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CN-121991159-A - Method for selectively synthesizing tanshinone IIB sodium sulfonate and tanshinone IIB

CN121991159ACN 121991159 ACN121991159 ACN 121991159ACN-121991159-A

Abstract

The invention discloses a method for selectively synthesizing tanshinone IIB sodium sulfonate and tanshinone IIB. The invention provides a method for selectively synthesizing tanshinone IIB sodium sulfonate or tanshinone IIB by a compound in a formula I, which comprises the following steps of (1) reacting the compound in the formula I with sulfuric acid in a solvent A to obtain tanshinone IIB sodium sulfonate when the tanshinone IIB sodium sulfonate is required to be synthesized, and (2) reacting the compound in the formula I with acid B in acetonitrile to obtain tanshinone IIB when the tanshinone IIB is required to be synthesized.

Inventors

  • WU LIANG
  • CAO JIAOJIAO
  • ZHANG YUXIN
  • TIAN PINGPING
  • YU WEI
  • JIANG XIMING

Assignees

  • 上海上药第一生化药业有限公司

Dates

Publication Date
20260508
Application Date
20260112

Claims (10)

  1. 1. A method for selectively synthesizing tanshinone IIB sodium sulfonate or tanshinone IIB by a compound of formula I, which is characterized by comprising the following steps: (1) When the tanshinone IIB sodium sulfonate needs to be synthesized, the method I is adopted, wherein in a solvent A, a compound in the formula I reacts with sulfuric acid to obtain the tanshinone IIB sodium sulfonate; (2) When tanshinone IIB is needed to be synthesized, the second method is adopted, namely, in acetonitrile, a compound in the formula I reacts with acid B to obtain tanshinone IIB; ; In the first method, the mol ratio of the compound shown in the formula I to the sulfuric acid is 1 (2-10); in the method I, the solvent A is tetrahydrofuran and/or methanol, and when the solvent A is methanol, the reaction temperature of the reaction is 60-80 ℃; in the second method, the mol ratio of the compound of the formula I to the acid B is 1 (20-60); in the second method, the acid B is sulfuric acid or hydrochloric acid.
  2. 2. A method for the selective synthesis of sodium tanshinone IIB sulfonate or tanshinone IIB according to claim 1 wherein the method meets one or more of the following conditions: (1) In the first method, the molar ratio of the compound of the formula I to the sulfuric acid is 1 (3-6); (2) In the first method, the molar volume ratio of the sulfuric acid to the solvent A is 0.05-0.1 mmol/mL; (3) In the first method, the molar concentration of the sulfuric acid is 1-3 mol/L; (4) In the first method, the mass-volume ratio of the compound of the formula I to the solvent A is 5-15 mg/mL; (5) In the first method, when the solvent A is tetrahydrofuran, the reaction temperature of the reaction is 40-60 ℃; (6) In a first method, when the solvent A is methanol, the reaction temperature of the reaction is 60 ℃, 62 ℃,65 ℃, 67 ℃, 70 ℃, 72 ℃, 75 ℃, 78 ℃ or 80 ℃; (7) The reaction material of the first method consists of the solvent A, sulfuric acid and a compound of the formula I; (8) The reaction material of the second method consists of acetonitrile, acid B and a compound shown in a formula I; (9) In the second method, the molar ratio of the compound of the formula I to the acid B is 1 (30-40); (10) In the second method, the molar concentration of the acid B is 8-14 mol/L; (11) In the second method, the mass-volume ratio of the compound of the formula I to acetonitrile is 5-30 mg/mL; (12) In the second method, the reaction temperature of the reaction is 40-80 ℃; (13) In the second method, when the acid B is sulfuric acid, the reaction time of the reaction is 1-8h; (14) In the second method, when the acid B is hydrochloric acid, the reaction time of the reaction is 5h, 5.5h, 6h, 6.5h, 7h, 7.5 or 8h.
  3. 3. A method for the selective synthesis of sodium tanshinone IIB sulfonate or tanshinone IIB according to claim 2 wherein the method meets one or more of the following conditions: (1) In method one, the molar ratio of the compound of formula I to the sulfuric acid is 1:3.6 or 1:5.4; (2) In method one, the molar volume ratio of the sulfuric acid to the solvent A is 0.068 mmol/mL or 0.072 mmol/mL; (3) In the first method, the molar concentration of the sulfuric acid is 1.8mol/L; (4) In method one, the mass to volume ratio of the compound of formula I to the solvent A is 6.43 mg/mL or 10.28 mg/mL; (5) In a first method, when the solvent a is tetrahydrofuran, the reaction temperature of the reaction is 40 ℃, 42 ℃, 44 ℃, 46 ℃, 48 ℃, 50 ℃, 52 ℃, 54 ℃, 56 ℃, 58 ℃ or 60 ℃; (6) In the first method, when the solvent A is methanol, the reaction temperature of the reaction is 70 ℃; (7) In method two, the molar ratio of the compound of formula I to the acid B is 1:30, 1:32, 1:34, 1:36, 1:38 or 1:40; (8) In the second method, the molar concentration of the acid B is 10-12 mol/L; (9) In the second method, the mass-volume ratio of the compound of the formula I to acetonitrile is 10.28 mg/mL or 20.56 mg/mL; (10) In method two, the reaction temperature of the reaction is 40 ℃, 42 ℃, 45 ℃, 48 ℃, 50 ℃, 52 ℃, 55 ℃, 58 ℃, 60 ℃, 62 ℃, 65 ℃, 68 ℃, 70 ℃, 72 ℃, 78 ℃ or 80 ℃; (11) In the second method, when the acid B is sulfuric acid, the reaction time of the reaction is 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h or 8h; (12) In the second method, when the acid B is hydrochloric acid, the reaction time of the reaction is 6 hours.
  4. 4. A method for the selective synthesis of sodium tanshinone IIB sulfonate or tanshinone IIB according to claim 3 wherein the method meets one or more of the following conditions: (1) In the first method, when the solvent A is tetrahydrofuran, the reaction temperature of the reaction is 50 ℃; (2) In a second method, the molar ratio of the compound of formula I to the acid B is 1:36; (3) In the second method, the molar concentration of the acid B is 12 mol/L; (4) In the second method, the reaction temperature of the reaction is 50 ℃ or 70 ℃; (5) In the second method, when the acid B is sulfuric acid, the reaction time of the reaction is 2 hours or 6 hours.
  5. 5. A method for selectively synthesizing sodium tanshinone IIB sulfonate or tanshinone IIB from a compound of formula I according to any one of claims 1 to 4, wherein the method one further comprises a process for refining sodium tanshinone IIB sulfonate, and the method two further comprises a process for refining tanshinone IIB; The refining method of the tanshinone IIB sodium sulfonate comprises the following steps of performing gradient elution on a reaction solution containing tanshinone IIB sodium sulfonate on a C18 chromatographic column by using a mobile phase to obtain tanshinone IIB sodium sulfonate, wherein the mobile phase comprises a mobile phase A and a mobile phase B, the mobile phase A is a triethylamine aqueous solution with the volume percentage of 0.1%, and the mobile phase B is a mixed solution of triethylamine with the volume percentage of 0.1%; The tanshinone IIB refining method comprises the following steps of purifying a tanshinone IIB-containing reaction solution by silica gel column chromatography, wherein the purified eluent is a chlorinated alkane solvent and an alcohol solvent.
  6. 6. A method for the selective synthesis of sodium tanshinone IIB sulfonate or tanshinone IIB according to claim 5 wherein the method meets one or more of the following conditions: (1) In the first method, the flow rate of the mobile phase A and the mobile phase B is 50mL/min; (2) In the first method, in the high performance liquid chromatography, the sample injection amount is 400mL; (3) In the first method, in the high performance liquid chromatography, the detector is an ultraviolet-visible absorption detector, and the detection wavelength of the detector is preferably 271nm; (4) In the first method, the model of the C18 chromatographic column is YMC-GEL ODS-AQ; (5) In the first method, the packing of the C18 chromatographic column is UniSil 10-100C 18Aq super water-resistant packing; (6) In the first method, the pore diameter of the filler is 10 nm; (7) In the first method, the particle size of the filler is 100 mu m; (8) In method one, the chromatographic column has a length of 600 mm; (9) In method one, the diameter of the chromatographic column is 50 mm; (10) In the first method, the using pressure of the chromatographic column is 0-10 MPa; (11) In the first method, the use temperature of the chromatographic column is 5-60 ℃; (12) The chlorinated alkane solvent is dichloromethane; (13) The alcohol solvent is methanol; (14) In the second method, the volume ratio of the chlorinated alkane to the alcohol solvent is (5-80): 1, preferably (10-50): 1; (15) In the second method, the eluent can be dried under the vacuum of 25-55 o C to obtain tanshinone IIB.
  7. 7. A method for the selective synthesis of sodium tanshinone IIB sulfonate or tanshinone IIB according to claim 6 wherein the method comprises one or both of the following conditions: (1) In a first method, the use temperature of the chromatographic column is 25 ℃; (2) The volume ratio of the chlorinated alkane to the alcohol solvent is (10-50): 1.
  8. 8. The method for selectively synthesizing sodium tanshinone IIB sulfonate or tanshinone IIB according to claim 5, wherein in the first method, the gradient elution is three-stage gradient elution, which comprises the following steps: step 1, in a first gradient, the volume percentage of the mobile phase A is 90-85%, and the volume percentage of the mobile phase B is 10-15%; step 2, in a second gradient, the volume percentage of the mobile phase A is 85-80%, and the volume percentage of the mobile phase B is 15-20%; step 3, in a third gradient, the volume percentage of the mobile phase A is 80-20%, and the volume percentage of the mobile phase B is 20-80%; Preferably, the method comprises the steps of, In the first gradient, the elution is for a period of time ranging from 5 to 20min, e.g., 10 min; in the second gradient, the elution is for a period of time ranging from 5 to 20min, e.g., 10 min; In a third gradient, the elution is for a period of time ranging from 40 to 90 min, e.g., 80 min; More preferably, the process is carried out, The gradient elution is as follows: 。
  9. 9. A method for synthesizing tanshinone IIB sodium sulfonate by using a compound of a formula I is characterized by comprising the following steps of reacting the compound of the formula I with sulfuric acid in a solvent A to obtain tanshinone IIB sodium sulfonate; ; the molar ratio of the compound of the formula I to the sulfuric acid is 1 (2-10); The solvent A is tetrahydrofuran and/or methanol, and when the solvent A is methanol, the reaction temperature of the reaction is 60-80 ℃; preferably, the reaction conditions, operation and refining processes of the process are as described in any one of the processes of claims 1-8.
  10. 10. A method for synthesizing tanshinone IIB by using a compound shown in a formula I is characterized by comprising the following steps of reacting the compound shown in the formula I with an acid B in acetonitrile to obtain tanshinone IIB; ; the molar ratio of the compound of formula I to the acid B is 1 (20-60); The acid B is sulfuric acid or hydrochloric acid; preferably, the reaction conditions and the operating and refining methods of the process are as described in any one of the second processes of claims 1-7.

Description

Method for selectively synthesizing tanshinone IIB sodium sulfonate and tanshinone IIB Technical Field The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for selectively synthesizing sodium tanshinone IIB sulfonate and tanshinone IIB. Background Tanshinone IIB is the main active ingredient of root of Salvia Miltiorrhiza, and is widely used for treating apoplexy and coronary heart disease. Tanshinone IIB can remarkably inhibit the cytotoxicity and apoptosis of rat cortical neurons induced by staurosporine in a concentration-dependent manner, and reduce DNA ladder-shaped strips caused by the staurosporine. Meanwhile, tanshinone IIB can inhibit the increase of rat cortical neuron Bax protein induced by staurosporine, and the decrease of bcl-2 and caspase-3 protein (Phytopherer. Res. 2008, 22, 846-850). Literature (SYNTHESIS OF NOVEL CHEMICAL PROBES FOR THE STUDY OF TANSHINONE BINDING PROTEINS, jin-Soo Lee et al, bioorganic & MEDICINAL CHEMISTRY LETTERS (2006)) also reports that novel diazoxide or biotin-labeled tanshinone probes are prepared from tanshinone IIB as a key intermediate, and have a strong inhibition effect on ranKL-induced osteoclast generation. CN103288916A discloses that tanshinone IIB and derivatives thereof have obvious cytotoxicity and certain radiosensitization on tumor cells, which also shows the application prospect in anti-tumor aspect. The tanshinone IIB sodium sulfonate obtained by sulfonation of tanshinone IIB has the effects of resisting atherosclerosis and expanding blood vessels, is one of important impurities in the tanshinone IIA sodium sulfonate bulk drug and preparation, and is used as a reference substance for detecting and controlling the content of the tanshinone IIB sodium sulfonate in the tanshinone IIA sodium sulfonate bulk drug and preparation. For example, the yield of tanshinone IIB sodium sulfonate and tanshinone IIB prepared in the prior art CN103819532A is low, the steps are complex, and the operation is complex. The extract containing tanshinone compound mixture is sulfonated, and then separated by HPLC to obtain tanshinone IIB sodium sulfonate. However, in the prior art, a chemical synthesis method is not utilized to directly obtain single tanshinone IB sodium sulfonate and tanshinone IIB. Therefore, the invention develops a method for selectively and chemically preparing tanshinone IB and tanshinone IIB sodium sulfonate. Disclosure of Invention The invention aims at overcoming the defects of the prior art and provides a method for selectively synthesizing sodium tanshinone IIB sulfonate and tanshinone IIB. Compared with the traditional process, the method for preparing tanshinone IIB sodium sulfonate and tanshinone IIB has the advantages of simple operation, high yield and high purity. The invention solves the technical problems through the following technical proposal. The invention provides a method for selectively synthesizing tanshinone IIB sodium sulfonate or tanshinone IIB by a compound shown in a formula I, which comprises the following steps: (1) When the tanshinone IIB sodium sulfonate needs to be synthesized, the method I is adopted, wherein in a solvent A, a compound in the formula I reacts with sulfuric acid to obtain the tanshinone IIB sodium sulfonate; (2) When tanshinone IIB is needed to be synthesized, the second method is adopted, namely, in acetonitrile, a compound in the formula I reacts with acid B to obtain tanshinone IIB; ; In the first method, the mol ratio of the compound shown in the formula I to the sulfuric acid is 1 (2-10); in the method I, the solvent A is tetrahydrofuran and/or methanol, and when the solvent A is methanol, the reaction temperature of the reaction is 60-80 ℃; in the second method, the mol ratio of the compound of the formula I to the acid B is 1 (20-60); in the second method, the acid B is sulfuric acid or hydrochloric acid. In one embodiment, in process one, the molar ratio of the compound of formula I and the sulfuric acid may be 1 (3-6), such as 1:3.6 or 1:5.4. In one embodiment, in method one, the molar volume ratio of the sulfuric acid to the solvent A is from 0.05 to 0.1 mmol/mL, such as 0.068 mmol/mL or 0.072 mmol/mL. In one embodiment, the sulfuric acid may be present in a molar concentration of 1 to 3 mol/L, for example 1.8mol/L. The molar concentration of sulfuric acid refers to the concentration of sulfuric acid added to the reaction system. In one embodiment, in method one, the mass to volume ratio of the compound of formula I to the solvent A may be 5-15 mg/mL, such as 6.43 mg/mL or 10.28 mg/mL. In one embodiment, when the solvent a is tetrahydrofuran, the reaction temperature of the reaction may be 40-60 ℃, such as 40 ℃, 42 ℃, 44 ℃, 46 ℃,48 ℃, 50 ℃, 52 ℃, 54 ℃, 56 ℃, 58 ℃, or 60 ℃, preferably 50 ℃. In one embodiment, when the solvent a is methanol, the reaction temperature of the reaction may be 60 ℃, 62 ℃, 65 ℃, 67 ℃, 70 ℃, 72 ℃, 75 ℃, 78 ℃, or 80 ℃,