CN113980087B

CN113980087B - Method for preparing tanshinone IIA sodium sulfonate

Info

Publication number: CN113980087B
Application number: CN202111296537.3A
Authority: CN
Inventors: 张耀华; 孙忠达; 叶金星; 丁金国; 俞伟; 江锡铭; 董莹; 刘蓓; 程瑞华; 孙茂林; 朱维平; 钱旭红; 梁超茗; 沈昕源; 曹黎明
Original assignee: Sph No1 Biochemical & Pharmaceutical Co ltd
Current assignee: Sph No1 Biochemical & Pharmaceutical Co ltd
Priority date: 2021-07-22
Filing date: 2021-11-03
Publication date: 2023-03-21
Anticipated expiration: 2041-11-03
Also published as: CN113980087A; CN217120212U

Abstract

The invention discloses a method for preparing tanshinone IIA sodium sulfonate. The method comprises the following steps: (1) Taking a mixed solution of tanshinone IIA, acetic anhydride and an organic solvent as a feed solution A, taking a mixed solution of sulfuric acid and acetic acid as a feed solution B, and carrying out continuous sulfonation reaction to obtain a reaction solution E; the reaction temperature is 0-50 ℃; (2) Taking water as a feeding liquid C, and carrying out hydration reaction with a reaction liquid E to obtain a reaction liquid F; taking dichloromethane as a feeding liquid D at the reaction temperature of 0-50 ℃ (3), and purifying the reaction liquid F to obtain a reaction liquid G; the reaction temperature is 0-50 ℃; (4) And (4) allowing the reaction solution G to enter a continuous separator to obtain an aqueous layer and an organic layer, and filtering the aqueous layer. The sulfonation reaction, the hydration reaction, the purification and the salt formation are carried out full-continuous reaction, so that the selectivity of the reaction, and the purity and the yield of the tanshinone IIA sodium sulfonate are effectively improved; realizing the high-efficiency preparation of the high-purity tanshinone IIA sodium sulfonate.

Description

Method for preparing tanshinone IIA sodium sulfonate

The present application claims priority from chinese patent application CN202110833061.6, filed on 22/07/2021. The present application refers to the above-mentioned chinese patent application in its entirety.

Technical Field

The invention relates to a method for preparing tanshinone IIA sodium sulfonate.

Background

Tanshinone IIA is a fat-soluble effective component extracted from traditional Chinese medicine salvia miltiorrhiza, metabolites in vivo can participate in various biochemical reactions of organisms, show various pharmacological actions, and is often used for treating diseases such as angina, hypertension, cardiovascular and cerebrovascular diseases and the like in clinic. However, the poor solubility in water and the poor absorption and utilization in vivo cause that the pharmacological action is not easy to be exerted, the onset time is slow, the administration dosage is large, and the bottleneck problem in the tanshinone medicament treatment is always solved. The tanshinone IIA sodium sulfonate is a water-soluble sodium salt formed by the tanshinone IIA after sulfonation reaction, improves the solubility of the tanshinone IIA in water due to the introduction of hydrophilic sulfonic acid groups, has incomparable superiority to the tanshinone IIA, and becomes an important cardiovascular medicament. The existing method for preparing tanshinone IIA sodium sulfonate mainly adopts a concentrated sulfuric acid sulfonation method, a large amount of chemical reagents which have high pollution to the environment, such as sulfuric acid, acetic anhydride and the like, are required to be used in the generation process, and meanwhile, polluted gases, such as hydrogen chloride and the like, can be generated in the production process. Therefore, how to adopt more environment-friendly preparation conditions has important significance for reducing or eliminating environmental pollution and protecting ecological environment.

The method for preparing the tanshinone IIA sodium sulfonate by utilizing the microreactor comprises a method for preparing the tanshinone II-a sodium sulfonate by utilizing a micro-reaction device, such as Guokay et al and Chinese patent with publication No. CN104910251A, wherein the method only carries out continuous sulfonation reaction, and both hydration salt-forming reaction and purification are carried out in intermittent operation. The post-treatment and separation steps of a batch processing scheme typically account for major equipment and time costs in the pharmaceutical manufacturing process, and purity and yield are to be improved.

Disclosure of Invention

The invention aims to overcome the defects of low reaction selectivity, low purity and high environmental pollution in the prior art, and provides a method for preparing tanshinone IIA sodium sulfonate efficiently and pollution-free by fully and continuously completing sulfonation reaction, hydration reaction, purification and salification by using a microreactor.

The invention solves the technical problems through the following technical scheme.

The invention provides a preparation method of tanshinone IIA sodium sulfonate, which comprises the following steps:

step S1: taking a mixed solution of tanshinone IIA, acetic anhydride and an organic solvent as a feeding solution A, taking a mixed solution of sulfuric acid and acetic acid as a feeding solution B, adding the feeding solution A and the feeding solution B into a first microreactor, carrying out continuous sulfonation reaction to obtain a reaction solution E, and allowing the reaction solution E to flow into a second microreactor; the reaction temperature of the continuous sulfonation reaction is 0-50 ℃;

step S2: adding water serving as a feeding liquid C into the second microreactor, and carrying out hydration reaction with the reaction liquid E to obtain a reaction liquid F, wherein the reaction liquid F flows into a third microreactor; the reaction temperature of the hydration reaction is 0-50 ℃;

and step S3: adding dichloromethane serving as a feeding liquid D into the third microreactor, and purifying the reaction liquid F to obtain a reaction liquid G; the reaction temperature of the purification is 0-50 ℃;

and step S4: and (3) allowing the reaction liquid G flowing out of the third microreactor to enter a continuous separator to obtain a water layer and an organic layer, and filtering the water layer.

Preferably, the method for preparing sodium tanshinone IIA sulfonate further comprises: after the step S4, recrystallizing and drying the filtered liquid obtained by filtering; the solvent for recrystallization is an organic solvent conventional in the art, preferably methanol.

In step S1, preferably, the molar ratio of the tanshinone IIA to the acetic anhydride is 1.

In step S1, the organic solvent is an organic solvent conventional in the art, and preferably, the organic solvent is dichloromethane or acetone.

In step S1, preferably, the sulfuric acid is concentrated sulfuric acid with a concentration of 18mol/L, and the acetic acid is 17.5mol/L.

In step S1, preferably, the reaction molar ratio of the tanshinone IIA and the sulfuric acid is 1.

In the step S1, preferably, the concentration of the tanshinone IIA is 0.03mol/L to 1.5mol/L.

In step S1, the retention volume of the first microreactor is preferably 10 to 100mL, such as 10mL, 30mL, 50mL, 60mL, 100mL.

In step S1, the first microreactor is a conventional microreactor in the art, and preferably, the first microreactor is made of glass.

In step S1, preferably, the feeding fluid a and the feeding fluid B are pumped into the first microreactor simultaneously.

In step S1, preferably, a discharge port of the first microreactor is directly connected to the second microreactor.

In step S1, the flow rate of the feed liquid A is preferably 1.0-30 mL/min, such as 1.5, 3.8, 4.5, 4.3, 5.4, 7.5, 8.6, 9.0, 10.8, 15, 18mL/min.

In step S1, the flow rate of the feed liquid B is preferably 0.5-10 mL/min, such as 0.5, 0.6, 1, 1.2, 1.5, 2.5, 3.5mL/min.

In step S1, the reaction temperature of the continuous sulfonation reaction is preferably 10 to 30 ℃, for example, 10, 25 ℃.

In step S1, preferably, the reaction residence time of the continuous sulfonation reaction is 3 to 12min.

In step S2, preferably, the retention volume of the second microreactor is 5 to 50mL, such as 5, 15, 20, 30, 50mL.

In step S2, the second microreactor is a conventional microreactor in the art, and preferably, the second microreactor is made of glass.

In step S2, preferably, a discharge port of the second microreactor is directly connected to the third microreactor.

In step S2, the flow rate of the feed liquid C is preferably 1-40 mL/min, such as 2.0, 5, 6.0, 10, 12, 20mL/min.

In step S2, the reaction temperature of the hydration reaction is preferably 10 to 30 ℃, for example, 10, 25 ℃.

In step S2, preferably, the reaction residence time of the hydration reaction is 0.5 to 3min.

In step S3, preferably, the third microreactor has a retention volume of 5 to 50mL, such as 5, 15, 20, 30, 50mL.

In step S3, the third microreactor is a conventional microreactor in the art, and preferably, the third microreactor is made of glass.

In step S3, preferably, the discharge port of the third reactor is connected to the continuous separator.

In step S3, the flow rate of the feeding liquid D is preferably 2-40 mL/min, such as 4.0, 5, 6.0, 10, 12, 20, 24, 40mL/min.

In step S3, the reaction temperature of the purification is preferably 10 to 30 ℃, for example 10, 25 ℃.

In step S3, preferably, the reaction residence time of the purification is 0.5 to 3min.

In step S4, the continuous separator is a continuous separator conventional in the art.

In step S4, the retention volume of the continuous separator is preferably 250 to 1000mL, such as 250, 500, 1000mL.

In step S4, preferably, after the aqueous layer is separated, the aqueous layer is further mixed with a saturated aqueous sodium chloride solution, and then the filtration is performed.

In the present invention, the pump is a pump conventionally used in the art.

In the invention, the reaction formula is as follows:

on the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: according to the invention, sulfonation reaction, hydration reaction, purification and salification are carried out in a series-connected microreactor to carry out full-continuous reaction, so that the reaction selectivity is effectively improved; the purity and the yield of the crude tanshinone IIA sodium sulfonate are improved; realizing the high-efficiency preparation of the high-purity tanshinone IIA sodium sulfonate;

by adopting a full-continuous production process, most of the reaction and post-treatment are carried out in a safe and closed environment, thereby effectively preventing pungent odor and harm to human bodies and the environment caused by the overflow of concentrated sulfuric acid, acetic acid, a solvent and the like; while the experiment operation is simplified, the occupied area of reaction equipment is reduced, the time of intermittent operation is avoided, the production efficiency is effectively improved, and the labor cost and the generation cost are reduced; the method and the process are simpler, green, safe and efficient, and the high-purity tanshinone IIA sodium sulfonate is continuously produced.

Drawings

FIG. 1 is a schematic structural view of a microreactor means used in the present invention.

In fig. 1, the reference numerals are illustrated as follows:

a: advection pump (tanshinone IIA/acetic anhydride/dichloromethane)

B: advection pump (sulfuric acid/acetic acid)

C: advection pump (Water)

D: advection pump (dichloromethane)

1: first microreactor

2: second microreactor

3: third microreactor

4: continuous separator

5: receiver with a plurality of receivers

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In this embodiment, the micro-reaction device is composed of four advection pumps, a peristaltic pump, three sets of micro-reactors and a micro-continuous separator, and is connected in detail as shown in fig. 1, the advection pump a and the advection pump B are used for feeding a feeding liquid a and a feeding liquid B respectively, and are connected with the first micro-reactor 1; the constant-flow pump C is used for feeding the feeding liquid C and is connected with the second microreactor 2 together with the discharge port of the first microreactor 1; the constant-flow pump D is used for feeding the feeding liquid D and is connected with the third microreactor 3 together with the discharge hole of the second microreactor 2; a discharge port of the third microreactor 3 is connected with the continuous separator 4, the upper layer is pumped out by a peristaltic pump and is guided into the receiver 5, and the lower layer is discharged from a liquid outlet of the continuous micro separator 4; the receiver 5 is filled with saturated sodium chloride aqueous solution, and the three microreactors are made of glass. The reagents used in the experiment are all of AR grade, and the reaction charge ratios in the examples are all molar ratios.

Example 1:

in the micro-reaction device, the connecting pipe is a 1/8 pipe made of polytetrafluoroethylene, the feeding pump is four advection pumps made of polytetrafluoroethylene, the retention volume of the first microreactor 1 is 50mL, the retention volume of the second microreactor 2 is 20mL, the retention volume of the third microreactor 3 is 20mL, the retention volume of the continuous separator 4 is 250mL, and the receiver 5 is a 2L round-bottom flask.

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.1 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 9.0mL/min, and the flow rate of the pump B is 1.0mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1, and the reaction charge ratio of the tanshinone IIA and the concentrated sulfuric acid is about 1. The reaction residence time for the continuous sulfonation reaction was 5min.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 25 ℃; the flow rate of the pump C is 10mL/min; the reaction residence time of the hydration reaction was 1min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 25 ℃; the flow rate of the pump D is 10mL/min; the reaction residence time for purification was 0.7min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 20mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.1%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 81.4%.

Example 2:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.1 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 10 ℃; the flow rate of the pump A is 4.5mL/min, and the flow rate of the pump B is 0.5mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1. The reaction residence time for the continuous sulfonation reaction was 10min.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 10 ℃; the flow rate of the pump C is 5mL/min; the reaction residence time of the hydration reaction was 2min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification is 10 ℃; the flow rate of the pump D is 5mL/min; the reaction residence time for purification was 1.3min

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 10mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.9%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 72.5%.

Example 3:

in the micro-reaction device, the connecting pipe is a 1/8 pipeline made of polytetrafluoroethylene, the feeding pump is four advection pumps made of polytetrafluoroethylene, the retention volume of the first microreactor 1 is 50mL, the retention volume of the second microreactor 2 is 20mL, the retention volume of the third microreactor 3 is 20mL, the retention volume of the continuous separator 4 is 250mL, and the receiver 5 is a 2L round-bottom flask.

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.1 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to make a volume of 500mL, as feed liquid B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 50 ℃; the flow rate of the pump A is 18mL/min, and the flow rate of the pump B is 2mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1. The reaction residence time for the continuous sulfonation reaction was 2.5min.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 50 ℃; the flow rate of the pump C is 20mL/min; the reaction residence time for the hydration reaction was 0.5min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification is 50 ℃; the flow rate of the pump D is 20mL/min; the reaction residence time for purification was 0.3min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 40mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.8%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with a yield of 75.1%.

Example 4:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.1 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 10.8mL/min, and the flow rate of the pump B is 1.2mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1. The reaction residence time for the continuous sulfonation reaction was 4.2min.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 25 ℃; the flow rate of the pump C is 12mL/min; the reaction residence time for the hydration reaction was 0.8min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 25 ℃; the flow rate of the pump D is 12mL/min; the reaction residence time for purification was 0.6min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 24mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.4%. Then recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with a yield of 80.6%.

Example 5:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.1 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into a first microreactor 1 through a feed pump A and a feed pump B respectively to carry out continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into a second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 8.6mL/min, and the flow rate of the pump B is 1.4mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1. The reaction residence time for the continuous sulfonation reaction was 5min.

Pumping water serving as a feed liquid C into the second microreactor 2 through a feed pump C, and carrying out hydration reaction on the water and a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into a third microreactor 3; the reaction temperature of the hydration reaction is 25 ℃; the flow rate of the pump C is 10mL/min; the reaction residence time of the hydration reaction was 1min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 25 ℃; the flow rate of the pump D is 10mL/min; the reaction residence time for purification was 0.6min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 20mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.9%. Then recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with a yield of 81.4%.

Example 6:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.1 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to make a volume of 500mL, as feed liquid B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 10 ℃; the flow rate of the pump A is 8.6mL/min, and the flow rate of the pump B is 1.4mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1. The reaction residence time for the continuous sulfonation reaction was 5min.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 10 ℃; the flow rate of the pump C is 10mL/min; the reaction residence time for the hydration reaction was 1min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification is 10 ℃; the flow rate of the pump D is 10mL/min; the reaction residence time for purification was 0.6min.

The four feed pumps A, B, C and D operate simultaneously, the reaction solution G flows into the continuous separator 4 to obtain a water layer and an organic layer, the organic layer is discharged out of the system, the water layer is introduced into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump, the flow rate of the peristaltic pump is 20mL/min, and the filtration is carried out to obtain a crude product of the sodium tanshinone IIA sulfonate, wherein the purity of the sodium tanshinone IIA sulfonate is 95.7%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 71.4%.

Example 7:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.1 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 50 ℃; the flow rate of the pump A is 8.6mL/min, and the flow rate of the pump B is 1.4mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 50 ℃; the flow rate of the pump C is 10mL/min; the reaction residence time of the hydration reaction was 1min.

Pumping dichloromethane serving as a feed liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification is 50 ℃; the flow rate of the pump D is 10mL/min; the reaction residence time for purification was 0.6min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 20mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.5%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 74.9%.

Example 8:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.1 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 4.3mL/min, and the flow rate of the pump B is 0.7mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1. The reaction residence time for the continuous sulfonation reaction was 10min.

Pumping water serving as a feed liquid C into the second microreactor 2 through a feed pump C, and carrying out hydration reaction on the water and a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into a third microreactor 3; the reaction temperature of the hydration reaction is 25 ℃; the flow rate of the pump C is 5mL/min; the reaction residence time of the hydration reaction was 2min.

Pumping dichloromethane serving as a feed liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 25 ℃; the flow rate of the pump D is 5mL/min; the reaction residence time for purification was 1.3min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 10mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.3%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 82.1%.

Example 9:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.1 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to make a volume of 500mL, as feed liquid B. Simultaneously pumping the feed liquid A and the feed liquid B into a first microreactor 1 through a feed pump A and a feed pump B respectively to carry out continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into a second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 8.6mL/min, and the flow rate of the pump B is 1.4mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1. The reaction residence time for the continuous sulfonation reaction was 5min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 25 ℃; the flow rate of the pump D is 20mL/min; the reaction residence time for purification was 0.6min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 20mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.0%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 80.7%.

Example 10:

in the micro-reaction device, the connecting pipe is a 1/8 pipeline made of polytetrafluoroethylene, the feeding pump is four advection pumps made of polytetrafluoroethylene, the retention volume of the first microreactor 1 is 10mL, the retention volume of the second microreactor 2 is 5mL, the retention volume of the third microreactor 3 is 5mL, the retention volume of the continuous separator 4 is 250mL, and the receiver 5 is a 2L round-bottom flask.

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (0.21 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 1.5mL/min, and the flow rate of the pump B is 0.5mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1, the reaction charge ratio of the tanshinone IIA and the concentrated sulfuric acid is 1.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 25 ℃; the flow rate of pump C was 2.0mL/min; the reaction residence time for the hydration reaction was 1.3min.

Pumping dichloromethane serving as a feed liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 25 ℃; the flow rate of the pump D is 2.0mL/min; the reaction residence time for purification was 0.8min.

The four feeding pumps A, B, C and D operate simultaneously, the reaction solution G flows into the continuous separator 4 to obtain a water layer and an organic layer, the organic layer is discharged out of the system, the water layer is introduced into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 4mL/min, and the crude product of the tanshinone IIA sodium sulfonate is obtained by filtering, wherein the purity of the tanshinone IIA sodium sulfonate is 95.1 percent. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 82.3%.

Example 11:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (0.41 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 10 ℃; the flow rate of the pump A is 1.5mL/min, and the flow rate of the pump B is 0.5mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1, the reaction charge ratio of the tanshinone IIA and the concentrated sulfuric acid is 1.

Pumping water serving as a feed liquid C into the second microreactor 2 through a feed pump C, and carrying out hydration reaction on the water and a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into a third microreactor 3; the reaction temperature of the hydration reaction is 10 ℃; the flow rate of the pump C is 2mL/min; the reaction residence time for the hydration reaction was 1.3min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification is 10 ℃; the flow rate of the pump D is 2mL/min; the reaction residence time for purification was 0.8min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 4mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.8%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 84.8%.

Example 12:

in the micro-reaction device, the connecting pipe is a 1/8 pipeline made of polytetrafluoroethylene, the feeding pump is four advection pumps made of polytetrafluoroethylene, the retention volume of the first microreactor 1 is 30mL, the retention volume of the second microreactor 2 is 15mL, the retention volume of the third microreactor 3 is 15mL, the retention volume of the continuous separator 4 is 250mL, and the receiver 5 is a 2L round-bottom flask.

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (0.61 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to make a volume of 500mL, as feed liquid B. Simultaneously pumping the feed liquid A and the feed liquid B into a first microreactor 1 through a feed pump A and a feed pump B respectively to carry out continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into a second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 50 ℃; the flow rate of the pump A is 4.5mL/min, and the flow rate of the pump B is 1.5mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 50 ℃; the flow rate of pump C was 6.0mL/min; the reaction residence time for the hydration reaction was 1.3min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification is 50 ℃; the flow rate of the pump D is 6mL/min; the reaction residence time for purification was 0.8min.

The four feed pumps A, B, C and D operate simultaneously, the reaction solution G flows into the continuous separator 4 to obtain a water layer and an organic layer, the organic layer is discharged out of the system, the water layer is introduced into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump, the flow rate of the peristaltic pump is 12mL/min, and the filtration is carried out to obtain a crude product of the sodium tanshinone IIA sulfonate, wherein the purity of the sodium tanshinone IIA sulfonate is 95.7%. Then recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with a yield of 82.4%.

Example 13:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (0.8 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to make a volume of 500mL, as feed liquid B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 4.5mL/min, and the flow rate of the pump B is 1.5mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 25 ℃; the flow rate of the pump C is 6mL/min; the reaction residence time for the hydration reaction was 1.3min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 25 ℃; the flow rate of the pump D is 6mL/min; the reaction residence time for purification was 0.8min.

The four feed pumps A, B, C and D operate simultaneously, the reaction solution G flows into the continuous separator 4 to obtain a water layer and an organic layer, the organic layer is discharged out of the system, the water layer is introduced into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump, the flow rate of the peristaltic pump is 12mL/min, and the filtration is carried out to obtain a crude product of the sodium tanshinone IIA sulfonate, wherein the purity of the sodium tanshinone IIA sulfonate is 94.5%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 81.5%.

Example 14:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.2 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 5.4mL/min, and the flow rate of the pump B is 0.6mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1.

The four feeding pumps A, B, C and D operate simultaneously, the reaction solution G flows into the continuous separator 4 to obtain a water layer and an organic layer, the organic layer is discharged out of the system, the water layer is introduced into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump, the flow rate of the peristaltic pump is 12mL/min, and the filtering is carried out to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.1 percent. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 82.4%.

Example 15:

in the micro-reaction device, the connecting pipe is a 1/8 pipeline made of polytetrafluoroethylene, the feeding pump is four advection pumps made of polytetrafluoroethylene, the retention volume of the first microreactor 1 is 60mL, the retention volume of the second microreactor 2 is 30mL, the retention volume of the third microreactor 3 is 30mL, the retention volume of the continuous separator 4 is 500mL, and the receiver 5 is a 2L round-bottom flask.

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (0.21 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 10.8mL/min, and the flow rate of the pump B is 1.2mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 25 ℃; the flow rate of the pump C is 12mL/min; the reaction residence time for the hydration reaction was 1.3min.

Pumping dichloromethane serving as a feed liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 25 ℃; the flow rate of the pump D is 12mL/min; the reaction residence time for purification was 0.8min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 24mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 94.9%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 82.8%.

Example 16:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (0.41 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to make a volume of 500mL, as feed liquid B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 10.8mL/min, and the flow rate of the pump B is 1.2mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1, the reaction charge ratio of the tanshinone IIA and the concentrated sulfuric acid is 1.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 24mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.5%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 82.3%.

Example 17:

in the micro-reaction device, the connecting pipe is a 1/8 pipeline made of polytetrafluoroethylene, the feeding pump is four advection pumps made of polytetrafluoroethylene, the retention volume of the first microreactor 1 is 60mL, the retention volume of the second microreactor 2 is 30mL, the retention volume of the third microreactor 3 is 30mL, the retention volume of the continuous separator 4 is 250mL, and the receiver 5 is a 2L round-bottom flask.

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (0.61 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 10.8mL/min, and the flow rate of the pump B is 1.2mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1, the reaction charge ratio of the tanshinone IIA and the concentrated sulfuric acid is 1.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 25 ℃; the flow rate of the pump D is 12mL/min; the reaction residence time for purification was 0.8min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 24mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 94.7%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 82.4%.

Example 18:

in the micro-reaction device, the connecting pipe is a 1/8 pipeline made of polytetrafluoroethylene, the feeding pump is four advection pumps made of polytetrafluoroethylene, the retention volume of the first microreactor 1 is 100mL, the retention volume of the second microreactor 2 is 50mL, the retention volume of the third microreactor 3 is 50mL, the retention volume of the continuous separator 4 is 1000mL, and the receiver 5 is a 2L round-bottom flask.

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (0.82 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to make a volume of 500mL, as feed liquid B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 18mL/min, and the flow rate of the pump B is 1mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 25 ℃; the flow rate of the pump C is 20mL/min; the reaction residence time for the hydration reaction was 1.3min.

Pumping dichloromethane serving as a feed liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 25 ℃; the flow rate of the pump D is 20mL/min; the reaction residence time for purification was 0.8min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 40mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 95.3%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 82.1%.

Example 19:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.2 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to make a volume of 500mL, as feed liquid B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 18mL/min, and the flow rate of the pump B is 1mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 25 ℃; the flow rate of the pump D is 20mL/min; the reaction residence time for purification was 0.8min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 40mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 96.0%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 82.9%.

Example 20:

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.4 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 25 ℃; the flow rate of the pump A is 18mL/min, and the flow rate of the pump B is 2mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 40mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 96.4%. Then recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with a yield of 84.1%.

In the preparation processes of examples 1-20, the crude tanshinone IIA sodium sulfonate with purity of more than 93% can be obtained by direct recrystallization, and the washing with petroleum ether and dichloromethane is not required.

Comparative example 1

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.1 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to be made up to 500mL as a feed solution B. Simultaneously pumping the feed liquid A and the feed liquid B into the first microreactor 1 through feed pumps A and B respectively to perform continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into the second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 55 ℃; the flow rate of the pump A is 9mL/min, and the flow rate of the pump B is 1mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1.

Pumping water serving as a feed liquid C into the second microreactor 2 through a feed pump C, and carrying out hydration reaction on the water and a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into a third microreactor 3; the reaction temperature of the hydration reaction is 55 ℃; the flow rate of the pump C is 10mL/min; the reaction residence time of the hydration reaction was 1min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification was 55 ℃; the flow rate of the pump D is 10mL/min; the reaction residence time for purification was 0.7min.

And (3) operating the four feeding pumps A, B, C and D simultaneously, allowing the reaction solution G to flow into the continuous separator 4 to obtain a water layer and an organic layer, discharging the organic layer out of the system, introducing the water layer into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump at the flow rate of 20mL/min, and filtering to obtain a crude product of the tanshinone IIA sodium sulfonate, wherein the purity of the tanshinone IIA sodium sulfonate is 87.6%. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 72.8%.

Comparative example 2

Dissolving tanshinone IIA (0.068 mol) and acetic anhydride (1.1 mol) with dichloromethane, and metering to 1L to obtain a feed solution A; 18mol/L concentrated sulfuric acid (1.8 mol) and 17.5mol/L acetic acid (about 7 mol) were taken to make a volume of 500mL, as feed liquid B. Simultaneously pumping the feed liquid A and the feed liquid B into a first microreactor 1 through a feed pump A and a feed pump B respectively to carry out continuous sulfonation reaction to obtain reaction liquid E, and enabling the reaction liquid E to flow into a second microreactor 2; the reaction temperature of the continuous sulfonation reaction is 60 ℃; the flow rate of the pump A is 9mL/min, and the flow rate of the pump B is 1mL/min; the reaction charge ratio of the tanshinone IIA and the acetic anhydride is about 1.

Pumping water serving as a feeding liquid C into the second microreactor 2 through a feeding pump C, and carrying out hydration reaction with a reaction liquid E flowing into the second microreactor 2 to obtain a reaction liquid F, wherein the reaction liquid F flows into the third microreactor 3; the reaction temperature of the hydration reaction is 60 ℃; the flow rate of the pump C is 10mL/min; the reaction residence time of the hydration reaction was 1min.

Pumping dichloromethane serving as a feeding liquid D into the third microreactor 3, and purifying a reaction liquid F flowing into the third microreactor 3 to obtain a reaction liquid G; the reaction temperature for purification is 60 ℃; the flow rate of the pump D is 10mL/min; the reaction residence time for purification was 0.7min.

The four feed pumps A, B, C and D operate simultaneously, the reaction solution G flows into the continuous separator 4 to obtain a water layer and an organic layer, the organic layer is discharged out of the system, the water layer is introduced into a receiver 5 containing a saturated sodium chloride aqueous solution through a peristaltic pump, the flow rate of the peristaltic pump is 20mL/min, and the filtration is carried out to obtain a crude product of the sodium tanshinone IIA sulfonate, wherein the purity of the sodium tanshinone IIA sulfonate is 82.3 percent at the moment. Recrystallizing with methanol to obtain pure tanshinone IIA sodium sulfonate with yield of 71.4%.

Claims

1. A preparation method of tanshinone IIA sodium sulfonate is characterized by comprising the following steps:

step S1: taking a mixed solution of tanshinone IIA, acetic anhydride and an organic solvent as a feeding solution A, taking a mixed solution of sulfuric acid and acetic acid as a feeding solution B, pumping the feeding solution A and the feeding solution B into a first microreactor, carrying out continuous sulfonation reaction to obtain a reaction solution E, and allowing the reaction solution E to flow into a second microreactor; the reaction temperature of the continuous sulfonation reaction is 0-50 ℃;

step S2: pumping water serving as a feeding liquid C into the second microreactor, carrying out hydration reaction with the reaction liquid E to obtain a reaction liquid F, and allowing the reaction liquid F to flow into a third microreactor; the reaction temperature of the hydration reaction is 0-50 ℃;

and step S3: pumping dichloromethane serving as a feeding liquid D into the third microreactor, and purifying the reaction liquid F to obtain a reaction liquid G; the reaction temperature of the purification is 0-50 ℃;

and step S4: feeding the reaction liquid G flowing out of the third microreactor into a continuous separator to obtain a water layer and an organic layer, and filtering the water layer;

in step S4, after the aqueous layer is separated, the aqueous layer is further mixed with a saturated aqueous sodium chloride solution, and then the filtration is performed;

in the step S1, the flow rate of the feeding liquid A is 4.3-7.5 mL/min or 9-18 mL/min;

in the step S1, the flow rate of the feeding liquid B is 0.6-10 mL/min;

in step S1, the reaction residence time of the continuous sulfonation reaction is 3 to 12min.

2. The method for preparing sodium tanshinone IIA sulfonate as claimed in claim 1, wherein the method for preparing sodium tanshinone IIA sulfonate further comprises: after step S4, the filtrate obtained by filtration is recrystallized and dried.

3. The method for preparing sodium tanshinone IIA sulfonate according to claim 2, wherein the solvent for recrystallization is methanol.

4. The method for preparing sodium tanshinone IIA sulfonate as claimed in claim 1, wherein, in step S1, the molar ratio of tanshinone IIA to acetic anhydride is 1;

and/or the organic solvent is dichloromethane or acetone;

and/or the sulfuric acid is concentrated sulfuric acid with the concentration of 18mol/L, and the acetic acid with the concentration of 17.5mol/L;

and/or the reaction molar ratio of the tanshinone IIA to the sulfuric acid is 1;

and/or the concentration of the tanshinone IIA is 0.03mol/L to 1.5mol/L.

5. The process for preparing sodium tanshinone IIA sulfonate as claimed in claim 4, wherein, in step S1, the molar ratio of tanshinone IIA to acetic anhydride is 1;

and/or the reaction molar ratio of the tanshinone IIA to the sulfuric acid is 1.

6. The process for preparing sodium tanshinone IIA sulfonate as claimed in claim 5, wherein in step S1, the molar ratio of tanshinone IIA to acetic anhydride is 1;

and/or, the reaction molar ratio of the tanshinone IIA and the sulfuric acid is 1.

7. The method for preparing sodium tanshinone IIA sulfonate as claimed in claim 1, wherein in step S1, the retention volume of the first microreactor is 10-100 mL;

and/or the first microreactor is made of glass;

and/or said feed fluid a and said feed fluid B are pumped simultaneously into said first microreactor;

and/or the discharge port of the first microreactor is directly connected with the second microreactor.

8. The method for preparing sodium tanshinone IIA sulfonate as claimed in claim 7, wherein in step S1, the retention volume of the first microreactor is 10mL, 30mL, 50mL, 60mL, 100mL.

9. The method for preparing sodium tanshinone IIA sulfonate, as claimed in claim 1, wherein, in step S1,

the flow rate of the feeding liquid A is 4.5, 4.3, 5.4, 7.5, 9.0, 10.8, 15 and 18mL/min;

and/or the flow rate of the feeding liquid B is 0.6, 1, 1.2, 1.5, 2.5 and 3.5mL/min;

and/or the reaction temperature of the continuous sulfonation reaction is 10-30 ℃.

10. The method for preparing sodium tanshinone IIA sulfonate as claimed in claim 1, wherein in step S1, the reaction temperature of the continuous sulfonation reaction is 10 ℃ and 25 ℃.

11. The method for preparing sodium tanshinone IIA sulfonate according to claim 1, wherein in step S2,

the retention volume of the second micro-reactor is 5-50 mL;

and/or the second micro-reactor is made of glass;

and/or a discharge port of the second microreactor is directly connected with the third microreactor;

and/or the flow rate of the feeding liquid C is 1-40 mL/min;

and/or the reaction temperature of the hydration reaction is 10-30 ℃;

and/or the reaction residence time of the hydration reaction is 0.5-3 min.

12. The method for preparing sodium tanshinone IIA sulfonate according to claim 11, wherein in step S2,

the retention volume of the second microreactor is 5, 15, 20, 30, 50mL;

and/or the flow rate of the feeding liquid C is 2.0, 5, 6.0, 10, 12 and 20mL/min;

and/or the reaction temperature of the hydration reaction is 10 and 25 ℃.

13. The method for preparing sodium tanshinone IIA sulfonate according to claim 1, wherein in step S3, the retention volume of the third microreactor is 5 to 50mL;

and/or the third micro-reactor is made of glass;

and/or a discharge port of the third microreactor is connected with the continuous separator;

and/or the flow rate of the feeding liquid D is 2-40 mL/min;

and/or the reaction temperature of the purification is 10-30 ℃;

and/or the reaction residence time of the purification is 0.5-3 min.

14. The method for preparing sodium tanshinone IIA sulfonate as claimed in claim 13, wherein in step S3, the retention volume of the third microreactor is 5, 15, 20, 30, 50mL;

and/or the flow rate of the feeding liquid D is 4.0, 5, 6.0, 10, 12, 20, 24, 40mL/min;

and/or the reaction temperature of the purification is 10 and 25 ℃.

15. The method for preparing sodium tanshinone IIA sulfonate according to claim 1, wherein the continuous separator has a retention volume of 250 to 1000mL in step S4.

16. The method for preparing sodium tanshinone IIA sulfonate according to claim 15, wherein the continuous separator has a retention volume of 250, 500, 1000mL in step S4.