WO2022021072A1

WO2022021072A1 - Preparation method for indocyanine green acid triethylamine salt

Info

Publication number: WO2022021072A1
Application number: PCT/CN2020/105216
Authority: WO
Inventors: 迟崇巍; 田捷; 何坤山
Original assignee: 北京数字精准医疗科技有限公司
Priority date: 2020-07-28
Filing date: 2020-07-28
Publication date: 2022-02-03
Also published as: CN112469698B; CN112469698A

Abstract

A preparation method for indocyanine green acid triethylamine salt, comprising the following steps: reacting 2, 3, 3-trimethyl-1-(4-sulfobutyl)-4, 5-benzindole betaine, 2-[6-(N-acetylanilino)-1, 3, 5-hexatriene-1-yl]-3, 3-dimethyl-1-(4-sulfobutyl)-4, 5-benzindole betaine and triethylamine in an organic solvent at the temperature of 0℃-40℃; and after the reaction is finished, adding the obtained product into methyl tertiary butyl ether or isopropyl ether to obtain a powdery indocyanine green acid triethylamine salt. The obtained powdery indocyanine green acid triethylamine salt solves the problem that the oily matter of indocyanine green acid triethylamine salt is difficult to industrially produce.

Description

The preparation method of indocyanine green acid triethylamine salt

technical field

The present invention relates to the technical field of medicine, in particular, to an indocyanine green acid triethylamine salt (hereinafter, sometimes referred to as "indocyanine green-06") as an intermediate for preparing medicinal solid indocyanine green preparation method.

Background technique

Fluorescence imaging is an imaging technique based on the injection of fluorescently labeled drugs or other substances into animals or humans and the detection of the location of the fluorescent labels. It has a unique position in modern medicine, mainly as other methods (eg, MRI, PET, Complementary imaging techniques such as SPECT, ultrasound echography, radiography or X-tomography) have important research value and application value in life science and biomedical research. In fluorescence imaging, as a class of near-infrared dyes, indocyanine green is widely used clinically due to its excellent fluorescence penetration, good imaging performance and better stability.

Patent Document 1 discloses an industrial synthesis method of indocyanine green, wherein 2,3,3-trimethyl-1-(4-sulfobutyl)-4,5-benzindolelactone is used salt and 2-[6-(N-acetylanilino)-1,3,5-hexatrien-1-yl]-3,3-dimethyl-1-(4-sulfobutyl)- 4,5-benzindole lactine salt is used as raw material, heated and refluxed for 15 minutes with triethylamine as base and absolute ethanol as solvent, cooled, extracted with ether, and poured out the supernatant to obtain The viscous material (ie, indocyanine green acid triethylamine salt) was directly used for salt formation without separation, thereby obtaining indocyanine green.

However, the method has the following shortcomings: firstly, the indocyanine green acid triethylamine salt formed by the intermediate step contains more impurities, and it is impossible to continuously and stably produce the qualified indole with high purity and stable quality through the intermediate control. The cyanine green acid triethylamine salt has great uncertainty in the process and does not meet the requirements of QBD; secondly, the obtained indocyanine green acid triethylamine salt is an oily substance, which will adhere to the kettle The bottom or the wall of the kettle is extremely difficult to scale up operation; thirdly, in the subsequent salt-forming process (ie, the preparation step of indocyanine green), since the amount of sodium iodide cannot be estimated, it will lead to the indocyanine in the obtained indocyanine. The sodium iodide in the green exceeds the standard.

prior art literature

Patent Document 1: CN104130178A

SUMMARY OF THE INVENTION

The problem to be solved by the invention

As mentioned above, indocyanine green acid triethylamine salt is a key intermediate in the preparation of indocyanine green. However, according to the information reported in Patent Document 1 and the results obtained by repeating the test of the Patent Document, the indocyanine green acid triethylamine salt prepared therefrom is an oily substance with poor purity, which cannot be used for intermediate purification and quality control. At the same time, because the literature technique cannot obtain the intermediate indocyanine green acid triethylamine salt that is easy to store and feed, so in the step of preparing the final product indocyanine green, the feeding amount of the sodium iodide used cannot be accurately calculated, resulting in gained The purity of the indocyanine green was poor and the batch-to-batch variation was large.

Technical means for solving technical problems

In view of the above problems in the prior art, the purpose of the present invention is to provide a method for preparing powdered triethylamine indocyanine green acid salt and a purification method for obtaining high-purity indocyanine green acid triethylamine salt.

The preparation method of indocyanine green acid triethylamine salt of the present invention comprises the following steps:

Make 2,3,3-trimethyl-1-(4-sulfobutyl)-4,5-benzindole lactine salt, 2-[6-(N-acetylanilino)-1, 3,5-Hexatrien-1-yl]-3,3-dimethyl-1-(4-sulfobutyl)-4,5-benzindolide and triethylamine in organic solvent the step of carrying out the reaction at a temperature of 0°C to 40°C; and

After the reaction is completed, the resultant is added to methyl tert-butyl ether or isopropyl ether to obtain a powdery indocyanine green acid triethylamine salt.

The preparation method of indocyanine green acid triethylamine salt of the present invention does not include the step of heating and refluxing.

In addition, the preparation method of indocyanine green acid triethylamine salt of the present invention preferably further comprises a step of purifying the obtained powdery indocyanine green acid triethylamine salt, that is, purifying the obtained powdery indocyanine green acid triethylamine salt After dissolving the acid triethylamine salt in ethanol, adding it to methyl tert-butyl ether, stirring and filtering to obtain high-purity powdery indocyanine green acid triethylamine salt. Among them, the volume ratio of ethanol and methyl tert-butyl ether is 1:6-13, preferably 1:6-10.

In addition, the present invention provides a powdery indocyanine green acid triethylamine salt obtained by the above-mentioned preparation method of the indocyanine green acid triethylamine salt.

In addition, the present invention also provides a method for purifying indocyanine green acid triethylamine salt, which comprises the following steps: after dissolving the indocyanine green acid triethylamine salt in ethanol, adding it to methyl tert-butyl ether , through stirring and filtration to obtain high-purity powder indocyanine green acid triethylamine salt.

Invention effect

The present invention can obtain powdery indocyanine green acid triethylamine salt, solve the problem that the indocyanine green acid triethylamine salt oil is difficult to be industrially produced, and at the same time ensure that the subsequent process steps can accurately calculate the feed ratio. Furthermore, through the purification method of the present invention, a high-purity indocyanine green acid triethylamine salt can be obtained, so that a high-purity indocyanine green product can be continuously and stably produced.

Description of drawings

FIG. 1 is a mass spectrum of indocyanine green acid triethylamine salt obtained by Example 1 of the present invention.

2 is a hydrogen spectrum of indocyanine green acid triethylamine salt obtained by Example 1 of the present invention.

3 is a graph of the purity data of the indocyanine green acid triethylamine salt obtained by Example 2 of the present invention.

4 is a graph of the purity data of the indocyanine green acid triethylamine salt with a purity of 97.77% obtained in Example 5 of the present invention.

FIG. 5 is a graph of the purity data of indocyanine green acid triethylamine salt with a purity of 99.05% finally obtained by Example 5 of the present invention.

detailed description

2,3,3-trimethyl-1-(4-sulfobutyl)-4,5-benzoindole lactine salt (indocyanine Green-03), 2-[6-(N-acetylanilino)-1,3,5-hexatrien-1-yl]-3,3-dimethyl-1-(4-sulfobutane) base)-4,5-benzoindole lactine (indocyanine green-05) was added to the organic solvent and stirred, and then triethylamine was added to carry out the reaction. Further, after the above reaction is completed, the resultant is added to methyl tert-butyl ether or isopropyl ether, thereby obtaining a powdery indocyanine green acid triethylamine salt.

This reaction step is preferably carried out under the protection of light shielding and inert gas, and the inert gas is preferably argon and nitrogen.

The organic solvent used in the above reaction is not particularly limited, for example, acetone, tetrahydrofuran, dichloromethane, ethyl acetate, acetonitrile, methanol, absolute ethanol, toluene and n-heptane can be used.

During the reaction, the molar ratio of the reaction raw materials indocyanine green-03 and indocyanine green-05 can be, for example, 1.0:0.8-1.5, preferably 1.0:0.9-1.2.

In the preparation method of the present invention, the impurity content in the reaction solution is significantly reduced by controlling the reaction temperature within the range of 0°C to 40°C without heating to reflux. Then through the research on the physical and chemical properties of indocyanine green acid triethylamine salt, on the basis of screening a large number of solvents, it was found that the reaction solution after the reaction was completely mixed with methyl tert-butyl ether or isopropyl ether, under stirring conditions A solid powder with better properties can be precipitated under the following conditions, and the crude indocyanine green acid triethylamine salt in powder form is obtained by filtration.

In the present invention, in order to obtain a powdered triethylamine salt of indocyanine green acid with better purity of pharmaceutical grade, it is preferable to further purify the above-mentioned obtained product. It was found that the above-mentioned crude indocyanine green acid triethylamine salt can be purified in a specific purification solvent, that is, in ethanol and methyl tert-butyl ether, to obtain high-purity powdery indocyanine green acid triethylamine in high yield. Ethylamine salt.

In the present invention, it is preferable to purify the crude product of the above indocyanine green acid triethylamine salt, that is, after dissolving the obtained powdery indocyanine green acid triethylamine salt in ethanol, add it to methyl tert-butyl ether, and pass through Stir and filter to obtain high-purity powdery indocyanine green acid triethylamine salt, wherein the volume ratio of ethanol and methyl tert-butyl ether is 1:6-13, preferably 1:6-10, so that The purity is greater than 99%. .

Example

Hereinafter, the technical solutions of the present invention will be specifically described based on the examples. However, the examples given are only for illustrating the present invention, and the present invention is not limited thereto.

It should be noted that the reagents and raw materials used in the examples are all commercially available.

Example 1:

Under nitrogen protection, the temperature was kept at 0 °C, and indocyanine green-05 (15.01 g), indocyanine green-03 (8.68 g), absolute ethanol (90 ml) were added to the reaction flask in turn, and triethylamine ( 2.80g), reacted for 3 hours. After the reaction was completed, it was added dropwise to 900 ml of methyl tert-butyl ether at -5 to 0° C., and the system precipitated a dispersed powdery solid, which was filtered under reduced pressure to obtain a black loose powder.

This powder was identified by mass spectrometry and hydrogen spectrum, and the obtained spectrum was shown in Figure 1 and Figure 2, and it was confirmed to be indocyanine green acid triethylamine salt.

¹ H-NMR (400MHz, DMSO-d ₆ ), δ 8.21(d, J=8.4Hz, 2H), 8.05-7.95(m, 6H), 7.63-7.59(m, 5H), 7.45(t, J=7.6Hz, 2H), 6.61 (t, J=12.4Hz, 2H), 6.37 (d, J=13.6Hz, 2H), 4.23 (t, J=4.8Hz, 4H), 3.19 (q, J= 7.6Hz,,6H), 2.92(t,J=7.2Hz,4H), 2.03-1.97(m,20H), 1.30(t,J=7.6Hz,9H); MS(M+H)=753.3

Example 2:

Under nitrogen protection, the temperature was kept at 25 ° C, and indocyanine green-05 (15.01 g), indocyanine green-03 (8.68 g), absolute ethanol (90 ml) were added to the reaction flask in turn, and triethylamine ( 2.80g), reacted for 3 hours. After the reaction was completed, it was added dropwise to 900 ml of methyl tert-butyl ether at -5 to 0° C., and the system precipitated a dispersed powdery solid, which was filtered under reduced pressure to obtain a black loose powder.

Identification was carried out in the same manner as in Example 1, and it was confirmed that the powder was indocyanine green acid triethylamine salt.

Example 3:

Under nitrogen protection, the temperature was kept at 40 ° C, and indocyanine green-05 (15.01 g), indocyanine green-03 (8.68 g), absolute ethanol (90 ml) were added to the reaction flask in turn, and triethylamine ( 2.80g), reacted for 3 hours. After the reaction was completed, it was added dropwise to 900 ml of methyl tert-butyl ether at -5 to 0° C., and the system precipitated a dispersed powdery solid, which was filtered under reduced pressure to obtain a black loose powder.

Example 4:

Under nitrogen protection, the temperature was kept at 25 ° C, and indocyanine green-05 (15.01 g), indocyanine green-03 (8.68 g), absolute ethanol (90 ml) were added to the reaction flask in turn, and triethylamine ( 2.80g), reacted for 3 hours. After the reaction was completed, it was added dropwise to 900 ml of isopropyl ether at -5 to 0° C., and the system precipitated a dispersed powdery solid, which was filtered under reduced pressure to obtain a black loose powder.

Comparative Example 1

Under nitrogen protection, the temperature was kept at 0 °C, and indocyanine green-05 (15.01 g), indocyanine green-03 (8.68 g), absolute ethanol (90 ml) were added to the reaction flask in turn, and triethylamine ( 2.80g), reacted for 3 hours. After the reaction is completed, add dropwise to 900ml of ethylene glycol dimethyl ether at -5～0℃. As a result, the viscous substance is adsorbed on the bottom of the bottle, and the supernatant is poured out to obtain a black oily viscous substance, which is not powdery. thing.

Comparative Example 2

Prepare according to the method described in the patent document (CN104130178A), as follows:

Indocyanine green-05 and indocyanine green-03 were mixed in a mass ratio of 1.7:1, that is, indocyanine green-05 (15.01g) and indocyanine green-03 (8.68g) were added to the reaction flask in turn. , 128ml of anhydrous ethanol, then add triethylamine which is 5% of the anhydrous ethanol mass under nitrogen protection, heat to 78 ℃ and reflux for 30 minutes, cool the reaction solution to 30 ℃ within 0.5 hours, then add anhydrous ethanol 2.15 times the volume of 275ml of ether, the viscous solid was adsorbed on the bottom of the reaction flask, and then the supernatant was poured out to obtain a black oily viscous substance, not powder.

Table 1

例example	反应温度℃Reaction temperature °C	析晶溶剂Crystallization solvent	产品状态product status
实施例1Example 1	00	乙醇和甲基叔丁基醚Ethanol and methyl tert-butyl ether	黑色固体粉末black solid powder
实施例2Example 2	2525	乙醇和甲基叔丁基醚Ethanol and methyl tert-butyl ether	黑色固体粉末black solid powder
实施例3Example 3	4040	乙醇和甲基叔丁基醚Ethanol and methyl tert-butyl ether	黑色固体粉末black solid powder
实施例4Example 4	2525	乙醇和异丙醚Ethanol and isopropyl ether	黑色固体粉末black solid powder
比较例1Comparative Example 1	00	乙醇和乙二醇二甲醚Ethanol and Glycol Dimethyl Ether	黑色粘稠物black sticky substance
比较例2Comparative Example 2	回流条件即78℃Reflux condition is 78℃	乙醇和乙醚Ethanol and ether	黑色粘稠物black sticky substance

The inventors measured the purity of the crude indocyanine green-06 obtained in Example 2. As a result, the purity was 94.71%. The specific data are shown in FIG. 3 . In order to obtain high-purity indocyanine green acid triethylamine salt, the inventors further performed purification steps. It should be noted that the purity data in the examples of the present invention and the comparative examples are all using high performance liquid chromatograph Agilent 1260 II, octadecylsilane bonded silica gel as filler, phosphate buffer (pH 5.8 )-acetonitrile-methanol (50:47:3) as the mobile phase for isocratic elution.

Example 5

12 ml of absolute ethanol was added to 4 g (purity of 94.71%) crude indocyanine green-06 obtained in Example 2, the sample was dissolved, and at -5 to 0° C., it was added dropwise to methyl 6 times the volume of ethanol. In tert-butyl ether, the mixture was stirred for 0.5 hours, and filtered under reduced pressure to obtain a powdery solid. The above-mentioned operation was repeated for the obtained powdery solid to obtain powdery indocyanine green-06 with a purity of 97.77%. The specific purity data is shown in FIG. 4 . Furthermore, the above operation was repeated for the powdered solid with a purity of 97.77%, and the purity was further improved to obtain a high-purity powdered indocyanine green-06 with a purity of 99.05%. The specific purity data is shown in Figure 5.

Example 6

12 ml of absolute ethanol was added to 4 g (purity of 94.71%) crude indocyanine green-06 obtained in Example 2, the sample was dissolved, and at -5 to 0 °C, it was added dropwise to methyl 10 times the volume of ethanol. In tert-butyl ether, the mixture was stirred for 0.5 hours, and filtered under reduced pressure to obtain a powdery solid. The obtained powdery solid was subjected to the above-mentioned operation twice again in the same manner as in Example 5, and the purity was measured in the same manner as in Example 5 to obtain high-purity powdery indocyanine green-06 with a purity of 99.00%.

Example 7

12 ml of absolute ethanol was added to 4 g (purity of 94.71%) crude indocyanine green-06 obtained in Example 2, the sample was dissolved, and at -5 to 0 °C, it was added dropwise to methyl 13 times the volume of ethanol. In tert-butyl ether, the mixture was stirred for 0.5 hours, and filtered under reduced pressure to obtain a powdery solid. The obtained powdery solid was subjected to the above-mentioned operation twice again in the same manner as in Example 5, and the purity was measured in the same manner as in Example 5 to obtain high-purity powdery indocyanine green-06 with a purity of 98.69%.

From the above Examples 5 to 7, it can be seen that the purity of crude indocyanine green-06 can be improved by using the purification reagent of ethanol:methyl tert-butyl ether=1:6 to 13, and high-purity powdery indocyanine can be obtained Green-06.

Comparative Example 3

12ml of absolute ethanol was added to the powdered indocyanine green-06 crude product with a purity of 97.77% in Example 5, the sample was dissolved, and it was added dropwise to methyl 15 times the volume of ethanol at -5 to 0°C. In tert-butyl ether, the mixture was stirred for 0.5 hours, and filtered under reduced pressure to obtain a powdery solid. The obtained powdery solid was continuously repeated twice to obtain powdery indocyanine green-06 with a purity of 97.83%.

It can be seen that even if the amount of methyl tert-butyl ether is increased to 15 times the volume of ethanol and the number of repeated operations is increased, the purity of indocyanine green-06 cannot be further improved.

Comparative Example 4

Add 12 ml of absolute ethanol to the crude indocyanine green-06 (purity 97.83%) obtained in Comparative Example 3, dissolve the sample, and add dropwise to isopropyl ether twice the volume of ethanol at -5 to 0 °C was stirred for 0.5 hours, and filtered under reduced pressure to obtain a powdery solid. The obtained powdery solid was continuously repeated twice to obtain powdery indocyanine green-06 with a purity of 97.97%, and there was no impurity removal effect.

Comparative Example 5

To the crude indocyanine green-06 (purity 97.83%) obtained in Comparative Example 3, add 12 ml of absolute ethanol, dissolve the sample, and add dropwise to isopropyl ether that is 5 times the volume of ethanol at -5 to 0 °C was stirred for 0.5 hours, and filtered under reduced pressure to obtain a powdery solid. The obtained powdery solid was continuously repeated twice to obtain powdery indocyanine green-06 with a purity of 97.95%, and there was no impurity removal effect.

Comparative Example 6

To the crude indocyanine green-06 (purity 97.83%) obtained in Comparative Example 3, add 12 ml of absolute ethanol, dissolve the sample, and add dropwise to isopropyl ether 10 times the volume of ethanol at -5 to 0 °C. was stirred for 0.5 hours, and filtered under reduced pressure to obtain a powdery solid. The obtained powdery solid was continuously repeated twice to obtain powdery indocyanine green-06 with a purity of 97.85%, and there was no impurity removal effect.

It can be seen from the data of Comparative Examples 4 to 6 that the purification reagent of ethanol:isopropyl ether=1:2 to 10 cannot further improve the purity of indocyanine green-06 and cannot reach the pharmaceutical grade.

Comparative Example 7

Add 12 ml of absolute ethanol to 4 g (purity of 94.71%) crude indocyanine green-06 obtained in Example 2, dissolve the sample, add 2.15 times the volume of ethanol at -5 to 0 °C, and stir for 0.5 After 12 hours, a viscous solid was obtained and adsorbed on the bottom of the reaction flask, then the supernatant was poured out, 12 ml of absolute ethanol and 2.15 times the volume of ethyl ether were added to the reaction flask, and after stirring for 0.5 hours, pour out the upper The supernatant was repeated twice to obtain a black oily viscous substance with a purity of 98.28%.

Comparative Example 8

The same procedure as in Comparative Example 7 was carried out except that the amount of diethyl ether was changed to 6 times the volume of ethanol to obtain a black oily viscous substance, 98.00%.

Comparative Example 9

12 ml of absolute ethanol was added to 4 g (purity of 94.71%) crude indocyanine green-06 obtained in Example 2, the sample was dissolved, and at -5 to 0° C., it was added dropwise to methyl ethyl 4 times the volume of ethanol. In tert-butyl ether, stirring for 0.5 hours, a viscous substance was obtained and adsorbed at the bottom of the reaction flask, then the supernatant was poured out, and 12 ml of absolute ethanol and 4 times the volume of ethanol were added to the reaction flask. Butyl ether, after stirring for 0.5 hours, the supernatant was poured out again, and the process was repeated twice to obtain a black oily viscous substance with a purity of 98.22%.

Comparative Example 10

At room temperature, 2 g of the crude indocyanine green-06 obtained in Example 2 was added to 10 ml of a solvent with a volume ratio of ethyl acetate: n-hexane = 5: 1, stirred for 0.5 hours, no solid was precipitated, and placed in a refrigerator for freezing After 24 hours, no solids were precipitated.

Comparative Example 11

At room temperature, 2 g of the crude indocyanine green-06 obtained in Example 2 was added to acetone, stirred for 0.5 hours, no solid was precipitated, and put into a refrigerator for 24 hours, and no solid was precipitated.

Comparative Example 12

At room temperature, 2 g of the crude indocyanine green-06 obtained in Example 2 was added to 6 ml of methanol, stirred for 0.5 hours, no solid was precipitated, 30 ml of methyl tert-butyl ether was added, and it was placed in a refrigerator for 24 hours, and there was no solid. Precipitate.

Comparative Example 13

At room temperature, 2 g of the crude indocyanine green-06 obtained in Example 2 was added to isopropanol, stirred for 0.5 hours, and no solid was precipitated. It was placed in a refrigerator for 24 hours, and no solid was precipitated.

Comparative Example 14

At room temperature, 2 g of the crude indocyanine green-06 obtained in Example 2 was added to n-butanol, stirred for 0.5 hours, and no solid was precipitated. It was placed in a refrigerator for 24 hours, and no solid was precipitated.

From the comparison of the above experimental examples 1 to 4 and comparative examples 1 and 2, it can be seen that the invention of the present application can obtain powdery products by reacting at a specific reaction temperature and precipitating in methyl tert-butyl ether or isopropyl ether. Indocyanine green acid triethylamine salt. From the comparative data of Examples 5 to 7 and Comparative Examples 3 to 14, it can be seen that by using a specific crystallization solvent, the purity can be further improved, and a powdery indocyanine green acid triethylamine salt of pharmaceutical grade can be obtained.

The above experimental results show that powdery indocyanine green acid triethylamine salt can be prepared by the present invention, the feeding ratio can be accurately calculated in the preparation of indocyanine green process, and the prepared indocyanine green product with stable iodine content can be obtained. , to ensure process stability. By controlling the relevant process parameters, the present invention reduces impurities in the reaction process, and the product quality of the indocyanine green is greatly improved. Furthermore, through the present invention, high-purity powdered triethylamine salt of indocyanine green acid can be prepared, and the product quality reaches the API level. The indocyanine green acid triethylamine salt can be directly used for the production of indocyanine green, and the indocyanine green that meets the standard of raw materials can be directly prepared.

To sum up, the present invention provides a process method for stably preparing indocyanine green acid triethylamine salt, and by controlling the quality of the key intermediate indocyanine green acid triethylamine salt, stable industrial production can be ensured A high-purity powdered indocyanine green product is obtained.

Claims

A kind of preparation method of indocyanine green acid triethylamine salt, is characterized in that, comprises the following steps:

Make 2,3,3-trimethyl-1-(4-sulfobutyl)-4,5-benzindole lactine salt, 2-[6-(N-acetylanilino)-1, 3,5-Hexatrien-1-yl]-3,3-dimethyl-1-(4-sulfobutyl)-4,5-benzindolide and triethylamine in organic solvent the step of carrying out the reaction at a temperature of 0°C to 40°C; and

After the reaction is completed, the resultant is added to methyl tert-butyl ether or isopropyl ether to obtain a powdery indocyanine green acid triethylamine salt.
The preparation method of indocyanine green acid triethylamine salt according to claim 1, is characterized in that,

In the preparation method, the step of heating and refluxing is not included.
The preparation method of indocyanine green acid triethylamine salt according to claim 1, is characterized in that,

It also includes the step of purifying the obtained powdery indocyanine green acid triethylamine salt, that is, after dissolving the obtained powdery indocyanine green acid triethylamine salt in ethanol, adding it to methyl tert-butyl ether , the high-purity powdery indocyanine green acid triethylamine salt is obtained by stirring and filtering, and the volume ratio of ethanol and methyl tert-butyl ether is 1:6-13.
The preparation method of indocyanine green acid triethylamine salt according to claim 3, is characterized in that,

The volume ratio of ethanol and methyl tert-butyl ether is 1:6-10.
A powdery indocyanine green acid triethylamine salt obtained by the preparation method of the indocyanine green acid triethylamine salt according to any one of claims 1-4.
A method for purifying indocyanine green acid triethylamine salt, comprising the steps of:

After dissolving indocyanine green acid triethylamine salt in ethanol, adding it to methyl tert-butyl ether, stirring and filtering to obtain high-purity powder indocyanine green acid triethylamine salt, ethanol and methyl tert-butyl The base ether is 1:6-13 in volume ratio.
purifying method according to claim 6, is characterized in that,

The volume ratio of ethanol and methyl tert-butyl ether is 1:6-10.