阅读说明：本技术 一种医药级二硫化二苯并噻唑的制备方法 (Preparation method of pharmaceutical-grade dibenzothiazyl disulfide ) 是由 刘振强 姜鹏鹏 孙美婷 刘艳君 张佳成 白伟东 于 2019-09-24 设计创作，主要内容包括：本发明公开了一种医药级二硫化二苯并噻唑的制备方法,包括以下步骤：步骤一、在反应器中加入粗品2-巯基苯并噻唑,用醇类溶剂和水组成的混合溶剂升温溶解；步骤二、在反应器中加入还原剂反应掉有色物质；步骤三、在反应器中加入吸附剂过滤掉不溶物质；步骤四、在反应器中加入分散剂乙醇胺,滴加双氧水,将2-巯基苯并噻唑氧化成二硫化二苯并噻唑,降温养晶、过滤、烘干,得到产品；步骤五、产生的母液取一半的量用至下一批,根据组分水,折合补加溶剂及水的量。本发明实现了“一锅法”有粗M制备医药级可用的精品DM,本发明方法成本低,即可制得高纯度符合医药使用的精品DM,又绿色环保；本发明适用于制备符合医药使用的高纯度精品DM。(The invention discloses a preparation method of pharmaceutical-grade dibenzothiazyl disulfide, which comprises the following steps: step one, adding crude 2-mercaptobenzothiazole into a reactor, and heating and dissolving the crude 2-mercaptobenzothiazole by using a mixed solvent consisting of an alcohol solvent and water; step two, adding a reducing agent into the reactor to react out colored substances; step three, adding an adsorbent into the reactor to filter out insoluble substances; adding a dispersant ethanolamine into the reactor, dropwise adding hydrogen peroxide, oxidizing the 2-mercaptobenzothiazole into dibenzothiazyl disulfide, cooling, growing crystals, filtering and drying to obtain a product; and step five, taking half of the amount of the generated mother liquor to be used in the next batch, and converting the amount of the added solvent and water into the amount of the added solvent and water according to the component water. The invention realizes that the crude M is used for preparing the medical grade available refined DM by the one-pot method, the cost of the method is low, the high-purity refined DM conforming to the medical use can be prepared, and the method is green and environment-friendly; the invention is suitable for preparing high-purity refined DM which is suitable for medical use.)

1. A preparation method of pharmaceutical-grade dibenzothiazyl disulfide is characterized by comprising the following steps: the method comprises the following steps:

step one, adding crude 2-mercaptobenzothiazole into a reactor, and heating and dissolving the crude 2-mercaptobenzothiazole by using a mixed solvent consisting of an alcohol solvent and water;

step two, adding a reducing agent into the reactor to react out colored substances;

step three, adding an adsorbent into the reactor to filter out insoluble substances;

adding a dispersant ethanolamine into the reactor, dropwise adding hydrogen peroxide, oxidizing the 2-mercaptobenzothiazole into dibenzothiazyl disulfide, cooling, growing crystals, filtering and drying to obtain a product;

and step five, taking half of the amount of the generated mother liquor to be used in the next batch, and converting the amount of the added solvent and water into the amount of the added solvent and water according to the component water.

2. The method of claim 1, wherein the pharmaceutical-grade dibenzothiazyl disulfide is prepared by: the alcohol solvent in the first step is one or more of methanol, ethanol and isopropanol, and the dosage proportion of the alcohol solvent is 3-15 times of the mass of the 2-mercaptobenzothiazole.

3. The method of claim 1, wherein the pharmaceutical-grade dibenzothiazyl disulfide is prepared by: the water in the first step accounts for 1% -10% of the volume of the mixed solvent; the temperature for dissolving the crude 2-mercaptobenzothiazole is 40 ℃ to 70 ℃.

4. The method of claim 1, wherein the pharmaceutical-grade dibenzothiazyl disulfide is prepared by: and the reducing agent in the second step is one or more of sulfurous acid, sodium metabisulfite, sodium hydrosulfite, sodium bisulfite and hydrogen sulfide, and the dosage of the reducing agent is 0.5-15% of the feeding mass of the crude 2-mercaptobenzothiazole.

5. The method of claim 1, wherein the pharmaceutical-grade dibenzothiazyl disulfide is prepared by: and the adsorbent in the third step is activated carbon, and the using amount of the activated carbon is 2-10% of the feeding mass of the crude 2-mercaptobenzothiazole.

6. The method of claim 1, wherein the pharmaceutical-grade dibenzothiazyl disulfide is prepared by: the addition amount of the ethanolamine in the step four is 0.5-10% of the feeding mass of the crude 2-mercaptobenzothiazole.

7. The method of claim 1, wherein the pharmaceutical-grade dibenzothiazyl disulfide is prepared by: in the fourth step, the molar ratio of hydrogen peroxide to the crude 2-mercaptobenzothiazole is 1-1.5:1, and the dropping time is 1-4 h.

8. The method of claim 1, wherein the pharmaceutical-grade dibenzothiazyl disulfide is prepared by: the temperature in the oxidation process in the fourth step is 40-70 ℃.

9. The method of claim 1, wherein the pharmaceutical-grade dibenzothiazyl disulfide is prepared by: in the fourth step, the temperature for cooling and growing the crystal is 5-25 ℃, and the time for growing the crystal is 30 minutes.

10. The method of claim 1, wherein the pharmaceutical-grade dibenzothiazyl disulfide is prepared by: and in the fifth step, the mother liquor needs to pass through a filter element of 0.45 um.

Technical Field

The invention belongs to the field of synthesis of medical intermediates, and particularly relates to a preparation method of high-purity refined dibenzothiazyl Disulfide (DM).

Background

DM, chemical name: dibenzothiazyl disulfide has the following chemical structural formula:

product performance and application

The vulcanization accelerator DM is a light yellow crystal, is slightly toxic, odorless and slightly bitter, is a general thiazole accelerator widely applied at present, and is also a very important drug synthesis intermediate. As a universal vulcanization accelerator for natural rubber, synthetic rubber and reclaimed rubber, the rubber can be quickly vulcanized at a common temperature, the vulcanization curve is relatively flat, DM is easily dispersed in the rubber material and is free from pollution, the vulcanization critical temperature is relatively high (130 ℃), the activity is enhanced when the temperature is higher than 140 ℃, and the vulcanization accelerator has remarkable aftereffect and is safe to operate.

The fine vulcanization accelerator DM is a key raw material for synthesizing the cephalosporin antibiotic drug precursor AE active ester. Cephalosporins are the most clinically used antibiotics at present, so the pursuit of high-quality DM has important medicinal value.

At present, there are two main ways for preparing pharmaceutical grade refined dibenzothiazyl disulfide: 1. dissolving the crude product M (2-mercaptobenzothiazole) by using an alkaline material, adding an adsorbent to remove undissolved substances, then regulating the pH value by using strong acid to separate out a refined product M, and dropwise adding hydrogen peroxide into the refined product M in an organic solvent system for oxidation to prepare a refined product DM; 2. dissolving industrial grade crude DM with solvent such as toluene at high temperature, decolorizing with adsorbent, and cooling to obtain refined DM.

The method 1 generates a large amount of waste salt, the solid-liquid treatment cost is high, and the method 2 has the problems of toxic and difficult recovery of the used solvent, high reaction energy consumption and the like; such as:

1) CN1876698A provides a production method of a rubber vulcanization accelerator, which is to dissolve crude M into M-Na salt by using an alkaline sodium solution, and dropwise add a mixed solution of hydrogen peroxide and sulfuric acid to oxidize M into DM, wherein the initial melting point of DM prepared by the method is only 173 ℃, and simultaneously, a large amount of sodium sulfate waste salt is generated, and the solid waste treatment is complex.

2) CN101899019A provides a method for preparing a medicinal raw material DM, which is to dissolve crude M with an alkaline sodium solution, add an isopropanol solvent, and dropwise add a mixed solution of hydrogen peroxide and sulfuric acid to oxidize M into DM, wherein the initial melting point of DM prepared by the method can reach 178 ℃, but the process also has the problems of large amount of waste solids and difficult recovery.

3) CN102285938A, which provides a method for refining DM, the method is that industrial crude DM is added into a mixed solution of ethyl acetate and ethanol, the temperature is raised for dissolution, active carbon is added for decoloration, filtration and cooling crystallization are carried out, thus obtaining the medical DM, the melting point of the product is above 180 ℃, and the yield of the product is 96%. The method is a method for finely synthesizing crude DM into pharmaceutical DM, and although the method obtains the DM suitable for pharmaceutical DM, the overall yield of the product is low due to a two-step method, and the process requires high temperature conditions, so that the reflux temperature of a solvent is reached, and the energy consumption is high.

4) CN102863401B provides a method for preparing a medicinal raw material DM, which comprises the steps of adding a fine product M into an isopropanol system, adding triethylbenzylammonium chloride as a catalyst, and dropwise adding hydrogen peroxide to oxidize the M into DM, wherein the melting point of the DM prepared by the method is 178 ℃, and the yield is more than 96%. The method is characterized in that a catalyst for improving the oxidability is used, but the process needs to use a fine product M, otherwise, the color and even the content of the product cannot be ensured.

5) CN107365281A, providing a method for preparing a medical raw material DM, dissolving M in ammonia water, adding urotropine and 1-amino-2-naphthylene-4-sulfonic acid as catalysts, dropwise adding hydrogen peroxide to oxidize M to obtain a crude product DM, heating the crude product DM with acetone or toluene, cooling and crystallizing to obtain the medical DM.

Two ways of refining the crude M into the refined M are 1, dissolving the crude M with alkali, decoloring and adjusting pH with acid to separate out the refined M, so that a large amount of waste water and waste salt difficult to recover are generated, wherein about 20 tons of waste water are generated for preparing 1 ton of refined M, and 425kg of sodium sulfate or 350kg of sodium chloride are generated. 2. The crude M is dissolved by acetone, and water is added to separate out the crude M after decoloration, so that colored groups in the crude M cannot be removed, the prepared refined M is still yellow instead of white (the crude M is white by an acid-base method), at least 5 times of solvent amount is needed for dissolving the crude M, water is added to reversely separate out the refined M, the water addition amount is at least 10 times of the M, the wastewater amount is huge, the treatment is difficult, the acetone is easy to control toxicity, and the price is relatively high.

In the preparation of DM by using refined M, generally, ferric sulfate, copper sulfate, cobalt sulfate and the like are added as catalysts in an organic phase, hydrogen peroxide is dropwise added to oxidize M into DM, and the catalyst is a non-ferrous metal salt, so that the catalyst is easy to color when remaining in a product, and the heavy metal ion wastewater is difficult to treat; triethylbenzylammonium chloride has also been reported as a catalyst, but is relatively expensive.

In general, the existing process can not prepare refined DM by a one-pot method, the product obtained by preparing refined M by an acid-base method is good, but M cannot be continuously oxidized into DM in a water phase; the method of refining M by using a solvent cannot remove colored groups, the decoloring effect is poor, and the prepared DM is light yellow, so that the color of the AE active ester prepared downstream is influenced.

Therefore, the technology needs to prepare high-purity competitive DM meeting the medical use by a one-pot method under the premise of low cost and environmental protection.

Disclosure of Invention

The invention provides a preparation method of medical-grade dibenzothiazyl disulfide, which realizes the preparation of medical-grade available refined DM from crude M by a one-pot method.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a preparation method of pharmaceutical-grade dibenzothiazyl disulfide comprises the following steps:

step one, adding crude 2-mercaptobenzothiazole into a reactor, and heating and dissolving the crude 2-mercaptobenzothiazole by using a mixed solvent consisting of an alcohol solvent and water;

step two, adding a reducing agent into the reactor to react out colored substances;

step three, adding an adsorbent into the reactor to filter out insoluble substances;

adding a dispersant ethanolamine into the reactor, dropwise adding hydrogen peroxide, oxidizing the 2-mercaptobenzothiazole into dibenzothiazyl disulfide, cooling, growing crystals, filtering and drying to obtain a product;

and step five, taking half of the amount of the generated mother liquor to be used in the next batch, and converting the amount of the added solvent and water into the amount of the added solvent and water according to the component water.

Further, the alcohol solvent in the first step is one or more of methanol, ethanol and isopropanol, and the dosage proportion of the alcohol solvent is 3-15 times of the mass of the 2-mercaptobenzothiazole feeding material.

Further, the water in the first step accounts for 1% -10% of the volume of the mixed solvent; the temperature for dissolving the crude 2-mercaptobenzothiazole is 40 ℃ to 70 ℃.

Furthermore, in the second step, the reducing agent is one or more of sulfurous acid, sodium metabisulfite, sodium hydrosulfite, sodium sulfite and hydrogen sulfide, and the dosage of the reducing agent is 0.5-15% of the mass of the crude 2-mercaptobenzothiazole feed.

Further, the adsorbent in the third step is activated carbon, and the using amount of the activated carbon is 2-10% of the mass of the crude 2-mercaptobenzothiazole.

Furthermore, the addition amount of the ethanolamine in the step IV is 0.5-10% of the feeding mass of the crude 2-mercaptobenzothiazole.

Furthermore, in the fourth step, the molar ratio of the hydrogen peroxide to the crude 2-mercaptobenzothiazole is 1-1.5:1, and the dropping time is 1-4 h.

Further, the temperature in the oxidation process in the fourth step is 40-70 ℃.

Furthermore, in the fourth step, the temperature for crystal growth is reduced to 5-25 ℃, and the crystal growth time is 30 minutes.

Further, in the fifth step, the mother liquor needs to pass through a filter element of 0.45 um.

Compared with the prior art, the invention has the following beneficial effects:

the method adopts the mixed solvent consisting of alcohol dissolution and water to dissolve M, replaces the acetone solvent to dissolve M, reduces the production safety risk and the solvent use cost, omits the process of preparing refined M by an acid-base method, and does not generate a large amount of salts which are difficult to treat; a reducing agent is added in the decoloring process, so that impurities with colored groups in the coarse M are reduced, and the decoloring effect in an organic system is ensured; ethanolamine with lower price is added before hydrogen peroxide is added, triethyl benzyl ammonium chloride with higher value is replaced, the reaction effect of catalytic oxidation is ensured, and ethanolamine serving as a surfactant not only improves the oxidation effect, but also ensures the dispersion effect of the system; after the generated mother liquor is filtered, the mother liquor is directly applied to a dissolving system without solvent recovery, so that the use of the solvent is reduced, and M which is not completely oxidized in the mother liquor is fully recycled; in conclusion, the method realizes the preparation of the medical grade available refined DM from the crude M by a one-pot method, has low cost, can prepare the high-purity refined DM conforming to the medical use, is green and environment-friendly, and is suitable for preparing the high-purity refined DM conforming to the medical use.

Detailed Description

The following description is given with reference to preferred embodiments. It should be understood that the preferred embodiments described herein are for purposes of illustration and explanation only and are not intended to limit the present invention.

The raw materials used in the examples were all commercially available raw materials except for those specifically mentioned.

Example 1

A preparation method of pharmaceutical-grade dibenzothiazyl disulfide comprises the following steps:

(1) in a 250ml reaction flask, 80ml ethanol, 5ml water, 10g crude M (2-mercaptobenzothiazole) were added, warmed to 65 ℃ and stirred rapidly until clear.

(2) 0.5g of sodium hydrosulfite is added to react for 30 minutes, and the color of the feed liquid gradually becomes light.

(3) 1.0g of activated carbon was added, stirred for 30 minutes and filtered.

(4) Controlling the temperature to 65 ℃, adding 0.5ml of ethanolamine, dropwise adding a mixed solution of hydrogen peroxide and ethanol into the filtrate, wherein the amount of hydrogen peroxide is 4.8ml and accounts for 13.2% of the mixed solution, the amount of ethanol accounts for 52% of the mixed solution, the dropwise adding time is 120 minutes, and stirring and reacting for 30 minutes.

(5) Cooling the temperature to 19 ℃ for growing the crystal for 30 minutes, filtering, washing with water, and drying to obtain a dry product DM9.25g with the purity of 99.2 percent and the melting point of 179.2-180.1 ℃.

Example 2

A preparation method of pharmaceutical-grade dibenzothiazyl disulfide comprises the following steps:

(1) 100 ml of methanol, 10ml of water and 10g of crude M (2-mercaptobenzothiazole) are added to a 250ml reaction flask, the temperature is raised to 56 ℃, and the mixture is rapidly stirred until the mixture is clear.

(2) 1ml of sulfurous acid is added, and the mixture is stirred and reacted for 30 minutes, and the color of the feed liquid gradually changes into light yellow.

(3) 1.0g of activated carbon was added, stirred for 30 minutes and filtered.

(4) Controlling the temperature to be 56 ℃, adding 0.5ml of ethanolamine, dropwise adding a mixed solution of hydrogen peroxide and methanol into the filtrate, wherein the amount of hydrogen peroxide is 4.6ml and accounts for 12.6% of the mixed solution, the amount of methanol accounts for 54% of the mixed solution, the dropwise adding time is 120 minutes, and stirring and reacting for 30 minutes.

(5) Cooling to 17 deg.C for 30 min, filtering, washing with water, washing with methanol, and oven drying to obtain dry product DM9.12g with purity of 99.4% and melting point of 179.5-180.7 deg.C.

Example 3

A preparation method of pharmaceutical-grade dibenzothiazyl disulfide comprises the following steps:

(1) 50ml of ethanol and 70ml of isopropanol, 5ml of water, 10g of crude M (2-mercaptobenzothiazole) are added to a 250ml reaction flask, the temperature is raised to 65 ℃, and the mixture is stirred rapidly until the mixture is clear.

(2) 0.5g of sodium hydrosulfite is added to react for 30 minutes, and the color of the feed liquid gradually becomes light.

(3) Adding 1.0 activated carbon, stirring for 30 minutes, and filtering.

(4) Controlling the temperature to 65 ℃, adding 0.5ml of ethanolamine, dropwise adding a mixed solution of hydrogen peroxide and ethanol into the filtrate, wherein the amount of hydrogen peroxide is 4.8ml and accounts for 13.2% of the mixed solution, the amount of ethanol accounts for 52% of the mixed solution, the dropwise adding time is 120 minutes, and stirring and reacting for 30 minutes.

(5) Cooling the temperature to 20 ℃ for crystal growing for 30 minutes, filtering, washing with water, and drying to obtain a dry product DM9.30g with the purity of 99.2 percent and the melting point of 179.5-180.3 ℃.

Example 4

A preparation method of pharmaceutical-grade dibenzothiazyl disulfide comprises the following steps:

(1) 80ml of ethanol, 5mml of water and 10g of crude product M (2-mercaptobenzothiazole) are added into a 250ml reaction bottle, the temperature is raised to 65 ℃, and the mixture is rapidly stirred until the mixture is dissolved.

(2) 0.3g sodium hydrosulfite and 0.2g sodium bisulfite were added, reacted for 30 minutes, and filtered.

(3) 1.0g of activated carbon was added, stirred for 30 minutes and filtered.

(4) Controlling the temperature to 65 ℃, adding 0.5ml of ethanolamine, dropwise adding a mixed solution of hydrogen peroxide and ethanol into the filtrate, wherein the amount of hydrogen peroxide is 4.8ml and accounts for 13.2% of the mixed solution, the amount of ethanol accounts for 52% of the mixed solution, the dropwise adding time is 120 minutes, and stirring and reacting for 30 minutes.

(5) Cooling to 15 deg.C, growing crystal for 30 min, filtering, washing with water, and oven drying to obtain dried product DM9.26g with purity of 99.2% and melting point of 179.0-180.3 deg.C

Example 5

A preparation method of pharmaceutical-grade dibenzothiazyl disulfide comprises the following steps:

(1) in a 250ml reaction flask, 80ml ethanol, 5ml water, 10g crude M (20-mercaptobenzothiazole) were added, warmed to 40 ℃ and stirred rapidly until clear.

(2) 0.5g of sodium hydrosulfite is added to react for 30 minutes, and the color of the feed liquid gradually becomes light.

(3) 1.0g of activated carbon was added, stirred for 30 minutes and filtered.

(4) Controlling the temperature to be 40 ℃, adding 0.5ml of ethanolamine, dropwise adding a mixed solution of hydrogen peroxide and ethanol into the filtrate, wherein the amount of hydrogen peroxide is 4.8ml and accounts for 13.2% of the mixed solution, the amount of ethanol accounts for 52% of the mixed solution, the dropwise adding time is 120 minutes, and stirring and reacting for 30 minutes.

(5) Cooling the temperature to 20 ℃ for crystal growing for 30 minutes, filtering, washing with water, and drying to obtain a dry product DM8.75g with the purity of 97.3 percent and the melting point of 176.8-177.3 ℃.

Example 6

A preparation method of pharmaceutical-grade dibenzothiazyl disulfide comprises the following steps:

(1) in a 250ml reaction flask, 80ml ethanol, 5ml water, 10g crude M (2-mercaptobenzothiazole) were added, warmed to 70 ℃ and stirred rapidly until clear.

(2) 0.5g of sodium hydrosulfite is added to react for 30 minutes, and the color of the feed liquid gradually becomes light.

(3) Activated carbon 1.0g was added, stirred for 30 minutes and filtered.

(4) Controlling the temperature to be 70 ℃, adding 0.5ml of ethanolamine, dropwise adding a mixed solution of hydrogen peroxide and ethanol into the filtrate, wherein the amount of hydrogen peroxide is 4.8ml and accounts for 13.2% of the mixed solution, the amount of ethanol accounts for 52% of the mixed solution, the dropwise adding time is 120 minutes, and stirring and reacting for 30 minutes.

(5) Cooling the temperature to 20 ℃ for crystal growth for 30 minutes, filtering, washing with water, and drying to obtain a dry product DM9.10g with the purity of 99.0 percent and the melting point of 179.0-179.8 ℃.

Example 7

A preparation method of pharmaceutical-grade dibenzothiazyl disulfide comprises the following steps:

(1) in a 250ml reaction flask, 80ml ethanol, 5ml water, 10g crude M (2-mercaptobenzothiazole) were added, warmed to 65 ℃ and stirred rapidly until clear.

(2) 0.5g of sodium hydrosulfite is added to react for 30 minutes, and the color of the feed liquid gradually becomes light.

(3) 1.0g of activated carbon was added, stirred for 30 minutes and filtered.

(4) Controlling the temperature to 65 ℃, adding 0.5ml of ethanolamine, dropwise adding a mixed solution of hydrogen peroxide and ethanol into the filtrate, wherein the amount of hydrogen peroxide is 4.8ml and accounts for 13.2% of the mixed solution, the amount of ethanol accounts for 52% of the mixed solution, the dropwise adding time is 120 minutes, and stirring and reacting for 30 minutes.

(5) Cooling the temperature to 9 ℃ for growing the crystal for 30 minutes, filtering, washing with water, and drying to obtain a dry product DM8.93g with the purity of 98.6 percent and the melting point of 178.6-179.3 ℃.

Example 8

A preparation method of pharmaceutical-grade dibenzothiazyl disulfide comprises the following steps:

(1) in a 250ml reaction flask, 80ml ethanol, 5ml water, 10g crude M (2-mercaptobenzothiazole) were added, warmed to 65 ℃ and stirred rapidly until clear.

(2) 0.5g of sodium hydrosulfite is added, stirred for 30 minutes and filtered.

(3) 1.0g of activated carbon was added, stirred for 30 minutes and filtered.

(4) Controlling the temperature to 65 ℃, adding 0.5ml of ethanolamine, dropwise adding a mixed solution of hydrogen peroxide and ethanol into the filtrate, wherein the amount of hydrogen peroxide is 4.8ml and accounts for 13.2% of the mixed solution, the amount of ethanol accounts for 52% of the mixed solution, the dropwise adding time is 120 minutes, and stirring and reacting for 30 minutes.

(5) Cooling to 5 ℃ for growing the crystal for 30 minutes, filtering, washing with water, and drying to obtain a dry product DM7.68g with the purity of 97.6 percent and the melting point of 176.1-177.0 ℃.

Example 9

A preparation method of pharmaceutical-grade dibenzothiazyl disulfide comprises the following steps:

(1) in a 250ml reaction flask, 80ml ethanol, 5ml water, 10g crude M (2-mercaptobenzothiazole) were added, warmed to 65 ℃ and stirred rapidly until clear.

(2) 0.5g of sodium hydrosulfite is added to react for 30 minutes, and the color of the feed liquid gradually becomes light.

(3) 1.0g of activated carbon was added, stirred for 30 minutes and filtered.

(4) Controlling the temperature to 65 ℃, adding 0.5ml of ethanolamine, dropwise adding a mixed solution of hydrogen peroxide and ethanol into the filtrate, wherein the amount of hydrogen peroxide is 4.8ml and accounts for 13.2% of the mixed solution, the amount of ethanol accounts for 52% of the mixed solution, the dropwise adding time is 120 minutes, and stirring and reacting for 30 minutes.

(5) Cooling to 25 deg.C for 30 min, filtering, washing with water, and oven drying to obtain dry product DM9.03g with purity of 99.0% and melting point of 179.8-180.5 deg.C.

Example 10

A preparation method of pharmaceutical-grade dibenzothiazyl disulfide comprises the following steps:

(1) in a 250ml reaction flask, 120ml isopropanol, 5ml water, 10g crude M (2-mercaptobenzothiazole) were added, warmed to 63 ℃ and stirred rapidly to dissolve.

(2) 0.5g of sodium metabisulfite is added, and the color of the feed liquid gradually becomes lighter.

(3) Adding 1.0g of activated carbon for decolorization, stirring for reaction for 30 minutes, and filtering.

(4) Controlling the temperature to 63 ℃, adding 0.5ml of ethanolamine, dropwise adding a mixed solution of hydrogen peroxide and isopropanol into the filtrate, wherein the amount of hydrogen peroxide is 4.6ml and accounts for 12.6% of the mixed solution, the amount of isopropanol accounts for 54% of the mixed solution, the dropwise adding time is 120 minutes, and stirring and reacting for 30 minutes.

(5) Cooling the temperature to 13 ℃ for growing the crystal for 30 minutes, filtering, washing with water, and drying to obtain a dry product DM9.31 with the purity of 99.4 percent and the melting point of 180.5-181.2 ℃.

Example 11

A method for preparing pharmaceutical-grade benzothiazole disulfide, in example 10, mother liquor is recycled, comprising the following steps:

(1) the mother liquor of example 10 was monitored for 2.7% water and half the amount of mother liquor (70ml) was taken.

(2) 55ml of isopropanol and 3ml of water are added, 10g of crude product M (2-mercaptobenzothiazole) are added, and the temperature is raised to 63 ℃ for dissolution.

(3) The subsequent steps are the same as in example 10 to obtain 9.35g of product with purity of 99.36% and melting point of 180.2-181.0 ℃.

Proved by verification, the mother liquor is continuously used for 4 batches, and the yield, the purity and the melting point of the product are not greatly changed. The following table specifically shows:

batches of	Appearance of the product	Yield of	Purity of	Melting Point
					Example 3	White powder	93.1％	99.4％	180.5-181.2℃
Example 4	White powder	93.5％	99.36％	180.2-181.0℃
					Mother liquor application-3	White powder	92.8％	99.42％	179.8-180.9℃
Mother liquor mechanically used-4	White powder	93.0％	99.35％	180.1-180.9℃
					Mother liquor application-5	White powder	93.2％	99.30％	180.2-181.1℃

Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the claims of the present invention.