CN1214002C - Process for synthesizing hydrate of calcium phenolsulfonate - Google Patents
Process for synthesizing hydrate of calcium phenolsulfonate Download PDFInfo
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- CN1214002C CN1214002C CN 01131818 CN01131818A CN1214002C CN 1214002 C CN1214002 C CN 1214002C CN 01131818 CN01131818 CN 01131818 CN 01131818 A CN01131818 A CN 01131818A CN 1214002 C CN1214002 C CN 1214002C
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- hydrate
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Abstract
The present invention relates to a process for synthesizing a hydrate of calcium dobesilate. Hydroquinone and concentrated sulfuric acid carry out sulfonation reaction to obtain white dope; the white dope is dissolved by adding alcohol water, and calcium carbonate is added for neutralization reaction; the Ph valve is regulated between 2.5 and 5; through filtration, the pressure reduction and the condensation of filtered solution, cooling, crystallization and crystallization suction filtration, white solid crude products are obtained; the crude product is dissolved in water, is carried out for hot filtration, the pressure reduction and the condensation of the filtered solution, crystallization by cooling, and suction filtration, is washed by the mixture of anhydrous alcohol and water, or one of the anhydrous alcohol and the water, and is dried to obtain the calcium dobesilate hydrate with high purity. The present invention has the advantages of mild processing condition, no use of inert gas protection, no use of toxic halogenated hydrocarbon solvent, and no need of intermediate product separation; in the refining process, the solvent, such as toluene, ethyl acetate, etc. are not used and are replaced by alcohol; the present invention decreases the varieties of used inflammable and explosive solvent in the process, is favourable for recovering solvent, simplifying the process operation, reducing the cost, enhancing the productive rate and governing pollution from sources, and is favorable for environment protection and industrial production.
Description
Technical field
The present invention relates to the synthesis technique of hydrate of calcium phenolsulfonate in the pharmaceutical industry.
Background technology
Dobesilate Calcium (Calcium dobesilate) chemical name is 2,5-dihydroxy benzenes sulfonic acid calcium system by French Carroin company in Initial Public Offering in 1971, be the capillary blood vessel circulation activator of widespread use in the world, be used to prevent and treat the multiple disease that capillary blood vessel cycle penalty causes.The synthetic process of this compound is studied report both at home and abroad probably to be had following several: (1) is starting raw material with the Resorcinol, through potassium bichromate and potassium hyposulfate addition, synthetic with calcium perchlorate displacement three-step reaction again, this method route is long, to the equipment requirements height, the three wastes are also difficult, and are big for environment pollution.(2) under the protection of rare gas element nitrogen, Resorcinol and concentrated acid sulfonation, the preparation of organic solvent ethyl acetate-ethanol azeotropic dehydration, this route organic solvent is difficult to be reclaimed, and logical nitrogen protection, complex process, productive rate is lower.(3) utilize Resorcinol in halohydrocarbon, to drip strong sulfuric acid response; again with lime carbonate in and the preparation; this route uses the big solvent tetracol phenixin or 1 of toxicity; the 2-ethylene dichloride; wherein 1; the 2-ethylene dichloride was classified as carcinogenic hydrocarbon in 1984 by U.S. environment chemistry association, was unfavorable for workman's physical and mental health and environment protection.(4) utilize Resorcinol in ether solvent (as ether) with vitriol oil low temperature under sulfonation, with in the lime carbonate and the preparation, this route cold operation, energy consumption is big, and with inflammable and explosive solvent ethers, is unfavorable for suitability for industrialized production and environment protection.
Summary of the invention
The invention provides a kind of hydrate of calcium phenolsulfonate synthesis technique; prepare hydrate of calcium phenolsulfonate with the lime carbonate neutralization reaction again with Resorcinol and vitriol oil Direct Sulfonation; the reaction conditions gentleness; the product purity height; technological operation is easy; do not use toxic reagent, help environment protection and suitability for industrialized production.
The objective of the invention is to realize in the following manner: the synthesis technique of hydrate of calcium phenolsulfonate, carry out sulfonation reaction with 75～98% vitriol oils of Resorcinol and 1～5 mol ratio, be warming up to 40～100 ℃, insulation reaction 1～3 hour gets white dope, is cooled to 5～50 ℃, add 50～90% ethanol water, stir, be warming up to 30～70 ℃ of dissolvings, add lime carbonate and carry out neutralization reaction, transfer pH value about 2.5～5, remove by filter calcium sulfate, filtrate decompression concentrates, cooling, 5～10 ℃ of crystallizations 4～6 hours, the crystallization suction filtration gets the white solid crude product, and filtrate is reclaimed, and mixes with water with 1～5 times crude product, stir, be warming up to 40～80 ℃ of dissolvings, heat filters insolubles, and filtrate decompression concentrates, to there being crystallization to occur, stop to concentrate 5～10 ℃ of crystallisation by cooling 4～6 hours, suction filtration, wash by 90～100% weight ratio mixed solvents with dehydrated alcohol and water, to the filtrate pH value be 4～6, mother liquor reclaims, dry high purity hydrate of calcium phenolsulfonate.
The sulfonation reaction temperature is 60～90 ℃, and the neutralization reaction temperature is 40～60 ℃, and ethanol water volume ratio concentration is 50～60% in the neutralization reaction, and refining solvent temperature is 60～75 ℃.
The present invention utilizes Resorcinol to be raw material; following and the vitriol oil Direct Sulfonation reaction of normal temperature; the vitriol oil is not only made sulphonating agent but also make solvent, processing condition gentleness, not blanketing with inert gas; do not use poisonous halogenated hydrocarbon solvent (as tetracol phenixin; 1, the 2-ethylene dichloride), intermediate product need not to separate; in the ethanol aqueous systems, use the lime carbonate neutralization reaction; utilize PH control terminal point, through distillation; the crystallization preparation is in process for refining; do not use solvent toluene; ethyl acetate etc. and use ethanol to replace; reduce inflammable and explosive solvent use kind in the technological process, help solvent and recycle, simplify technological operation; reduce cost; improve productive rate, pollute from watershed management, no matter to operator; working condition; environment; all make to pollute and reduce to minimum, help environment protection and suitability for industrialized production.Product is tested by analysis, content (anhydrous) 〉=99%, warp
1HNMR,
13CNMR, IR, UV, MS ultimate analysis, structure meets following formula:
Embodiment
Embodiment 1:
In Resorcinol 44 grams, 53.5 milliliters of adding reaction flasks of the vitriol oil (90% weight ratio), stir on the limit, the limit is warming up to 75 ℃, and the insulated and stirred reaction was cooled to 25 ℃ after 3 hours, add 200 milliliters in 60% (V/V) ethanol water, be warming up to 50 ℃, after stirring and dissolving is complete, add about 60 grams of powder lime carbonate, transfer pH value about 3.0, stopped reaction removes by filter calcium sulfate, concentrating under reduced pressure P=0.085MPa, T＜60 ℃, after having tiny crystallization to occur, stop to concentrate, place crystallization after 6 hours in 8 ℃, filter, dry that crude product 75 restrains.
75 gram crude products and 20 ml waters are added in the reaction flask, stir on the limit, be warming up to 65 ℃, after the dissolving, heat filters insolubles, filtrate decompression is concentrated, P=0.08～0.95MPa, T＜60 ℃ are to there being tiny crystallization to occur, stop to concentrate, put to room temperature, be cooled to 8 ± 1 ℃ of crystallizations 6 hours, suction filtration, filter is done the back and is washed 2～3 times for 10 milliliters with 95% (weight ratio) ethanol water, making the filtrate pH value is 4～6, drying, and mother liquor reclaims to such an extent that finished product 68 restrains, yield (mole) 77.9%, content (anhydrous)＞99.5%.
This finished product after testing, the result is as follows:
Project measured value standard index
1, acidity (pH value) 5.0 4.5～6.0
2, solution colour and clarity＜1
#(turbid mark)＜
(yellow)＜1
#(turbid)＜1
#(Huang)
3, vitriol＜300ppm＜300ppm
4, molysite＜10ppm＜10ppm
5, heavy metal＜15ppm＜15ppm
6, moisture content 4.8% 4.0～6.0%
7, Resorcinol＜0.1%＜0.1%
8, content (anhydrous) 100.3% 99～102%
This finished product detection result meets Europe pharmacopeia (1997), British Pharmacopoeia (1998) regulation.
Embodiment 2
In Resorcinol 880 grams, 800 milliliters of adding reaction flasks of the vitriol oil (93% weight ratio), be warming up to 95 ℃ under stirring, insulation reaction gets the canescence dope after 2 hours, be cooled to 40 ℃, add 4000 milliliters in 55% (V/V) ethanol water, after being warming up to 55 ℃ of dissolvings, add about 800 grams of powder lime carbonate, transfer PH to be about 5, stopped reaction, remove calcium sulfate by same process, technological processs such as concentrating under reduced pressure, crystallization, drying get about 1500 grams of crude product.
Above crude product is added reaction flask with 700 ml waters, stir and to be warming up to 50 ℃, after the dissolving, heat filters insolubles, press the same process aftertreatment, finished product 1430 restrains, yield (mole) is about 82%, content (anhydrous)＞99.5%.
This finished product after testing, the result is as follows:
Project measured value standard index
1, acidity (pH value) 4.9 4.5～6.0
2, solution colour and clarity＜1
#(turbid mark)＜1
#(yellow)＜1
#(turbid)＜1
#(Huang)
3, vitriol＜300ppm＜300ppm
4, molysite＜10ppm＜10ppm
5, heavy metal＜15ppm＜15ppm
6, moisture content 5.0% 4.0～6.0%
7, Resorcinol＜0.1%＜0.1%
8, content (anhydrous) 100.9% 99～102%
This finished product detection result meets Europe pharmacopeia (1997), British Pharmacopoeia (1998) regulation.
Claims (2)
1, the synthesis technique of hydrate of calcium phenolsulfonate is characterized in that: 75～98% vitriol oils with Resorcinol and 1～5 mol ratio carry out sulfonation reaction, are warming up to 40～100 ℃, insulation reaction 1～3 hour gets white dope, is cooled to 5～50 ℃, add 50～90% ethanol water, stir, be warming up to 30～70 ℃ of dissolvings, add lime carbonate and carry out neutralization reaction, transfer pH value about 2.5～5, remove by filter calcium sulfate, filtrate decompression concentrates, cooling, 5～10 ℃ of crystallizations 4～6 hours, the crystallization suction filtration gets the white solid crude product, and filtrate is reclaimed, and mixes with water with 1～5 times crude product, stir, be warming up to 40～80 ℃ of dissolvings, heat filters insolubles, and filtrate decompression concentrates, to there being crystallization to occur, stop to concentrate 5～10 ℃ of crystallisation by cooling 4～6 hours, suction filtration, wash by 90～100% weight ratio mixed solvents with dehydrated alcohol and water, to the filtrate pH value be 4～6, mother liquor reclaims, dry high purity hydrate of calcium phenolsulfonate.
2, the synthesis technique of hydrate of calcium phenolsulfonate as claimed in claim 1, it is characterized in that: the sulfonation reaction temperature is 60～90 ℃, the neutralization reaction temperature is 40～60 ℃, and ethanol water volume ratio concentration is 50～60% in the neutralization reaction, and refining solvent temperature is 60～75 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01131818 CN1214002C (en) | 2001-12-11 | 2001-12-11 | Process for synthesizing hydrate of calcium phenolsulfonate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 01131818 CN1214002C (en) | 2001-12-11 | 2001-12-11 | Process for synthesizing hydrate of calcium phenolsulfonate |
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| CN1359897A CN1359897A (en) | 2002-07-24 |
| CN1214002C true CN1214002C (en) | 2005-08-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 01131818 Expired - Lifetime CN1214002C (en) | 2001-12-11 | 2001-12-11 | Process for synthesizing hydrate of calcium phenolsulfonate |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101849930B (en) * | 2009-03-31 | 2012-04-04 | 符健 | Chemical medicament for treating cardiac and cerebral diseases and preparation method thereof |
| CN101880248B (en) * | 2010-06-13 | 2012-07-18 | 宁夏康亚药业有限公司 | Synthetic reaction of calcium dobesilate hydrate |
| CN102219715B (en) * | 2011-04-26 | 2013-11-13 | 北京振东光明药物研究院有限公司 | Method for preparing medicinal high-purity calcium dobesilate |
| CN104447428A (en) * | 2014-12-07 | 2015-03-25 | 河南领先科技药业有限公司 | Preparation method of etamsylate |
| CN105418466A (en) * | 2015-11-09 | 2016-03-23 | 石家庄市华新药业有限责任公司 | Calcium dobesilate compound and preparation method thereof |
| US10644342B2 (en) * | 2016-03-03 | 2020-05-05 | Lockheed Martin Energy, Llc | Coordination complexes containing monosulfonated catecholate ligands and methods for producing the same |
| CN110092736A (en) * | 2018-12-05 | 2019-08-06 | 湖北广辰药业有限公司 | A kind of Calcium Dobesilate preparation method reducing oxybenzene disulfonic acid calcium impurities content |
| CN112834697A (en) * | 2020-12-30 | 2021-05-25 | 西南石油大学 | Mixed gas supply type visual natural gas hydrate experiment system |
| CN115819290A (en) * | 2022-11-22 | 2023-03-21 | 中楚鑫新材料科技(荆州)有限公司 | Preparation method of 2, 5-dihydroxy benzene sulfonic acid calcium monohydrate |
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