CN103739662A - Preparation method of sodium tanshinone IIA sulfonate - Google Patents
Preparation method of sodium tanshinone IIA sulfonate Download PDFInfo
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- CN103739662A CN103739662A CN201310669822.4A CN201310669822A CN103739662A CN 103739662 A CN103739662 A CN 103739662A CN 201310669822 A CN201310669822 A CN 201310669822A CN 103739662 A CN103739662 A CN 103739662A
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Abstract
The invention provides a preparation method of sodium tanshinone IIA sulfonate. The preparation method is as follows: in an organic solvent, using sulfur trioxide or a sulfur trioxide compound for performing sulfonation reaction on tanshinone IIA, after the reaction, filtering the reaction solution, and washing with the organic solvent for removing unreacted raw materials and other impurities soluble in the organic solvent, dissolving an obtained filter cake to transfer into the sodium tanshinone IIA sulfonate with a sodium containing reagent. Preparation methods of the sodium tanshinone IIA sulfonate in the prior art mainly uses a mixed solvent comprising concentrated sulfuric acid, acetic acid and acetic anhydride for the sulfonation reaction, the chemical reagents themself have strong corrosivity, and the use amounts are very large, so that serious pollution to the environment is caused. The preparation method adopts a new method for sulfonation reaction of the tanshinone IIA, and the used reagents are completely consumed at the end of the reaction, so that no pollution to the environment may be caused. The by-products of the product prepared by the method are less, and the yield and the purity of the product are higher than that of existing techniques.
Description
Invention field
The present invention relates to a kind of preparation method of sodium tanshinone IIA sulfate, by Tanshinone II A is carried out to sulfonation reaction with sulphur trioxide or sulphur trioxide mixture in organic solvent, after finishing, reaction washs by reacting liquid filtering and with organic solvent, remove unreacted raw material and other soluble impurity in organic solvent, after the filter cake obtaining dissolves, with containing sodium reagent, convert it into sodium tanshinone IIA sulfate.
Background technology
Tanshinone II A is from labiate salviamiltiorrhizabung (Slavia miltiorrhiza Bge.), to extract the fat-soluble effective constituent obtaining, its meta-bolites in vivo can participate in the multiple biochemical reaction of body, show multiple pharmacological effect, clinically through being usually used in the treatment of stenocardia, hypertension and cardio-cerebrovascular diseases.But because of its poor solubility in water, in body, degree of absorbing is poor, make pharmacological action be difficult for performance, onset time is slow, and taking dose is large, is the bottleneck problem in TANSHINONES pharmacological agent always.Sodium tanshinone IIA sulfate is the water-soluble sodium salt of one that Tanshinone II A forms after sulfonation reaction, owing to having introduced hydrophilic sulfonic acid group, improved its solvability in water, make it demonstrating the incomparable superiority of Tanshinone II A aspect the diseases such as treatment coronary heart diseases and angina pectoris, myocardial infarction, become important cardiovascular drugs.China's cardiovascular patient ratio in crowd is higher, and this drug market demand is increases trend year by year.But the main method that adopts concentrated acid sulfonation of the method needs of preparing at present sodium tanshinone IIA sulfate, in generative process, need to use a large amount of sulfuric acid, acetic acid and acetic anhydride etc. to there is highly polluted chemical reagent to environment, also can produce in process of production the dusty gass such as hydrogenchloride simultaneously.Therefore how to adopt the preparation condition of environmental protection more, for reducing or eliminating environmental pollution, preserve the ecological environment and have great importance.
Summary of the invention
For the above-mentioned weak point of prior art, the object of the present invention is to provide a kind of preparation method of sodium tanshinone IIA sulfate.Application the method avoids using the chemical reagents such as sulfuric acid, acetic acid and the acetic anhydride of high pollution, greatly reduces the pollution of even eliminating environment.
Above-mentioned purpose of the present invention is realized by following technical scheme:
A preparation method for sodium tanshinone IIA sulfate, comprises the following step:
(1) Tanshinone II A is dissolved in organic solvent, is stirred to material dissolution;
(2) sulphur trioxide or sulphur trioxide mixture are joined in above-mentioned Tanshinone II A solution;
(3) reaction solution is stirred or heating, complete to raw material reaction;
(4) by above-mentioned reacting liquid filtering, filter cake organic solvent washing;
(5) filter cake obtaining is suspended in solvent, then adds containing sodium reagent obtained Tanshinone II A sulfonated bodies is changed into sodium salt, concentrated remove portion solvent and cooling after separate out solid, after filtering, washing and be dried, obtain sodium tanshinone IIA sulfate product.
The preparation method of described sodium tanshinone IIA sulfate, the organic solvent of step (1) is ketone, acetonitrile, methylene dichloride, the chloroform, 1 of the straight or branched of carboxylicesters, C3～C10 carbon, 2-ethylene dichloride, benzene,toluene,xylene, trimethylbenzene, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, pyridine, tetrahydrofuran (THF), methyl-sulphoxide, DMF, N,N-dimethylacetamide.
The preparation method of described sodium tanshinone IIA sulfate, described carboxylicesters is the ester forming ester, the fragrance forming carboxylicesters, the fragrance being formed by the straight or branched carboxylic acid of C1～C20 carbon and the straight or branched alcohol of C1～C20 carbon or the carboxylic acid that contains aromatic group or the alcohol that contains aromatic group.
The preparation method of described sodium tanshinone IIA sulfate, the sulphur trioxide mixture of step (2) is sulphur trioxide-pyridine mixture, sulphur trioxide-DMF mixture, sulphur trioxide-Trimethylamine 99 mixture, sulphur trioxide-triethylamine mixture, sulphur trioxide-diisopropyl ethyl amine mixture.
The preparation method of described sodium tanshinone IIA sulfate, the ratio of the Tanshinone II A of step (2) and sulphur trioxide or sulphur trioxide mixture is 1:(0.2-10.0).
The temperature of reaction of preparation method's step (3) of described sodium tanshinone IIA sulfate is subzero 10 ℃ to 150 ℃ above freezing.
The preparation method of described sodium tanshinone IIA sulfate, the organic solvent of step (4) is ketone, acetonitrile, methylene dichloride, the chloroform, 1 of the straight or branched of alcohol, C3～C10 carbon of the straight or branched of carboxylicesters, C1～C10 carbon, 2-ethylene dichloride, benzene,toluene,xylene, trimethylbenzene, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, pyridine, tetrahydrofuran (THF), methyl-sulphoxide, DMF, N,N-dimethylacetamide.
The preparation method of described sodium tanshinone IIA sulfate, described carboxylicesters is the ester forming ester, the fragrance forming carboxylicesters, the fragrance being formed by the straight or branched carboxylic acid of C1～C10 carbon and the straight or branched alcohol of C1～C10 carbon or the carboxylic acid that contains aromatic group or the alcohol that contains aromatic group.
The preparation method of described sodium tanshinone IIA sulfate, the solvent of step (5) is ketone, acetonitrile, methyl-sulphoxide, the N of the straight or branched of straight or branched alcohol, C3～C10 carbon of water, C1～C10 carbon, dinethylformamide, N,N-dimethylacetamide.
The preparation method of described sodium tanshinone IIA sulfate, step (5) containing sodium reagent be sodium carbonate, sodium bicarbonate, sodium hydroxide, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC, sodium-chlor, sodium sulfate, sodium methylate, sodium ethylate.
The existing sodium tanshinone IIA sulfate of preparing mainly adopts the mixed solvent of the vitriol oil, acetic acid and acetic anhydride composition to carry out sulfonation reaction, but these chemical reagents itself have severe corrosive, and usage quantity is very large, therefore environment is caused to serious pollution.The present invention has adopted a kind of new method to carry out sulfonation reaction to Tanshinone II A, and reagent used is substantially completely consumed after reaction finishes, and therefore can environment not produced and be polluted.The product by product that simultaneously adopts the method to obtain is few, and the yield of product and purity are higher than prior art.
Accompanying drawing explanation
Fig. 1 is preparation technology's schema of the present invention;
Embodiment
Below in conjunction with accompanying drawing, further illustrate essentiality content of the present invention with embodiments of the invention, but with this, do not limit the present invention.
Embodiment 1:
100 grams of tanshinone IIAs are joined to stirring and dissolving in the acetonitrile solvent of 800 milliliters, then add 60 grams of sulphur trioxide-pyridine mixtures.Reaction soln is heated to 65 degrees Celsius and stirring, after reaction finishes, is cooled to room temperature.By reacting liquid filtering, acetonitrile washing 3-4 time for filter cake.Filter cake is suspended in 200 ml waters, adds saturated sodium bicarbonate aqueous solution to pH value 7.5～9.0.Aqueous solution part is revolved and boiled off except rear crystallisation by cooling, obtain 124 grams of red-brown sodium tanshinone IIA sulfate products, yield 92%.
Embodiment 2:
100 grams of tanshinone IIAs are joined to stirring and dissolving in the ethyl acetate solvent of 800 milliliters, then add 90 grams of sulphur trioxide-diisopropyl ethyl amine mixtures.Reaction soln is heated to reflux and stir, after reaction finishes, is cooled to room temperature.By reacting liquid filtering, ethyl acetate washing 3-4 time for filter cake.Filter cake is suspended in 200 milliliters of ethanol, adds saturated sodium bicarbonate aqueous solution to pH value 7.5～9.0.Ethanolic soln part is revolved and boiled off except rear crystallisation by cooling, obtain 117 grams of red-brown sodium tanshinone IIA sulfate products, yield 87%.
Embodiment 3:
100 grams of tanshinone IIAs are joined to stirring and dissolving in the DMF solvent of 500 milliliters, then add 65 grams of sulphur trioxide-DMF mixtures.Reaction soln is heated to 100 degrees Celsius and stirring, after reaction finishes, is cooled to room temperature.By reacting liquid filtering, DMF washing 3-4 time for filter cake.Filter cake is suspended in 200 milliliters of ethanol, adds saturated aqueous sodium hydroxide solution to pH value 7.5～9.0.Ethanolic soln part is revolved and boiled off except rear crystallisation by cooling, obtain 125 grams of red-brown sodium tanshinone IIA sulfate products, yield 93%.
Embodiment 4:
100 grams of tanshinone IIAs are joined to stirring and dissolving in the acetone solvent of 600 milliliters, then add 28 grams of sulphur trioxides.Reaction soln is finished in stirring at room to reaction.By reacting liquid filtering, filter cake washing with acetone 3-4 time.Filter cake is suspended in 200 milliliters of Virahols, adds saturated aqueous sodium carbonate to pH value 7.5～9.0.Aqueous isopropanol part is revolved and boiled off except rear crystallisation by cooling, obtain 113 grams of red-brown sodium tanshinone IIA sulfate products, yield 85%.
Embodiment 5:
By 100 grams of tanshinone IIAs join 600 milliliters 1, stirring and dissolving in 2-dichlorobenzene solvent, then adds 60 grams of sulphur trioxide-pyridine mixtures.Reaction soln is heated to 150 degrees Celsius and is stirred to reaction end.By reacting liquid filtering, ethyl acetate washing 3-4 time for filter cake.Filter cake is suspended in 200 milliliters of Virahols, adds saturated aqueous sodium carbonate to pH value 7.5～9.0.Aqueous isopropanol part is revolved and boiled off except rear crystallisation by cooling, obtain 120 grams of red-brown sodium tanshinone IIA sulfate products, yield 89%.
Claims (10)
1. a preparation method for sodium tanshinone IIA sulfate, comprises the following step:
(1) Tanshinone II A is dissolved in organic solvent, is stirred to material dissolution;
(2) sulphur trioxide or sulphur trioxide mixture are joined in above-mentioned Tanshinone II A solution;
(3) reaction solution is stirred or heating, complete to raw material reaction;
(4) by above-mentioned reacting liquid filtering, filter cake organic solvent washing;
(5) filter cake obtaining is suspended in solvent, then adds containing sodium reagent obtained Tanshinone II A sulfonated bodies is changed into sodium salt, concentrated remove portion solvent and cooling after separate out solid, after filtering, washing and be dried, obtain sodium tanshinone IIA sulfate product.
2. the preparation method of sodium tanshinone IIA sulfate as claimed in claim 1, the organic solvent that it is characterized in that step (1) is ketone, acetonitrile, methylene dichloride, the chloroform, 1 of the straight or branched of carboxylicesters, C3～C10 carbon, 2-ethylene dichloride, benzene,toluene,xylene, trimethylbenzene, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, pyridine, tetrahydrofuran (THF), methyl-sulphoxide, DMF, N,N-dimethylacetamide.
3. the preparation method of sodium tanshinone IIA sulfate as claimed in claim 2, is characterized in that described carboxylicesters is the ester forming ester, the fragrance forming carboxylicesters, the fragrance being formed by the straight or branched carboxylic acid of C1～C20 carbon and the straight or branched alcohol of C1～C20 carbon or the carboxylic acid that contains aromatic group or the alcohol that contains aromatic group.
4. the preparation method of sodium tanshinone IIA sulfate as claimed in claim 1, the sulphur trioxide mixture that it is characterized in that step (2) is sulphur trioxide-pyridine mixture, sulphur trioxide-DMF mixture, sulphur trioxide-Trimethylamine 99 mixture, sulphur trioxide-triethylamine mixture, sulphur trioxide-diisopropyl ethyl amine mixture.
5. the preparation method of sodium tanshinone IIA sulfate as claimed in claim 1, is characterized in that the Tanshinone II A of step (2) and the ratio of sulphur trioxide or sulphur trioxide mixture are 1:(0.2-10.0).
6. the preparation method of sodium tanshinone IIA sulfate as claimed in claim 1, the temperature of reaction that it is characterized in that step (3) is subzero 10 ℃ to 150 ℃ above freezing.
7. the preparation method of sodium tanshinone IIA sulfate as claimed in claim 1, the organic solvent that it is characterized in that step (4) be the straight or branched of alcohol, C3～C10 carbon of the straight or branched of carboxylicesters, C1～C10 carbon ketone, acetonitrile,, methylene dichloride, chloroform, 1,2-ethylene dichloride benzene,toluene,xylene, trimethylbenzene, chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, pyridine, tetrahydrofuran (THF), methyl-sulphoxide, N, dinethylformamide, N,N-dimethylacetamide.
8. the preparation method of sodium tanshinone IIA sulfate as claimed in claim 7, is characterized in that described carboxylicesters is the ester forming ester, the fragrance forming carboxylicesters, the fragrance being formed by the straight or branched carboxylic acid of C1～C10 carbon and the straight or branched alcohol of C1～C10 carbon or the carboxylic acid that contains aromatic group or the alcohol that contains aromatic group.
9. the preparation method of sodium tanshinone IIA sulfate as claimed in claim 1, the solvent that it is characterized in that step (5) is ketone, acetonitrile, methyl-sulphoxide, the N of the straight or branched of straight or branched alcohol, C3～C10 carbon of water, C1～C10 carbon, dinethylformamide, N,N-dimethylacetamide.
10. the preparation method of sodium tanshinone IIA sulfate as claimed in claim 1, what it is characterized in that step (5) is sodium carbonate, sodium bicarbonate, sodium hydroxide, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC, sodium-chlor, sodium sulfate, sodium methylate, sodium ethylate containing sodium reagent.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910251A (en) * | 2014-11-27 | 2015-09-16 | 江苏柯菲平医药股份有限公司 | Method for preparation of sodium tanshinone II-a sulfonate by microreaction device |
| CN109988220A (en) * | 2017-12-31 | 2019-07-09 | 上海星叶医药科技有限公司 | A kind of preparation method of green syt tanshinone IIA sodium sulfonate |
| CN115403642A (en) * | 2022-08-04 | 2022-11-29 | 李玉山 | Preparation method of rutin sulfate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102040644A (en) * | 2009-11-03 | 2011-05-04 | 刘力 | Tanshinone derivative as well as preparation and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102040644A (en) * | 2009-11-03 | 2011-05-04 | 刘力 | Tanshinone derivative as well as preparation and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 宋相丹等: "磺化剂及磺化工艺技术研究进展", 《当代化工》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910251A (en) * | 2014-11-27 | 2015-09-16 | 江苏柯菲平医药股份有限公司 | Method for preparation of sodium tanshinone II-a sulfonate by microreaction device |
| CN109988220A (en) * | 2017-12-31 | 2019-07-09 | 上海星叶医药科技有限公司 | A kind of preparation method of green syt tanshinone IIA sodium sulfonate |
| CN115403642A (en) * | 2022-08-04 | 2022-11-29 | 李玉山 | Preparation method of rutin sulfate |
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Effective date of registration: 20161031 Address after: 310000, room 7, 603, China Road, Shangcheng District, Zhejiang, Hangzhou Patentee after: Chinese Medicine Holdings Ltd. Address before: 650201 Yunnan Province, Kunming City Blue Black Road No. 132 Patentee before: Kunming Institute of Botany, Chinese Academy of Sciences |
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Granted publication date: 20160928 Termination date: 20211210 |