Preparation method of high-purity fluorescein sodium

Abstract

The application discloses a preparation method of high-purity fluorescein sodium. The fluorescein is synthesized from o-phthalic anhydride and resorcinol under the catalysis of sodium bisulfate or potassium bisulfate without using an organic solvent as a solvent, and then the fluorescein is used to prepare fluorescein diacetate; and the high-purity fluorescein sodium is obtained through a synthesis route of saponification, acidification and salt formation. The synthesis route has mild reaction conditions, simple operation steps, no organic solvent, avoids the generation of organic solvent pollution, has low raw material and auxiliary material consumption, low production cost, high purity of reactants and high yield.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical drugs, in particular to a preparation method of high-purity fluorescein sodium. BACKGROUND

[0002] At present, there are two strategies for the synthesis of fluorescein sodium. One is to use phthalic anhydride and resorcinol to synthesize fluorescein under the catalysis of concentrated sulfuric acid or boron trifluoride, and then to react the fluorescein with sodium hydroxide solution to obtain fluorescein sodium. The other is the diacetyl fluorescein derivative method, that is, using industrial-grade fluorescein as the starting material, after simple post-treatment and purification, the fluorescein reacts with acylating reagent to generate diacetyl fluorescein derivative, and then after saponification and acidification, the fluorescein reacts with sodium hydroxide to obtain high-purity fluorescein sodium.

[0003] Method one:

[0004]

[0005] The F-C acylation reaction of phthalic anhydride and resorcinol is carried out under the catalysis of boron trifluoride or concentrated sulfuric acid, and then the intermediate reacts with one molecule of resorcinol to carry out Michael addition reaction, and the addition reaction carries out intramolecular dehydration condensation to generate fluorescein with mixed lactone structure and quinone structure. The fluorescein reacts with sodium hydroxide solution to generate fluorescein sodium.

[0006] Method two:

[0007]

[0008] Phthalic acid reacts with resorcinol under the action of methanesulfonic acid to generate fluorescein, and then the fluorescein reacts with sodium hydroxide solution to generate fluorescein sodium.

[0009] The starting materials of the two synthesis methods are different, but both are phthalic acid or anhydride and phenol as starting materials, which undergo F-C acylation reaction and condensation reaction under acidic conditions to generate fluorescein, and then the fluorescein is salted with sodium hydroxide.

[0010] In method one, boron trifluoride is used as a catalyst, which increases the production cost and has certain risk in operation, and is not suitable for industrial production. Sulfuric acid is used as a catalyst, which is low in cost and suitable for industrial production, but has the disadvantages of generating sulfonation by-products which are difficult to remove, and environmental pressure of using concentrated sulfuric acid.

[0011] In method two, methanesulfonic acid is used as a catalyst, and there are more sulfonation by-products, and the reactivity of phthalic acid is lower than that of phthalic anhydride, so the yield of fluorescein is low. SUMMARY

[0012] In order to overcome the prior art, the present application provides a kind of fluorescent sodium preparation method with mild reaction condition, simple step operation, no organic solvent, while raw material consumption is less, low cost, high purity, with phthalic anhydride and resorcinol as starting material, under the condition of no organic solvent as solvent, sodium bisulfate or potassium bisulfate is catalyzed to synthesize and obtain fluorescein, then fluorescein is used to prepare fluorescein diacetate, and high-purity fluorescein sodium is obtained by the synthesis route of saponification, acidification and salt formation.

[0013] The technical scheme adopted by the present application to solve its technical problems is:

[0014] A kind of fluorescent sodium preparation method, and the synthesis reaction route is:

[0015] ,

[0016] It specifically includes the following steps:

[0017] (1) condensation reaction: in the reactor, phthalic anhydride, resorcinol, potassium bisulfate or sodium bisulfate is added, and the temperature is raised to 190~210 DEG C, the solid is melted into solution, and then stirred for 20~30 minutes, after thickening, stop stirring, and keep warm for 2h, after dissolving by adding 5%~6% sodium hydroxide solution, slowly drop 6mol / L hydrochloric acid to adjust pH=1~2 at 2~8 DEG C, get red precipitate, filter, filter cake is stirred for 30 minutes at 80 DEG C with purified water, filter, get red precipitate, dry, get fluorescein;

[0018] (2) acetylation: in the reactor, fluorescein and acetic anhydride are added, the temperature is raised to 100~110 DEG C, and the reaction is kept for 3~5 hours, then the temperature is lowered to crystallize, filter, dry, and then beat with acetone and methyl tert-butyl ether at room temperature, filter, dry, and get yellow powder diacetyl fluorescein;

[0019] (3) salt formation: in the reactor, diacetyl fluorescein is added, 6 times the volume of 1mol / L sodium hydroxide solution is added, the temperature is raised to 80 DEG C, and the stirring is fully carried out until the solid is completely dissolved, then filter, the temperature is lowered to 2~8 DEG C, and then slowly drop glacial acetic acid into the filtrate to adjust pH=1~2, filter, the filter cake is washed with purified water, 4 times the volume of purified water is added to the filter cake, 20% sodium hydroxide solution is added to adjust pH=8.0~9.0, after stirring to dissolve clear at 40~50 DEG C, active carbon is added, stir for 1 hour, then filter, and the filtrate is vacuum rotary dried, and then dried at 120 DEG C for 6 hours, to get orange-red solid fluorescein sodium.

[0020] Preferably, in step (1), the mass ratio of phthalic anhydride, resorcinol and potassium bisulfate or sodium bisulfate is 1:1.8~2.0:0.05~0.07, and the amount of sodium hydroxide solution is 9 times the volume based on 1g of phthalic anhydride.

[0021] Preferably, the mass ratio of fluorescein to acetic anhydride in step (2) is 1:2-3.

[0022] Preferably, the amount of acetone and methyl tert-butyl ether used in step (2) is 2 times and 1 times the volume, respectively.

[0023] The preparation method of fluorescein sodium according to the present application has the following advantages over the prior art:

[0024] The synthetic route has mild reaction conditions, simple step operation, no organic solvent, avoids the generation of organic solvent pollution, uses less raw and auxiliary materials, reduces production cost, has high purity of reactants and high yield. DETAILED DESCRIPTION

[0025] The present application will be described in detail below with reference to examples, but should not be construed as limiting the application. Example 1

[0026] Into a glass bottle, 20 g of phthalic anhydride, 36 g of resorcinol and 1.4 g of potassium bisulfate were added, and the temperature was raised to 200°C. After the solid was melted into a solution and stirred for 30 minutes, the stirring was stopped after the solution became thick, and the reaction was maintained at 200°C for 2 hours to obtain fluorescein solid. The fluorescein solid was dissolved in 5% sodium hydroxide solution, and 6 mol / L hydrochloric acid was slowly added at 8°C to adjust the pH to 1.0 to obtain a red precipitate. The precipitate was filtered, and the filter cake was stirred in distilled water at 80°C for 30 minutes and then filtered to obtain a red precipitate. The precipitate was dried to obtain 40.3 g of fluorescein with a purity of 87% and a yield of 89.8%.

[0027] Into a three-necked glass bottle, 40 g of fluorescein and 80 ml of acetic anhydride were added, and the temperature was raised to 110°C. The reaction was maintained at 110°C for 4 hours, and then the temperature was lowered to precipitate crystals. The crystals were filtered and dried, and then 2 times the volume of acetone and 1 times the volume of methyl tert-butyl ether were added to the crystals, respectively, to make a slurry at room temperature. The slurry was filtered and dried to obtain 31 g of diacetyl fluorescein in the form of yellow powder with a purity of 99.54% and a yield of 59.8%.

[0028] Into a reactor, 30 g of diacetyl fluorescein was added, and 6 times the volume of 1 mol / L sodium hydroxide solution was added. The temperature was raised to 80°C, and the mixture was stirred until the solid was completely dissolved. The mixture was filtered, and the temperature was lowered to 8°C. Glacial acetic acid was slowly added to the filtrate to adjust the pH to 2.0. The mixture was filtered, and the filter cake was washed with purified water. 4 times the volume of purified water was added to the filter cake, and 20% sodium hydroxide solution was added to adjust the pH to 8.0. After the mixture was stirred at 45°C until it became clear, activated carbon was added. After stirring for 1 hour, the mixture was filtered, and the filtrate was vacuum rotary evaporated and dried at 90°C for 6 hours to obtain 25 g of orange-red solid fluorescein sodium with a purity of 99.94% and a yield of 92.5%.

[0029] NMR data as follows:1H NMR (400 MHz, D2O): δ 6.52 (dd, 2H), 6.91 (d, 1H), 6.40 (d, 1H), 6.91 (d, 1H) 6.52 (dd, 2H), 6.40 (d, 1H), 7.75 (d, 1H), 7.44 (td, 1H), 7.23 (td, 1H), 6.55 (d, 1H). Example 2

[0030] Into a glass bottle, 50 g of phthalic anhydride, 90 g of resorcinol, 3.5 g of potassium hydrogen sulfate were added, and the temperature was raised to 195°C. After the solid was melted into a solution and stirred for 25 minutes, the stirring was stopped after the solution became thick, and the reaction was maintained for 2 h. Fluorescein solid was obtained. After the solid was dissolved with 5% sodium hydroxide solution, 6 mol / L hydrochloric acid was slowly added dropwise at 5°C to adjust the pH to 2.0. A red precipitate was obtained, which was filtered. The filter cake was stirred in distilled water at 80°C for 30 minutes, filtered, and dried to obtain 98.7 g of fluorescein with a purity of 86% and a yield of 88.1%.

[0031] Into a three-necked glass bottle, 98 g of fluorescein, 196 ml of acetic anhydride were added, and the temperature was raised to 100°C. The reaction was maintained for 3 h, and the product was crystallized after cooling. After filtration and drying, the product was washed with 2 times the volume of acetone and 1 times the volume of methyl tert-butyl ether at room temperature, respectively, and then filtered and dried to obtain 78.8 g of yellow powder of diacetyl fluorescein with a purity of 99.6% and a yield of 64%.

[0032] Into a reactor, 78 g of diacetyl fluorescein was added, and 6 times the volume of 1 mol / L sodium hydroxide solution was added. The temperature was raised to 80°C, and the stirring was maintained until the solid was completely dissolved. After filtration, the temperature was lowered to 2°C, and glacial acetic acid was slowly added dropwise to the filtrate to adjust the pH to 1.0. After filtration, the filter cake was washed with purified water. The filter cake was added to 4 times the volume of purified water, and 20% sodium hydroxide solution was added to adjust the pH to 9.0. After the solution was dissolved by stirring at 50°C, activated carbon was added, and the stirring was maintained for 1 h. After filtration, the filtrate was vacuum dried, and the product was dried at 90°C for 6 h to obtain 64.5 g of orange-red solid fluorescein sodium with a purity of 99.7% and a yield of 91.4%.

[0033] NMR data as follows:1H NMR (400 MHz, D2O): δ 6.52 (dd, 2H), 6.91 (d, 1H), 6.40 (d, 1H), 6.91 (d, 1H) 6.52 (dd, 2H), 6.40 (d, 1H), 7.75 (d, 1H), 7.44 (td, 1H), 7.23 (td, 1H), 6.55 (d, 1H). Example 3

[0034] Into a glass bottle, 30 g of phthalic anhydride, 54 g of resorcinol, and 1.5 g of sodium bisulfate were added, and the temperature was raised to 210°C. After the solid was melted into a solution and stirred for 20 minutes, stirring was stopped after the solution became thick, and the reaction was maintained for 2 h. Fluorescein solid was obtained, which was dissolved with 5% sodium hydroxide solution, and the pH was adjusted to 1.0 by slowly adding 6 mol / L hydrochloric acid at 2°C. A red precipitate was obtained, which was filtered, stirred in distilled water at 80°C for 30 minutes, filtered, dried, and red precipitate was obtained. After drying, 59.1 g of fluorescein was obtained, with a purity of 86.7% and a yield of 87.8%.

[0035] Into a three-necked glass bottle, 59 g of fluorescein, 118 ml of acetic anhydride were added, and the temperature was raised to 105°C. After the reaction was maintained for 4 h, the temperature was lowered to induce crystallization, and the product was filtered and dried. The product was then washed with 2 volumes of acetone and 1 volume of methyl tert-butyl ether at room temperature, filtered, and dried. 44.3 g of yellow powder of diacetyl fluorescein was obtained, with a purity of 99.6% and a yield of 60%.

[0036] Into a reactor, 44 g of diacetyl fluorescein was added, and 6 volumes of 1 mol / L sodium hydroxide solution was added. The temperature was raised to 80°C, and the solid was completely dissolved by stirring. After filtration, the temperature was lowered to 5°C, and glacial acetic acid was slowly added to the filtrate to adjust the pH to 2.0. After filtration, the filter cake was washed with purified water. 4 volumes of purified water was added to the filter cake, and 20% sodium hydroxide solution was added to adjust the pH to 8.0. After the solution was dissolved by stirring at 40°C, activated carbon was added, and the mixture was stirred for 1 h. After filtration, the filtrate was vacuum dried, and the product was dried at 90°C for 6 h. 35.7 g of orange-red solid sodium fluorescein was obtained, with a purity of 99.6% and a yield of 90%.

[0037] NMR data are as follows: 1H NMR (400 MHz, D2O): δ 6.52 (dd, 2H), 6.91 (d, 1H), 6.40 (d, 1H), 6.91 (d, 1H), 6.52 (dd, 2H), 6.40 (d, 1H), 7.75 (d, 1H), 7.44 (td, 1H), 7.23 (td, 1H), 6.55 (d, 1H). Example 4

[0038] Into a glass bottle, 70 g of phthalic anhydride, 126 g of resorcinol, and 4.7 g of sodium bisulfate were added, and the temperature was raised to 200°C. After the solid was melted into a solution and stirred for 30 minutes, stirring was stopped after the solution became thick, and the reaction was maintained for 2 h. Fluorescein solid was obtained, which was dissolved with 5% sodium hydroxide solution, and the pH was adjusted to 2.0 by slowly adding 6 mol / L hydrochloric acid at 8°C. A red precipitate was obtained, which was filtered, stirred in distilled water at 80°C for 30 minutes, filtered, dried, and red precipitate was obtained. After drying, 137.7 g of fluorescein was obtained, with a purity of 85.9% and a yield of 87%.

[0039] Into a three-necked glass flask, 137 g of fluorescein, 274 ml of acetic anhydride were added, and the temperature was raised to 108°C, and the reaction was maintained for 5 h. The temperature was then lowered to precipitate the crystals, which were filtered and dried. The product was then washed with 2 volumes of acetone and 1 volume of methyl tert-butyl ether, respectively, at room temperature, filtered and dried to obtain 104.7 g of yellow powder of diacetyl fluorescein, with a purity of 99.7% and a yield of 61%.

[0040] Into a reactor, 104 g of diacetyl fluorescein was added, and 6 volumes of 1 mol / L sodium hydroxide solution was added to raise the temperature to 80°C, and the mixture was stirred until the solid was completely dissolved. The solution was then filtered, and the temperature was lowered to 2°C. Glacial acetic acid was then added dropwise to the filtrate to adjust the pH to 1.0. The mixture was then filtered, and the filter cake was washed with purified water. The filter cake was then added to 4 volumes of purified water, and 20% sodium hydroxide solution was added to adjust the pH to 9.0. The mixture was then stirred at 40°C until it was clear. Activated carbon was then added, and the mixture was stirred for 1 h before being filtered. The filtrate was then vacuum dried, and dried at 90°C for 6 h to obtain 84.6 g of orange-red solid sodium fluorescein, with a purity of 99.75% and a yield of 90%.

[0041] NMR data are as follows: 1H NMR (400 MHz, D2O): δ 6.52 (dd, 2H), 6.91 (d, 1H), 6.40 (d, 1H), 6.91 (d, 1H), 6.52 (dd, 2H), 6.40 (d, 1H), 7.75 (d, 1H), 7.44 (td, 1H), 7.23 (td, 1H), 6.55 (d, 1H).

[0042] Although the present application has been described in detail with general description and specific embodiments above, some modifications or improvements can be made to the present application, which will be apparent to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present application are within the scope of the present application.

Claims

1. A method for preparing sodium fluorescein, characterized in that: The synthetic reaction route is: ， The specific steps include: (1) Condensation reaction: Add phthalic anhydride, resorcinol, potassium bisulfate or sodium bisulfate to the reactor, heat to 190℃~210℃, stir for 20~30 minutes after the solid melts into solution, stop stirring after it becomes thick, keep warm and react for 2 hours, add 5%~6% sodium hydroxide to dissolve, slowly add 6mol / L hydrochloric acid at 2~8℃ to adjust the pH to 1~2, and obtain a red precipitate. Filter, stir the filter cake with purified water at 80℃ for 30 minutes, filter, and obtain a red precipitate. Dry and obtain fluorescein. (2) Acetylation: Add fluorescein and acetic anhydride to the reactor, heat to 100-110°C, keep the temperature for 3-5 hours, cool to crystallize, filter, dry, and then slurry with acetone and methyl tert-butyl ether at room temperature, filter, and dry to obtain yellow powdered diacetyl fluorescein. (3) Salt formation: Add diacetyl fluorescein to the reactor, add 6 times the volume of 1 mol / L sodium hydroxide solution, heat to 80 ° C and stir thoroughly until the solid is completely dissolved, filter, cool to 2~8 ° C and slowly add glacial acetic acid to the filtrate to adjust the pH to 1~2, filter, wash the filter cake with purified water, add 4 times the volume of purified water to the filter cake, add 20% sodium hydroxide solution to adjust the pH to 8.0~9.0, stir at 40~50 ° C to dissolve clearly, add activated carbon, stir for 1 hour and filter, vacuum dry the filtrate, and dry at 120 ° C for 6 hours to obtain orange-red solid fluorescein sodium.

2. The preparation method according to claim 1, wherein: In the step (1), the mass ratio of phthalic anhydride, resorcinol and potassium bisulfate or sodium bisulfate is 1:1.8-2.0:0.05-0.07, and the amount of sodium hydroxide solution used is 9 times the volume based on 1g of phthalic anhydride.

3. The preparation method according to claim 1, wherein: In the step (2), the mass ratio of fluorescein to acetic anhydride is 1:2-3.

4. The preparation method according to claim 1, wherein: In the step (2), the amounts of acetone and methyl tert-butyl ether used are 2 volumes and 1 volume, respectively.

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