Continuous preparation method of tanshinone IIA sodium sulfonate based on single-tube thin-layer liquid membrane reactor

Abstract

The invention discloses a continuous preparation method of sodium tanshinone IIA sulfonate based on a single-tube thin-layer liquid membrane reactor. Comprising the following steps: (1) dissolving tanshinone IIA in an organic solvent as a feed liquid; (2) reacting gas-phase sulfur dioxide with air, and cooling to obtain sulfur trioxide mixed gas; (3) enabling the feed liquid and sulfur trioxide mixed gas to enter a single-tube thin-layer liquid membrane reactor in a parallel flow or reverse flow manner, and carrying out continuous sulfonation reaction to obtain reaction liquid; and (4) adding a sodium salt aqueous solution into the reaction solution to carry out salt forming reaction, centrifuging, drying and purifying to obtain the tanshinone IIA sodium sulfonate. According to the invention, a novel method is adopted to carry out sulfonation reaction on tanshinone IIA, and sulfur trioxide is basically completely consumed after the reaction is finished, so that the generation of waste acid is greatly reduced, and the method has important significance on environmental protection and cost reduction. The green, safe, efficient and continuous preparation of the high-purity tanshinone IIA sodium sulfonate is realized.

Description

Technical Field

[0001] The present invention relates to a continuous preparation method of sodium tanshinone IIA sulfonate, and particularly to a continuous preparation method of sodium tanshinone IIA sulfonate based on a single-tube thin-layer liquid film reactor. Background Art

[0002] Tanshinone IIA is a liposoluble active ingredient extracted from Salvia miltiorrhiza Bunge, a traditional Chinese medicine of the Labiatae family. Its metabolites in vivo can participate in various biochemical reactions of the body, showing various pharmacological effects, and is often used clinically for the treatment of diseases such as angina pectoris, hypertension, and cardiovascular and cerebrovascular diseases. However, due to its poor solubility in water and poor absorption and utilization in vivo, its pharmacological effects are not easily exerted, the onset time is slow, and the dosage is large, which has always been a bottleneck problem in the treatment of tanshinone drugs. Sodium tanshinone IIA sulfonate is a water-soluble sodium salt formed by the sulfonation reaction of tanshinone IIA. Due to the introduction of a hydrophilic sulfonic acid group, its solubility in water is improved, and it has advantages that tanshinone IIA cannot match, becoming an important cardiovascular drug.

[0003] At present, the methods for preparing sodium tanshinone IIA sulfonate mainly use concentrated sulfuric acid or sulfur trioxide complex for sulfonation. In the sulfuric acid sulfonation process, a large amount of highly polluting sulfonation reagents such as sulfuric acid, acetic acid, and acetic anhydride are required. At the same time, polluting gases such as hydrogen chloride are also generated during the production process. The large use of sulfuric acid poses a huge challenge to production safety. Moreover, whether the sulfuric acid sulfonation is carried out in a batch reactor or in a continuous flow, after the sulfonation reaction is completed, it is necessary to go through hydration, purification with dichloromethane, and then carry out a salt-forming reaction. After the reaction, complex post-treatment processes such as filtration, washing, decolorization, and recrystallization are still required. The production efficiency is low, a large amount of waste chemicals are generated, the cost is high, and the product purity is also unsatisfactory. Currently, reports on the continuous synthesis of sodium tanshinone IIA sulfonate using sulfuric acid as a sulfonating agent use a tubular microchannel reactor as a carrier, and the reduction in acid consumption and wastewater generation cannot meet industrial requirements. Moreover, the corrosiveness of concentrated acid poses a huge challenge to the selection of the material of the tubular reactor (CN 113861263 A; CN 103772479 A; CN113980087 A). Sulfur trioxide complex is very active and has a large heat effect of reaction. The sulfonation process of sulfur trioxide complex in a batch reactor is prone to cause local overheating of the material and coking. During the reaction process, it is necessary to pay special attention to controlling the temperature and feeding order, and dissipating heat in time to prevent explosion accidents. Moreover, the product has a high viscosity, which is not conducive to heat dissipation, and it is difficult to prevent or reduce side reactions such as polysulfonation and sulfone formation. The entire sulfonation process has a large operation difficulty, high danger, harsh reaction conditions, poor reagent stability, poor safety, and poor experimental repeatability, posing great challenges to production and the environment and unable to achieve industrial production (CN103739662 A).

[0004] The auxiliary operation time of the batch reactor is long, the reaction cycle is long, the reaction time and output are greatly limited, continuous production cannot be achieved, large-scale production is impossible, the reactor consumes a large amount of energy, and the product quality is difficult to stabilize. For a sulfonation reaction that is fast and highly exothermic, its rapid heat dissipation requirement cannot be met, and side products such as polysulfonation and sulfone are easily generated. Moreover, the operation of the reactor is relatively dangerous and strict safety measures are required to ensure the safety of operators. The single-tube thin-layer liquid film reactor is an absorption reaction device in which the liquid forms a thin film along the tube wall or plate surface due to the action of gravity and contacts the gas countercurrently or cocurrently. It has the following characteristics: The gas and liquid do not penetrate each other, the pressure drop of the equipment is very small, and a relatively high gas load is allowed; the falling film is relatively small, and special fluctuations can be generated on the surface to increase mass transfer, and the backmixing is relatively small, the heat transfer and mass transfer efficiency are relatively high, and the total amount of fluid transfer generated per unit energy consumption is large; the liquid film descending along the wall can be cooled by a partition wall, which can be used for absorption processes with high heat effects and can make the process approach isothermal operation.

[0005] As a green and efficient sulfonating agent, sulfur trioxide does not produce water during the sulfonation process, only the theoretical amount of sulfur trioxide is required, the utilization rate of the sulfonating agent is high, the cost is low, and the generation of waste acid can be fundamentally avoided. Combining the characteristics of the single-tube thin-layer liquid film reactor, using sulfur trioxide to sulfonate tanshinone IIA in the single-tube thin-layer liquid film reactor has important significance for reducing or eliminating environmental pollution, reducing production costs, realizing industrial production, improving production efficiency and protecting the ecological environment, and can effectively break through the technical barriers faced by current industrial production using sulfuric acid and batch reactors. Summary of the Invention

[0006] The purpose of the present invention is to provide a continuous preparation technology of sodium tanshinone IIA sulfonate based on a single-tube thin-layer liquid film reactor, in which sulfur trioxide is basically completely consumed after the reaction, greatly reducing the generation of waste acid. This method avoids the use of highly polluting reagents such as sulfuric acid, acetic acid and acetic anhydride and reduces the use of organic solvents. It has important significance for environmental protection and cost reduction. And the continuous operation of the sulfonation process improves the yield, realizing the green, safe and efficient continuous preparation of high-purity sodium tanshinone IIA sulfonate.

[0007] The present invention solves the above technical problems through the following solutions:

[0008] A continuous preparation method of sodium tanshinone IIA sulfonate based on a single-tube thin-layer liquid film reactor, characterized in that the method comprises the following steps:

[0009] (1) Dissolve tanshinone IIA in an organic solvent to obtain a feed liquid, and the concentration of tanshinone IIA in the organic solvent is 0.01 - 0.1 moL / L;

[0010] (2) React sulfur dioxide in the gas phase with air, with the volume ratio of sulfur dioxide to air being (1:1) - (1:50), and cool to 20 - 80 °C to obtain a sulfur trioxide mixed gas;

[0011] (3) Feed the feed liquid and the sulfur trioxide mixed gas into a single-tube thin-layer liquid film reactor in a co-current or counter-current manner through a feed pump to carry out a continuous sulfonation reaction to obtain a reaction liquid; among them, the feeding ratio of the feed liquid and the sulfur trioxide mixed gas is based on the molar ratio of tanshinone IIA to sulfur trioxide being (1:1) - (1:30);

[0012] (4) Add a sodium salt aqueous solution with a concentration of 0.7 - 7 mo1 / L to the reaction liquid for a salt formation reaction, and obtain the finished product of sodium tanshinone IIA sulfonate through centrifugation, drying, and purification; among them, the volume ratio of the sodium salt aqueous solution to the reaction liquid is 1:2 - 1:20

[0013] The organic solvent described in step (1) is selected from at least one or a mixture of two or more of dichloromethane, 1,2-dichloroethane, tetrachloroethane, N,N-dimethylacetamide, N,N-dimethylformamide, chloroform, 2-methyl sulfoxide, 4-methyl-2-pentanone, tetrahydrofuran, ethyl acetate, methanol, pyrimidine, ether, and methyl tert-butyl ether; the tanshinone IIA in the feed liquid A is preferably 0.05 - 0.1 moL / L in the organic solvent.

[0014] In step (2), the volume ratio of the sulfur dioxide to the air is preferably 1:5 - 1:20; the gas cooling temperature is 30 - 50 °C.

[0015] In step (3), the feeding ratio of the feed liquid and the sulfur trioxide mixed gas is preferably based on the molar ratio of tanshinone IIA to sulfur trioxide being 1:1.5 - 1:10.

[0016] In step (3), the temperature of the continuous sulfonation reaction is 0 - 60 °C, preferably 0 - 50 °C;

[0017] The residence time of the continuous sulfonation reaction is 0.1 - 15 min, preferably 0.5 - 5 min;

[0018] The diameter of the single-tube thin-layer liquid film reactor is 1 - 50 mm, preferably 5 - 25 mm;

[0019] The flow rate of the feed liquid pumped into the single-tube thin-layer liquid film reactor is 10 - 150 mL / min, preferably 50 - 120 mL / min;

[0020] The flow rate of the sulfur trioxide mixed gas entering the single-tube thin-layer liquid film reactor is 0.1 - 20 L / min, preferably 0.5 - 15 L / min;

[0021] The feed pump is a horizontal flow pump made of Hastelloy or polytetrafluoroethylene.

[0022] In step (4), the sodium salt in the sodium salt aqueous solution is an inorganic acid sodium salt and / or an organic acid sodium salt, and the concentration of the sodium salt aqueous solution is 3-7 mol / L.

[0023] Preferably, the inorganic acid sodium salt includes one or more of sodium chloride, sodium bromide, sodium iodide, sodium sulfate, sodium bisulfate, sodium carbonate, sodium bicarbonate, sodium nitrate, sodium phosphate, sodium hydrogen phosphate and sodium dihydrogen phosphate;

[0024] Preferably, the organic acid sodium salt includes one or more of sodium formate, sodium acetate, sodium oxalate, sodium citrate and sodium phenylcyclate.

[0025] In the present invention, the reaction formula is as follows:

[0026]

[0027] Beneficial Effects

[0028] The positive and progressive effects of the present invention are:

[0029] The present invention provides a continuous preparation technology of sodium tanshinone IIA sulfonate based on a single tube thin layer liquid film reactor, in which gaseous sulfur trioxide is basically completely consumed after the reaction is completed, which greatly reduces the generation of waste acid and the use of organic solvents, and has important significance for environmental protection and cost reduction. The single tube thin layer liquid film reactor is used to greatly shorten the reaction time, realize industrial-grade continuous sulfonation, and realize the green, safe, and efficient continuous preparation of high-purity sodium tanshinone IIA sulfonate. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is a schematic diagram of the preparation method of sodium tanshinone ⅡA sulfonate in Example 1 of this application.

[0031] The following are the descriptions of the reference numerals:

[0032] Air compressor 1

[0033] Flow Control Hub 2

[0034] Tube furnace 3

[0035] Exhaust gas absorption pipe 4

[0036] Single tube thin layer liquid film reactor 5

[0037] Hot and cold cycle machine 6

[0038] Feed pump 7

[0039] Figure 2Schematic diagram of the single-tube thin-layer liquid film reactor in Example 1. The reactor is a commercially available product, and the manufacturer is China National Research Institute of Daily Chemical Industry Co., Ltd.

[0040] Figure 3 This is the liquid chromatography diagram of sodium tanshinone ⅡA sulfonate in Example 1 of this application. Detailed implementation mode

[0041] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications. All reagents and raw materials of the present invention are commercially available.

[0042] The detailed connection in this example is as Figure 1 shown. All reagents used are of AR grade, and the reaction feed ratios described in the examples are all molar ratios.

[0043] Example 1

[0044] In the single-tube thin-layer liquid film reactor, the feed pump is a peristaltic pump made of polytetrafluoroethylene. The diameter of the single-tube thin-layer liquid film reactor is 10 mm, and the retention volume is 118 mL.

[0045] Take tanshinone ⅡA (0.08 moL), dissolve it with dichloromethane and make up the volume to 1000 mL. Add 100 g of 3A molecular sieve and let it stand for 24 h to obtain the feed liquid. Control the ratio of sulfur dioxide to air to be 1:10 to produce sulfur trioxide mixed gas, and use a cooling device to cool the sulfur trioxide mixed gas to 25 °C. The flow rate of the feed liquid peristaltic pump is 50 mL / min, and the flow rate of the sulfur trioxide mixed gas is 1.344 L / min. The molar ratio of tanshinone ⅡA to sulfur trioxide is 1:1.5. Control the sulfonation temperature to be 25 °C, and the residence time of the continuous sulfonation reaction is 2.2 min. Feed the feed liquid and the sulfur trioxide mixed gas into the single-tube thin-layer liquid film reactor simultaneously from the upper end in parallel. After the reaction is stable, collect the reaction liquid, add saturated brine (the volume ratio of saturated brine to the reaction liquid is 1:4), filter and dry to obtain sodium tanshinone ⅡA sulfonate. Figure 3 This is the liquid chromatography diagram of the product. The peak with a retention time of 19.17 min in the figure is the characteristic peak of sodium tanshinone ⅡA sulfonate. Its yield can be calculated to be 96.5% by the standard curve method.

[0046] Example 2

[0047] In the single-tube thin-layer liquid film reactor, the feed pump is a peristaltic pump made of polytetrafluoroethylene. The diameter of the single-tube thin-layer liquid film reactor is 20 mm, and the retention volume is 472 mL.

[0048] Take tanshinone ⅡA (0.08 moL), dissolve it with chloroform and make up the volume to 1000 mL. Add 100 g of 3A molecular sieve and let it stand for 24 h to obtain the feed liquid. Control the ratio of sulfur dioxide to air to be 1:10 to produce sulfur trioxide mixed gas, and use a cooling device to cool the sulfur trioxide mixed gas to 30 °C. The flow rate of the feed liquid peristaltic pump is 100 mL / min, and the flow rate of sulfur trioxide is 3.584 L / min. The molar ratio of tanshinone ⅡA to sulfur trioxide is 1:2. Control the sulfonation temperature to be 30 °C, and the residence time of the continuous sulfonation reaction is 4.72 min. Respectively introduce the feed liquid and the sulfur trioxide mixed gas into the single-tube thin-layer liquid film reactor from the upper and lower ends in a countercurrent manner. After the reaction is stable, collect the reaction liquid, add saturated sodium carbonate (the volume ratio of saturated sodium carbonate to the reaction liquid is 1:6), filter and dry to obtain sodium tanshinone ⅡA sulfonate, and the yield is 82.8%.

[0049] Example 3

[0050] In the single-tube thin-layer liquid film reactor, the feed pump is a peristaltic pump made of Hastelloy. The diameter of the single-tube thin-layer liquid film reactor is 15 mm, and the retention volume is 354 mL.

[0051] Take tanshinone ⅡA (0.05 moL), dissolve it with N,N-dimethylformamide and make up the volume to 1000 mL to obtain the feed liquid. Control the ratio of sulfur dioxide to air to be 1:5 to produce sulfur trioxide mixed gas, and use a cooling device to cool the sulfur trioxide mixed gas to 40 °C. The flow rate of the feed liquid peristaltic pump is 100 mL / min, and the flow rate of sulfur trioxide is 1.68 L / min. The molar ratio of tanshinone ⅡA to sulfur trioxide is 1:3. Control the sulfonation temperature to be 20 °C, and the residence time of the continuous sulfonation reaction is 3.54 min. Introduce the feed liquid and the sulfur trioxide mixed gas into the single-tube thin-layer liquid film reactor from the upper end in a co-current manner at the same time. After the reaction is stable, collect the reaction liquid, add saturated sodium formate (the volume ratio of saturated sodium formate to the reaction liquid is 1:12), filter and dry to obtain sodium tanshinone ⅡA sulfonate, and the yield is 81.0%.

[0052] Example 4

[0053] In the single-tube thin-layer liquid film reactor, the feed pump is a peristaltic pump made of Hastelloy. The diameter of the single-tube thin-layer liquid film reactor is 20 mm, and the retention volume is 472 mL.

[0054] Take tanshinone ⅡA (0.05 moL), dissolve it with methyl tert-butyl ether and make up the volume to 1000 mL to obtain the feed solution. Control the ratio of sulfur dioxide to air at 1:12 to produce sulfur trioxide mixed gas, and use a cooling device to cool the sulfur trioxide mixed gas to 10 °C. The flow rate of the feed solution peristaltic pump is 100 mL / min, and the flow rate of sulfur trioxide is 6.72 L / min. The molar ratio of tanshinone ⅡA to sulfur trioxide is 1:5. Control the sulfonation temperature at 10 °C, and the residence time of the continuous sulfonation reaction is 4.72 min. Respectively introduce the feed solution and the sulfur trioxide mixed gas into the single-tube thin-layer liquid film reactor from the upper and lower ends in a countercurrent manner. After the reaction is stable, collect the reaction solution, add saturated sodium chloride solution (the volume ratio of the saturated sodium chloride solution to the reaction solution is 1:14), filter and dry to obtain sodium tanshinone ⅡA sulfonate, and the yield is 96.3%.

[0055] Example 5

[0056] In the single-tube thin-layer liquid film reactor, the feed pump is a peristaltic pump made of Hastelloy. The diameter of the single-tube thin-layer liquid film reactor is 10 mm, and the retention volume is 118 mL.

[0057] Take tanshinone ⅡA (0.08 moL), dissolve it with tetrachloroethane and make up the volume to 1000 mL, add 100 g of 3A molecular sieve, and let it stand for 24 h to obtain the feed solution. Control the ratio of sulfur dioxide to air at 1:15 to produce sulfur trioxide mixed gas, and use a cooling device to cool the sulfur trioxide mixed gas to 15 °C. The flow rate of the feed solution peristaltic pump is 50 mL / min, and the flow rate of sulfur trioxide is 9.41 L / min. The molar ratio of tanshinone ⅡA to sulfur trioxide is 1:7. Control the sulfonation temperature at 15 °C, and the residence time of the continuous sulfonation reaction is 2.4 min. Respectively introduce the feed solution and the sulfur trioxide mixed gas into the single-tube thin-layer liquid film reactor from the upper and lower ends in a countercurrent manner. After the reaction is stable, collect the reaction solution, add saturated sodium oxalate solution (the volume ratio of the saturated sodium oxalate solution to the reaction solution is 1:16), filter and dry to obtain sodium tanshinone ⅡA sulfonate, and the yield is 80.8%.

[0058] Example 6

[0059] In the single-tube thin-layer liquid film reactor, the feed pump is a peristaltic pump made of polytetrafluoroethylene. The diameter of the single-tube thin-layer liquid film reactor is 30 mm, and the retention volume is 706 mL.

[0060] Take tanshinone IIA (0.08 moL), dissolve it with ether and make up the volume to 1000 mL. Add 100 g of 3A molecular sieve and let it stand for 24 h to obtain the feed liquid. Control the ratio of sulfur dioxide to air at 1:10 to produce sulfur trioxide mixed gas, and use a cooling device to cool the sulfur trioxide mixed gas to 15 °C. The flow rate of the feed liquid peristaltic pump is 100 mL / min, and the flow rate of sulfur trioxide is 1.97 L / min. The molar ratio of tanshinone IIA to sulfur trioxide is 1:1.1. Control the sulfonation temperature at 20 °C, and the residence time of the continuous sulfonation reaction is 7.06 min. Simultaneously introduce the feed liquid and the sulfur trioxide mixed gas into the single-tube thin-layer liquid film reactor from the upper end in parallel. After the reaction is stable, collect the reaction liquid, add saturated sodium citrate (the volume ratio of saturated sodium citrate to the reaction liquid is 1:7), filter and dry to obtain sodium tanshinone IIA sulfonate, with a yield of 91.82%.

[0061] Example 7

[0062] In the single-tube thin-layer liquid film reactor, the feed pump is a peristaltic pump made of polytetrafluoroethylene. The diameter of the single-tube thin-layer liquid film reactor is 30 mm, and the retention volume is 706 mL.

[0063] Take tanshinone IIA (0.05 moL), dissolve it with tetrahydrofuran and make up the volume to 1000 mL to obtain the feed liquid A. Control the ratio of sulfur dioxide to air at 1:10 to produce sulfur trioxide mixed gas, and use a cooling device to cool the sulfur trioxide mixed gas to 20 °C. The flow rate of the feed liquid peristaltic pump is 100 mL / min, and the flow rate of sulfur trioxide is 11.2 L / min. The molar ratio of tanshinone IIA to sulfur trioxide is 1:10. Control the sulfonation temperature at 10 °C, and the residence time of the continuous sulfonation reaction is 7.06 min. Simultaneously introduce the feed liquid and the sulfur trioxide mixed gas into the single-tube thin-layer liquid film reactor from the upper end in parallel. After the reaction is stable, collect the reaction liquid, add saturated sodium dihydrogen phosphate (the volume ratio of saturated sodium dihydrogen phosphate to the reaction liquid is 1:10), filter and dry to obtain sodium tanshinone IIA sulfonate, with a yield of 90.8%.

[0064] Comparative Example 1

[0065] Take tanshinone IIA (0.004 moL), dissolve it with dichloromethane and make up the volume to 50 mL, and pour it into a 250 mL three-necked flask. Prepare 0.8 g of solid sulfur trioxide, dissolve it with dichloromethane and make up the volume to 50 mL. Insert a thermometer below the liquid level of the flask, place the flask in a water bath, and keep it at a constant temperature of 20 °C. Then, under magnetic stirring, slowly add 40 mL of 0.2 moL / L sulfur trioxide solution within 30 min. The molar ratio of tanshinone IIA to sulfur trioxide is 1:2. After the addition, stir magnetically for 2 h. Immediately add 25 mL of saturated brine after the reaction is completed, filter and dry to obtain sodium tanshinone IIA sulfonate, with a yield of 28.8%.

[0066] Comparative Example 2

[0067] Take 0.5 g of tanshinone IIA, add 24 mL of glacial acetic acid and 4 mL of acetic anhydride, place them in a 100 mL three-necked flask, insert a thermometer below the liquid level of the flask, put the flask into a water bath, and keep it at a constant temperature of 15 °C. Then, slowly add 2 mL of a mixed solution of concentrated sulfuric acid / glacial acetic acid (1 / 1) dropwise under magnetic stirring; after the addition is complete, stir magnetically for 1 h, then pour the reaction solution slowly into an equal volume of distilled water, immediately add 20 mL of saturated sodium chloride aqueous solution, filter and dry to obtain sodium tanshinone IIA sulfonate, and the yield is 65.67%.

[0068] Comparative Example 3

[0069] Take tanshinone IIA (0.004 moL), dissolve it with dichloromethane and make up the volume to 50 mL as feed solution A; take 3.4 mL of concentrated sulfuric acid and 0.85 mL of acetic acid as feed solution B. Pump feed solutions A and B into a microchip reactor simultaneously by peristaltic pumps A and B respectively, and control the total flow rate to be 9.6 ml / min. The molar ratio of tanshinone IIA to concentrated sulfuric acid is 1:16, control the sulfonation temperature to be 20 °C, and the residence time of the continuous sulfonation reaction is 5 min. After the reaction is stable, pass the reaction solution into a cyclone separator, add saturated brine (the volume ratio of saturated brine to the reaction solution is 1:4), filter and dry to obtain sodium tanshinone IIA sulfonate, and the yield is 85%.

[0070] Compared with Comparative Example 1 and Comparative Example 2, the yield of the target product in Examples 1-7 is higher and the reaction time is greatly shortened; compared with Comparative Example 3, the preparation process in Examples 1-7 is more economical and efficient, the production efficiency is significantly improved, and the sulfonating agent is basically completely consumed, greatly reducing the waste acid discharge and solvent consumption, which is of great significance for protecting the ecological environment and controlling production costs. At the same time, compared with the comparative examples, the preparation method provided by the present invention is more simple and safe to operate, can be continuously produced, and improves the production safety.

[0071] The above description is only a preferred embodiment of the present invention, and does not impose any form of limitation on the present invention. Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art of this patent, without departing from the scope of the technical solution of the present invention, can make some changes or modifications to the above-mentioned disclosed technical content to be equivalent embodiments with equivalent changes. However, as long as it does not depart from the content of the technical solution of the present invention, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A continuous preparation method of sodium tanshinone IIA sulfonate based on a single-tube thin-layer liquid film reactor, characterized in that, The method includes the following steps: (1) Dissolve tanshinone IIA in an organic solvent to obtain a feed solution, where the concentration of tanshinone IIA in the organic solvent is 0.01 - 0.1 moL / L; (2) React gaseous sulfur dioxide with air, with the volume ratio of sulfur dioxide to air being (1:1) - (1:50), and cool to 20 - 80 °C to obtain a sulfur trioxide mixed gas; (3) Feed the feed solution and the sulfur trioxide mixed gas into a single - tube thin - layer liquid - film reactor in a co - current or counter - current manner through a feed pump to carry out a continuous sulfonation reaction to obtain a reaction solution; among them, the feeding ratio of the feed solution and the sulfur trioxide mixed gas is such that the molar ratio of tanshinone IIA to sulfur trioxide is (1:1) - (1:30); (4) Add a sodium salt aqueous solution with a concentration of 0.7 - 7 mo1 / L to the reaction solution for a salt - formation reaction, and obtain the finished product of sodium tanshinone IIA sulfonate through centrifugation, drying, and purification; among them, the volume ratio of the sodium salt aqueous solution to the reaction solution is 1:2 - 1:

20.

2. The preparation method according to claim 1, characterized in that, The organic solvent in step (1) is at least one or a mixture of two or more selected from dichloromethane, 1,2 - dichloroethane, tetrachloroethane, N,N - dimethylacetamide, N,N - dimethylformamide, chloroform, 2 - methyl sulfoxide, 4 - methyl - 2 - pentanone, tetrahydrofuran, ethyl acetate, methanol, pyrimidine, ether, and methyl tert - butyl ether; the concentration of tanshinone IIA in the organic solvent of feed solution A is 0.05 - 0.1 moL / L.

3. The preparation method according to claim 1, characterized in that, In step (2), the volume ratio of sulfur dioxide to air is 1:5 - 1:20; the gas cooling temperature is 30 - 50 °C.

4. The preparation method according to claim 1, characterized in that, In step (3), the feeding ratio of the feed solution and the sulfur trioxide mixed gas is such that the molar ratio of tanshinone IIA to sulfur trioxide is (1:1.5) - (1:10).

5. The preparation method according to claim 1, characterized in that, The temperature of the continuous sulfonation reaction is 0 - 60 °C, and the residence time of the continuous sulfonation reaction is 0.1 - 15 min; The diameter of the single - tube thin - layer liquid - film reactor is 1 - 50 mm, the flow rate of the feed solution pumped into the single - tube thin - layer liquid - film reactor is 10 - 150 mL / min, and the flow rate of the sulfur trioxide mixed gas entering the single - tube thin - layer liquid - film reactor is 0.1 - 20 L / min; The feed pump is a peristaltic pump, and the material is Hastelloy or polytetrafluoroethylene.

6. The preparation method according to claim 1, wherein, In step (4), the sodium salt in the sodium salt aqueous solution is an inorganic sodium salt and / or an organic sodium salt, and the concentration of the sodium salt aqueous solution is 3 - 7 mo1 / L.

7. The preparation method according to claim 5, characterized in that, In step (3), the temperature of the continuous sulfonation reaction is 0 - 50 °C, and the residence time of the continuous sulfonation reaction is 0.5 - 5 min; The diameter of the single - tube thin - layer liquid - film reactor is 5 - 25 mm, the flow rate of the feed solution pumped into the single - tube thin - layer liquid - film reactor is 50 - 120 mL / min, and the flow rate of the sulfur trioxide mixed gas entering the single - tube thin - layer liquid - film reactor is 0.5 - 15 L / min.

8. The preparation method according to claim 6, characterized in that, The inorganic sodium salts include one or more of sodium chloride, sodium bromide, sodium iodide, sodium sulfate, sodium bisulfate, sodium carbonate, sodium bicarbonate, sodium nitrate, sodium phosphate, sodium hydrogen phosphate and sodium dihydrogen phosphate; the organic sodium salts include one or more of sodium formate, sodium acetate, sodium oxalate, sodium citrate and sodium benzoate.

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