2019-12-16 设计创作，主要内容包括：本发明公开了一种近红外染料的制备方法,本发明首先以戊二烯醛缩二苯胺盐酸盐(Ⅱ)经乙酰化反应制备N-苯基-N-(1e,3e,5e)-5(苯基亚胺)戊-1,3-二烯基-1-基)乙酰胺(Ⅲ)；其次,以1,1,2-三甲基-1H-苯并[e]吲哚(Ⅳ)和3-溴丙酸、碘化钾经取代反应制备3-(2-羧基-乙基)-1,1,2-三甲基-1H-苯并[e]吲哚碘化盐(Ⅴ)；最后,将化合物Ⅲ和化合物Ⅴ在微波辅助条件下进行缩合反应制备Cypate(Ⅰ)。该方法生产的Cypate的产率可达80％以上,产品纯度好且质量稳定,且该制备方法具有操作简便、效率高和环境友好等优点,为Cypate的大规模生产和普及应用奠定了基础。(The invention discloses a preparation method of near-infrared dye, which comprises the steps of firstly preparing N-phenyl-N- (1e,3e, 5e) -5 (phenylimine) penta-1, 3-dienyl-1-yl) acetamide (III) by carrying out acetylation reaction on glutaral-dehyde anilide hydrochloride (II); secondly, preparing 3- (2-carboxyl-ethyl) -1,1, 2-trimethyl-1H-benzo [ e ] indole iodide (V) by using 1,1, 2-trimethyl-1H-benzo [ e ] Indole (IV), 3-bromopropionic acid and potassium iodide through substitution reaction; and finally, carrying out condensation reaction on the compound III and the compound V under the microwave-assisted condition to prepare the Cypate (I). The yield of the Cypate produced by the method can reach more than 80%, the product has good purity and stable quality, and the preparation method has the advantages of simple and convenient operation, high efficiency, environmental protection and the like, and lays a foundation for the large-scale production, popularization and application of the Cypate.)

1. A method for preparing a near-infrared dye having a chemical name of 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1, 1-diethyl-1, 3-dihydro-2H-2-benzo [ E ] indole ]1-1,3, 5-heptotrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ E ] indole, comprising the steps of:

s1: synthesizing N-phenyl-N- (1e,3e, 5e) -5 (phenylimine) penta-1, 3-dienyl-1-yl) acetamide (III), and preparing N-phenyl-N- (1e,3e, 5e) -5 (phenylimine) penta-1, 3-dienyl-1-yl) acetamide (III) by acetylation reaction of glutarenal dianiline hydrochloride (II);

s2: synthesizing 3- (2-carboxyl-ethyl) -1,1, 2-trimethyl-1H-benzo [ e ] indole iodide (V), and preparing 3- (2-carboxyl-ethyl) -1,1, 2-trimethyl-1H-benzo [ e ] indole iodide (V) by substitution reaction of 1,1, 2-trimethyl-1H-benzo [ e ] Indole (IV), 3-bromopropionic acid and potassium iodide;

s3: synthesis of 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1, 1-diethyl-1, 3-dihydro-2H-2-benzo [ E ] indole ]1-1,3, 5-heptyltrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ E ] indole (I), preparation of 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1 by condensation of Compound III, prepared in step S1, and Compound V, prepared in step S2, under microwave-assisted conditions, 1-diethyl-1, 3-dihydro-2H-2-benzo [ e ] indole ]1-1,3, 5-heptatrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ e ] indole (I).

2. The method for preparing a near-infrared dye according to claim 1, wherein the condensation reaction in step S3 is carried out in a solvent; the solvent is one of acetonitrile, methanol, ethanol or isopropanol; or the solvent is a mixed solution of one of acetonitrile, methanol, ethanol or isopropanol and water.

3. The method of claim 2, wherein the solvent in step S3 is a mixture of acetonitrile and water, and the volume ratio of acetonitrile to water is 19: 1.

4. The method for preparing the near-infrared dye according to claim 1, wherein the condensation reaction temperature in the step S3 is 40-80 ℃ and the reaction time is 15-30 min.

5. The method for preparing a near-infrared dye according to claim 4, wherein the condensation reaction temperature in the step S3 is 70 ℃ and the reaction time is 20 min.

6. The method for preparing a near-infrared dye according to claim 1, wherein the molar ratio of the compound III to the compound V in the step S3 is 1: 1-1.5.

7. The process for preparing a near-infrared dye according to claim 6, wherein the molar ratio of the compound III to the compound V in the step S3 is 1: 1.1.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a preparation method of a near-infrared dye, which has an English name of Cypate and a chemical name of 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1, 1-diethyl-1, 3-dihydro-2H-2-benzo [ E ] indole ]1-1,3, 5-heptatrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ E ] indole.

Background

The tumor photothermal therapy is a novel tumor therapy technology which is widely researched in recent years, and the photothermal reagent generates local high temperature under the irradiation of specific wavelength light to cause apoptosis or necrosis of focus tumor cells, so that the tumor photothermal therapy has the characteristics of short treatment time, obvious curative effect, small toxic and side effects on human bodies and the like. Cypate is a novel near-infrared dye, is a derivative of indocyanine green (ICG), has the advantages of stable structure, low hepatotoxicity, small cytotoxicity, high quantum yield, high photothermal conversion efficiency and the like compared with ICG, and can be widely applied to nano-targeting drug delivery systems such as liposome, micelle and mesoporous silicon nanoparticles for tumor photothermal therapy.

Cypate has the chemical name 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1, 1-diethyl-1, 3-dihydro-2H-2-benzo [ E ] indole ]1-1,3, 5-heptatrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ E ] indole and has the molecular structural formula of formula 1:

the prior literature (J.Am.chem.Soc.2003,125,26, 7766-: synthesizing N-phenyl-N- (1e,3e, 5e) -5 (phenylimine) penta-1, 3-dienyl-1-yl) acetamide (III) by glutaral aldehyde biuret hydrochloride (II) under the action of acetic anhydride; reacting 1,1, 2-trimethyl-1H-benzo [ e ] Indole (IV) with 3-bromopropionic acid to obtain 3- (2-carboxyl-ethyl) -1,1, 2-trimethyl-1H-benzo [ e ] indole bromide salt (V); finally, 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1, 1-diethyl-1, 3-dihydro-2H-2-benzo [ E ] indole ]1-1,3, 5-heptatrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ E ] indole (I) is obtained by condensation reaction of (III) and (V), and the specific synthetic route is shown as formula 2:

the synthesis method has certain defects: (1) acetic anhydride is needed in the synthesis process of the intermediate (III), the acetic anhydride is a chemical product easy to prepare toxic substances, the purchase and the management are strict and complicated, and a byproduct, namely acetic acid, is generated in the reaction process, so that the separation and the purification of a target product are relatively difficult, and the reaction of the acetic anhydride is incomplete; (2) the condensation reaction of (III) and (V) is incomplete, the reaction yield is only 61%, and the purity of the target product is not high.

In summary, the existing synthesis technology of the Cypate has the defects of low yield, low purity and complex operation, thereby seriously affecting the production scale and the popularization and application of the Cypate. Therefore, the development of new preparation methods to improve the purity and synthesis efficiency of the Cypate is an urgent technical problem to be solved.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provide a preparation method of a near-infrared dye, the yield of the Cypate (compound I) produced by the method can reach more than 80%, the product purity is good, the quality is stable, the preparation method has the advantages of simplicity and convenience in operation, high efficiency, environmental friendliness and the like, and a foundation is laid for large-scale production, popularization and application of the Cypate.

In order to achieve the above objects, the present invention provides a method for preparing a near infrared dye having a chemical name of 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1, 1-diethyl-1, 3-dihydro-2H-2-benzo [ E ] indole ]1-1,3, 5-heptyltrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ E ] indole, comprising the steps of:

s1: synthesizing N-phenyl-N- (1e,3e, 5e) -5 (phenylimine) penta-1, 3-dienyl-1-yl) acetamide (III), and preparing N-phenyl-N- (1e,3e, 5e) -5 (phenylimine) penta-1, 3-dienyl-1-yl) acetamide (III) by acetylation reaction of glutarenal dianiline hydrochloride (II);

s2: synthesizing 3- (2-carboxyl-ethyl) -1,1, 2-trimethyl-1H-benzo [ e ] indole iodide (V), and preparing 3- (2-carboxyl-ethyl) -1,1, 2-trimethyl-1H-benzo [ e ] indole iodide (V) by substitution reaction of 1,1, 2-trimethyl-1H-benzo [ e ] Indole (IV), 3-bromopropionic acid and potassium iodide;

s3: synthesis of 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1, 1-diethyl-1, 3-dihydro-2H-2-benzo [ E ] indole ]1-1,3, 5-heptyltrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ E ] indole (I), preparation of 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1 by condensation of Compound III, prepared in step S1, and Compound V, prepared in step S2, under microwave-assisted conditions, 1-diethyl-1, 3-dihydro-2H-2-benzo [ e ] indole ]1-1,3, 5-heptatrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ e ] indole (I).

Preferably, the condensation reaction in the step S3 is performed in a solvent; the solvent is one of acetonitrile, methanol, ethanol or isopropanol; or the solvent is a mixed solution of one of acetonitrile, methanol, ethanol or isopropanol and water.

In a more preferable embodiment, the solvent in step S3 is a mixture of acetonitrile and water, and the volume ratio of acetonitrile to water is 19: 1.

The preferable technical scheme is that in the step S3, the condensation reaction temperature is 40-80 ℃, and the reaction time is 15-30 min.

Further preferably, in the step S3, the condensation reaction temperature is 70 ℃ and the reaction time is 20 min.

In the preferable technical scheme, the molar ratio of the compound III to the compound V in the step S3 is 1: 1-1.5.

In a further preferred embodiment, the molar ratio of compound III to compound V in step S3 is 1: 1.1.

The invention has the advantages and beneficial effects that:

the condensation reaction yield of 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1, 1-diethyl-1, 3-dihydro-2H-2-benzo [ E ] indole ]1-1,3, 5-heptatrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ E ] indole (I) prepared by the method of the invention can reach more than 80%, and the product purity is better, namely 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1, 1-diethyl-1, lays a foundation for the large-scale production and the popularization and application of the 3-dihydro-2H-2-benzo [ e ] indole ]1-1,3, 5-heptyltrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ e ] indole (I).

Drawings

FIG. 1 is a scheme for the synthesis of a near-infrared dye (compound I) according to the invention;

FIG. 2 is a nuclear magnetic spectrum of a near-infrared dye (compound I) prepared in example 1.

Detailed Description

The following description of the embodiments of the present invention will be made with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.

As shown in FIG. 1, examples 1 to 2 Synthesis of 3- (2-carboxyethyl) -2- { (1E,3E,5E,7E) -7- [3- (2-carboxyethyl) -1, 1-diethyl-1, 3-dihydro-2H-2-benzo [ E ] indole ]1-1,3, 5-heptotrienyl } -1, 1-dimethyl-1H-2H-3-benzo [ E ] indole (I) according to the preparation method of the present invention.