WO2022021072A1 - Procédé de préparation de sel de triéthylamine d'acide vert d'indocyanine - Google Patents
Procédé de préparation de sel de triéthylamine d'acide vert d'indocyanine Download PDFInfo
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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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- Prior art keywords
- indocyanine green
- triethylamine salt
- acid triethylamine
- green acid
- purity
- Prior art date
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 title claims abstract description 109
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 title claims abstract description 84
- 229960004657 indocyanine green Drugs 0.000 title claims abstract description 84
- 239000002253 acid Substances 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 51
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 111
- 238000000034 method Methods 0.000 claims description 21
- 239000000843 powder Substances 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 10
- -1 5-benzindole lactine salt Chemical class 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 3
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 abstract 4
- MRUOEOGYSDTCDK-UHFFFAOYSA-N 1h-cyclopenta[c]quinoline Chemical compound C1=CC=CC2=C3CC=CC3=CN=C21 MRUOEOGYSDTCDK-UHFFFAOYSA-N 0.000 abstract 2
- 229960003237 betaine Drugs 0.000 abstract 2
- 239000007787 solid Substances 0.000 description 37
- 230000000052 comparative effect Effects 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 239000011345 viscous material Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
Images
Classifications
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Indole Compounds (AREA)
Abstract
L'invention concerne un procédé de préparation de sel de triéthylamine d'acide vert d'indocyanine, comprenant les étapes suivantes, consistant à : faire réagir de la 2,3,3-triméthyl-1-(4-sulfobutyl)-4, 5-benzindolbétaïne, de la 2-[6-(N-acétylanilino)-1,3,5-hexatrién-1-yl]-3,3-diméthyl-1-(4-sulfobutyl)-4,5-benzindolbétaïne et de la triéthylamine dans un solvant organique à la température de 0°C-40°C ; et après la fin de la réaction, ajouter le produit obtenu dans du méthyl-tert-butyléther ou de l'isopropyléther pour obtenir un sel pulvérulent de triéthylamine d'acide vert d'indocyanine. Le sel pulvérulent de triéthylamine d'acide vert d'indocyanine obtenu résout le problème selon lequel la matière huileuse du sel de triéthylamine d'acide vert d'indocyanine est difficile à produire industriellement.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202080003806.XA CN112469698B (zh) | 2020-07-28 | 2020-07-28 | 吲哚菁绿酸三乙胺盐的制备方法 |
| PCT/CN2020/105216 WO2022021072A1 (fr) | 2020-07-28 | 2020-07-28 | Procédé de préparation de sel de triéthylamine d'acide vert d'indocyanine |
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| PCT/CN2020/105216 WO2022021072A1 (fr) | 2020-07-28 | 2020-07-28 | Procédé de préparation de sel de triéthylamine d'acide vert d'indocyanine |
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| 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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| 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 |
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| 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 |
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| 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 |
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| 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)
| 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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| CN112469698A (zh) | 2021-03-09 |
| CN112469698B (zh) | 2023-05-02 |
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