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Preparation process of tetramethyl rhodamine

A preparation process and tetramethyl technology, applied in the direction of organic chemistry and the like, can solve the problems of high price of tetramethyl rhodamine, cumbersome purification process, difficult batch preparation, etc., and achieve low cost, simplified operation steps, and low equipment requirements. Effect

Active Publication Date: 2017-09-15
北京欧凯纳斯生化科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Tetramethylrhodamine has very broad application prospects. The existing preparation methods include traditional direct condensation synthesis, stepwise condensation synthesis, condensation of aminophenol and aldehyde compounds, aminophenol and 1-hydroxy-3-oxo -1,3-dihydroisobenzofuran-5-carboxylic acid condensation oxidation reaction; the yield of the above preparation method is low (generally only more than ten percent), and the purification process is cumbersome (preparative column purification), resulting in tetramethyl Rhodamine is very expensive
This synthetic method first obtains the isomer mixture of the 5-position substituent and the 6-position substituent, and most of these 5-position and 6-position substituent isomers are separated by chromatographic methods (such as preparative column or silica gel column chromatography) , this separation method has high cost and can only obtain gram-level or even milligram-level finished products, which is difficult to prepare in batches

Method used

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  • Preparation process of tetramethyl rhodamine
  • Preparation process of tetramethyl rhodamine
  • Preparation process of tetramethyl rhodamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Synthesis of 5(6)-tetramethylrhodamine: 4 kilograms of N,N-dimethyl-m-aminophenol and 2680 grams of trimellitic trianhydride, and 20L o-dichlorobenzene were added to a 50L tank with a thermometer and stirring Inside the glass reactor. Remove the air in the reaction kettle, feed nitrogen gas, gradually heat up the reaction system to 40°C, add 500 grams of methanesulfonic acid, heat up the reaction system to 150°C, react for 4 hours, and observe that a large amount of solids are formed and precipitate out of the system And adhere to the inner wall of the reactor. After stopping the reaction, let it stand for 15 minutes, and the reaction was completed.

[0059] Sampling and detection showed that the conversion rate of trimellitic trianhydride was 99%, and the yield of 5(6)-tetramethylrhodamine was 82%. The o-dichlorobenzene solvent will be released from the lower discharge port of the reaction kettle, add 20L methanol into the reaction kettle, stir and slowly heat to 50°...

Embodiment 2

[0061] Purification of 5(6)-tetramethylrhodamine: 4780 g of crude 5(6)-tetramethylrhodamine obtained in Example 1 and 20 L of acetonitrile were added to a 50 L glass reactor with a thermometer and stirring. Remove the air in the reaction kettle, feed nitrogen, and gradually heat up the reaction system to 80°C, heat it for about 1 hour, the solid in the system dissolves completely, then stop heating, stop stirring, let it stand to room temperature, and find that there is solid precipitation. Continue to stand still for 12 hours, filter; repeat this process again after the filtrate is concentrated, merge the filter cake twice, wash twice with cooling 2L acetonitrile, dry to get 4386 grams of 5(6)-tetramethylrhodamine pure product , is a dark green solid with a yield of 72% and a purity of 97.6%, of which 5-tetramethylrhodan accounts for 54.49%, and 6-tetramethylrhodan accounts for 43.04%.

[0062] Such as figure 1 with figure 2 Shown, 1H-NMR: (400MHz, CD3OD, ppm) δ: 6.983-6.9...

Embodiment 3

[0064] 5,6-Tetramethylrhodamine ammonium salt preparation: 4300 grams of 5 (6)-tetramethylrhodamine pure product that embodiment 2 is made and 43L dioxane add 100L glass reaction that has thermometer and stirring In the kettle, heat to 40°C and stir for 2 hours to fully dissolve the solid. After the solid is fully dissolved, stop heating, gradually cool the reaction system to room temperature, and add 3036 g of diisopropylamine dropwise. During the dropwise addition, heat is released and the reaction is controlled. The system temperature does not exceed 30°C. The system gradually turned into a purple-black solution. After the dropwise addition, continue to stir for 1 hour. The system turns into a purple-red suspension. Stop stirring and let it stand for 1 hour. It is found that a large amount of red solids are precipitated. Continue to stand for 2 hours and filter with suction. The cake was 5-tetramethylrhodamine diisopropylamine salt, and the filter cake was washed with 5 L o...

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Abstract

The invention relates to a preparation process of tetramethyl rhodamine, which comprises the following steps: performing cyclization reaction on m-hydroxy-N,N'-dimethylaniline and 1,2,4-benzenetricarboxylic anhydride as raw materials to directly prepare a 5(6)-tetramethyl rhodamine isomer mixture, purifying by recrystallization, reacting the isomer mixture and an organic amine to form a salt, splitting by using different solubility of the two salts in a solvent, and removing salts by an acid-out method to prepare 5-tetramethyl rhodamine and 6-tetramethyl rhodamine. The preparation process disclosed by the invention has the advantages of simple operation, low requirements on equipment, low cost, high equipment service efficiency, and so on, and can achieve the requirements for industrial production and application.

Description

technical field [0001] The invention relates to a preparation process of a fluorescent dye, in particular to a preparation process of tetramethylrhodamine. Background technique [0002] Rhodamine-based compounds are dyes based on xanthene. Due to their special structure, compared with other commonly used fluorescent dyes, rhodamine-based fluorescent dyes have the following advantages: good photostability, insensitive to pH, wide wavelength range and high fluorescence quantum yield. Therefore, it is widely used in pharmacology, physiology, molecular biology, cell biology, molecular genetics, environmental chemistry, single molecule detection, information science, fluorescent labeling, laser dyes, etc. Among them, tetramethylrhodamine (TAMRA) has the advantages of strong lipophilicity, small Stokes shift, high fluorescence quantum yield, long emission wavelength and large absorption coefficient, and is widely used in DNA sequencing, immunofluorescent staining, and labeled an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/82
CPCC07D311/82
Inventor 余明辉陈豪王峰华林
Owner 北京欧凯纳斯生化科技有限公司