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Preparation method of high-purity fluorescein sodium

A technology of sodium fluorescein and fluorescein, applied in the direction of organic chemistry, can solve the problems of increasing production costs, increasing preparation costs, and the quality of pharmaceutical-grade finished products cannot be guaranteed.

Active Publication Date: 2012-04-04
北京化药科创医药科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the catalyst DMF has certain toxicity, which increases the chance of contact between the reactant and the toxic reagent, and is more difficult to control the safety of making medicinal fluorescein sodium. Although it can be removed during the reaction, it undoubtedly increases the production cost.
The operation of this method is more complicated, and the quality of the finished product of pharmaceutical grade cannot be guaranteed.
[0009] Gao Ganshan et al. (Gao Ganshan, Li Fuwei, Lu Ruimin. Research on the purification process of fluorescein and fluorescein disodium salt. Shandong Chemical Industry [J]. 2008 (37): 1-2) (hereinafter referred to as prior art 3) discloses a The purification process of fluorescein and fluorescein disodium. This process uses sodium fluorescein as raw material and glacial acetic acid as the acetylation reagent. Under the action of a certain catalyst, acetylated fluorescein is obtained after catalyzed acetylation, and then purified by alkali Fluorescein is obtained after acidification and acidification. In this method, there are also raw materials and catalysts. Because the catalyst has certain toxicity to the human body, when making pharmaceutical grade fluorescein and fluorescein disodium, it is necessary to increase the impurity removal of the catalyst. The process, whether in the reaction or the purification project, increases the preparation cost, and also needs to increase the limited detection items of the catalyst in the quality detection

Method used

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  • Preparation method of high-purity fluorescein sodium
  • Preparation method of high-purity fluorescein sodium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Take 50.0 g of crude sodium fluorescein and 230 ml of acetic anhydride in a round bottom flask, and heat to reflux for 30 min. TLC inspection showed that sodium fluorescein had completely reacted. Cool down to below 25°C in an ice bath, and keep warm for 20 minutes to fully crystallize. Add 100ml of water, stir, and keep the temperature below 25°C. After dropping, stir for 10 minutes, filter with suction, wash the filter cake with water until the filtrate is colorless, and dry the filter cake to obtain crude diacetylfluorescein in light yellow crystals, yield: 90.7%

[0026] TLC conditions: Chloroform: Methanol: Ammonia = 30:15:1

[0027] Table 1 present invention and prior art acetylation reaction contrast

[0028]

Embodiment 2

[0030] Obtain 45.0g of crude acetyl fluorescein, add 200ml of dichloromethane, 40ml of petroleum ether (60-90), heat to reflux, cool and add 1.0g of activated carbon, reflux for 30 minutes, filter while it is hot, the mother liquor precipitates solid at room temperature, suction filter, and dry. About 40 g of the diacetylated compound in the form of white needle crystals was obtained. Yield: 89%.

Embodiment 3

[0032] Take 42.0g of refined diacetylated fluorescein and 160ml of distilled water in a reaction bottle, add NaOH solution (20.0g of NaOH, 40ml of distilled water), heat, and keep the reaction solution at 80°C for 40 minutes. Add 2.0 g of activated carbon, stir for 20 minutes, cool to room temperature, and filter. The filter cake was washed with 20ml of water and sucked dry. The filtrate was cooled, and dilute hydrochloric acid was slowly added dropwise to adjust the pH to 2.0 to obtain a red precipitate. After filtering, the filter cake was fully washed with distilled water, drained, and the filter cake was vacuum-dried to constant weight to obtain fluorescein. Yield: 97%.

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Abstract

The invention relates to a preparation method of high-purity fluorescein sodium. The preparation method comprises the following steps of: acetylating by using crude fluorescein sodium as the raw material and acetic anhydride as an acetylation reagent; recrystallizing the acetylated fluorescein; hydrolyzing; and salifying to obtain high-purity fluorescein sodium. In the preparation process of the obtained fluorescein sodium, the acetylation solvent is mild and can finish a reaction in a relatively short time without adding a catalyst so that the reaction cost is lower and the obtained product is safer.

Description

technical field [0001] The invention relates to a preparation method of high-purity fluorescein sodium. Background technique [0002] Fluorescein sodium (Fluorescein sodium) is 9-(o-carboxyphenyl)-6-hydroxy-3H-anth-3-one disodium salt, and its molecular structure is as follows: [0003] [0004] Fluorescein sodium is a diagnostic drug for fundus contrast. It cannot stain normal corneal epithelium, but can stain damaged corneal epithelium green, thereby showing corneal damage, ulcers and other lesions. [0005] Sodium fluorescein is generally obtained from the thermal condensation of resorcinol and phthalic anhydride to form a salt, and contains a large amount of impurities, mainly including unreacted resorcinol, phenolphthalein and acridine yellow. The injection prepared in this way is very dark in color, opaque, and has relatively large clinical side effects. Therefore, the preparation of high-purity sodium fluorescein is necessary. [0006] The traditional method of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/82
Inventor 关屹闫冬刘再波
Owner 北京化药科创医药科技发展有限公司
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