Method for recovering 2-mercaptobenzothiazole from cephalosporin production mother liquor

Abstract

The invention discloses a method for recovering 2-mercaptobenzothiazole from cephalosporin production mother liquor, which comprises the following steps: S1, standing the cephalosporin production mother liquor, carrying out phase separation, and removing a water phase to obtain a dichloromethane solution I; s2, adding solid sodium hydroxide into the dichloromethane solution I, and refluxing to obtain a dichloromethane solution II; s3, filtering the dichloromethane solution II, adding acidic water into filtrate, mixing, adjusting the pH to be acidic, stirring, splitting phases, taking a dichloromethane phase, washing with clear water, and standing to obtain a dichloromethane solution III; s4, activated carbon is added into the third dichloromethane solution for decoloration, stirring and filtering are conducted, and a fourth dichloromethane solution is obtained; and S5, adding an n-butanol-n-hexane-toluene solution into the dichloromethane solution IV, carrying out reduced pressure distillation, filtering, washing and drying to obtain the 2-mercaptobenzothiazole. According to the method disclosed by the invention, the 2-mercaptobenzothiazole can be recovered from the mixed solution of various cephalosporin production mother solutions in a high-yield and high-purity manner, and the method is free of alkaline wastewater and environment-friendly.

Description

Technical Field

[0001] The present invention relates to a method for recovering 2-mercaptobenzothiazole from the mother liquor in cephalosporin production, belonging to the technical fields of medicine and chemical engineering. Background Art

[0002] 2-Mercaptobenzothiazole, also known as accelerator M, is an organic compound with the chemical formula C7H5NS2. It is a light yellow crystalline powder and is widely used in the production of rubber products, such as tires, rubber hoses, rubber seals, etc. It can improve the processing performance, physical properties and durability of rubber. It can also be used as a catalyst or intermediate for certain chemical reactions. It can also be used in the fields of coatings, plastics, adhesives, etc. to improve the performance and stability of products. Or it can be used as a sensitive reagent for detecting gold, bismuth, cadmium, cobalt, mercury, nickel, lead, thallium and zinc. The uses of 2-mercaptobenzothiazole are relatively extensive and the demand is high.

[0003] The dichloromethane mother liquor generated during the preparation of cephalosporin raw materials and intermediates such as cefotaxime acid, ceftriaxone acid, cefepime hydrochloride, ceftazidime, GCLE, etc. contains a large amount of 2-mercaptobenzothiazole by-products. Many enterprises choose to simply treat and then directly discharge it, which will not only cause environmental pollution, but also lead to a large waste of the by-product 2-mercaptobenzothiazole.

[0004] Patent CN201810915904.5, a comprehensive recovery method of 2-mercaptobenzothiazole, triethylamine and dichloromethane in the dichloromethane mother liquor of ceftriaxone sodium, is a complete set of comprehensive recovery schemes for the dichloromethane mother liquor of ceftriaxone sodium. The method for recovering 2-mercaptobenzothiazole is to add water to the dichloromethane mother liquor of ceftriaxone sodium, and adjust its pH value to be alkaline with an alkali, with the pH value being 12-13.5, stir and stand for phase separation to obtain organic phase 1 and aqueous phase 1; add acid to the obtained aqueous phase 1 to adjust its pH value to 6-9, so that 2-mercaptobenzothiazole precipitates, filter, wash with water and dry to obtain 2-mercaptobenzothiazole.

[0005] However, the above method will generate a large amount of alkaline wastewater with a high COD, which is difficult to treat and causes environmental pollution; and the recovered 2-mercaptobenzothiazole is a khaki solid (normally it should be a light yellow solid), with unqualified appearance. At best, it is a crude product and cannot be used directly, and further refining is still required.

[0006] Patent CN201110276382.7, a method for recovering 2-mercaptobenzothiazole from the crystallization mother liquor of ceftriaxone sodium, comprises the following steps: ① adjusting the pH value of the crystallization mother liquor of ceftriaxone sodium to 2.0 - 5.0 with a sulfuric acid solution; ② heating and distilling the mother liquor obtained in step ① to distill out the solvent, and controlling the total amount of the distilled solvent within 75 - 90% of the total amount of the mother liquor, and reserving the residual solution after distillation; ③ cooling the residual solution obtained in step ② to 0 - 35°C and filtering, and reserving the filtrate; ④ adding water with a volume 1 - 5 times that of the filtrate to the filtrate obtained in step ③, stirring to precipitate solids; filtering out the solids obtained in step ④, washing with water and drying to obtain the target product 2-mercaptobenzothiazole.

[0007] However, the recovery rate of the above method is relatively low and the utilization rate is low. At the same time, the components in the crystallization mother liquor of ceftriaxone sodium are relatively complex and contain a large amount of water-insoluble substances. Since the crystallization system of this patent is aqueous-phase crystallization, it will lead to a high content of product impurities. Moreover, aqueous-phase crystallization and water washing will cause difficulties in product drying, high water content, and under the state of relatively high temperature and large humidity for a long time, it will cause product degradation. Summary of the Invention

[0008] The present invention provides a method for recovering 2-mercaptobenzothiazole from the mother liquor in cephalosporin production to solve the above technical problems, which can realize the recovery of 2-mercaptobenzothiazole in the mixed solution of various mother liquors in cephalosporin production, with relatively high recovery rate and purity. The recovered 2-mercaptobenzothiazole is a qualified light yellow solid with low water content; at the same time, the added solid sodium hydroxide can be recycled and reused, and no alkaline wastewater is generated, which is environmentally friendly.

[0009] To solve the above technical problems, the technical solution adopted by the present invention is:

[0010] A method for recovering 2-mercaptobenzothiazole from the mother liquor in cephalosporin production comprises the following steps:

[0011] S1. Let the mother liquor in cephalosporin production stand for a period of time, separate the phases, remove the aqueous phase to obtain dichloromethane solution I;

[0012] S2. Add solid sodium hydroxide to dichloromethane solution I, reflux and react for a period of time to obtain dichloromethane solution II;

[0013] S3. Filter dichloromethane solution II, recover solid sodium hydroxide, add acidic water to the filtrate and mix, adjust the pH to acidic, stir, separate the phases, take the dichloromethane phase, wash with clear water, let stand for a period of time to obtain dichloromethane solution III;

[0014] S4. Add activated carbon to dichloromethane solution III for decolorization, stir, filter to obtain dichloromethane solution IV;

[0015] In S5, n-butanol - n-hexane - toluene solution is added to dichloromethane solution IV, and then vacuum distillation is carried out until the crystallization end point. After filtration, washing and drying, 2-mercaptobenzothiazole is obtained.

[0016] A further improvement of the technical solution of the present invention is that: the cephalosporin production mother liquor includes one or more of dichloromethane mother liquors generated during the preparation of cefotaxime acid, ceftriaxone acid, cefepime hydrochloride, GCLE, and ceftazidime.

[0017] A further improvement of the technical solution of the present invention is that: the standing time in S1 is more than 24h.

[0018] A further improvement of the technical solution of the present invention is that: in S2, a high-efficiency reflux device is used for reflux, and the reflux time is 30 - 60 min.

[0019] A further improvement of the technical solution of the present invention is that: the added weight of solid sodium hydroxide in S2 is 2 - 5% of the volume of dichloromethane solution I.

[0020] A further improvement of the technical solution of the present invention is that: the acidic water in S3 is an aqueous solution of sulfuric acid, hydrochloric acid, phosphoric acid or acetic acid, and the pH is 4 - 6.

[0021] A further improvement of the technical solution of the present invention is that: in S3, stirring is carried out for 30 min and standing is carried out for more than 60 min.

[0022] A further improvement of the technical solution of the present invention is that: in S4, it is specified that stirring is carried out for 30 min at 10 °C for decolorization.

[0023] A further improvement of the technical solution of the present invention is that: in the n-butanol - n-hexane - toluene solution in S5, the volume ratio of n-butanol : n-hexane : toluene is 2:6:2, and the added amount is 1 / 3 - 1 / 2 of the volume of dichloromethane solution IV.

[0024] A further improvement of the technical solution of the present invention is that: the specific operation of vacuum distillation in S5 is as follows:

[0025]

[0026]

[0027] Due to the adoption of the above technical solution, the technical progress achieved by the present invention is:

[0028] The technology of the present invention has strong inclusiveness, and can recover 2-mercaptobenzothiazole in the mother liquors of various cephalosporin products together or separately. Moreover, it can effectively control the number of crystal nuclei and the crystal growth rate, control the product quality, and achieve relatively high recovery rate and purity. At the same time, the solid sodium hydroxide added can be recycled, and no alkaline wastewater is generated, which is environmentally friendly.

[0029] The technology of the present invention has low requirements for organic solvents such as n-butanol, n-hexane, and toluene used. It does not require rectification for preparation, and can be reused only after simple distillation. In addition, dichloromethane has a low boiling point, is easy to distill, and has low energy consumption.

[0030] The 2-mercaptobenzothiazole recovered by the present invention is a qualified light yellow solid with low water content, and can meet the direct use requirements without refining. Specific embodiments

[0031] A method for recovering 2-mercaptobenzothiazole from the mother liquor in cephalosporin production, comprising the following steps:

[0032] S1. Let the mother liquor in cephalosporin production stand for more than 24 hours to separate phases, remove the aqueous phase, and obtain dichloromethane solution I. The step of removing the aqueous phase is crucial. The longer the standing time, the more aqueous phase is removed, and the less likely the subsequent layering is.

[0033] Among them, the mother liquor in cephalosporin production includes one or more of dichloromethane mother liquors generated during the preparation of cefotaxime acid, ceftriaxone acid, cefepime hydrochloride, GCLE, and ceftazidime. It can recover 2-mercaptobenzothiazole from the mixed mother liquor in the production process of various cephalosporin drugs, without limiting a certain cephalosporin production mother liquor, and has stronger applicability.

[0034] S2. Add solid sodium hydroxide to dichloromethane solution I, with the added weight being 2-5% of the volume of dichloromethane solution I, and reflux for 30-60 minutes to obtain dichloromethane solution II. In S1, the aqueous phase is removed as much as possible, and the solid sodium hydroxide still exists in solid form after adding. By refluxing, the solid sodium hydroxide is stirred and contacted with dichloromethane solution I as much as possible, so that various related substances in the solution are destroyed by the solid base, forming substances that can be dissolved in the n-butanol-n-hexane-toluene solution subsequently, and improving the purity of the final product.

[0035] S3. Filter dichloromethane solution II to recover solid sodium hydroxide, which can realize the recycling of solid sodium hydroxide. At the same time, no alkaline wastewater is generated, which is environmentally friendly; add acidic water to the filtrate and mix, adjust the pH to 4-6, stir for 30 minutes, separate phases, take the dichloromethane phase, wash with clear water, and let it stand for more than 60 minutes to obtain dichloromethane solution III. Among them, the acidic water is an aqueous solution of sulfuric acid, hydrochloric acid, phosphoric acid or acetic acid, and the pH is 4-6.

[0036] S4. Add activated carbon to the dichloromethane solution for decolorization, stir at 10 °C for 30 min, and filter to obtain dichloromethane solution IV.

[0037] S5. Add the n-butanol-n-hexane-toluene solution to dichloromethane solution IV, and perform vacuum distillation until the crystallization end point. After filtration, washing, and drying, 2-mercaptobenzothiazole is obtained.

[0038] Among them, the volume ratio of n-butanol:n-hexane:toluene in the n-butanol-n-hexane-toluene solution is 2:6:2, and the addition amount is 1 / 3 - 1 / 2 of the volume of dichloromethane solution IV.

[0039] The specific operation of vacuum distillation is as follows:

[0040] Operation process Time Evaporation amount of dichloromethane Stirring speed HZ Temperature °C First distillation 15 - 20 min 30-35％ 45-50 10-20 Crystal cultivation 30 min —— 20-30 15-20 Second distillation 60 - 90 min 20-25％ 20-30 15-20 Third distillation 30 - 60 min 15-20％ 25-35 15-20 Fourth distillation To the end To 90% 25-35 15-20 Crystal cultivation 30 - 60 min —— 20-30 10-15 。

[0041] The present invention will be further described in detail below with reference to the embodiments:

[0042] Example 1: (Single cephalosporin production mother liquor)

[0043] Take 500 ml of dichloromethane waste liquid from the production of cefotaxime acid, let it stand for more than 24 h, and separate the phases to obtain dichloromethane solution I;

[0044] Add 10 g of solid sodium hydroxide to dichloromethane solution I and reflux for 30 min in a high-efficiency reflux device to obtain dichloromethane solution II;

[0045] After filtering and recovering solid sodium hydroxide from dichloromethane solution II, add 50 ml of hydrochloric acid aqueous solution with a pH of 4 and mix. After stirring for 30 min, separate the phases. The dichloromethane phase is washed once with 50 ml of clear water, and after standing for more than 60 min, dichloromethane solution III is obtained;

[0046] Add 1.5 g of activated carbon to dichloromethane solution III for decolorization, stir at 10 °C for 30 min, and filter to obtain dichloromethane solution IV;

[0047] Add 600 ml of n-butanol-n-hexane-toluene solution (ratio 2:6:2) to dichloromethane solution IV, perform vacuum distillation (control the temperature at 10 - 20 °C). After the feed liquid becomes turbid, stop distillation, crystallize at 15 - 20 °C for 30 min, and then perform vacuum distillation until the crystallization end point. The crystallization process is as follows;

[0048] Serial number Crystallization process Time Amount of dichloromethane Stirring speed HZ Temperature °C 1 First distillation 15 min 30％ 45-50 10-20 2 Crystal cultivation 30 min —— 20-30 15-20 3 Second distillation 60 min 25％ 20-30 15-20 4 Third distillation 30 min 15％ 25-35 15-20 5 Fourth distillation To the end To 90% 25-35 15-20 6 Crystal cultivation 30 min —— 20-30 10-15

[0049] After filtration, washing, and drying, 2-mercaptobenzothiazole is obtained, with a yield of 95.5%; purity of 99.68%; appearance color: light yellow; moisture content: 0.32%.

[0050] Example 2:

[0051] Take 500 ml of dichloromethane waste liquid from cefotaxime acid production, stand for more than 24 h, separate the phases to obtain dichloromethane solution I;

[0052] Add 25 g of solid sodium hydroxide to dichloromethane solution I and reflux for 60 min in a high-efficiency reflux device to obtain dichloromethane solution II;

[0053] After filtering and recovering the solid sodium hydroxide from dichloromethane solution II, add 50 ml of hydrochloric acid aqueous solution with a pH of 6, mix, stir for 30 min, separate the phases, wash the dichloromethane phase with 50 ml of water once, stand for more than 60 min, and obtain dichloromethane solution III;

[0054] Add 1.5 g of activated carbon to dichloromethane solution III for decolorization, stir at 10 °C for 30 min. Filter to obtain dichloromethane solution IV;

[0055] Add 800 ml of n-butanol - n-hexane - toluene (ratio 2:6:2) solution to dichloromethane solution IV, carry out vacuum distillation (temperature controlled at 10 - 20 °C), stop distillation when the feed liquid becomes turbid, crystallize at 15 - 20 °C for 30 min, and then carry out vacuum distillation until the crystallization end point. The crystallization process is as follows;

[0056] Serial number Crystallization process Time Amount of dichloromethane Stirring speed HZ Temperature °C 1 First distillation 20 min 35％ 45-50 10-20 2 Crystal cultivation 30 min —— 20-30 15-20 3 Second distillation 90 min 30％ 20-30 15-20 4 Third distillation 60 min 20％ 25-35 15-20 5 Fourth distillation To the end To 90% 25-35 15-20 6 Crystal cultivation 60 min —— 20-30 10-15

[0057] After filtering, washing, and drying, 2-mercaptobenzothiazole is obtained, yield: 95.4%; purity: 99.70%; appearance color: light yellow; moisture: 0.39%.

[0058] Example 3:

[0059] Take 500 ml of dichloromethane waste liquid from cefepime hydrochloride production, stand for more than 24 h, separate the phases to obtain dichloromethane solution I;

[0060] Add 20 g of solid sodium hydroxide to dichloromethane solution I and reflux for 45 min in a high-efficiency reflux device to obtain dichloromethane solution II;

[0061] After filtering and recovering the solid sodium hydroxide from dichloromethane solution II, add 50 ml of hydrochloric acid aqueous solution with a pH of 5, mix, stir for 30 min, separate the phases, wash the dichloromethane phase with 50 ml of water once, stand for more than 60 min, and obtain dichloromethane solution III;

[0062] Add 1.5 g of activated carbon to dichloromethane solution III for decolorization, stir at 10 °C for 30 min. Filter to obtain dichloromethane solution IV;

[0063] Add 600 ml of n-butanol - n-hexane - toluene (ratio 2:6:2) solution to the dichloromethane solution, and perform vacuum distillation (temperature controlled at 10 - 20 °C). After the feed liquid becomes turbid, stop the distillation, and perform crystal cultivation at 15 - 20 °C for 30 min, then perform vacuum distillation until the crystallization end point. The crystallization process is as follows;

[0064]

[0065]

[0066] After filtration, washing, and drying, 2-mercaptobenzothiazole is obtained, with a yield of 95.2%; purity of 99.67%; appearance color: light yellow; moisture content: 0.36%.

[0067] Example 4:

[0068] Take 500 ml of dichloromethane waste liquid from cefazidime production, let it stand for more than 24 h, and separate the phases to obtain dichloromethane solution I;

[0069] Add 15 g of solid sodium hydroxide to dichloromethane solution I and reflux in a high-efficiency reflux device for 50 min to obtain dichloromethane solution II;

[0070] After filtering and recovering solid sodium hydroxide from dichloromethane solution II, add 50 ml of hydrochloric acid aqueous solution with a pH of 5.5 and mix. After stirring for 30 min, separate the phases. The dichloromethane phase is washed once with 50 ml of clear water, and after standing for more than 60 min, dichloromethane solution III is obtained;

[0071] Add 1.5 g of activated carbon to dichloromethane solution III for decolorization and stir at 10 °C for 30 min. Filter to obtain dichloromethane solution IV;

[0072] Add 700 ml of n-butanol - n-hexane - toluene (ratio 2:6:2) solution to dichloromethane solution IV, and perform vacuum distillation (temperature controlled at 10 - 20 °C). After the feed liquid becomes turbid, stop the distillation, and perform crystal cultivation at 15 - 20 °C for 30 min, then perform vacuum distillation until the crystallization end point. The crystallization process is as follows;

[0073] Serial number Crystallization process Time Amount of dichloromethane Stirring speed HZ Temperature °C 1 First distillation 15 min 35％ 45-50 10-20 2 Crystal cultivation 30 min —— 20-30 15-20 3 Second distillation 60 min 30％ 20-30 15-20 4 Third distillation 30 min 25％ 25-35 15-20 5 Fourth distillation To the end To 90% 25-35 15-20 6 Crystal cultivation 30 min —— 20-30 10-15

[0074] After filtration, washing, and drying, 2-mercaptobenzothiazole is obtained, with a yield of 95.3%; purity of 99.70%; appearance color: light yellow; moisture content: 0.40%.

[0075] Example 5: (Mother liquors from various cephalosporin productions)

[0076] Take 125 ml each of dichloromethane waste liquids from cefotaxime acid, ceftriaxone acid, cefepime hydrochloride, and cefazidime production, mix them, let them stand for more than 24 h, and separate the phases to obtain dichloromethane solution I;

[0077] Add 10 g of solid sodium hydroxide to dichloromethane solution I and reflux for 30 min in a high-efficiency reflux device to obtain dichloromethane solution II.

[0078] After filtering dichloromethane solution II to recover solid sodium hydroxide, add 50 ml of hydrochloric acid aqueous solution with a pH of 4, mix, stir for 30 min and then separate the phases. Wash the dichloromethane phase with 50 ml of water once again, let it stand for more than 60 min, and obtain dichloromethane solution III.

[0079] Add 1.5 g of activated carbon to dichloromethane solution III for decolorization and stir at 10 °C for 30 min. Filter to obtain dichloromethane solution IV.

[0080] Add 600 ml of n-butanol-n-hexane-toluene (ratio 2:6:2) solution to dichloromethane solution IV and perform vacuum distillation (temperature controlled at 10 - 20 °C). Stop distillation after the feed liquid becomes turbid, perform crystal cultivation at 15 - 20 °C for 30 min, and then perform vacuum distillation until the crystallization end point. The crystallization process is as follows;

[0081] Serial number Crystallization process Time Amount of dichloromethane Stirring speed HZ Temperature °C 1 First distillation 15 min 30％ 45-50 10-20 2 Crystal cultivation 30 min —— 20-30 15-20 3 Second distillation 60 min 25％ 20-30 15-20 4 Third distillation 30 min 15％ 25-35 15-20 5 Fourth distillation To the end To 90% 25-35 15-20 6 Crystal cultivation 30 min —— 20-30 10-15

[0082] After filtration, washing and drying, 2-mercaptobenzothiazole is obtained. Yield: 95.3%; Purity: 99.70%; Appearance color: light yellow; Moisture: 0.33%.

[0083] Example 6: (Process parameter adjustment)

[0084] Take 125 ml each of dichloromethane waste liquid from the production of cefotaxime acid, ceftriaxone acid, cefepime hydrochloride, and ceftazidime, let it stand for more than 24 h, separate the phases, and obtain dichloromethane solution I.

[0085] Add 25 g of solid sodium hydroxide to dichloromethane solution I and reflux for 60 min in a high-efficiency reflux device to obtain dichloromethane solution II.

[0086] After filtering dichloromethane solution II to recover solid sodium hydroxide, add 50 ml of hydrochloric acid aqueous solution with a pH of 6, mix, stir for 30 min and then separate the phases. Wash the dichloromethane phase with 50 ml of water once again, let it stand for more than 60 min, and obtain dichloromethane solution III.

[0087] Add 1.5 g of activated carbon to dichloromethane solution III for decolorization and stir at 10 °C for 30 min. Filter to obtain dichloromethane solution IV.

[0088] Add 800 ml of a solution of n-butanol - n-hexane - toluene (ratio 2:6:2) to the dichloromethane solution, and perform vacuum distillation (temperature controlled at 10 - 20 °C). After the feed liquid becomes turbid, stop the distillation, perform crystal cultivation at 15 - 20 °C for 30 min, and then perform vacuum distillation until the crystallization end point. The crystallization process is as follows;

[0089] Serial number Crystallization process Time Amount of dichloromethane Stirring speed HZ Temperature °C 1 First distillation 20 min 35％ 45-50 10-20 2 Crystal cultivation 30 min —— 20-30 15-20 3 Second distillation 90 min 30％ 20-30 15-20 4 Third distillation 60 min 20％ 25-35 15-20 5 Fourth distillation To the end To 90% 25-35 15-20 6 Crystal cultivation 60 min —— 20-30 10-15

[0090] After filtration, washing, and drying, 2-mercaptobenzothiazole is obtained. Yield: 95.5%; Purity: 99.72%; Appearance color: light yellow; Moisture: 0.34%.

[0091] Example 7:

[0092] Take 125 ml each of the dichloromethane waste liquids produced in the production of cefotaxime acid, ceftriaxone acid, cefepime hydrochloride, and ceftazidime, let stand for more than 24 h, separate the phases, and obtain dichloromethane solution I;

[0093] Add 20 g of solid sodium hydroxide to dichloromethane solution I and reflux in a high-efficiency reflux device for 45 min to obtain dichloromethane solution II;

[0094] After filtering and recovering solid sodium hydroxide from dichloromethane solution II, add 50 ml of a hydrochloric acid aqueous solution with a pH of 5 and mix. After stirring for 30 min, separate the phases. The dichloromethane phase is washed once with 50 ml of clear water, and after standing for more than 60 min, dichloromethane solution III is obtained;

[0095] Add 1.5 g of activated carbon to dichloromethane solution III for decolorization and stir at 10 °C for 30 min. Filter to obtain dichloromethane solution IV;

[0096] Add 700 ml of a solution of n-butanol - n-hexane - toluene (1 / 3 - 1 / 2 of dichloromethane, ratio 2:6:2) to dichloromethane solution IV, perform vacuum distillation (temperature controlled at 10 - 20 °C). After the feed liquid becomes turbid, stop the distillation, perform crystal cultivation at 15 - 20 °C for 30 min, and then perform vacuum distillation until the crystallization end point. The crystallization process is as follows;

[0097] Serial number Crystallization process Time Amount of dichloromethane Stirring speed HZ Temperature °C 1 First distillation 18 min 35％ 45-50 10-20 2 Crystal cultivation 30 min —— 20-30 15-20 3 Second distillation 75 min 30％ 20-30 15-20 4 Third distillation 40 min 25％ 25-35 15-20 5 Fourth distillation To the end To 90% 25-35 15-20 6 Crystal cultivation 30 min —— 20-30 10-15

[0098] After filtration, washing, and drying, 2-mercaptobenzothiazole is obtained. Yield: 95.4%; Purity: 99.69%; Appearance color: light yellow; Moisture: 0.40%.

[0099] Example 8:

[0100] Take 125 ml each of the dichloromethane waste liquids produced in the production of cefotaxime acid, ceftriaxone acid, cefepime hydrochloride, and ceftazidime, let stand for more than 24 h, separate the phases, and obtain dichloromethane solution I;

[0101] Add 10 g of solid sodium hydroxide to dichloromethane solution I and reflux in a high-efficiency reflux device for 30 min to obtain dichloromethane solution II;

[0102] After filtering dichloromethane solution II to recover solid sodium hydroxide, add 50 ml of hydrochloric acid aqueous solution with a pH of 4 and mix. After stirring for 30 min, separate the phases. Wash the dichloromethane phase once with 50 ml of clear water. After standing for more than 60 min, obtain dichloromethane solution III;

[0103] Add 1.5 g of activated carbon to dichloromethane solution III for decolorization and stir at 10 °C for 30 min. Filter to obtain dichloromethane solution IV;

[0104] Add 600 ml of n-butanol - n-hexane - toluene (ratio 2:6:2) solution to dichloromethane solution IV and distill under reduced pressure (control the temperature at 10 - 20 °C). Stop distillation after the feed liquid becomes turbid. Crystallize at 15 - 20 °C for 30 min, and then distill under vacuum until the crystallization end point. The crystallization process is as follows;

[0105]

[0106]

[0107] After filtration, washing and drying, obtain 2-mercaptobenzothiazole. Yield: 95.4%; Purity: 99.69%; Appearance color: light yellow; Moisture: 0.35%.

[0108] Comparative Example 1: (Example 1 in Patent CN201810915904.5)

[0109] Take 3 L of cefotaxime sodium dichloromethane mother liquor (M content: 4 wt%, triethylamine content: 3 wt%, dichloromethane content: 91.5 wt%, impurity 1.5 wt%), add 3 L of water, adjust the pH value to 12 with 30 wt% sodium hydroxide solution. Control the temperature at 10 - 15 °C during the adjustment process and stir vigorously for 1 hour. Let it stand and separate the phases to obtain organic phase 1 and aqueous phase 1; Adjust the pH value of aqueous phase 1 to 6 with 92.5 wt% sulfuric acid. Control the temperature at 15 °C - 20 °C during this process. A large amount of khaki solid precipitates, and then filter, wash with water and dry to obtain 146.1 g of 2-mercaptobenzothiazole, with a content of 98.56% (determined by liquid chromatography, quantitative analysis, dry basis content), a recovery rate of 92.3%, and a large amount of alkaline wastewater is generated.

[0110] Comparative Example 2: (Replace the cefotaxime sodium dichloromethane mother liquor in Comparative Example 1 with a cefotaxime and cefotaxime sodium dichloromethane mixed mother liquor)

[0111] Take 3 L of the dichloromethane mixed mother liquor of ceftazidime and ceftriaxone sodium, add 3 L of water, adjust the pH value to 12 with 30 wt% sodium hydroxide solution, control the temperature at 10 - 15 °C during the adjustment process, stir vigorously for 1 hour, let it stand for phase separation to obtain organic phase 1 and aqueous phase 1; adjust the pH value of aqueous phase 1 to 6 with 92.5 wt% sulfuric acid, control the temperature at 15 °C - 20 °C during this process, a large amount of khaki solids will precipitate, then filter, wash with water, and dry to obtain 135.2 g of 2-mercaptobenzothiazole, with a content of 98.11% (determined by liquid chromatography, quantitative analysis, dry content), a recovery rate of 91.5%, and a large amount of alkaline wastewater is generated.

[0112] Comparative Example 3: (Example 1 in Patent CN201110276382.7)

[0113] ① In a 2000 mL round-bottom flask, add 1600 m of the ceftriaxone sodium mother liquor, and adjust the pH = 5.0 with a sulfuric acid solution with a mass concentration of 98%;

[0114] ② Heat and distill the mother liquor obtained in step ①, distill out 1200 mL of the solvent, and reserve the residual solution after distillation;

[0115] ③ Cool the residual solution obtained in step ② to 10 °C, a small amount of solids will precipitate, filter, filter out the solids, and reserve the filtrate;

[0116] ④ Add water with a volume 4 times that of the filtrate to the filtrate obtained in step ③ and stir, and a large amount of solids will precipitate;

[0117] ⑤ Filter out the solids obtained in step ④, wash with water and dry to obtain the target product 2-mercaptobenzothiazole, weigh 12.1 g, and the recovery rate is 93.9%; take a sample and detect it by high performance liquid chromatography, and the content is 98.12% (dry content).

[0118] Comparative Example 4: (Compared with Example 1, the standing and water phase removal process in step S1 is omitted, and directly dissolve after adding solid sodium hydroxide)

[0119] Take 500 ml of the dichloromethane waste liquid produced in the production of cefotaxime acid, add 10 g of solid sodium hydroxide and reflux for 30 min, and the solid sodium hydroxide dissolves (after the sodium hydroxide dissolves, a high-concentration or supersaturated sodium hydroxide solution will be formed) to obtain dichloromethane solution 1;

[0120] Filter dichloromethane solution 1 (no sodium hydroxide is recovered), adjust the pH value to 5 with concentrated hydrochloric acid water, stir for 30 min and then separate the phases, wash the dichloromethane phase with 50 ml of clear water once, and after standing for more than 60 min, obtain dichloromethane solution 2;

[0121] Add 1.5 g of activated carbon to dichloromethane solution 2 for decolorization, and stir at 10 °C for 30 min. Filter to obtain dichloromethane solution 3;

[0122] Add 600 ml of a solution of n-butanol - n-hexane - toluene (ratio 2:6:2) to the dichloromethane solution, and distill under reduced pressure (temperature controlled at 10 - 20 °C). After the feed liquid becomes turbid, stop distillation, perform crystal cultivation at 15 - 20 °C for 30 min, and then perform vacuum distillation until the crystallization end point. The crystallization process is as follows;

[0123]

[0124]

[0125] After filtration, washing, and drying, 2-mercaptobenzothiazole is obtained, with a yield of 84.5%; purity of 97.6%; appearance color: light brown; moisture content: 0.34%.

[0126] Comparative Example 5: (Compared with Example 1, add a solution of isopropanol - n-hexane - toluene (2:6:2) in S5)

[0127] Take 500 ml of the dichloromethane waste liquid from cefotaxime acid production, let it stand for more than 24 h, separate the phases, and obtain the first dichloromethane solution;

[0128] Add 10 g of solid sodium hydroxide to the first dichloromethane solution and reflux for 30 min to obtain the second dichloromethane solution;

[0129] After filtering and recovering the solid sodium hydroxide from the second dichloromethane solution, add 50 ml of a hydrochloric acid aqueous solution with a pH of 4, mix, stir for 30 min, separate the phases, wash the dichloromethane phase with 50 ml of water once, and let it stand for more than 60 min to obtain the third dichloromethane solution;

[0130] Add 1.5 g of activated carbon to the third dichloromethane solution for decolorization, stir at 10 °C for 30 min. Filter to obtain the fourth dichloromethane solution;

[0131] Add 600 ml of a solution of isopropanol - n-hexane - toluene (2:6:2) to the fourth dichloromethane solution, distill under reduced pressure (temperature controlled at 10 - 20 °C). After the feed liquid becomes turbid, stop distillation, perform crystal cultivation at 15 - 20 °C for 30 min, and then perform vacuum distillation until the crystallization end point. The crystallization process is as follows;

[0132] Serial number Crystallization process Time Amount of dichloromethane Stirring speed HZ Temperature °C 1 Distillation 150 min 30％ 45-50 10-20 2 Crystal cultivation 30 min —— 20-30 15-20 3 Second distillation 60 min 25％ 20-30 15-20 4 Third distillation 30 min 15％ 25-35 15-20 5 Fourth distillation To the end To 90% 25-35 15-20 6 Crystal cultivation 30 min —— 20-30 10-15

[0133] After filtration, washing, and drying, 2-mercaptobenzothiazole is obtained, with a yield of 92.0%; purity of 98.28%; appearance color: light yellow; moisture content: 0.40%.

[0134] Comparative Example 6: (Compared with Example 1, the vacuum distillation operation is changed)

[0135] Take 500 ml of the dichloromethane waste liquid produced in the production of cefotaxime acid, let it stand for more than 24 h, separate the phases, and obtain dichloromethane solution I;

[0136] Add 10 g of solid sodium hydroxide to dichloromethane solution I and reflux for 30 min to obtain dichloromethane solution II;

[0137] After filtering dichloromethane solution II, add 50 ml of hydrochloric acid aqueous solution with pH 4 and mix. After stirring for 30 min, separate the phases. Wash the dichloromethane phase with 50 ml of water once again. After standing for more than 60 min, obtain dichloromethane solution III;

[0138] Add 1.5 g of activated carbon to dichloromethane solution III for decolorization and stir at 10 °C for 30 min. Filter to obtain dichloromethane solution IV;

[0139] Add 600 ml of a solution of n-butanol - n-hexane - toluene (1 / 3 - 1 / 2 of dichloromethane, with a ratio of 2:6:2) to dichloromethane solution IV, and perform vacuum distillation (control the temperature at 10 - 20 °C). Stop distillation when the feed liquid becomes turbid, perform crystal cultivation at 15 - 20 °C for 30 min, and then perform vacuum distillation until the crystallization end point. The crystallization process is as follows;

[0140] Serial number Crystallization process Time Amount of dichloromethane Stirring speed HZ Temperature °C 1 Distillation 150 min 90％ 25-35 10-20 2 Crystal cultivation 30 min —— 20-30 10-15

[0141] After filtration, washing, and drying, obtain 2-mercaptobenzothiazole. Yield: 94.2%; Purity: 96.32%; Appearance color: yellow; Moisture content: 1.41%.

[0142] Comparative Example 7: (Compared with Example 1, the vacuum distillation operation is changed)

[0143] Take 500 ml of the dichloromethane waste liquid produced in the production of cefotaxime acid, let it stand for more than 24 h, separate the phases, and obtain dichloromethane solution I;

[0144] Add 10 g of solid sodium hydroxide to dichloromethane solution I and reflux for 30 min to obtain dichloromethane solution II;

[0145] After filtering dichloromethane solution II, add 50 ml of hydrochloric acid aqueous solution with pH 4 and mix. After stirring for 30 min, separate the phases. Wash the dichloromethane phase with 50 ml of water once again. After standing for more than 60 min, obtain dichloromethane solution III;

[0146] Add 1.5 g of activated carbon to dichloromethane solution III for decolorization and stir at 10 °C for 30 min. Filter to obtain dichloromethane solution IV;

[0147] Add 600 ml of a solution of n-butanol - n-hexane - toluene (1 / 3 - 1 / 2 of dichloromethane, ratio 2:6:2) to the dichloromethane solution, and perform vacuum distillation (temperature controlled at 10 - 20 °C). After the feed liquid becomes turbid, stop distillation, perform crystal cultivation at 15 - 20 °C for 30 min, and then perform vacuum distillation until the crystallization end point. The crystallization process is as follows;

[0148] Serial number Crystallization process Time Amount of dichloromethane Stirring speed HZ Temperature °C 1 First distillation 60 min 60％ 45-50 10-20 2 Crystal cultivation 30 min —— 20-30 15-20 3 Second distillation 30 min 30％ 20-30 15-20 5 Crystal cultivation 30 min —— 20-30 10-15

[0149] After filtration, washing, and drying, 2-mercaptobenzothiazole is obtained. Yield: 93.5%; Purity: 98.46%; Appearance color: yellow; Moisture: 0.73%.

[0150] Compare the results of the comparative example and the example:

[0151] 1. After the change in the distillation process, it seriously affects the control of the number of crystal nuclei and the growth of crystals, thereby affecting the product purity, color, moisture, and yield.

[0152] 2. Changes in the process of standing for water removal will result in a strong alkaline sodium hydroxide solution with high concentration or supersaturation, causing serious damage and resulting in low product yield and poor quality.

[0153] 3. The selection of the n-butanol - n-hexane - toluene solution combined with the reflux of solid sodium hydroxide in the early stage greatly improves the product yield and purity.

[0154] 4. Aqueous phase crystallization will cause the product to have too much moisture. Prolonged exposure to high temperature and high humidity will cause the product to degrade.

Claims

1. A method for recovering 2-mercaptobenzothiazole from the mother liquor in cephalosporin production, characterized in that, It includes the following steps: S1. Let the cephalosporin production mother liquor stand for a period of time, separate the phases, remove the aqueous phase, and obtain dichloromethane solution I; S2. Add solid sodium hydroxide to dichloromethane solution I, carry out a reflux reaction for a period of time, and obtain dichloromethane solution II; S3. Filter dichloromethane solution II, recover solid sodium hydroxide, add acidic water to the filtrate and mix, adjust the pH to acidic, stir, separate the phases, take the dichloromethane phase, wash with clear water, let it stand for a period of time, and obtain dichloromethane solution III; S4. Add activated carbon to dichloromethane solution III for decolorization, stir, filter, and obtain dichloromethane solution IV; S5. Add n-butanol-n-hexane-toluene solution to dichloromethane solution IV, carry out vacuum distillation until the crystallization end point, filter, wash, and dry to obtain 2-mercaptobenzothiazole.

2. The method for recovering 2-mercaptobenzothiazole from the cephalosporin production mother liquor according to claim 1, wherein: The cephalosporin production mother liquor includes one or more of dichloromethane mother liquors generated during the preparation of cefotaxime acid, ceftriaxone acid, cefepime hydrochloride, GCLE, and ceftazidime.

3. The method for recovering 2-mercaptobenzothiazole from the cephalosporin production mother liquor according to claim 1, characterized in that: The standing time in S1 is more than 24 h.

4. A method for recovering 2-mercaptobenzothiazole from the cephalosporin production mother liquor according to claim 1, characterized in that: In S2, a high-efficiency reflux device is used for reflux, and the reflux time is 30 - 60 min.

5. The method for recovering 2-mercaptobenzothiazole from the cephalosporin production mother liquor according to claim 1, characterized in that: The added weight of solid sodium hydroxide in S2 is 2 - 5% of the volume of dichloromethane solution I.

6. A method for recovering 2-mercaptobenzothiazole from the cephalosporin production mother liquor according to claim 1, characterized in that: The acidic water in S3 is an aqueous solution of sulfuric acid, hydrochloric acid, phosphoric acid, or acetic acid, and the pH is 4 - 6.

7. A method for recovering 2-mercaptobenzothiazole from the cephalosporin production mother liquor according to claim 1, characterized in that: In S3, stir for 30 min and let it stand for more than 60 min.

8. A method for recovering 2-mercaptobenzothiazole from the cephalosporin production mother liquor according to claim 1, characterized in that: In S4, it is specified to stir for 30 min at 10 °C for decolorization.

9. The method for recovering 2-mercaptobenzothiazole from the cephalosporin production mother liquor according to claim 1, characterized in that: In the n-butanol-n-hexane-toluene solution in S5, the volume ratio of n-butanol : n-hexane : toluene is 2:6:2, and the added amount is 1 / 3 - 1 / 2 of the volume of dichloromethane solution IV.

10. A method for recovering 2-mercaptobenzothiazole from the cephalosporin production mother liquor according to claim 1, characterized in that: The specific operation of the vacuum distillation in S5 is as follows: 。

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