Method for preparing 3-hydroxytanshinone IIA sodium sulfonate

Abstract

The invention discloses a method for preparing 3-hydroxytanshinone IIA sodium sulfonate, and particularly discloses a preparation method of a compound shown as a formula II. The preparation method comprises the following steps: in an organic solvent, in the presence of acid, carrying out a reaction as shown in the specification on a tanshinone IIA sodium sulfonate derivative as shown in a formula I to obtain a compound as shown in a formula II, wherein the *-labeled carbon atom is of an R configuration, an S configuration or a mixture of the R configuration and the S configuration; the molar ratio of the acid to the tanshinone IIA sodium sulfonate derivative as shown in the formula I is (1-10): 1; the acid is hydrochloric acid, sulfuric acid and p-toluenesulfonic acid. The method has the advantages of high yield and high purity. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for preparing 3-hydroxytanshinone IIA sodium sulfonate. Background Art

[0002] 3alpha-Hydroxytanshinone IIA sodium sulfonate is an important class of tanshinone IIA sodium sulfonate derivatives, which can be efficiently prepared by simple hydrolysis. The literature (Development and structure-activity relationships of tanshinones as selective 11β-hydroxysteroid dehydrogenase 1inhibitors, Xu Deng et al., Natural Products and Bioprospecting (2022)) also reported that 3alpha-hydroxytanshinone IIA and derivatives prepared with it as an intermediate have an inhibitory effect on 11β-HSD1 in 3T3-L1 adipocytes and ob / ob mouse livers, and can be further studied as anti-diabetic drugs. CN109824753A discloses the use of 3alpha-hydroxytanshinone IIA sodium sulfonate as an intermediate to prepare drugs for IDO or TOO-mediated diseases (such as glioblastoma, mesothelioma, head and neck cancer, non-small cell lung cancer, bladder cancer, breast cancer and metabolic disorder-related diseases).

[0003] Patent CN 102002092B reports that 3alpha-hydroxytanshinone IIA sodium sulfonate is one of the important impurities in tanshinone IIA sodium sulfonate raw materials and preparations, and also provides a method for extracting 3alpha-hydroxytanshinone IIA sodium sulfonate using a preparative liquid phase, and using this as a reference substance to detect and control the content of 3alpha-hydroxytanshinone IIA sodium sulfonate in tanshinone IIA sodium sulfonate raw materials and preparations. However, there is currently no method for obtaining 3alpha-hydroxytanshinone IIA sodium sulfonate using chemical synthesis in the prior art. Therefore, the present invention develops a method for chemically preparing 3alpha-hydroxytanshinone IIA sodium sulfonate. Summary of the invention

[0004] The technical problem to be solved by the present invention is to overcome the low yield of preparing 3-hydroxytanshinone IIA sodium sulfonate in the prior art, and it is almost impossible to directly prepare 3-hydroxytanshinone IIA sodium sulfonate from 3-hydroxytanshinone IIA by sulfonation. To this end, the present invention provides a method for preparing 3-hydroxytanshinone IIA sodium sulfonate using a tanshinone IIA sodium sulfonate derivative as a raw material. Compared with the traditional process, the present invention is simple in operation for preparing 3-hydroxytanshinone IIA sodium sulfonate, and has a higher yield or purity.

[0005] The present invention provides a method for preparing a compound as shown in Formula II, which comprises the following steps:

[0006] In an organic solvent, in the presence of an acid, the sodium tanshinone IIA sulfonate derivative shown in formula I is subjected to the following reaction to obtain a compound shown in formula II;

[0007] ;

[0008] Among them, the carbon atoms marked with * are R configuration, S configuration, or a mixture of R configuration and S configuration;

[0009] The molar ratio of the acid to the sodium tanshinone IIA sulfonate derivative as shown in formula I is (1-10):1;

[0010] The acid is hydrochloric acid, sulfuric acid and p-toluenesulfonic acid.

[0011] In some embodiments, the sodium tanshinone IIA sulfonate derivative as shown in formula I is , the compound as shown in formula II is .

[0012] In some embodiments, the organic solvent is selected from one or more of alcohol, nitrile or ether solvents. Preferably, the organic solvent is selected from one or more of methanol, ethanol, acetonitrile and 1,4-dioxane.

[0013] In some embodiments, the molar volume ratio of the sodium tanshinone IIA sulfonate derivative as shown in formula I to the solvent is 0.01-0.1 mol / L, preferably, the molar volume ratio of the sodium tanshinone IIA sulfonate derivative as shown in formula I to the solvent is 0.01-0.05 mol / L, more preferably, the molar volume ratio of the sodium tanshinone IIA sulfonate derivative as shown in formula I to the solvent is 0.02 mol / L or 0.04 mol / L.

[0014] In some embodiments, the sulfuric acid participates in the reaction in the form of a 1-15 mol / L sulfuric acid aqueous solution. Preferably, the sulfuric acid participates in the reaction in the form of a 1.8 mol / L or 9.0 mol / L sulfuric acid aqueous solution.

[0015] In some embodiments, the hydrochloric acid participates in the reaction in the form of a 1-12 mol / L hydrochloric acid aqueous solution. Preferably, the hydrochloric acid participates in the reaction in the form of a 1.8 mol / L or 12.0 mol / L hydrochloric acid aqueous solution.

[0016] In some embodiments, the molar ratio of the acid to the sodium tanshinone IIA sulfonate derivative as shown in formula I is (3-8):1. Preferably, the molar ratio of the acid to the sodium tanshinone IIA sulfonate derivative as shown in formula I is 3.6:1 or 7.2:1.

[0017] In some embodiments, the organic solvent is methanol, the acid is 1.8 mol / L sulfuric acid or 12 mol / L hydrochloric acid, and the molar ratio of the acid to the sodium tanshinone IIA sulfonate derivative shown in Formula I is (3-8):1, for example (3.6-7.2):1.

[0018] In some embodiments, the reaction temperature is the conventional temperature of the reaction in the art, preferably, the reaction temperature is 60-70°C, more preferably, the reaction temperature is 60°C or 70°C.

[0019] In some embodiments, the progress of the reaction can be detected by conventional monitoring methods in the art (such as TLC, HPLC or NMR). Generally, the reaction endpoint is when the reaction starting materials disappear or no longer react, or when the product no longer increases. Preferably, the reaction time is 2-6 hours, for example, 2 hours or 6 hours.

[0020] In some embodiments, the reaction materials of the reaction consist of the organic solvent, the acid and the sodium tanshinone IIA sulfonate derivative as shown in Formula I.

[0021] In some embodiments, the preparation method comprises the following steps (a) and (b):

[0022] (a) mixing the organic solvent and the sodium tanshinone IIA sulfonate derivative as shown in formula I to obtain a mixed solution;

[0023] (b) mixing the acid with the mixed solution obtained in step (a), and reacting the mixture to obtain the compound shown in formula II.

[0024] In some embodiments, the organic solvent is one or more selected from methanol, ethanol, acetonitrile and 1,4-dioxane; the molar volume ratio of the sodium tanshinone IIA sulfonate derivative as shown in Formula I to the solvent is 0.02 mol / L or 0.04 mol / L; the sulfuric acid participates in the reaction in the form of a 1.8 mol / L or 9.0 mol / L sulfuric acid aqueous solution; the hydrochloric acid participates in the reaction in the form of a 1.8 mol / L or 12.0 mol / L hydrochloric acid aqueous solution; the molar ratio of the acid to the sodium tanshinone IIA sulfonate derivative as shown in Formula I is 3.6:1 or 7.2:1.

[0025] In some embodiments, the preparation method further comprises a method for purifying the compound as shown in Formula II, which comprises the following steps:

[0026] Using high performance liquid chromatography, the reaction solution containing the compound represented by formula II is subjected to gradient elution on a C18 chromatographic column to obtain the compound represented by formula II;

[0027] The mobile phase includes mobile phase A and mobile phase B, wherein the mobile phase A is a 0.1% by volume triethylamine aqueous solution;

[0028] The mobile phase B is a mixture of triethylamine and methanol with a volume percentage of 0.1%.

[0029] In some embodiments, the flow rate of mobile phase A and mobile phase B is 50 mL / min.

[0030] In some embodiments, in the high performance liquid chromatography method, the injection volume is 200 mL.

[0031] In some embodiments, in the high performance liquid chromatography, the detector is an ultraviolet visible absorption detector, and the detection wavelength of the detector is preferably 271 nm.

[0032] In some embodiments, the filler material of the C18 chromatographic column is UniSil C18 Aq super water resistant filler.

[0033] In some embodiments, the pore size of the filler is 10 nm.

[0034] In some embodiments, the filler has a particle size of 100 μm.

[0035] In some embodiments, the length of the chromatography column is 600 mm.

[0036] In some embodiments, the chromatography column has a diameter of 50 mm.

[0037] In some embodiments, the operating pressure of the chromatographic column is 0-10 MPa.

[0038] In some embodiments, the operating temperature of the chromatographic column is 5 to 60 o C, preferably 25 o C.

[0039] In some embodiments, the gradient elution is a three-stage gradient elution, which comprises the following steps:

[0040] Step 1: In the first gradient, the volume percentage of the mobile phase A is 90% to 85%, and the volume percentage of the mobile phase B is 10% to 15%;

[0041] Step 2: In the second gradient, the volume percentage of the mobile phase A is 85% to 80%, and the volume percentage of the mobile phase B is 15% to 20%;

[0042] Step 3: In the third gradient, the volume percentage of the mobile phase A is 80% to 20%, and the volume percentage of the mobile phase B is 20% to 80%;

[0043] Preferably,

[0044] In the first gradient, the elution time is 5-20 min, for example 10 min;

[0045] In the second gradient, the elution time is 5-20 min, for example 10 min;

[0046] In the third gradient, the elution time is 40-90 min, for example 80 min;

[0047] More preferably,

[0048] The gradient elution is:

[0049]

[0050] In some embodiments, the method for purifying the compound as shown in Formula II further comprises a post-treatment step, wherein the post-treatment step comprises concentration and drying;

[0051] The concentration can be conventional in the art, such as concentration under reduced pressure;

[0052] The drying may be a conventional drying step in the art; preferably, freeze drying, the freeze drying temperature may be -40°C to -30°C, and the freeze drying time may be 24 to 72 hours.

[0053] In some embodiments, in the method for purifying the compound of Formula II, if the purity of the compound of Formula II cannot meet the requirements, the eluate obtained after the gradient elution can be subjected to a second elution and concentration.

[0054] In some embodiments, when the eluent is eluted and concentrated for the second time, the elution operation method is: dilute the eluent obtained after the gradient elution to obtain eluent A; after concentrating and removing the organic phase, dilute the eluent A by 1-2 times, and perform a second elution and concentration using the high performance liquid chromatography method as described above.

[0055] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0056] The positive and progressive effects of the present invention are:

[0057] (1) The preparation method of the present invention uses the sodium tanshinone ⅡA sulfonate derivative shown in formula I as a raw material, and selectively removes a sulfonyl group to obtain a compound shown in formula II;

[0058] (2) The yield or purity of the compound represented by Formula II obtained by the preparation method of the present invention is high. DETAILED DESCRIPTION

[0059] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0060] The sodium tanshinone IIA sulfonate derivative (Compound 1) used in the following examples can be extracted from the reaction solution obtained in the preparation process of sodium tanshinone IIA sulfonate described in Example 20 described in patent document CN 113861263 A published by Shanghai No. 1 Biochemical Pharmaceutical Co., Ltd.

[0061] Proton spectrum data of compound 1: 1 H NMR (600 MHz, Methanol-d4) δ 7.82 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 4.43 (dd, J = 7.8, 2.4 Hz, 1H), 3.45 (dt, J =19.2, 6.6 Hz, 1H), 3.25 (dt, J = 19.2, 6.6 Hz, 1H), 2.47 (s, 3H), 2.33 – 2.23(m, 2H), 1.42 (s, 3H), 1.40 (s, 3H).

[0062] The following examples use Shimadzu LC-2030C Plus high performance liquid phase for purity detection and analysis. Chromatographic conditions: ZORBAX SB-C18 column (4.6×150 mm, 5-micton), mobile phase A: 20 mM KH2PO4+0.5% triethylamine (pH4.0)-methanol (60:40), mobile phase B: 20 ​​mM KH2PO4+0.5% triethylamine (pH 4.0)-methanol (20:80). Gradient elution program: flow rate 1.0 mL / min, column temperature 25°C, detection wavelength 271 nm, injection volume 10 μL.

[0063]

[0064] Example 1

[0065] (1) Preparation of 3alpha-hydroxytanshinone IIA sulfonate sodium

[0066] Weigh 514 mg of sodium tanshinone IIA sulfonate derivative (compound 1, 1 mmol, 1.0 equiv) into a 10 mL single-necked flask, add 50 mL of methanol, stir, then add 2 mL of 1.8 mol / L sulfuric acid (3.6 mmol, 3.6 equiv), heat to 60 ° C, stir for 6 h, and cool to room temperature to obtain a reaction solution containing 3alpha-hydroxytanshinone IIA sodium sulfonate. HPLC detection showed that the raw materials had been completely reacted, and the content of the product 3alpha-hydroxytanshinone IIA sodium sulfonate (compound 2) was 88.4%.

[0067] (2) Purification of 3alpha-hydroxytanshinone IIA sulfonate sodium

[0068] After removing the solvent from the above reaction solution, water was added to dilute it to 200 mL, and methanol was added to prepare a 10% methanol aqueous solution. The crude product was loaded using a loading system, and then eluted from a high performance liquid reverse phase preparative column, and the eluate with a retention time of 40-45 min was collected.

[0069] The chromatographic conditions are:

[0070] Mobile phase A is a 0.1% by volume triethylamine aqueous solution, and mobile phase B is a 0.1% by volume mixture of triethylamine and methanol;

[0071] The flow rate was 50 mL / min; the detection wavelength was 271 nm; the injection volume was 200 mL;

[0072] The column temperature of the chromatographic column was 25°C;

[0073]

[0074] After obtaining the eluate, it was tested by HPLC, and samples with a purity greater than 98% were retained. After being concentrated under reduced pressure to remove methanol, the mixture was freeze-dried at -40°C to 30°C for 24-72h to obtain 252 mg of a red solid with a yield of 81%.

[0075] The high-resolution mass spectrum of the red solid 3alpha-hydroxytanshinone IIA sodium sulfonate obtained in this example is C 19 H 18 NaO7S(M+Na) + = 413.0655, 1 H NMR and 13 C NMR is as follows:

[0076] 1 H NMR (400 MHz, D2O) δ 7.57 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 3.67 (d, J = 6.4 Hz, 1H), 3.33 (s, 1H), 2.86 – 2.73 (m, 1H), 2.71 – 2.66 (m, 1H), 2.30 (s, 3H), 1.80 – 1.78 (m, 1H), 1.76 – 1.75 (m, 1H), 1.29 (s, 3H), 1.22 (s, 3H).

[0077] 13 C NMR (101 MHz, D2O) δ 181.4, 174.7, 160.3, 150.2, 149.7, 143.5,135.0, 125.6, 124.7, 121.6, 121.1, 119.3, 73.6, 39.5, 28.3, 26.2, 25.0, 24.5,8.7.

[0078] Example 2

[0079] (1) Preparation of 3alpha-hydroxytanshinone IIA sulfonate sodium

[0080] Weigh 1.03 g of sodium tanshinone IIA sulfonate derivative as shown in formula 1 (compound 1, 2.0 mmol, 1.0 equiv) into a 10 mL single-necked flask, add 100 mL of methanol, stir, then add 1.2 mL of 12 mol / L hydrochloric acid (14.4 mmol, 7.2 equiv) and heat to 70 ° C. Stir for 2 h and cool to room temperature to obtain a reaction solution containing 3alpha-hydroxytanshinone IIA sodium sulfonate. HPLC detection shows that the raw materials have been completely reacted, and the content of the product 3alpha-hydroxytanshinone IIA sodium sulfonate (compound 2) is 86.5%.

[0081] (2) Purification of 3alpha-hydroxytanshinone IIA sulfonate sodium

[0082] After removing the solvent from the above reaction solution, water was added to dilute it to 300 mL, and methanol was added to prepare a 10% methanol aqueous solution. The crude product was loaded using a loading system and then eluted from a high performance liquid reverse phase preparative column, and the eluate with a retention time of 41-47 min was collected.

[0083] The chromatographic conditions are:

[0084] Mobile phase A is a 0.1% by volume triethylamine aqueous solution, and mobile phase B is a 0.1% by volume mixture of triethylamine and methanol;

[0085] The flow rate was 50 mL / min; the detection wavelength was 271 nm; the injection volume was 300 mL;

[0086] The column temperature of the chromatographic column was 25°C;

[0087]

[0088] After obtaining the eluate, HPLC was used for detection, and samples with a purity greater than 98% were retained. After concentration to remove methanol, lyophilization was performed to obtain 471 mg of a red solid with a yield of 76%. The structural characterization data of the red solid were the same as those in Example 1.

[0089] Example 3

[0090] 51.4 mg of the sodium tanshinone IIA sulfonate derivative shown in formula I (compound 1, 0.1 mmol, 1.0 equiv) was weighed into a 10 mL single-necked flask, 5 mL of ethanol was added, and the mixture was stirred. Subsequently, 200 μL of 1.8 mol / L sulfuric acid (0.36 mmol, 3.6 equiv) was added and heated to 60 ° C. The mixture was stirred for 6 h. The reaction solution was taken for HPLC detection. The content of the sodium 3-alpha hydroxytanshinone IIA sulfonate product (compound 2) was 79.6%, and no subsequent preparation treatment was performed.

[0091] Example 4

[0092] 51.4 mg of the sodium tanshinone IIA sulfonate derivative shown in formula I (compound 1, 0.1 mmol, 1.0 equiv) was weighed into a 10 mL single-necked flask, 5 mL of 1,4-dioxane was added, and the mixture was stirred. Subsequently, 200 μL of 1.8 mol / L sulfuric acid (0.36 mmol, 3.6 equiv) was added and heated to 60 ° C. The mixture was stirred for 6 h. The reaction solution was taken for HPLC detection. The content of the sodium 3-alpha hydroxytanshinone IIA sulfonate product (compound 2) was 82.0%, and no subsequent preparation treatment was performed.

[0093] Example 5

[0094] 51.4 mg of the sodium tanshinone IIA sulfonate derivative shown in formula I (compound 1, 0.1 mmol, 1.0 equiv) was weighed into a 10 mL single-necked flask, 5 mL of acetonitrile was added, and the mixture was stirred. Subsequently, 200 μL of 1.8 mol / L sulfuric acid (0.36 mmol, 3.6 equiv) was added and heated to 60 ° C. The mixture was stirred for 6 h. The reaction solution was taken for HPLC detection. The content of the sodium 3-alpha hydroxytanshinone IIA sulfonate product (compound 2) was 78.4%, and no subsequent preparation treatment was performed.

[0095] Example 6

[0096] 51.4 mg of the sodium tanshinone IIA sulfonate derivative shown in formula I (compound 1, 0.1 mmol, 1.0 equiv) was weighed into a 10 mL single-necked flask, 5 mL of 1,4-dioxane was added, and the mixture was stirred. Subsequently, 40 μL of 9.0 mol / L sulfuric acid (0.36 mmol, 3.6 equiv) was added and heated to 70 ° C. The mixture was stirred for 2 h. The reaction solution was taken for HPLC detection. The content of the sodium 3-alpha hydroxytanshinone IIA sulfonate product (compound 2) was 72.4%, and no subsequent preparation treatment was performed.

[0097] Example 7

[0098] 51.4 mg of the sodium tanshinone IIA sulfonate derivative shown in formula I (compound 1, 0.1 mmol, 1.0 equiv) was weighed into a 10 mL single-necked flask, 5 mL of acetonitrile was added, and the mixture was stirred. Subsequently, 62 mg of p-toluenesulfonic acid (0.36 mmol, 3.6 equiv) was added and heated to 70 ° C. The mixture was stirred for 6 h. The reaction solution was taken for HPLC detection. The content of the sodium 3-hydroxytanshinone IIA sulfonate product (compound 2) was 77.5%, and no subsequent preparation treatment was performed.

[0099] Example 8

[0100] 51.4 mg of the sodium tanshinone IIA sulfonate derivative shown in Formula 1 (compound 1, 0.1 mmol, 1.0 equiv) was weighed into a 10 mL single-necked flask, 5 mL of acetonitrile was added, and the mixture was stirred. Subsequently, 200 μL of 1.8 mol / L hydrochloric acid (0.36 mmol, 3.6 equiv) was added and heated to 70 ° C. The mixture was stirred for 6 h. The reaction solution was taken for HPLC detection. The content of the sodium 3-alpha hydroxytanshinone IIA sulfonate product (compound 2) was 57.8%, and no subsequent preparation treatment was performed.

[0101] Comparative Example 1

[0102] 51.4 mg of the sodium tanshinone IIA sulfonate derivative shown in Formula 1 (compound 1, 0.1 mmol, 1.0 equiv) was weighed into a 10 mL single-necked flask, 5 mL of dichloromethane was added, and the mixture was stirred. Subsequently, 1000 μL of 1.8 mol / L sulfuric acid (1.8 mmol, 18.0 equiv) was added and heated to 60 ° C. The mixture was stirred for 6 h. The reaction solution was taken for HPLC detection. There was almost no sodium 3-alpha hydroxytanshinone IIA sulfonate product (compound 2), and no subsequent treatment was performed.

[0103] Comparative Example 2

[0104] 51.4 mg of the sodium tanshinone IIA sulfonate derivative shown in Formula 1 (compound 1, 0.1 mmol, 1.0 equiv) was weighed into a 10 mL single-necked flask, 5 mL of water was added, and the mixture was stirred. Subsequently, 1000 μL of 1.8 mol / L sulfuric acid (1.8 mmol, 18.0 equiv) was added and heated to 60 ° C. The mixture was stirred for 6 h. The reaction solution was taken for HPLC detection. There was almost no sodium 3-alpha hydroxytanshinone IIA sulfonate product (compound 2), and no subsequent treatment was performed.

[0105] Comparative Example 3

[0106] 51.4 mg of the sodium tanshinone IIA sulfonate derivative shown in Formula 1 (compound 1, 0.1 mmol, 1.0 equiv) was weighed into a 10 mL single-necked flask, 5 mL of acetonitrile was added, and the mixture was stirred. Subsequently, 200 μL of 1.8 mol / L acetic acid (0.36 mmol, 3.6 equiv) was added and heated to 70 °C. The mixture was stirred for 6 h, and the reaction solution was taken for HPLC detection. There was almost no sodium 3-alpha hydroxytanshinone IIA sulfonate product (compound 2), and no subsequent treatment was performed.

[0107] Comparative Example 4

[0108] 51.4 mg of the sodium tanshinone IIA sulfonate derivative shown in Formula 1 (compound 1, 0.1 mmol, 1.0 equiv) was weighed into a 10 mL single-necked flask, 5 mL of acetonitrile was added, and the mixture was stirred. Subsequently, 200 μL of 1.8 mol / L phosphoric acid (0.36 mmol, 3.6 equiv) was added and heated to 70 °C. The mixture was stirred for 6 h, and the reaction solution was taken for HPLC detection. There was almost no sodium 3-alpha hydroxytanshinone IIA sulfonate product (compound 2), and no subsequent treatment was performed.

Claims

1. A method for preparing a compound as shown in formula II, characterized in that: It includes the following steps: In an organic solvent, in the presence of an acid, the sodium tanshinone IIA sulfonate derivative shown in formula I is subjected to the following reaction to obtain a compound shown in formula II; ； Among them, the carbon atoms marked with * are R configuration, S configuration, or a mixture of R configuration and S configuration; The molar ratio of the acid to the sodium tanshinone IIA sulfonate derivative as shown in formula I is (1-10):1; The acid is hydrochloric acid, sulfuric acid and p-toluenesulfonic acid.

2. The method for preparing the compound of formula II as claimed in claim 1, characterized in that: It meets one or more of the following conditions: (1) The sodium tanshinone IIA sulfonate derivative as shown in formula I is , the compound as shown in formula II is ; (2) The organic solvent is selected from one or more of alcohol, nitrile or ether solvents; (3) The molar volume ratio of the sodium tanshinone IIA sulfonate derivative represented by formula I to the solvent is 0.01-0.1 mol / L; (4) The sulfuric acid participates in the reaction in the form of a 1-15 mol / L sulfuric acid aqueous solution; (5) The hydrochloric acid participates in the reaction in the form of a 1-12 mol / L hydrochloric acid aqueous solution; (6) The molar ratio of the acid to the sodium tanshinone IIA sulfonate derivative shown in Formula I is (3-8):1; (7) The reaction temperature is 60-70°C; (8) The reaction time of the reaction is 2-6 hours; The reaction materials of the reaction described in (9) are composed of the organic solvent, acid and the sodium tanshinone IIA sulfonate derivative shown in formula I.

3. The method for preparing the compound of formula II as claimed in claim 2, characterized in that: It meets one or more of the following conditions: (1) The organic solvent is selected from one or more of methanol, ethanol, acetonitrile and 1,4-dioxane; (2) The molar volume ratio of the sodium tanshinone IIA sulfonate derivative represented by formula I to the solvent is 0.01-0.05 mol / L; (3) The sulfuric acid participates in the reaction in the form of a 1.8 mol / L or 9.0 mol / L sulfuric acid aqueous solution; (4) The hydrochloric acid participates in the reaction in the form of a 1.8 mol / L or 12.0 mol / L hydrochloric acid aqueous solution; and (5) the molar ratio of the acid to the sodium tanshinone IIA sulfonate derivative as shown in formula I is 3.6:1 or 7.2:

1.

4. The method for preparing the compound of formula II as claimed in claim 3, characterized in that: The molar volume ratio of the sodium tanshinone IIA sulfonate derivative shown in formula I to the solvent is 0.02 mol / L or 0.04 mol / L.

5. The method for preparing the compound of formula II as claimed in claim 1, characterized in that: The organic solvent is methanol, the acid is 1.8 mol / L sulfuric acid or 12 mol / L hydrochloric acid, and the molar ratio of the acid to the sodium tanshinone IIA sulfonate derivative shown in formula I is (3-8):1, for example (3.6-7.2):

1.

6. The method for preparing the compound of formula II as claimed in claim 1, characterized in that: The preparation method comprises the following steps (a) and (b): (a) mixing the organic solvent and the sodium tanshinone IIA sulfonate derivative as shown in formula I to obtain a mixed solution; (b) mixing the acid with the mixed solution obtained in step (a), and reacting the mixture to obtain the compound shown in formula II.

7. The method for preparing the compound of formula II as claimed in claim 1, characterized in that: The preparation method also includes a purification method of the compound shown in Formula II, which comprises the following steps: Using high performance liquid chromatography, the reaction solution containing the compound shown in Formula II is subjected to gradient elution on a C18 chromatographic column to obtain the compound shown in Formula II; The mobile phase includes mobile phase A and mobile phase B, wherein the mobile phase A is a 0.1% by volume triethylamine aqueous solution; The mobile phase B is a mixture of triethylamine and methanol with a volume percentage of 0.1%.

8. The method for preparing the compound of formula II as claimed in claim 7, characterized in that: The method for refining the compound as shown in Formula II satisfies one or more of the following conditions: (1) The flow rate of mobile phase A and mobile phase B is 50 mL / min; (2) In the high performance liquid chromatography method, the injection volume is 200 mL; (3) The filler of the C18 chromatographic column is UniSil C18Aq ultra-water-resistant filler; (4) The pore size of the filler is 10 nm; (5) The particle size of the filler is 100 μm; (6) The length of the chromatographic column is 600 mm; (7) The diameter of the chromatographic column is 50 mm; (8) The operating pressure of the chromatographic column is 0~10MPa; The operating temperature of the chromatographic column described in (9) is 5 to 60 o C, preferably 25 o C.

9. The method for preparing the compound of formula II as claimed in claim 8, characterized in that: The gradient elution is a three-stage gradient elution, which comprises the following steps: Step 1: In the first gradient, the volume percentage of the mobile phase A is 90% to 85%, and the volume percentage of the mobile phase B is 10% to 15%; Step 2: In the second gradient, the volume percentage of the mobile phase A is 85% to 80%, and the volume percentage of the mobile phase B is 15% to 20%; Step 3: In the third gradient, the volume percentage of the mobile phase A is 80% to 20%, and the volume percentage of the mobile phase B is 20% to 80%; Preferably, In the first gradient, the elution time is 5-20 min, for example 10 min; In the second gradient, the elution time is 5-20 min, for example 10 min; In the third gradient, the elution time is 40-90 min, for example 80 min; More preferably, The gradient elution is: 。 10. The method for preparing the compound of formula II as claimed in claim 9, characterized in that: The method for refining the compound as shown in Formula II further comprises a post-treatment step, wherein the post-treatment step comprises concentration and drying; The concentration may be reduced pressure concentration; The drying may be freeze drying, the freeze drying temperature may be -40°C to -30°C, and the freeze drying time may be 24 to 72 hours.

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