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WO2022021072A1 - 吲哚菁绿酸三乙胺盐的制备方法 - Google Patents

吲哚菁绿酸三乙胺盐的制备方法 Download PDF

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WO2022021072A1
WO2022021072A1 PCT/CN2020/105216 CN2020105216W WO2022021072A1 WO 2022021072 A1 WO2022021072 A1 WO 2022021072A1 CN 2020105216 W CN2020105216 W CN 2020105216W WO 2022021072 A1 WO2022021072 A1 WO 2022021072A1
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indocyanine green
triethylamine salt
acid triethylamine
green acid
purity
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PCT/CN2020/105216
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English (en)
French (fr)
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迟崇巍
田捷
何坤山
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北京数字精准医疗科技有限公司
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Priority to PCT/CN2020/105216 priority Critical patent/WO2022021072A1/zh
Priority to CN202080003806.XA priority patent/CN112469698B/zh
Publication of WO2022021072A1 publication Critical patent/WO2022021072A1/zh

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    • 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
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/84—Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/03—Monoamines
    • C07C211/05—Mono-, di- or tri-ethylamine

Definitions

  • 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.
  • indocyanine green-06 an indocyanine green acid triethylamine salt
  • 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.
  • 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.
  • 2,3,3-trimethyl-1-(4-sulfobutyl)-4,5-benzindolelactone is used salt and 2-[6-(N-acetylanil
  • 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.
  • Patent Document 1 CN104130178A
  • indocyanine green acid triethylamine salt is a key intermediate in the preparation of indocyanine green.
  • 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.
  • 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:
  • the preparation method of indocyanine green acid triethylamine salt of the present invention does not include the step of heating and refluxing.
  • 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.
  • the volume ratio of ethanol and methyl tert-butyl ether is 1:6-13, preferably 1:6-10.
  • 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.
  • 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.
  • 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.
  • FIG. 1 is a mass spectrum of indocyanine green acid triethylamine salt obtained by Example 1 of the present invention.
  • Example 2 is a hydrogen spectrum of indocyanine green acid triethylamine salt obtained by Example 1 of the present invention.
  • Example 3 is a graph of the purity data of the indocyanine green acid triethylamine salt obtained by Example 2 of the present invention.
  • Example 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.
  • the preparation method of indocyanine green acid triethylamine salt of the present invention comprises the following steps:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%.
  • 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.
  • Example Reaction temperature °C Crystallization solvent product status Example 1 0 Ethanol and methyl tert-butyl ether black solid powder
  • Example 2 25 Ethanol and methyl tert-butyl ether black solid powder
  • Example 3 40 Ethanol and methyl tert-butyl ether black solid powder
  • Example 4 25 Ethanol and isopropyl ether black solid powder Comparative Example 1 0 Ethanol and Glycol Dimethyl Ether black sticky substance Comparative Example 2 Reflux condition is 78°C Ethanol and ether 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 .
  • 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 2 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.
  • Example 2 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.
  • Example 2 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.
  • Example 2 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.
  • 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.
  • the present invention reduces impurities in the reaction process, and the product quality of the indocyanine green is greatly improved.
  • 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.
  • 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.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Indole Compounds (AREA)

Abstract

一种吲哚菁绿酸三乙胺盐的制备方法，包括如下步骤：使2，3，3-三甲基-1-(4-磺基丁基)-4，5-苯并吲哚内胺盐、2-[6-(N-乙酰基苯胺基)-1，3，5-己三烯-1-基]-3，3-二甲基-1-(4-磺基丁基)-4，5-苯并吲哚内胺和三乙胺在有机溶剂中在0℃～40℃的温度下进行反应的步骤；以及反应完毕后将所得物加入甲基叔丁基醚或者异丙醚中、得到粉末状吲哚菁绿酸三乙胺盐的步骤。得到的粉末状吲哚菁绿酸三乙胺盐，解决了吲哚菁绿酸三乙胺盐油状物难以工业化生产的问题。

Description

吲哚菁绿酸三乙胺盐的制备方法 技术领域
本发明涉及医药技术领域，具体而言，涉及一种作为药用固体吲哚菁绿制备中间体的吲哚菁绿酸三乙胺盐(以下，有时称为“吲哚菁绿-06”)的制备方法。
背景技术
荧光成像是一种基于将带荧光标记的药物或者其他物质注入动物或人并且检测荧光标记定位的成像技术，其在近代医疗中具有独特的地位，主要是作为其他方法(例如，MRI、PET、SPECT、超声回波描技术、放射摄影术或X-断层摄影术)的互补成像技术，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。在荧光成像中，吲哚菁绿作为一类近红外染料，以其优异的荧光穿透力、良好的显像性以及较佳的稳定性正在临床上广泛使用。
专利文献1公开了一种吲哚菁绿的工业化合成方法，其中，以2，3，3-三甲基-1-(4-磺基丁基)-4，5-苯并吲哚内胺盐和2-[6-(N-乙酰基苯胺基)-1，3，5-己三烯-1-基]-3，3-二甲基-1-(4-磺基丁基)-4，5-苯并吲哚内胺盐为原料，在以三乙胺为碱、无水乙醇为溶剂的条件下加热回流反应15分钟，冷却，加入乙醚萃取，倾倒出上清液，将得到的粘稠物(即，吲哚菁绿酸三乙胺盐)不经分离，直接用于成盐，从而得到吲哚菁绿。
但是，该方法存在如下缺点：一是，通过中间步骤所形成的吲哚菁绿酸三乙胺盐含有较多的杂质，无法通过中间体控制持续稳定生产出纯度高、质量稳定合格的吲哚菁绿酸三乙胺盐，工艺存在较大不确定性，不符合QBD的要求；二是，得到的吲哚菁绿酸三乙胺盐是一个油状物，这种油状物会粘附在釜底或者釜壁，极难放大操作；三是，在后续的成盐过程(即，吲哚菁绿的制备步骤)中，因无法估算碘化钠的用量，所以会导致在所得的吲哚菁绿中碘化钠超标。
现有技术文献
专利文献1：CN104130178A
发明内容
发明所要解决的课题
如上所述，吲哚菁绿酸三乙胺盐是制备吲哚菁绿的关键中间体。但是，根据专利文献1报道的信息以及重复该专利文献的试验所得的结果，由此制备得到的吲哚菁绿酸三乙胺盐是油状物，纯度较差，无法进行中间体纯化和质量控制；同时，由于文献工艺无法得到易于储存和投料的中间体吲哚菁绿酸三乙胺盐，所以在制备最终产物吲哚菁绿的步骤中无法准确计算所用碘化钠的投料量，导致所得的吲哚菁绿的纯度较差、且批间差异较大。
用于解决技术课题的技术手段
鉴于上述现有技术中存在的问题，本发明的目的在于提供一种制备粉末状吲哚菁绿酸三乙胺盐的方法以及获得高纯度吲哚菁绿酸三乙胺盐的纯化方法。
本发明的吲哚菁绿酸三乙胺盐的制备方法，包括如下步骤：
使2，3，3-三甲基-1-(4-磺基丁基)-4，5-苯并吲哚内胺盐、2-[6-(N-乙酰基苯胺基)-1，3，5-己三烯-1-基]-3，3-二甲基-1-(4-磺基丁基)-4，5-苯并吲哚内胺和三乙胺在有机溶剂中在0℃～40℃的温度下进行反应的步骤；以及
反应完毕后将所得物加入甲基叔丁基醚或者异丙醚中、得到粉末状吲哚菁绿酸三乙胺盐的步骤。
本发明的吲哚菁绿酸三乙胺盐的制备方法，不包括进行加热回流的步骤。
另外，本发明的吲哚菁绿酸三乙胺盐的制备方法优选还包括将所得的粉末状吲哚菁绿酸三乙胺盐进行纯化的步骤，即，将所得的粉末状吲哚菁绿酸三乙胺盐溶解于乙醇后，加入到甲基叔丁基醚中，经搅拌、过滤得到高纯粉末状吲哚菁绿酸三乙胺盐。其中，乙醇与甲基叔丁基醚以体积比计为1：6～13，优选为1：6～10。
此外，本发明提供一种粉末状吲哚菁绿酸三乙胺盐，其通过上述的吲哚菁绿酸三乙胺盐的制备方法得到。
另外，本发明还提供一种吲哚菁绿酸三乙胺盐的纯化方法，其包括如下步骤：将吲哚菁绿酸三乙胺盐溶解于乙醇后，加入到甲基叔丁基醚中，经搅拌、 过滤得到高纯粉末状吲哚菁绿酸三乙胺盐。
发明效果
通过本发明，能够得到粉末状吲哚菁绿酸三乙胺盐，解决了吲哚菁绿酸三乙胺盐油状物难以工业化生产的问题，同时保证了后续工艺步骤能够准确计算投料比。进而，通过本发明的纯化方法，能够得到高纯的吲哚菁绿酸三乙胺盐，从而能够持续稳定生产出高纯的吲哚菁绿产品。
附图说明
图1为通过本发明的实施例1得到的吲哚菁绿酸三乙胺盐的质谱。
图2为通过本发明的实施例1得到的吲哚菁绿酸三乙胺盐的氢谱。
图3为通过本发明的实施例2得到的吲哚菁绿酸三乙胺盐的纯度数据图。
图4为在本发明的实施例5中得到的纯度为97.77％的吲哚菁绿酸三乙胺盐的纯度数据图。
图5为通过本发明的实施例5最终得到的纯度为99.05％的吲哚菁绿酸三乙胺盐的纯度数据图。
具体实施方式
本发明的吲哚菁绿酸三乙胺盐的制备方法，包括如下步骤：
Figure PCTCN2020105216-appb-000001
在反应温度为0℃～40℃的条件下，将2，3，3-三甲基-1-(4-磺基丁基)-4，5-苯并吲哚内胺盐(吲哚菁绿-03)、2-[6-(N-乙酰基苯胺基)-1，3，5-己三烯-1-基]-3，3-二甲基-1-(4-磺基丁基)-4，5-苯并吲哚内胺(吲哚菁绿-05)加入有机溶剂中搅拌，然后加入三乙胺进行反应。进而，在上述反应完毕后，将所得物加入甲基叔丁基醚或异丙醚中，从而得到粉末状吲哚菁绿酸三乙胺盐。
该反应步骤优选在避光和非活性气体保护下进行，所述非活性气体优选为 氩气、氮气。
上述反应中所用的有机溶剂，没有特殊的限制，例如可以使用丙酮、四氢呋喃、二氯甲烷、乙酸乙酯、乙腈、甲醇、无水乙醇、甲苯和正庚烷。
反应过程中，反应原料吲哚菁绿-03与吲哚菁绿-05的摩尔比例如可以为1.0：0.8～1.5，优选为1.0：0.9～1.2。
在本发明的制备方法中，不进行加热回流，而是通过将反应温度控制在0℃～40℃的范围内，使反应液中杂质含量明显降低。然后通过对吲哚菁绿酸三乙胺盐的理化性质的研究，在筛选大量溶剂的基础上，发现将反应完全后的反应液与甲基叔丁基醚或异丙醚混合，在搅拌条件下可以析出性状较好的固体粉末，经过过滤得到粉末状吲哚菁绿酸三乙胺盐粗品。
在本发明中，为了得到达到药用级别纯度的纯度更好的粉末状吲哚菁绿酸三乙胺盐，优选进一步针对上述所得物进行纯化处理，发明人通过大量溶剂的筛选试验，惊奇地发现上述吲哚菁绿酸三乙胺盐粗品通过在特定的纯化溶剂、即在乙醇以及甲基叔丁基醚中进行精制，能够以高收率得到高纯的粉末状吲哚菁绿酸三乙胺盐。
本发明优选针对上述吲哚菁绿酸三乙胺盐粗品进行纯化，即，将所得的粉末状吲哚菁绿酸三乙胺盐溶解于乙醇后，加入到甲基叔丁基醚中，经搅拌、过滤从而得到高纯粉末状吲哚菁绿酸三乙胺盐，其中，乙醇与甲基叔丁基醚以体积比计为1：6～13，优选为1：6～10，从而使纯度大于99％。。
实施例
以下，基于实施例对本发明的技术方案进行具体说明。但是，所给出的实施例只是用于说明本发明，本发明并不限定于此。
需要说明的是，实施例中所用试剂和原料均市售可得。
实施例1：
氮气保护下，温度保持在0℃，依次向反应瓶中加入吲哚菁绿-05(15.01g)、吲哚菁绿-03(8.68g)、无水乙醇(90ml)，加入三乙胺(2.80g)，反应3小时。反应完毕，在-5～0℃下，滴加到900ml甲基叔丁基醚中，体系析出分散的粉末状固体，减压过滤，得到黑色松散粉末。
针对此粉末进行质谱和氢谱鉴定，所得图谱如图1和图2所示，经确认为 吲哚菁绿酸三乙胺盐。
1H-NMR(400MHz,DMSO-d 6),)δ8.21(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
实施例2：
氮气保护下，温度保持在25℃，依次向反应瓶中加入吲哚菁绿-05(15.01g)、吲哚菁绿-03(8.68g)、无水乙醇(90ml)，加入三乙胺(2.80g)，反应3小时。反应完毕，在-5～0℃下，滴加到900ml甲基叔丁基醚中，体系析出分散的粉末状固体，减压过滤，得到黑色松散粉末。
与实施例1相同地进行鉴定，确认该粉末为吲哚菁绿酸三乙胺盐。
实施例3：
氮气保护下，温度保持在40℃，依次向反应瓶中加入吲哚菁绿-05(15.01g)、吲哚菁绿-03(8.68g)、无水乙醇(90ml)，加入三乙胺(2.80g)，反应3小时。反应完毕，在-5～0℃下，滴加到900ml甲基叔丁基醚中，体系析出分散的粉末状固体，减压过滤，得到黑色松散粉末。
与实施例1相同地进行鉴定，确认该粉末为吲哚菁绿酸三乙胺盐。
实施例4：
氮气保护下，温度保持在25℃，依次向反应瓶中加入吲哚菁绿-05(15.01g)、吲哚菁绿-03(8.68g)、无水乙醇(90ml)，加入三乙胺(2.80g)，反应3小时。反应完毕，在-5～0℃下，滴加到900ml异丙醚中，体系析出分散的粉末状固体，减压过滤，得到黑色松散粉末。
与实施例1相同地进行鉴定，确认该粉末为吲哚菁绿酸三乙胺盐。
比较例1
氮气保护下，温度保持在0℃，依次向反应瓶中加入吲哚菁绿-05(15.01g)、吲哚菁绿-03(8.68g)、无水乙醇(90ml)，加入三乙胺(2.80g)，反应3小时。反应完毕，在-5～0℃下，滴加到900ml乙二醇二甲醚中，结果，粘稠物吸附在瓶底，倒出上清液，得到黑色的油状粘稠物，不是粉状物。
比较例2
根据专利文献(CN104130178A)记载的方法进行制备，具体如下：
将吲哚菁绿-05和吲哚菁绿-03按照质量比1.7:1混合，即向反应瓶中依次加入吲哚菁绿-05(15.01g)、吲哚菁绿-03(8.68g)，128ml的无水乙醇，氮气保护下再加入为无水乙醇质量5％的三乙胺，加热到78℃回流30分钟后，将反应液在0.5小时内冷却到30℃，然后加入无水乙醇体积的2.15倍即275ml的乙醚，粘稠的固体吸附在反应瓶底部，然后将上清液倒出，得到黑色的油状粘稠物，不是粉状物。
表1
例 反应温度℃ 析晶溶剂 产品状态
实施例1 0 乙醇和甲基叔丁基醚 黑色固体粉末
实施例2 25 乙醇和甲基叔丁基醚 黑色固体粉末
实施例3 40 乙醇和甲基叔丁基醚 黑色固体粉末
实施例4 25 乙醇和异丙醚 黑色固体粉末
比较例1 0 乙醇和乙二醇二甲醚 黑色粘稠物
比较例2 回流条件即78℃ 乙醇和乙醚 黑色粘稠物
发明人针对实施例2所得的吲哚菁绿-06粗品进行纯度测定，结果，其纯度为94.71％，具体数据如图3所示。为了获得高纯度吲哚菁绿酸三乙胺盐，发明人进一步进行了纯化步骤。需要说明的是，本发明的实施例及比较例中的纯度数据均是使用高效液相色谱仪Agilent 1260 Ⅱ、采用十八烷基硅烷键合硅胶为填充剂、以磷酸盐缓冲液(pH 5.8)-乙腈-甲醇(50:47:3)为流动相进行等度洗脱所得。
实施例5
向实施例2所得的吲哚菁绿-06粗品4g(纯度为94.71％)中加入12ml的无水乙醇，样品溶解，在-5～0℃下，滴加到为乙醇体积6倍的甲基叔丁基醚中，搅拌0.5小时，减压过滤，得到粉末状固体。将所得的粉末状固体重复进行上述操作，得到纯度为97.77％的粉末状吲哚菁绿-06，具体纯度数据如图4所示。进而，将纯度为97.77％的粉末状固体再一次重复上述操作，纯度进一步提升，得到纯度为99.05％的高纯粉末状吲哚菁绿-06，具体纯度数据如图5所示。
实施例6
向实施例2所得的吲哚菁绿-06粗品4g(纯度为94.71％)中加入12ml的无水乙醇，样品溶解，在-5～0℃下，滴加到为乙醇体积10倍的甲基叔丁基醚中，搅拌0.5小时，减压过滤，得到粉末状固体。与实施例5相同地将得到的粉末状固体再次进行2次上述操作，与实施例5相同地进行纯度测定，得到纯度为99.00％的高纯粉末状吲哚菁绿-06。
实施例7
向实施例2所得的吲哚菁绿-06粗品4g(纯度为94.71％)中加入12ml的无水乙醇，样品溶解，在-5～0℃下，滴加到为乙醇体积13倍的甲基叔丁基醚中，搅拌0.5小时，减压过滤，得到粉末状固体。与实施例5相同地将得到的粉末状固体再次进行2次上述操作，与实施例5相同地进行纯度测定，得到纯度为98.69％的高纯粉末状吲哚菁绿-06。
通过上述实施例5～7可知，通过使用乙醇：甲基叔丁基醚＝1：6～13的纯化试剂，能够提高粗品吲哚菁绿-06的纯度，获得高纯度的粉末状吲哚菁绿-06。
比较例3
向实施例5中的纯度为97.77％的粉末状吲哚菁绿-06粗品中加入12ml的无水乙醇，样品溶解，在-5～0℃下，滴加到为乙醇体积15倍的甲基叔丁基醚中，搅拌0.5小时，减压过滤，得到粉末状固体。将得到的粉末状固体继续重复这种操作2次，得到粉末状吲哚菁绿-06，纯度为97.83％。
由此可见，即使将甲基叔丁基醚的量提高至乙醇体积的15倍、并增加重复操作的次数，也不能进一步提高吲哚菁绿-06的纯度。
比较例4
向比较例3所得的吲哚菁绿-06粗品(纯度为97.83％)中加入12ml的无水乙醇，样品溶解，在-5～0℃下，滴加到为乙醇体积2倍的异丙醚中，搅拌0.5小时，减压过滤，得到粉末状固体。将得到的粉末状固体继续重复这种操作2次，得到纯度为97.97％的粉末状吲哚菁绿-06，没有除杂效果。
比较例5
向比较例3所得的吲哚菁绿-06粗品(纯度为97.83％)中加入12ml的无水乙醇，样品溶解，在-5～0℃下，滴加到为乙醇体积5倍的异丙醚中，搅拌0.5小时，减压过滤，得到粉末状固体。将得到的粉末状固体继续重复这种操作2 次，得到纯度为97.95％的粉末状吲哚菁绿-06，没有除杂效果。
比较例6
向比较例3所得的吲哚菁绿-06粗品(纯度为97.83％)中加入12ml的无水乙醇，样品溶解，在-5～0℃下，滴加到为乙醇体积10倍的异丙醚中，搅拌0.5小时，减压过滤，得到粉末状固体。将得到的粉末状固体继续重复这种操作2次，得到纯度为97.85％的粉末状吲哚菁绿-06，没有除杂效果。
通过比较例4～6的数据可知，采用乙醇：异丙醚＝1：2～10的纯化试剂，无法进一步提高吲哚菁绿-06的纯度，不能达到药用级别。
比较例7
向实施例2所得的吲哚菁绿-06粗品4g(纯度为94.71％)中加入12ml的无水乙醇，样品溶解，在-5～0℃下，加入为乙醇体积2.15倍的乙醚，搅拌0.5小时，得到粘稠的固体并吸附在反应瓶底部，然后将上清液倒出，向反应瓶中继续加入12ml的无水乙醇和2.15倍乙醇体积的乙醚，搅拌0.5小时后，重新倒出上清液，如此反复2次，得到黑色的油状粘稠物，纯度为98.28％。
比较例8
除了将乙醚的量变为乙醇体积的6倍之外，与比较例7相同地进行，得到黑色的油状粘稠物，98.00％。
比较例9
向实施例2所得的吲哚菁绿-06粗品4g(纯度为94.71％)中加入12ml的无水乙醇，样品溶解，在-5～0℃下，滴加到为乙醇体积4倍的甲基叔丁基醚中，搅拌0.5小时，得到粘稠的物并吸附在反应瓶底部，然后将上清液倒出，向反应瓶中继续加入12ml的无水乙醇和4倍乙醇体积的甲基叔丁基醚，搅拌0.5小时后，重新倒出上清液，如此反复2次，得到黑色的油状粘稠物，纯度为98.22％。
比较例10
室温条件下，将实施例2所得的吲哚菁绿-06粗品2g加入到10ml体积比为乙酸乙酯：正己烷＝5：1的溶剂中，搅拌0.5小时，没有固体析出，放入冰箱冷冻24小时，没有固体析出。
比较例11
室温条件下，将实施例2所得的吲哚菁绿-06粗品2g加入到丙酮中，搅拌0.5小时，没有固体析出，放入冰箱冷冻24小时，没有固体析出。
比较例12
室温条件下，将实施例2所得的吲哚菁绿-06粗品2g加入到6ml甲醇中，搅拌0.5小时，没有固体析出，加入30ml甲基叔丁基醚，放入冰箱冷冻24小时，没有固体析出。
比较例13
室温条件下，将实施例2所得的吲哚菁绿-06粗品2g加入到异丙醇中，搅拌0.5小时，没有固体析出，放入冰箱冷冻24小时，没有固体析出。
比较例14
室温条件下，将实施例2所得的吲哚菁绿-06粗品2g加入到正丁醇中，搅拌0.5小时，没有固体析出，放入冰箱冷冻24小时，没有固体析出。
通过上述实验例1～4以及比较例1、2的对比可知，本申请发明通过在特定的反应温度下进行反应并在甲基叔丁基醚或异丙醚中进行析出，能够得到粉末状的吲哚菁绿酸三乙胺盐。通过实施例5～7以及比较例3～14的比较数据可知，通过使用特定的析晶溶剂，能够进一步提高纯度，从而得到达药用级别的粉末状吲哚菁绿酸三乙胺盐。
上述实验结果表明，通过本发明能够制备得到粉末状的吲哚菁绿酸三乙胺盐，在制备吲哚菁绿工艺中可以准确计算投料比，制备得到的碘含量稳定的吲哚菁绿产品，保证工艺稳定性。本发明通过控制相关工艺参数，反应过程中杂质较少，吲哚菁绿的产品质量大幅提升。进而，通过本发明可以制备得到高纯的粉末状吲哚菁绿酸三乙胺盐，产品质量达到原料药级别。该吲哚菁绿酸三乙胺盐可以直接用于吲哚菁绿的生产，直接制备得到符合原料药标准的吲哚菁绿。
综上所述，本发明提供了一种稳定制备吲哚菁绿酸三乙胺盐的工艺方法，通过控制关键中间体吲哚菁绿酸三乙胺盐的质量，能够保证在工业上稳定生产出高纯的粉末状吲哚菁绿产品。

Claims (7)

  1. 一种吲哚菁绿酸三乙胺盐的制备方法，其特征在于，包括如下步骤：
    使2，3，3-三甲基-1-(4-磺基丁基)-4，5-苯并吲哚内胺盐、2-[6-(N-乙酰基苯胺基)-1，3，5-己三烯-1-基]-3，3-二甲基-1-(4-磺基丁基)-4，5-苯并吲哚内胺和三乙胺在有机溶剂中在0℃～40℃的温度下进行反应的步骤；以及
    反应完毕后将所得物加入甲基叔丁基醚或者异丙醚中、得到粉末状吲哚菁绿酸三乙胺盐的步骤。
  2. 根据权利要求1所述的吲哚菁绿酸三乙胺盐的制备方法，其特征在于，
    所述制备方法中，不包括进行加热回流的步骤。
  3. 根据权利要求1所述的吲哚菁绿酸三乙胺盐的制备方法，其特征在于，
    还包括将所得的粉末状吲哚菁绿酸三乙胺盐进行纯化的步骤，即，将所得的粉末状吲哚菁绿酸三乙胺盐溶解于乙醇后，加入到甲基叔丁基醚中，经搅拌、过滤得到高纯粉末状吲哚菁绿酸三乙胺盐，乙醇与甲基叔丁基醚以体积比计为1：6～13。
  4. 根据权利要求3所述的吲哚菁绿酸三乙胺盐的制备方法，其特征在于，
    乙醇与甲基叔丁基醚以体积比计为1：6～10。
  5. 一种粉末状吲哚菁绿酸三乙胺盐，其通过权利要求1-4中任一项所述的吲哚菁绿酸三乙胺盐的制备方法得到。
  6. 一种吲哚菁绿酸三乙胺盐的纯化方法，其特征在于，包括如下步骤：
    将吲哚菁绿酸三乙胺盐溶解于乙醇后，加入到甲基叔丁基醚中，经搅拌、过滤得到高纯粉末状吲哚菁绿酸三乙胺盐，乙醇与甲基叔丁基醚以体积比计为1：6～13。
  7. 根据权利要求6所述的纯化方法，其特征在于，
    乙醇与甲基叔丁基醚以体积比计为1：6～10。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114685348A (zh) * 2022-04-14 2022-07-01 华南理工大学 一种具有aie性质的近红外花菁类光敏剂及其制备方法与应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115093362B (zh) * 2022-07-04 2023-05-23 深圳市罗素医药有限公司 一种吲哚菁绿的纯化方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2895955A (en) * 1957-06-05 1959-07-21 Eastman Kodak Co Tricarbocyanine infrared absorbing dyes
CN104130178A (zh) * 2014-06-30 2014-11-05 辽宁天医生物制药股份有限公司 一种药用吲哚菁绿的工业化合成方法
CN106631979A (zh) * 2016-09-28 2017-05-10 北京数字精准医疗科技有限公司 一种吲哚菁绿及其制备方法与应用
US20180346728A1 (en) * 2015-12-01 2018-12-06 Dishman Pharmaceuticals And Chemicals Limited Process for the preparation of indocyanine green

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108264475A (zh) * 2016-12-30 2018-07-10 中国科学院深圳先进技术研究院 吲哚菁绿衍生物及制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2895955A (en) * 1957-06-05 1959-07-21 Eastman Kodak Co Tricarbocyanine infrared absorbing dyes
CN104130178A (zh) * 2014-06-30 2014-11-05 辽宁天医生物制药股份有限公司 一种药用吲哚菁绿的工业化合成方法
US20180346728A1 (en) * 2015-12-01 2018-12-06 Dishman Pharmaceuticals And Chemicals Limited Process for the preparation of indocyanine green
CN106631979A (zh) * 2016-09-28 2017-05-10 北京数字精准医疗科技有限公司 一种吲哚菁绿及其制备方法与应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114685348A (zh) * 2022-04-14 2022-07-01 华南理工大学 一种具有aie性质的近红外花菁类光敏剂及其制备方法与应用

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