A process for the preparation of 2-chloro-6-mercaptobenzoic acid

Abstract

The application provides a preparation method of 2-chloro-6-sulfhydryl benzoic acid. Specifically provided is a preparation method of 2-chloro-6-sulfhydryl benzoic acid, which comprises the following steps: mixing a divalent palladium catalyst, a phosphine ligand, an alcohol solvent and an aromatic solvent in a protective atmosphere, adding water to pre-activate to obtain a reaction liquid; mixing the reaction liquid, a compound 2, 6-dichlorobenzoic acid, a sulfuration reagent and an inorganic base in a protective atmosphere to perform a sulfuration reaction, adding a reducing metal and an acid to react to obtain 2-chloro-6-sulfhydryl benzoic acid. The preparation method provided by the application is simple in operation, high in yield and capable of being scaled up to industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a method for preparing 2-chloro-6-mercaptobenzoic acid. Background Technology

[0002] 2-Chloro-6-mercaptobenzoic acid (CAS: 20324-51-0) is an extremely important pharmaceutical and pesticide intermediate. It can be used to synthesize a variety of industrial reagents, such as for the production of the herbicide pyrithiobacodium. It is chemically stable and has a wide range of applications.

[0003] The key steps in synthesizing 2-chloro-6-mercaptobenzoic acid lie in the selective introduction of the thiol group and the scale-up of the process. Existing technologies, such as CN103360288A, disclose a method for preparing 6-chloro-2-mercaptobenzoic acid, which achieves a yield of up to 88% in water through a two-step process of thiolation and hydrolysis. However, this synthesis process is energy-intensive, requiring high-temperature and high-pressure reaction conditions and wasting a significant amount of water resources. Furthermore, existing technologies also disclose a process for preparing 2-chloro-6-mercaptobenzoic acid from 2-chloro-6-aminobenzoic acid via diazotization and sulfidation reactions. This process suffers from high substrate costs, demanding reaction conditions, and unstable diazotization intermediates, making it unsuitable for industrial-scale production.

[0004] Therefore, it is of great importance to develop a mature, simple, mild, and high-yield method for synthesizing 2-chloro-6-mercaptobenzoic acid, which also has significant pharmaceutical value. Summary of the Invention

[0005] This invention provides a method for preparing 2-chloro-6-mercaptobenzoic acid, comprising the following steps: reacting compound 2 with a sulfiding reagent in the presence of water and an inorganic base in an alcohol solvent and an aromatic solvent, under the catalysis of a palladium catalyst and a phosphine ligand; adding a reducing metal and an acid to react and obtain compound 3; .

[0006] In this invention, the preparation method preferably includes the following reaction steps: Step (a): In a protective atmosphere, a palladium catalyst, a phosphine ligand, an alcohol solvent and an aromatic solvent are mixed, and water is added for pre-activation to obtain reaction solution 1.

[0007] Step (b): In a protective atmosphere, the reaction solution obtained in step (a), compound 2, sulfiding reagent and inorganic base are mixed and a sulfidation reaction is carried out to obtain reaction solution 2.

[0008] Step (c): Add a reducing metal and react with an acid to obtain compound 3.

[0009] In this invention, the protective atmosphere is an inert gas, such as nitrogen or argon.

[0010] In this invention, the water in step (a) and the solvent can be used together (i.e., the solvent contains water) or used separately.

[0011] In this invention, the palladium catalyst can be a conventional divalent palladium salt for this type of reaction in the art, for example... or .

[0012] In this invention, the phosphine ligand may be 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl or 1,1'-bis(diphenylphosphine)ferrocene, preferably 1,1'-bis(diphenylphosphine)ferrocene.

[0013] In this invention, the alcohol solvent may be C 1-4 Alcohol solvents, such as methanol, ethanol or tert-butanol.

[0014] In this invention, the aromatic solvent can be conventional in the art, such as benzene or toluene.

[0015] In this invention, the sulfiding agent can be a thiosulfate, such as sodium thiosulfate.

[0016] In this invention, the inorganic base may be a carbonate, such as sodium carbonate, potassium carbonate, or cesium carbonate.

[0017] In this invention, the reducing metal may be zinc.

[0018] In this invention, the acid is used in solution form, and the acid solution may be a hydrochloric acid solution, such as a 10% hydrochloric acid aqueous solution.

[0019] In this invention, the molar ratio of the palladium catalyst to the phosphine ligand can be 1:(0.8-5), for example 1:1, 1:3, 1:4 or 1:1.2.

[0020] In this invention, the volume ratio of the alcohol solvent to the aromatic solvent can be 1:(0.5-3), for example 1:1.5.

[0021] In this invention, the molar volume ratio of the palladium catalyst to the solvent (referring to alcohol solvents and aromatic solvents) can be (0.01-0.1):10 mol / L, for example 0.05:10 mol / L.

[0022] In this invention, the molar ratio of the palladium catalyst to the compound can be (0.5-4):10, for example 1:10, 2:10 or 3:10.

[0023] In this invention, the molar ratio of compound 2 to water in step (a) can be 10:(0.5-4), for example 10:1, 10:2 or 10:3.

[0024] In this invention, the molar ratio of compound 2 to the sulfiding reagent can be 1:(0.8-4), for example 1:2.5 or 1:1.2.

[0025] In this invention, the molar ratio of compound 2 to the inorganic base can be 1:(0.8-4), for example 1:2 or 1:1.

[0026] In this invention, the amount of reducing metal used is conventional in the art. For example, the molar ratio of compound 2 to the reducing metal (e.g., zinc powder) can be 1:(1-20), such as 1:10 or 1:15.2.

[0027] In this invention, the amount of acid used is conventional in the art, for example, 10% hydrochloric acid (HCl solution with HCl mass content of 10%) is used, and the molar volume ratio of compound 2 to acid solvent can be (0.1-1):5 mol / L, for example 0.1:1 mol / L.

[0028] In this invention, the pre-activation reaction temperature in step (a) can be from room temperature to 120 degrees Celsius, for example, 40-60 degrees Celsius, preferably 55 degrees Celsius.

[0029] In this invention, the vulcanization reaction temperature in step (b) can be 70-90 degrees Celsius, for example, 80 degrees Celsius.

[0030] In this invention, step (b) can be monitored using conventional methods in the art, such as thin-layer chromatography or nuclear magnetic resonance, preferably until compound 2 no longer converts to the reaction endpoint. The reaction time can be 20-30 hours, for example, 24 hours.

[0031] In this invention, after step (b) is completed, it is preferable to remove the solvent before proceeding to step (3). The solvent removal is carried out, for example, by filtration or washing with an ether (e.g., diethyl ether).

[0032] In this invention, the reaction temperature in step (c) can be from -5 degrees Celsius to room temperature, for example, 0 degrees Celsius (carried out in an ice-water bath).

[0033] In this invention, after step (c) is completed, the following post-processing steps may be included: extraction with chloroform, washing (e.g., washing with water and saturated saline solution in sequence), drying, to obtain compound 3.

[0034] In this invention, the preparation method of the 2-chloro-6-mercaptobenzoic acid preferably includes the following steps: Step (a): mixing the divalent palladium salt and the phosphine ligand, adding an alcohol solvent, an aromatic solvent and water in a protective gas atmosphere, and activating by heating.

[0035] Step (b): Add the compound 2, the sulfiding reagent, and the inorganic base, mix them, and react them at 70-85 degrees Celsius in a protective gas atmosphere. After the reaction is complete, filter.

[0036] Step (c): The solid is added to a reducing metal and acid solution to react. After the reaction is complete, the solid is extracted, washed, and dried to obtain 2-chloro-6-mercaptobenzoic acid.

[0037] In this invention, the method for preparing 2-chloro-6-mercaptobenzoic acid may further include the following steps: reacting compound 1 with a strong acid reagent to obtain compound 2; .

[0038] In this invention, the strong acid reagent can be a sulfuric acid reagent, such as concentrated sulfuric acid.

[0039] In this invention, the 2-chloro-6-mercaptobenzoic acid is prepared by a one-pot method, and the resulting compound 2 is directly subjected to the sulfidation reaction.

[0040] In this invention, the molar volume ratio of compound 1 to the acid reagent can be 1:(1-5)mol / L, for example 1:3mol / L.

[0041] In this invention, the sulfuric acid reagent can be reused, for example, by vacuum concentration, washing with ether solvents, vacuum concentration, and then reused.

[0042] The advantages of the process of this invention are: the process provided by this invention is easy to operate, simple to operate, mild conditions, high yield, and easy to scale up production. Detailed Implementation

[0043] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0044] In this invention, reagents, ligands and intermediates for which no preparation method is given are all purchased from commercial sources, such as Sinopharm Reagent, Aladdin Reagent and Bailingwei Technology Co., Ltd.

[0045] Example 1: Compound 1 (10 mol, 1.72 kg) was mixed with 1 L of concentrated sulfuric acid and 1 L of water, and heated with stirring at 60°C for 1.5 hours. The reaction was monitored by thin-layer chromatography (TLC) until completion. The mixture was poured in portions into 60 L of water containing crushed ice, filtered, dried, and the filtrate was recovered and reused. A nearly white solid precipitate was obtained (9.32 mol, 1.78 kg, yield 93.2%). 1H-NMR (DMSO-d6, 300 MHz, ppm): 13.81 (br,1H), 7.65(t,1H), 7.18-7.24 (m, 2H).

[0046] Example 2: ;Will (0.05 mmol, 11.2 mg) and Xphos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 0.15 mmol, 71.5 mg) were mixed, vacuumed, and backfilled three times with argon. Then tert-butanol (4 mL) / toluene (6 mL) and water (180 μL) were added; then compound 2 (0.5 mmol, 94.98 mg) and sodium thiosulfate were added. (0.63 mmol, 100 mg) and cesium carbonate (1 mmol, 325.8 mg) were mixed and stirred at 80°C for 8 hours. The mixture was filtered, and the filter cake was washed with 5 mL of diethyl ether. The solid was added to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL), and stirred for 1 hour under ice water cooling. Chloroform was added for extraction, and the mixture was washed successively with 5 mL of water and saturated brine. The product was dried over anhydrous sodium sulfate and cooled to give solid product 3 (0.2 mmol, 37.59 mg, 40% yield). 1 H-NMR (DMSO, 400 MHz,) 14.01(s,1H), 7.98 (d, J= 2.4 Hz 1H), 7.65 (dd J=8.7,2.Hz 1H), 7.60 (d,J= 8.7 Hz 1H).

[0047] Example 3: The same reaction conditions as in Example 2 were used, with the only difference being... Different dosages are used, with the catalyst system being: A mixture prepared with Xphos at a molar ratio of 1:3. The initial dosage and test results are shown in Table 1.

[0048] Table 1:

[0049] As shown in Table 1 and the experimental results of Example 2, although increasing the amount of Pd catalyst can improve the reaction conversion rate, the overall yield still does not exceed 50%; it can be seen that when The optimal overall reaction is achieved when the amount used is 0.1 equivalent of compound 2.

[0050] Example 4: [The sentence is incomplete and requires more context to be translated accurately.] Compound 2 (0.05 mmol, 11.2 mg) and Xphos (0.15 mmol, 71.5 mg) were mixed, evacuated, and backfilled three times with argon. Then, tert-butanol (4 mL) / toluene (6 mL) and water (180 μL) were added. Then, compound 2 (0.5 mmol, 94.98 mg) and sodium thiosulfate were added. A mixture of zinc powder (0.63 mmol, 100 mg) and cesium carbonate (1 mmol, 325.8 mg) was reacted under the conditions shown in Table 2 below, and the reaction was monitored until completion. The mixture was filtered, and the filter cake was washed with 5 mL of diethyl ether. The solid was added to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL), and stirred for 1 hour under ice water cooling. The mixture was then extracted with chloroform, washed successively with 5 mL of water and saturated brine, dried over anhydrous sodium sulfate, and cooled to obtain the product. The yield was calculated, as shown in Table 2.

[0051] Table 2:

[0052] Table 2 shows that when the temperature is below 50°C, the reaction is incomplete within an 8-hour timeframe. However, when the temperature is not less than 60°C, the reaction is complete within the 8-hour reaction timeframe. Surprisingly, the reaction could not proceed under microwave conditions. These experimental results indicate that when the reaction temperature is above 60°C, temperature has no significant effect on the reaction yield. Therefore, the optimal reaction conditions are between 60-120°C, and more preferably between 60-80°C.

[0053] Example 5: [The sentence is incomplete and requires more context to be translated accurately.] Compound 2 (0.05 mmol, 11.2 mg) and Xphos (0.15 mmol, 71.5 mg) were mixed, evacuated, and backfilled three times with argon. Then, tert-butanol (4 mL) and toluene (6 mL) were added, followed by compound 2 (0.5 mmol, 94.98 mg) and sodium thiosulfate. (0.63 mmol, 100 mg), cesium carbonate (1 mmol, 325.8 mg), and water as shown in Table 3 were mixed. The mixture was evacuated and backfilled three times with argon gas. The reaction was stirred at 80°C, and the reaction was monitored until completion. The mixture was filtered, and the filter cake was washed with 5 mL of diethyl ether. The solid was added to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL). The mixture was stirred for 1 hour under ice water cooling. Chloroform was added for extraction, and the mixture was washed successively with 5 mL of water and saturated brine. The product was dried over anhydrous sodium sulfate and cooled to obtain the product. The yield was calculated, as shown in Table 3.

[0054] Table 3:

[0055] As shown in Table 3, the reaction proceeds smoothly when the water content in the reaction system is greater than 5 mmol. Since the solvent usually contains water, the reaction can usually proceed normally without the addition of additional water.

[0056] Example 6: [The sentence is incomplete and requires more context to be translated accurately.] (0.05 mmol, 11.2 mg) and the ligand shown in Table 4 below (0.15 mmol, 71.5 mg) were mixed, vacuumed, and backfilled three times with argon. Then tert-butanol (4 mL) / toluene (6 mL) and water (180 μL) were added; then compound 2 (0.5 mmol, 94.98 mg) and sodium thiosulfate were added. Mix 0.63 mmol (100 mg) of zinc powder and cesium carbonate (1 mmol, 325.8 mg), evacuate and backfill with argon three times, and stir at 80°C. Filter, wash the filter cake with 5 mL of diethyl ether, add the solid to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL), stir for 1 hour under ice water cooling, extract with chloroform, wash successively with 5 mL of water and saturated brine, dry with anhydrous sodium sulfate, cool to obtain the product, and calculate the yield, as shown in Table 4.

[0057] Table 4:

[0058] As shown in Table 4, replacing the ligand with dppf increased the reaction yield to over 80%.

[0059] Example 7: [The sentence is incomplete and requires more context to be translated accurately.] (0.05 mmol, 11.2 mg) and dppf (0.06 mmol, 33.3 mg) were mixed, then tert-butanol (4 mL) / toluene (6 mL) were added, followed by water (180 μL); then compound 2 (0.5 mmol, 94.98 mg) and sodium thiosulfate were added. Mix (0.63 mmol, 100 mg) of the base (1 mmol) shown in Table 5 below, evacuate and backfill with argon three times, and stir at 80°C for 24 hours. Filter, wash the filter cake with 5 mL of diethyl ether, add the solid to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL), stir for 1 hour under ice water cooling, extract with chloroform, wash successively with 5 mL of water and saturated brine, dry with anhydrous sodium sulfate, and cool to obtain the product, as shown in Table 5 below.

[0060] Table 5:

[0061] As shown in Table 5, the K2CO3 reaction conditions are optimal.

[0062] Example 8: [The sentence is incomplete and requires more context to be translated accurately.] The compound (0.05 mmol, 11.2 mg) and dppf (0.06 mmol, 33.3 mg) were mixed and then added to 10 mL of the solvent listed in Table 6 below, followed by 180 μL of water. Then, compound 2 (0.5 mmol, 94.98 mg) and sodium thiosulfate were added. (0.63 mmol, 100 mg) of zinc powder and (1 mmol, 106 mg) of sodium carbonate were mixed and stirred at 80°C for 24 hours. The mixture was filtered, and the filter cake was washed with 5 mL of diethyl ether. The solid was added to zinc powder (7.6 mmol, 0.5 g) and hydrochloric acid (10%, 5 mL), and stirred for 1 hour under ice water cooling. Chloroform was added for extraction, and the mixture was washed successively with 5 mL of water and saturated brine. The product was dried over anhydrous sodium sulfate and cooled to obtain the product, as shown in Table 6.

[0063] Table 6:

[0064] As shown in Table 6, the mixed solvent system is more suitable for this reaction, which may be related to the mass and heat transfer characteristics of the reaction system. Choosing an alcohol / aromatic solvent is more conducive to the reaction.

[0065] Application Example 1: .

[0066] Step 1: Mix compound 1 (10 mol, 1.72 kg) with 1 L concentrated sulfuric acid and 1 L water, stir and heat at 60°C for 1.5 hours, and monitor the reaction for completion by thin-layer chromatography (TLC). Pour the mixture into 2 L of water containing crushed ice in portions, filter and dry, recover the filtrate for reuse, and obtain compound 2.

[0067] Step 2: (1 mol, 224 g) and dppf (1.2 mol, 665.3 g) were mixed, evacuated, and backfilled three times with argon gas. Then, tert-butanol (1.6 L) / toluene (2.4 L) was added, followed by water (20 mol, 360 g), and then mixed with compound 2 obtained in step 1. Sodium thiosulfate was added. 12.7 mol (2 kg) of zinc powder and 20 mol (2.1 kg) of potassium carbonate were mixed, and the mixture was evacuated and backfilled three times with argon gas. The mixture was stirred at 80°C and the reaction was monitored until completion. The mixture was filtered, and the filter cake was washed with 100 L of diethyl ether. The solid was added to zinc powder (15 mol, 980 g) and hydrochloric acid (10%, 1 L). The mixture was stirred under ice water cooling, extracted with chloroform, and washed successively with 10 L of water and saturated brine. The mixture was dried over anhydrous sodium sulfate and cooled to give 1.78 kg of a pale yellow product. The two-step yield was approximately 93.35%.

[0068] Surprisingly, the overall yield of compound 3 from compound 1 was higher when the process was scaled up using a one-pot method than when it was performed stepwise. This is likely due to the one-pot method reducing losses by eliminating the need to separate intermediates. Therefore, the method described in this invention can produce compound 3 in large quantities.

Claims

1. A method for preparing 2-chloro-6-mercaptobenzoic acid, characterized in that, The preparation method includes the following reaction steps: Compound 1 was reacted with sulfuric acid to obtain compound 2; ; Step (a): In a protective atmosphere, a divalent palladium catalyst, a phosphine ligand, an alcohol solvent, and an aromatic solvent are mixed, and water is added for pre-activation to obtain a reaction solution; The divalent palladium catalyst is used in the form of a divalent palladium salt, which is Pd(OAc)2. The phosphine ligand is 1,1'-bis(diphenylphosphine)ferrocene; the alcohol solvent is tert-butanol; and the aromatic solvent is toluene. The molar ratio of the divalent palladium catalyst to the phosphine ligand is 1:(0.8-3). The volume ratio of the alcohol solvent to the aromatic solvent is 1:(0.5-3); The molar ratio of the divalent palladium catalyst to the compound is (0.5-4):10; The pre-activation reaction temperature in step (a) is from room temperature to 55 degrees Celsius; Step (b): In a protective atmosphere, the reaction solution obtained in step (a), compound 2, sulfiding reagent and inorganic base are mixed and a sulfidation reaction is carried out to obtain the reaction solution; The inorganic base is a weak carbonate salt, and the weak carbonate salt is potassium carbonate; The molar ratio of compound 2 to the inorganic base is 1:(0.8-4). The molar ratio of compound 2 to the sulfiding agent is 1:(0.8-4). The vulcanization reaction temperature in step (b) is 70-90 degrees Celsius; The sulfiding agent is a thiosulfate; ; Step (c): Add a reducing metal and react with an acid to obtain compound 3; the reducing metal is zinc.

2. The method for preparing 2-chloro-6-mercaptobenzoic acid as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The protective atmosphere is an inert gas, wherein the inert gas is nitrogen or argon; (2) The acid is used in the form of hydrochloric acid aqueous solution; (3) After step (b) is completed, remove the solvent and proceed to step (c).

3. The method for preparing 2-chloro-6-mercaptobenzoic acid as described in claim 2, characterized in that, It satisfies one or more of the following conditions: (1) The thiosulfate is sodium thiosulfate; (2) The solvent removal is a filtration operation.

4. The method for preparing 2-chloro-6-mercaptobenzoic acid as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The molar ratio of compound 2 to water in step (a) is 10:(0.5-4); (2) The molar ratio of compound 2 to the reducing metal is 1:(1-20); (3) The reaction temperature in step (c) is from -5 degrees Celsius to room temperature.

5. The method for preparing 2-chloro-6-mercaptobenzoic acid as described in claim 4, characterized in that, It satisfies one or more of the following conditions: (1) The molar ratio of the divalent palladium catalyst to the phosphine ligand is 1:1, 1:3 or 1:1.2; (2) The volume ratio of the alcohol solvent to the aromatic solvent is 1:1.5; (3) The molar ratio of the divalent palladium catalyst to the compound 2 is 1:10, 2:10 or 3:10; (4) The molar ratio of compound 2 to water in step (a) is 10:1, 10:2 or 10:3; (5) The molar ratio of compound 2 to the sulfiding reagent is 1:2.5 or 1:1.2; (6) The molar ratio of compound 2 to the inorganic base is 1:2 or 1:1; (7) The molar ratio of compound 2 to the reducing metal is 1:10 or 1:15.2; (8) The pre-activation reaction temperature in step (a) is 55 degrees Celsius; (9) The vulcanization reaction temperature in step (b) is 80 degrees Celsius; (10) The reaction temperature in step (c) is 0 degrees Celsius.

6. The method for preparing 2-chloro-6-mercaptobenzoic acid as described in claim 1, characterized in that, After step (c) is completed, the following post-processing steps are included: chloroform extraction, washing, drying, to obtain compound 3.

7. The method for preparing 2-chloro-6-mercaptobenzoic acid as described in claim 1, characterized in that, It includes the following steps: Step (a): Mix the divalent palladium salt and the phosphine ligand, add the alcohol solvent, the aromatic solvent and water in a protective gas atmosphere, and heat to activate; The phosphine ligand is 1,1'-bis(diphenylphosphine)ferrocene; the alcohol solvent is tert-butanol; the aromatic solvent is toluene; and the divalent palladium salt is Pd(OAc)2. The molar ratio of the divalent palladium catalyst to the phosphine ligand is 1:(0.8-3). The volume ratio of the alcohol solvent to the aromatic solvent is 1:(0.5-3); The molar ratio of the divalent palladium catalyst to the compound is (0.5-4):10; Step (b): Add the compound 2, the sulfiding reagent, and the inorganic base, mix them, and react them at 70-85 degrees Celsius in a protective gas atmosphere. After the reaction is complete, filter the mixture. The inorganic base is a weak carbonate salt, and the weak carbonate salt is potassium carbonate; The molar ratio of compound 2 to the inorganic base is 1:(0.8-4). The molar ratio of compound 2 to the sulfiding agent is 1:(0.8-4). Step (c): The solid is added to a reducing metal and an acid solution to react. After the reaction is complete, the solid is extracted, washed, and dried to obtain 2-chloro-6-mercaptobenzoic acid; the reducing metal is zinc.

8. The method for preparing 2-chloro-6-mercaptobenzoic acid as described in claim 1, characterized in that, The preparation method of 2-chloro-6-mercaptobenzoic acid is a one-pot method, and the product obtained in step (a) is directly carried out in the next step of sulfidation reaction.

9. The method for preparing 2-chloro-6-mercaptobenzoic acid as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The sulfuric acid mentioned is concentrated sulfuric acid; (2) The molar volume ratio of compound 1 to sulfuric acid is 1:(1-5) mol / L; (3) The sulfuric acid is concentrated under reduced pressure, washed with ether solvent, and then concentrated under reduced pressure for reuse.

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