Preparation method of pharmaceutical grade dibenzothiazyl disulfide

Abstract

The invention discloses a preparation method of pharmaceutical grade dibenzothiazyl disulfide, and relates to the technical field of medicines. A small amount of sulfuric acid is used for soaking to remove part of developing inorganic impurities, then a polar solvent is used for sectional purification, and the purified M can be directly used for preparing DM without drying. The one-step method provided by the invention is relatively high in yield, does not use a catalyst or a dispersing agent, and is relatively low in process cost; a small amount of inorganic acid is used in the preparation process, so that the generation of waste salt is greatly reduced, and the environmental protection pressure is relieved.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a method for preparing pharmaceutical-grade dibenzothiazole disulfide. Background Art

[0002] Dibenzothiazyl disulfide (DM) is an excellent rubber vulcanization accelerator, widely used in the rubber industry. It is also a highly active pharmaceutical intermediate, commonly used in the pharmaceutical and chemical fields. Dibenzothiazyl disulfide (DM) can be prepared by oxidation of 2-mercaptobenzothiazole (M), for example:

[0003] Patent CN104327011A discloses a two-step method for synthesizing pharmaceutical-grade DM. The raw material M is first dissolved by adding a 1.1 molar ratio of alkali, and after filtering out the insoluble matter, it is extracted by acid precipitation to obtain a high-purity primary refined M. The raw material M is then added to tetrahydrofuran, completely dissolved, and then decolorized with activated carbon. After cooling and crystallization, a white secondary refined M is obtained. The secondary refined M is subjected to an oxygen oxidation process to obtain the product DM, which meets the standards for pharmaceutical-grade DM and has a two-step yield of approximately 54%. This method uses an acid-base purification method. Producing 1 ton of pharmaceutical-grade DM generates approximately 21 tons of saline wastewater, which puts a relatively large environmental burden. The yield is low and is unsuitable for current production environments.

[0004] Patent CN112625002A uses an alcohol aqueous solution to dissolve the material, followed by the addition of a reducing agent to react and remove some of the color-forming impurities. Activated carbon is then used for further decolorization and adsorption of insoluble matter. A dispersant is then added dropwise, and pharmaceutical-grade DM is produced via hydrogen peroxide oxidation, yielding approximately 90% and a melting point of approximately 179°C. While the addition of a reducing agent in this method can react and remove some of the color-forming impurities, rigid structures contained in M, such as benzothiazole, remain unreacted and remain color-forming impurities, leading to deviations in the color and melting point of the product.

[0005] Patent CN 115716811 A uses a mixed solvent of lipid solvents and protic solvents to dissolve industrial-grade M. Subsequently, the color-developing impurities contained in the industrial-grade M are removed by adding an organophosphorus chelating agent and adjusting the pH value. Subsequently, pharmaceutical-grade DM is produced in a one-step hydrogen peroxide oxidation process. The yield is marked as 96.91% in the patent, the melting point is 180.8°C, and the bulk density is 0.55g / mL.

[0006] Patent CN201910906432A discloses a method for preparing pharmaceutical-grade DM by decolorizing an industrial-grade promoter M in an alcohol solvent using a reducing agent and activated carbon, adding a small amount of dispersant, and then oxidizing it with hydrogen peroxide in one step. This scheme also synthesizes pharmaceutical-grade DM in one step, which improves the color and melting point of the product. However, a large amount of activated carbon is still used for impurity adsorption in the production process, and a large amount of waste carbon needs to be processed during the production process. In addition, the bulk density of the obtained product is poor, reaching only 0.2-0.3g / mL, which cannot meet the standard requirement of 0.4g / ml for pharmaceutical-grade DM.

[0007] Patent CN102285938A uses recrystallization from ethyl acetate and ethanol, and adds activated carbon for decolorization and impurity removal. Although the purity can reach over 99%, the color after crystallization is still dark and cannot be white. In addition, the raw material requirements are high, requiring the crude DM to have a purity of 98%, which far exceeds the industrial-grade DM standard, so the cost is relatively high.

[0008] Patent CN103145642A uses an immersion washing method to achieve a purity of over 99%, but its color after crystallization is still dark and cannot be white. It also has high requirements for raw materials, requiring the purity of crude DM to be 98%, which far exceeds the industrial-grade DM standard. Therefore, the cost is relatively high and it does not have the value of industrial production.

[0009] The current methods for preparing pharmaceutical-grade dibenzothiazole disulfide (DM) have the following problems: (1) The one-step synthesis of pharmaceutical-grade DM is relatively lengthy, resulting in low yields and waste of resources. In addition, it is necessary to adjust the pH value and add a dispersant, which puts great pressure on the environmental protection. (2) The acid-base method for preparing pharmaceutical-grade M uses a large amount of acid and base. The production of one ton of pharmaceutical-grade M will produce about 21 tons of salt-containing wastewater, and a large amount of activated carbon is required for decolorization. The environmental pressure is huge, and the yield of this method is often low and the cost is high, resulting in the acid-base method for purifying M being on the verge of being eliminated. (3) The solvents used in the solvent method for refining M or DM often have high boiling points, and there are problems with recycling and application. In addition, the organic color-forming impurities contained in M ​​or DM are often not fully removed, resulting in poor product color.

[0010] Therefore, there is an urgent need to improve the preparation method of pharmaceutical-grade dibenzothiazyl disulfide (DM) to reduce the generation of waste salt and reduce process costs while increasing the yield.

[0011] In view of this, the present invention is proposed. Summary of the Invention

[0012] The present invention aims to provide a method for preparing pharmaceutical-grade dibenzothiazole disulfide, thereby reducing waste salt generation, improving product yield, and reducing process costs.

[0013] The present invention is achieved in that:

[0014] In a first aspect, the present invention provides a method for preparing pharmaceutical-grade dibenzothiazole disulfide, comprising:

[0015] Mixing industrial-grade 2-mercaptobenzothiazole with an inorganic acid solution, soaking the mixture at 55° C. to 65° C., and then performing solid-liquid separation to obtain a separated liquid and a first solid material;

[0016] The first solid material and the polar solvent are mixed and dissolved at 55°C-65°C, then mixed with primary water to remove the precipitated solid, and then mixed with secondary water to obtain the second solid material after solid-liquid separation;

[0017] The second solid material is mixed with an organic solvent to prepare a slurry, and then mixed with an oxidant to carry out an oxidation reaction.

[0018] In an optional embodiment, the inorganic acid solution is a sulfuric acid solution, and the mass fraction of the sulfuric acid solution is 1%-3%;

[0019] Preferably, the mass ratio of industrial grade 2-mercaptobenzothiazole to sulfuric acid solution is 1:(3-7);

[0020] And / or, the purity of the industrial-grade 2-mercaptobenzothiazole is 96%-98%.

[0021] In an optional embodiment, the soaking time of industrial-grade 2-mercaptobenzothiazole in the inorganic acid solution is 1 h to 5 h;

[0022] And / or, the separated liquid is allowed to stand to precipitate insoluble matter and then reused.

[0023] In an optional embodiment, the polar solvent is selected from at least one of N,N-dimethylformamide, 1,4-dioxane, ethanol and methanol;

[0024] And / or, the mass ratio of industrial-grade 2-mercaptobenzothiazole to polar solvent is 1:(8-12).

[0025] In an optional embodiment, the first solid material is mixed with a polar solvent and then heated to 55° C.-65° C. for dissolution, and then water is gradually added once within 1 hour.

[0026] In an optional embodiment, the mass ratio of industrial-grade 2-mercaptobenzothiazole to primary water is 1:(0.3-1.5).

[0027] In an optional embodiment, the mass ratio of industrial-grade 2-mercaptobenzothiazole to secondary water is 1:(1.5-10).

[0028] In an optional embodiment, the second solid material is mixed with an organic solvent at 30° C. to 45° C. to prepare a slurry for 0.3 h to 1.0 h, and then an oxidant is added dropwise within 1 h to perform an oxidation reaction;

[0029] And / or, the oxidant is selected from at least one of hydrogen peroxide, sodium nitrite, sodium hypochlorite, chlorine and oxygen.

[0030] In an optional embodiment, the organic solvent is selected from at least one of methanol, isopropanol, n-butanol and ethanol;

[0031] And / or, the mass ratio of industrial-grade 2-mercaptobenzothiazole to the organic solvent is 1:(3-7).

[0032] In an optional embodiment, the amount of the oxidant is adjusted so that the amount of the oxidant added is 1.1-1.3 equivalents of industrial-grade 2-mercaptobenzothiazole.

[0033] The present invention has the following beneficial effects: First, a small amount of sulfuric acid is used to partially remove color-forming inorganic impurities, followed by staged purification using a polar solvent. The purified M can be directly prepared into DM without drying. The one-step method provided by the present invention offers high yields and does not require the use of catalysts or dispersants, resulting in low process costs. The use of a small amount of inorganic acid during the preparation process significantly reduces the generation of waste salts, alleviating environmental pressures. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0035] Figure 1 A process flow chart for preparing pharmaceutical-grade dibenzothiazole disulfide provided in an embodiment of the present invention;

[0036] Figure 2 HPLC spectrum of the product prepared in Example 1 (converted external standard content is 99.51%);

[0037] Figure 3 This is the HPLC spectrum of the product prepared in Example 1 (the converted external standard content is 99.58%). DETAILED DESCRIPTION

[0038] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.

[0039] In response to the problems of existing methods for preparing pharmaceutical-grade dibenzothiazole disulfide (DM), such as complicated steps, the use of large amounts of decolorizing agents such as activated carbon, and the generation of large amounts of waste salt, the inventors have optimized the preparation method of DM. During the preparation process, a small amount of acid is used to soak industrial-grade 2-mercaptobenzothiazole (M), which significantly reduces the generation of waste salt and alleviates environmental pressure. The one-step method provided by the present invention has a high yield and does not use catalysts or dispersants, thereby reducing process costs.

[0040] The present invention provides a method for preparing pharmaceutical-grade dibenzothiazole disulfide. Figure 1 As shown, including:

[0041] S1, acid leaching separation

[0042] Industrial-grade 2-mercaptobenzothiazole (industrial-grade M) is mixed with an inorganic acid solution (dilute acid) and soaked at 55°C-65°C. Solid-liquid separation is then performed to obtain a separated liquid (filtrate) and a first solid material (filter cake). Leaching with an inorganic acid solution can remove some of the color-forming inorganic impurities, achieving the purpose of preliminary purification.

[0043] It should be noted that industrial-grade M often contains a small amount of metal impurities, which are usually colored. In addition, metal impurities will affect the solubility of pharmaceutical-grade M. Soaking in dilute sulfuric acid solution can effectively remove metal impurities.

[0044] Specifically, industrial-grade 2-mercaptobenzothiazole can be a commercially available material with a purity of 96%-98%, such as 96% purity and a melting point of about 169° C. The immersion temperature in the inorganic acid solution can be 55° C., 58° C., 60° C., 63° C., 65° C., etc.

[0045] In some embodiments, the inorganic acid solution can be a sulfuric acid solution having a mass fraction of 1% to 3%, such as 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, etc. The mass ratio of industrial-grade 2-mercaptobenzothiazole to sulfuric acid solution is 1:(3-7), such as 1:3, 1:4, 1:5, 1:6, 1:7, etc. The concentration and amount of sulfuric acid solution are preferably within the above ranges to better remove color-forming inorganic impurities.

[0046] Furthermore, the soaking time of industrial-grade 2-mercaptobenzothiazole in the inorganic acid solution is 1 h to 5 h, such as 1 h, 2 h, 3 h, 4 h, 5 h, etc. After soaking, solid-liquid separation can be performed by filtration, and the obtained separated liquid (filtrate) is allowed to stand for 1 day to remove impurities such as precipitated insoluble matter, which can be reused.

[0047] S2, polar solvent staged purification

[0048] The first solid material and a polar solvent are mixed and dissolved at 55°C-65°C (to obtain solution M), then mixed with primary water to remove precipitated solid impurities, and then mixed with secondary water. After solid-liquid separation, a second solid material (filter cake) and a filtrate are obtained, which is recycled. The second solid material is a high-purity 2-mercaptobenzothiazole, which is oxidized to produce pharmaceutical-grade DM.

[0049] It should be noted that because Accelerator M contains a thiol group, it is slightly soluble in water and is more soluble in polar solvents. However, some impurities, such as benzothiazole, anilinobenzothiazole, and diphenylthiourea, are insoluble in water and can be removed in this step. Furthermore, these impurities also include isomers with the same molecular mass as Accelerator M, whose specific structures are unknown.

[0050] In some embodiments, the polar solvent is selected from at least one of N,N-dimethylformamide (DMF), 1,4-dioxane, ethanol, and methanol. The polar solvent can be any one or more of the above, preferably DMF, as the raw materials are readily available and the impurity removal effect is good. The mass ratio of industrial-grade 2-mercaptobenzothiazole to the polar solvent is 1:(8-12), such as 1:8, 1:9, 1:10, 1:11, 1:12, etc.

[0051] Furthermore, the first solid material is mixed with a polar solvent and heated to 55°C-65°C to dissolve. Primary water is then gradually added over 1 hour to remove the precipitated dark yellow solid. The mass ratio of industrial-grade 2-mercaptobenzothiazole to primary water is 1:(0.3-1.5), such as 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc. The amount of primary water is preferably within the above range to better remove impurities.

[0052] Furthermore, the mass ratio of industrial-grade 2-mercaptobenzothiazole to secondary water is 1:(1.5-10), such as 1:1.5, 1:2.0, 1:3.0, 1:4.0, 1:5.0, 1:6.0, 1:7.0, 1:8.0, 1:9.0, 1:9.5, 1:10.0, etc. The amount of secondary water is preferably within the above range, which can better remove impurities.

[0053] S3, oxidation reaction

[0054] The second solid material is mixed with an organic solvent to prepare a slurry, and then mixed with an oxidant to carry out an oxidation reaction. After the oxidation reaction, pharmaceutical-grade dibenzothiazole disulfide is prepared.

[0055] In some embodiments, the organic solvent is selected from at least one of methanol, isopropanol, n-butanol, and ethanol, and the organic solvent may be any one or more of the above. The mass ratio of industrial-grade 2-mercaptobenzothiazole to the organic solvent is 1:(3-7), such as 1:3, 1:4, 1:5, 1:6, 1:7, etc. The type of oxidant is not limited, such as at least one of hydrogen peroxide, sodium nitrite, sodium hypochlorite, chlorine, and oxygen, preferably hydrogen peroxide. Hydrogen peroxide is also a type of bleaching agent. Compared with pharmaceutical-grade M, the preparation of DM does not require the use of sodium sulfite bleaching.

[0056] In actual operation, the second solid material is mixed with an organic solvent at 30°C-45°C for 0.3-1.0 hour, and then hydrogen peroxide is added dropwise within 1 hour for oxidation reaction. After the reaction is completed, solid-liquid separation is performed by filtration or other methods. Specifically, the slurrying temperature can be 30°C, 35°C, 40°C, 45°C, etc., and the mixing and slurrying time can be 0.3 hour, 0.5 hour, 0.8 hour, 1.0 hour, etc.

[0057] Furthermore, by adjusting the amount of oxidant used, the amount of oxidant (e.g., hydrogen peroxide) added is adjusted to be 1.1-1.3 equivalents of industrial-grade 2-mercaptobenzothiazole, i.e., the amount of oxidant added is 1.1-1.3 times the theoretical amount, resulting in a slight excess of oxidant and sufficient oxidation of the raw material. Specifically, theoretically, 2 mol of 2-mercaptobenzothiazole corresponds to 1 mol of hydrogen peroxide, and the actual amount of hydrogen peroxide used is 1.1-1.3 of the theoretical amount.

[0058] The features and performance of the present invention are further described in detail below with reference to the embodiments.

[0059] Example 1

[0060] This embodiment provides a method for preparing pharmaceutical-grade dibenzothiazole disulfide, and the steps are as follows:

[0061] (1) 200 g of industrial grade M (purchased from Lianyungang Shengao Chemical Technology Co., Ltd., purity 96%, melting point 169 ° C) was mixed with 1 kg of 2% (mass fraction, the same below) sulfuric acid solution, heated to 60 ° C and soaked for 2 h, filtered, and the filtrate was allowed to stand for 1 day. After removing the precipitated insoluble matter, it can be reused.

[0062] (2) Add 2 kg of DMF to the filter cake obtained in step (1), mix thoroughly, heat to 60°C and dissolve completely, then slowly add 100 g of water within 1 hour, remove the precipitated dark yellow solid, add 1.9 kg of water, and filter.

[0063] (3) The filter cake obtained in step (2) was added with 1 kg of methanol and slurried at 39° C. for 0.5 h. Then, 87.79 g (1.2 equivalents of M, concentration 27.5%) of hydrogen peroxide was added dropwise within 1 h. After the reaction was completed, 182 g of a white product was obtained by filtration, with a yield of 91%, a purity of 99.5%, a melting point of 181.8° C., and a bulk density of 0.45 g / mL.

[0064] The HPLC spectrogram of the product prepared in Test Example 1 is as follows Figure 2 and Figure 3 , the area normalization method showed 99.7%, and the external standard content was 99.51% (see Figure 2 ) and 99.58% (see Figure 3 ).

[0065] Example 2

[0066] The main difference from Example 1 is that the concentration of dilute sulfuric acid is reduced. The specific steps are as follows:

[0067] (1) Mix 200g of industrial grade M (purity 96%, melting point 169°C) with 1kg of 1% sulfuric acid solution, heat to 60°C and soak for 2h, filter, let the filtrate stand for 1 day, remove the precipitated insoluble matter, and then reuse it.

[0068] (2) Add 2 kg of DMF solution to the filter cake obtained in step (1), mix thoroughly, heat to 60°C, and slowly add 100 g of water within 1 hour to completely dissolve the filter cake. After removing the precipitated dark yellow solid, add 1.9 kg of water and filter.

[0069] (3) The filter cake obtained in step (2) was added with 1 kg of methanol and slurried at 39° C. for 0.5 h. Then, 87.79 g (1.2 equivalents of M, concentration 27.5%) of hydrogen peroxide was added dropwise within 1 h. After the reaction was completed, 182.5 g of a white product was obtained by filtration, with a yield of 91.80%, a purity of 99.0%, a melting point of 179.8° C., and a bulk density of 0.45 g / mL.

[0070] Example 3

[0071] This embodiment provides a method for preparing pharmaceutical-grade dibenzothiazole disulfide, and the steps are as follows:

[0072] (1) Mix 200g of industrial grade M (purity 96%, melting point 169°C) with 1kg of 2% sulfuric acid solution, heat to 60°C and soak for 2h, filter, let the filtrate stand for 1 day, remove the precipitated insoluble matter, and then reuse it.

[0073] (2) Add 2 kg of 1,4-dioxane solution to the filter cake obtained in step (1), mix thoroughly, heat to 60°C, and slowly add 80 g of water within 1 hour to remove the precipitated dark yellow solid. Then, add 300 g of water and filter.

[0074] (3) The filter cake obtained in step (2) was added with 1 kg of methanol and slurried at 39° C. for 0.5 h. Then, 87.79 g (1.2 equivalents of M, concentration 27.5%) of hydrogen peroxide was added dropwise within 1 h. After the reaction was completed, 182 g of a white product was obtained by filtration, with a yield of 91%, a purity of 99.3%, a melting point of 181.2° C., and a bulk density of 0.45 g / mL.

[0075] Example 4

[0076] This embodiment provides a method for preparing pharmaceutical-grade dibenzothiazole disulfide, and the steps are as follows:

[0077] (1) Mix 200g of industrial grade M (purity 96%, melting point 169°C) with 1kg of 2% sulfuric acid solution, heat to 60°C and soak for 2h, filter, let the filtrate stand for 1 day, remove the precipitated insoluble matter, and then reuse it.

[0078] (2) Add 2 kg of ethanol to the filter cake obtained in step (1), mix thoroughly, heat to 60°C until completely dissolved, then slowly add 200 g of water within 1 hour, remove the precipitated dark yellow solid, add 800 g of water, and filter.

[0079] (3) The filter cake obtained in step (2) was added with 1 kg of methanol and slurried at 39° C. for 0.5 h. Then, 87.79 g (1.2 equivalents of M, concentration 27.5%) of hydrogen peroxide was added dropwise within 1 h. After the reaction was completed, 183.7 g of a white product was obtained by filtration, with a yield of 92.77%, a purity of 98.6%, a melting point of 176.3° C., and a bulk density of 0.45 g / mL.

[0080] Example 5

[0081] This embodiment provides a method for preparing pharmaceutical-grade dibenzothiazole disulfide, and the steps are as follows:

[0082] (1) Mix 200g of industrial grade M (purity 96%, melting point 169°C) with 1kg of 2% sulfuric acid solution, heat to 60°C and soak for 2h, filter, let the filtrate stand for 1 day, remove the precipitated insoluble matter, and then reuse it.

[0083] (2) Add 2 kg of methanol to the filter cake obtained in step (1), mix thoroughly, heat to 60°C until completely dissolved, then slowly add 200 g of water within 1 hour, remove the precipitated dark yellow solid, add 800 g of water, and filter.

[0084] (3) The filter cake obtained in step (2) was added with 1 kg of methanol and slurried at 39° C. for 0.5 h. Then, 87.79 g (1.2 equivalents of M, concentration 27.5%) of hydrogen peroxide was added dropwise within 1 h. After the reaction was completed, 183.4 g of a white product was obtained by filtration, with a yield of 92.26%, a purity of 98.9%, a melting point of 178.3° C., and a bulk density of 0.45 g / mL.

[0085] Example 6

[0086] As in Example 1, the filter cake obtained in step (2) was mixed with 10 times the mass of water, and a small amount of tetrabutylammonium iodide (5‰ of the mass of M) was added. After nitrogen displacement, the temperature was raised to 70°C with stirring, and oxygen was introduced at a pressure of 0.4 MPa. The reaction was considered complete until no oxygen consumption occurred within 10 minutes. The mixture was filtered and washed with water. After drying, the yield was 91%, the purity was 99.4%, the melting point was 181.3, and the bulk density was 0.45 g / mL.

[0087] Example 7

[0088] As in Example 1, the filter cake obtained in step (2) was mixed with 10 times the mass of water, 12.9 g of sodium nitrite was added, and 13.2 g of 70% dilute sulfuric acid was slowly added dropwise. After the reaction was completed, the mixture was filtered and washed with water. After drying, the yield was 91%, the purity was 99.5%, the melting point was 181.6, and the bulk density was 0.45 g / mL.

[0089] Comparative Example 1

[0090] The main difference from Example 1 is that no dilute sulfuric acid soaking is performed. The steps are as follows:

[0091] (1) 200 g of industrial grade M (purity 96%, melting point 169°C) was thoroughly mixed with 2 kg of DMF solution, and then the mixture was heated to 60°C until completely dissolved. 100 g of water was slowly added within 1 h. After removing the precipitated dark yellow solid, 1.9 kg of water was added and the mixture was filtered.

[0092] (2) The filter cake obtained in step (1) was added with 1 kg of methanol and slurried at 39° C. for 0.5 h. Then, 87.79 g (1.2 equivalents of M, concentration 27.5%) of hydrogen peroxide was added dropwise within 1 h. After the reaction was completed, 183.5 g of a white product was obtained by filtration, with a yield of 92.23%, a purity of 98.5%, a melting point of 178.8° C., and a bulk density of 0.45 g / mL.

[0093] Comparative Example 2

[0094] The only difference from Example 1 is that DMF is replaced by an equal amount of isopropanol.

[0095] The results showed that the product had a yield of 92.18%, a purity of 98.13%, a melting point of 177.2° C., and a bulk density of 0.45 g / mL.

[0096] Comparative Example 3

[0097] The only difference from Example 1 is that DMF is replaced by an equal amount of n-butanol.

[0098] The results showed that the product had a yield of 92.27%, a purity of 97.73%, a melting point of 176.5° C., and a bulk density of 0.45 g / mL.

[0099] Comparative Example 4

[0100] The only difference from Example 1 is that the amount of water added in the first step is increased to 200 g, and the amount of water added in the second step is reduced to 1.7 kg.

[0101] The results showed that the product had a yield of 89.05%, a purity of 99.50%, a melting point of 181.8° C., and a bulk density of 0.45 g / mL.

[0102] Comparative Example 5

[0103] The only difference from Example 1 is that the amount of water added for the second time is reduced to 1.5 kg.

[0104] The results showed that the yield of the obtained product was changed to 85.8%, the purity was 99.56, the melting point was 181.9°C, and the bulk density was 0.45 g / mL.

[0105] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A method for preparing pharmaceutical-grade dibenzothiazole disulfide, characterized in that: include: Mixing industrial-grade 2-mercaptobenzothiazole with an inorganic acid solution, soaking the mixture at 55° C. to 65° C., and then performing solid-liquid separation to obtain a separated liquid and a first solid material; The first solid material and a polar solvent are mixed and dissolved at 55° C. to 65° C., then mixed with primary water to remove precipitated solids, and then mixed with secondary water to obtain a second solid material after solid-liquid separation; The second solid material is mixed with an organic solvent to prepare a slurry, and then mixed with an oxidant to carry out an oxidation reaction.

2. The preparation method according to claim 1, characterized in that The inorganic acid solution is a sulfuric acid solution, and the mass fraction of the sulfuric acid solution is 1%-3%; Preferably, the mass ratio of the industrial-grade 2-mercaptobenzothiazole to the sulfuric acid solution is 1:(3-7); And / or, the purity of the industrial-grade 2-mercaptobenzothiazole is 96%-98%.

3. The preparation method according to claim 1 or 2, characterized in that The soaking time of the industrial-grade 2-mercaptobenzothiazole in the inorganic acid solution is 1 h to 5 h; And / or, the separated liquid is allowed to stand to precipitate insoluble matter and then reused.

4. The preparation method according to claim 1, characterized in that The polar solvent is selected from at least one of N,N-dimethylformamide, 1,4-dioxane, ethanol and methanol; And / or, the mass ratio of the industrial-grade 2-mercaptobenzothiazole to the polar solvent is 1:(8-12).

5. The preparation method according to claim 1, characterized in that The first solid material and the polar solvent are mixed and heated to 55° C.-65° C. to dissolve, and then the primary water is gradually added within 1 hour.

6. The preparation method according to claim 5, characterized in that The mass ratio of the industrial-grade 2-mercaptobenzothiazole to the primary water is 1:(0.3-1.5).

7. The preparation method according to claim 1, characterized in that The mass ratio of the industrial-grade 2-mercaptobenzothiazole to the secondary water is 1:(1.5-10).

8. The preparation method according to claim 1, characterized in that The second solid material and the organic solvent are mixed and slurried at 30° C. to 45° C. for 0.3 h to 1.0 h, and then an oxidant is added dropwise within 1 h to carry out an oxidation reaction; And / or, the oxidant is selected from at least one of hydrogen peroxide, sodium nitrite, sodium hypochlorite, chlorine and oxygen.

9. The preparation method according to claim 8, characterized in that The organic solvent is selected from at least one of methanol, isopropanol, n-butanol and ethanol; And / or, the mass ratio of the industrial-grade 2-mercaptobenzothiazole to the organic solvent is 1:(3-7).

10. The preparation method according to claim 8, characterized in that By adjusting the amount of the oxidant, the amount of the oxidant added is set to 1.1-1.3 equivalents of the industrial-grade 2-mercaptobenzothiazole.

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