CN101270124B - Novel method for purifying and preparing high-purity fluorandiol and fluorandiol salt - Google Patents
Novel method for purifying and preparing high-purity fluorandiol and fluorandiol salt Download PDFInfo
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- CN101270124B CN101270124B CN2008100160081A CN200810016008A CN101270124B CN 101270124 B CN101270124 B CN 101270124B CN 2008100160081 A CN2008100160081 A CN 2008100160081A CN 200810016008 A CN200810016008 A CN 200810016008A CN 101270124 B CN101270124 B CN 101270124B
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Abstract
The present invention discloses a new method for purifying high-purity fluorescein and fluorescein salt. In the method, catalyst is added into certain reaction medium, so that the purified material reacts with acetylation reagent to form diacetyl fluorescein, thus impurities are separated by the different characteristics of the impurities and the diacetyl fluorescein, and after saponification, acidification and salification, the purifying high-purity fluorescein or fluorescein salt can be obtained. Suitable for mass production, the method has the advantages of simple process, easy practical operation and environment-friendliness.
Description
Technical field
The present invention relates to the novel method of a kind of purifying and preparing high-purity fluorescein and fluorescein salt, belong to the chemical purification field.
Background technology
High purity uranine yellow salt is widely used in the injection formulations of eyeground radiography, and highly purified uranine yellow generally is to make from highly purified fluorescein, so prepare highly purified fluorescein sodium salt, key is to make highly purified fluorescein.
The industry fluorescein generally is to get from Resorcinol and phthalic anhydride thermal condensation, wherein contain a large amount of impurity, mainly contain unreacted Resorcinol and phenolphthalein and Vetaflavin etc., traditional fluorescein method of purification is to be dissolved in the alkali lye with fluorescein, use activated carbon adsorption impurity, fluorescein is separated out in acidifying again, repeats then repeatedly that alkali is molten, the process of acidifying, filtration washing.Though this technology can obtain meeting the product that pharmacopeia requires, and can find with HPLC or tlc analysis, still has the more intense impurity of some polarity not to be removed.The key of problem is, these impurity are soluble in water under alkaline condition, and this moment, gac obviously reduced its adsorptivity, and under acidic conditions, these impurity are easy to again and the fluorescein co-precipitation.So be difficult to obtain highly purified fluorescein with traditional method.
" P280 pages or leaves such as Han Guang pasture have been introduced with the method for fluorescein recrystallization and have been purified for organic preparation chemistry handbook, middle volume.Because fluorescence have the red variant of two kinds of variants-be insoluble to alcohol ether and is dissolved in methyl alcohol and the yellow variant of alcoholic acid, yellow variant is heated and easily changes stable red variant into.When the preparation fluorescein, what the low temperature acidifying was separated out is yellow variant, and this kind variant dissolves in methyl alcohol or ethanol.But the yellow variant of separating out from water contains large quantity of moisture, is not easy to filter, and also is not easy drying, and in heat drying or heating for dissolving process, yellow variant easily changes undissolved red variant into, and is very difficult in the actually operating, and productive rate is low, the waste water generation is big.
Summary of the invention
In order to overcome above-mentioned technical difficulty, the present invention utilizes fluorescein or uranine to form the method for di-acetyl fluorescein, has greatly improved fluorescein and separate impurities effect.When preparation di-acetyl fluorescein, when the crystallization of di-acetyl fluorescein was separated out, because intensive polar solvents such as use glacial acetic acids, most of impurity was removed owing to being soluble in solvent.The di-acetyl fluorescein of this moment is owing to be soluble in many organic solvents, and as ethyl acetate etc., and the polarity of impurity is more intense, in the poor slightly solvent of polarity, with gac or silica gel adsorption, can remove impurity well.Thereby obtain highly purified di-acetyl fluorescein.Can be easy to obtain highly purified fluorescein and fluorescein salt through saponification, acidifying, salify again.Reaction equation is as follows:
The novel method of purifying and preparing high-purity fluorescein of the present invention and fluorescein salt has following advantage:
1, compared with former technology, operation reduces, and is simple to operate, is convenient to realize industrialization.
2, the diacetyl compound forms beautiful large-scale crystallization easily, is very easy to separate with impurity, is convenient to purify with refining.
3, owing to avoided repeatedly acid-alkali refining operation, thereby greatly reduce the generation of waste water, helped environment protection treating.
4, solvent for use can repeat to recycle, and the residue behind the recovery solvent is the impurity enriched thing, is convenient to focus on.
5, productive rate still is that product purity all is greatly improved.
Below by embodiment the present invention is specifically described
Embodiment one:
Take by weighing fluorescein crude product 100g in the 1000ml there-necked flask, add glacial acetic acid 430ml, diacetyl oxide 73.5g (0.72mol), pyridine 34ml, stirring heating is back to fluorescein and all dissolves, and continues stirring reaction 30 minutes, gets light orange solution.Cool to room temperature is separated out tabular crystal, filters, and, washs with the 50ml ether to closely colourless with the cold methanol washing again.The gained solid is dried to constant weight in 50～60 ℃, obtains pure product di-acetyl fluorescein 101.2g.(productive rate: mp:203～205 ℃ 81.0%).Thin layer is shown as single point.
Pure product di-acetyl fluorescein 100g (0.24mol) is joined in the 1000ml there-necked flask, add 266ml methyl alcohol, stir, slowly add 257g21% sodium methoxide solution (1.00mol), fully stirring reaction to solid matter dissolves fully, get red solution, continued stirring reaction 30 minutes, slowly add 300ml36% acetate then, stirring reaction 5 hours, filter,, be washed with water to light yellow again with the washing of 50ml cold methanol.The gained solid in 100 ℃, 30mmHg vacuum-drying to constant weight, pure product fluorescein 73.4g, productive rate: 92.0%.Tlc analysis is shown as one matter, HPLC purity 99.8%.
Accurately take by weighing pure product fluorescein 49.83g (0.15mol), analytical pure anhydrous sodium carbonate 16.05g (0.15mol), blend adds the 150ml water dissolution in evaporating dish, and heating evaporation is to doing in vapor bath.Be transferred in the vacuum-drying mutually, be dried to constant weight, grind, get orange powder shape material uranine yellow salt 56.40g, productive rate 100%, HPLC purity 99.8% in 100～115 ℃/30mmHg.
Embodiment two:
Take by weighing fluorescein crude product 100g in the 1000ml there-necked flask, add acetone 550ml, diacetyl oxide 73.5g (0.72mol), pyridine 34ml, stirring heating is back to fluorescein and all dissolves, and continues stirring reaction 30 minutes, gets light orange solution.Cool to room temperature is separated out tabular crystal, filters, extremely closely colourless with the cold methanol washing, vacuum-drying, the gained solid is the reflux dissolving in ethyl acetate, adding gac 10g refluxed 15 minutes, filtered while hot, the gained filtrate decompression is concentrated into 300ml, crystallisation by cooling, filter, cold methanol washing, gained solid are dried to constant weight in 50～60 ℃, pure product di-acetyl fluorescein 87.3g.(productive rate: mp:203～205 ℃ 69.9%).Thin layer is shown as single point.
Pure product di-acetyl fluorescein 75g (0.18mol) is joined in the 1000ml there-necked flask, add 200ml methyl alcohol, stir, slowly add 156g20% sodium hydroxide solution (0.78mol), fully stirring reaction to solid matter dissolves fully, get red solution, continued stirring reaction 30 minutes, slowly add 225g36% acetate then, stirring reaction 5 hours, filter,, be washed with water to light yellow again with the washing of 50ml cold methanol.The gained solid in 100 ℃, 30mmHg vacuum-drying to constant weight, pure product fluorescein 55.0g, productive rate: 91.9%.Tlc analysis is shown as one matter, HPLC purity 99.6%.
Accurately take by weighing pure product fluorescein 49.83g (0.15mol), analytical pure anhydrous sodium carbonate 16.05g (0.15mol), blend adds the 150ml water dissolution in evaporating dish, and heating evaporation is to doing in vapor bath.Be transferred in the vacuum-drying mutually, be dried to constant weight, grind, get orange powder shape material uranine yellow salt 56.40g, productive rate 100%, HPLC purity 99.6% in 100～115 ℃/30mmHg.
Embodiment three
Take by weighing crude product uranine yellow salt 112.9g in the 1000ml there-necked flask, add dimethyl formamide 350ml, diacetyl oxide 73.5g (0.72mol), pyridine 15ml, stirring heating refluxed 2 hours, got light orange suspension liquid body.Filtering by-product acetic acid sodium while hot, the filtrate cool to room temperature is separated out tabular crystal, filters, to closely colourless, again with the washing of 50ml ether, the gained solid is dried to constant weight in 50～60 ℃ with the cold methanol washing, pure product di-acetyl fluorescein 92.8g.(productive rate: mp:203～205 ℃ 74.3%).Thin layer is shown as single point.
Pure product di-acetyl fluorescein 91.6g (0.22mol) is joined in the 1000ml there-necked flask, add 200ml water, stir, slowly add 200g20% sodium hydroxide solution (1.00mol), fully stirring reaction to solid matter dissolves fully, get red solution, continue stirring reaction 30 minutes, and slowly added 300ml36% acetate then, stirring reaction 5 hours, filter, be washed with water to light yellow.The gained solid in 100 ℃, 30mmHg vacuum-drying to constant weight, pure product fluorescein 69.8g, productive rate: 95.5%.Tlc analysis is shown as one matter, HPLC purity 99.5%.
Accurately take by weighing pure product fluorescein 49.83g (0.15mol), analytical pure anhydrous sodium carbonate 16.05g (0.15mol), blend adds the 150ml water dissolution in evaporating dish, and heating evaporation is to doing in vapor bath.Be transferred in the vacuum-drying mutually, be dried to constant weight, grind, get orange powder shape material uranine yellow salt 56.40g, productive rate 100%, HPLC purity 99.5% in 100～115 ℃/30mmHg.
Embodiment four
Take by weighing fluorescein crude product 100g in the 1000ml there-necked flask, add glacial acetic acid 430ml, Acetyl Chloride 98Min. 113g (1.44mol), pyridine 34ml, stirring heating is back to fluorescein and all dissolves, and continues stirring reaction 30 minutes, gets light orange solution.Cool to room temperature is separated out tabular crystal, filters, and to closely colourless, again with the washing of 50ml ether, the gained solid is dried to constant weight in 50～60 ℃, obtains pure product di-acetyl fluorescein 106.3g with the cold methanol washing.(productive rate: mp:203～205 ℃ 85.1%).Thin layer is shown as single point.
Subsequent operations is with embodiment one, gained fluorescein and uranine purity 99.6%.
Embodiment five
Take by weighing fluorescein crude product 100g in the 1000ml there-necked flask, add acetone 550ml, Acetyl Chloride 98Min. 113g (1.44mol), pyridine 34ml, stirring heating is back to fluorescein and all dissolves, and continues stirring reaction 30 minutes, gets light orange solution.Cool to room temperature is separated out tabular crystal, filters, and is extremely closely colourless with the cold methanol washing, vacuum-drying.The gained solid is the reflux dissolving in ethyl acetate, adds gac and refluxes filtered while hot 15 minutes.The gained filtrate decompression is concentrated into 300ml, and crystallisation by cooling filters, the cold methanol washing, the gained solid is dried to constant weight in 50～60 ℃, pure product di-acetyl fluorescein 94.4g.(productive rate: mp:203～205 ℃ 75.6%).Thin layer is shown as single point.
Subsequent operations is with embodiment two, gained fluorescein and uranine purity 99.2%.
Embodiment six
Take by weighing crude product uranine yellow salt 112.9g in the 1000ml there-necked flask, add dimethyl formamide 350ml, Acetyl Chloride 98Min. 113g (1.44mol), pyridine 15ml, stirring heating refluxed 2 hours, got light orange suspension liquid body.Filtering by product sodium-chlor while hot, the filtrate cool to room temperature is separated out tabular crystal, filters, to closely colourless, again with the washing of 50ml ether, the gained solid is dried to constant weight in 50～60 ℃ with the cold methanol washing, pure product di-acetyl fluorescein 97.4g.(productive rate: mp:203～205 ℃ 77.9%).Thin layer is shown as single point.
Subsequent operations is with embodiment three, gained fluorescein and uranine purity 99.5%.
Claims (6)
1. the novel method of purifying and preparing high-purity fluorescein and fluorescein salt; the method is characterized in that: this method utilization adds catalyzer in certain reaction medium react purification raw material and acetylation reagent; form the di-acetyl fluorescein; thereby utilize the different chemical polarity of impurity and di-acetyl fluorescein; impurity is separated; obtain highly purified fluorescein, fluorescein salt through saponification, acidifying, salify again, chemical equation is as follows:
2. a kind of according to claim 1 novel method of purify high purity fluorescein and fluorescein salt is characterized in that: acetylation reagent is diacetyl oxide or Acetyl Chloride 98Min..
3. a kind of according to claim 1 novel method of purify high purity fluorescein and fluorescein salt is characterized in that: reaction medium is glacial acetic acid, acetone or dimethyl formamide.
4. a kind of according to claim 1 novel method of purify high purity fluorescein and fluorescein salt is characterized in that: when gained di-acetyl fluorescein compound separates with impurity, with the method for recrystallization or silica gel adsorption.
5. a kind of according to claim 1 novel method of purify high purity fluorescein and fluorescein salt is characterized in that: the purification raw material is the fluorescein or the sodium salt of fluorescein.
6. a kind of according to claim 1 novel method of purify high purity fluorescein and fluorescein salt is characterized in that: catalysts is a pyridine compounds and their.
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| CN102898858B (en) * | 2012-10-19 | 2014-10-01 | 中国乐凯集团有限公司 | Preparation method of 3', 6'-dimethoxy fluorane yellow thermosensitive dye |
| JP2017095453A (en) * | 2015-11-12 | 2017-06-01 | 参天製薬株式会社 | High-purity fluorescein sodium |
| EP3604292B1 (en) * | 2018-08-01 | 2023-01-18 | Delmar Chemicals Inc. | Process for preparing fluorescein quinoid form |
| CN113461651A (en) * | 2021-08-20 | 2021-10-01 | 山东绅联药业有限公司 | Purification method of high-purity fluorescein |
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| CN1911917A (en) * | 2006-08-15 | 2007-02-14 | 沈阳中科靓马生物工程有限公司 | Compound for preparing fluorescein and its preparation method |
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