A method for preparing cefoperazone

Abstract

The application provides a preparation method of cefoperazone, which comprises the following steps: providing a 7-TMCA solution; providing a HO-EPCP acyl chloride solution; adding the HO-EPCP acyl chloride solution into the 7-TMCA solution drop by drop under the condition of-30 to-20 DEG C, and continuing to react under the condition of-30 to-20 DEG C after the addition is completed to obtain a reaction solution containing cefoperazone. The preparation method of cefoperazone can effectively reduce the content of impurity H in cefoperazone. Experiments prove that the content of impurity H in cefoperazone can be reduced to less than 0.15%, the yield of cefoperazone reaches more than 90%, the purity of cefoperazone reaches more than 99.6%, and the content of other impurities is less than 0.15%, so that the cefoperazone prepared by the method can be used to prepare cefoperazone sodium which completely meets the quality standard of cefoperazone sodium raw medicine.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a preparation method of cefoperazone. BACKGROUND

[0002] Cefoperazone sodium is a third-generation cephalosporin antibiotic with broad-spectrum antibacterial effect and can be used for treating various bacterial infections. Cefoperazone is an important intermediate of cefoperazone sodium raw material medicine, and its chemical structural formula is as follows:

[0003] The existing cefoperazone is mainly prepared by the reaction of 7-TMCA (cefuroxime mother nucleus,

[0004] ) and HO-EPCP acyl chloride .

[0005] The latest quality standard of cefoperazone sodium raw material medicine of pharmaceutical enterprises more strictly limits the content of known impurities, the content of other total impurities except known impurities and the content of other single impurities except known impurities in cefoperazone sodium products. Experimental results show that the content of other single impurities except known impurities is the most difficult to control, and the internal release standard of pharmaceutical enterprises requires that the content of other single impurities of cefoperazone sodium is less than or equal to 0.1%, and the content of other single impurities of the intermediate cefoperazone is less than or equal to 0.15%.

[0006] According to the determination by high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four general rules 0512), the impurity peak area of cefoperazone and cefoperazone sodium at the relative retention time of 1.18 (RRT = 1.18) is large, which is the main factor affecting the quality of cefoperazone sodium products. The structure of the impurity (marked as impurity H) at RRT = 1.18 is confirmed, and the structural formula of the impurity H is as follows:

[0007] Impurity H

[0008] It can be seen that the impurity H is derived from cefoperazone, and reducing the content of impurity H in cefoperazone is the key to reducing the content of impurity H in cefoperazone sodium. According to the relevant experimental results, the content of impurity H is reduced by about 50% when cefoperazone is converted into cefoperazone sodium. If cefoperazone sodium needs to meet the requirement that other single impurities are less than or equal to 0.1%, it is necessary to require that the content of impurity H in cefoperazone is less than or equal to 0.15%. The content of impurity H is higher than 0.3% when cefoperazone is prepared by the reaction of existing 7-TMCA and HO-EPCP acyl chloride. Since the content of impurity H is relatively low (less than 0.8%), it is difficult to reduce the content of impurity H to less than or equal to 0.15% while ensuring the yield of cefoperazone even through post-treatment process. Therefore, it is necessary to develop a preparation method of cefoperazone which can effectively reduce the content of impurity H. SUMMARY

[0009] The purpose of the present invention is to provide a method for preparing cefoperazone which can effectively reduce the content of impurity H.

[0010] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0011] A method for preparing cefoperazone, comprising:

[0012] Providing 7-TMCA solution;

[0013] Providing HO-EPCP acyl chloride solution;

[0014] The HO-EPCP acyl chloride solution was added dropwise to the 7-TMCA solution at -30 to -20°C. After the addition was complete, the mixture was kept at -30 to -20°C to obtain a reaction solution containing cefoperazone.

[0015] Preferably, the molar ratio of 7-TMCA in the 7-TMCA solution to HO-EPCP in the HO-EPCP acyl chloride solution is 1:(1.05-1.15).

[0016] Further preferably, the molar ratio of 7-TMCA in the 7-TMCA solution to HO-EPCP in the HO-EPCP acyl chloride solution is 1:(1.05-1.1).

[0017] Still further preferably, the molar ratio of 7-TMCA in the 7-TMCA solution to HO-EPCP in the HO-EPCP acyl chloride solution is 1:(1.05-1.08).

[0018] According to some embodiments, the HO-EPCP acyl chloride solution is prepared by dropwise adding phosphorus oxychloride to a solution consisting of HO-EPCP, N,N-dimethylacetamide, and acetonitrile at -30 to -20°C, and then continuing to heat at -30 to -20°C to obtain the HO-EPCP acyl chloride solution.

[0019] Preferably, the molar ratio of HO-EPCP to phosphorus oxychloride is 1:(1.05-1.10).

[0020] More preferably, the molar ratio of HO-EPCP to phosphorus oxychloride is 1:(1.05-1.07).

[0021] Preferably, the mass ratio of the HO-EPCP to N,N-dimethylacetamide and acetonitrile is 1:(2-5):(2-5).

[0022] Further preferably, the mass ratio of the HO-EPCP to N,N-dimethylacetamide and acetonitrile is 1:(4-5):(3-4).

[0023] More preferably, the mass ratio of the HO-EPCP to N,N-dimethylacetamide and acetonitrile is 1:(4.5-5):(3.5-4).

[0024] Preferably, the insulation reaction time in the preparation method of the HO-EPCP acyl chloride solution is 0.4 to 0.6 h.

[0025] According to some embodiments, the 7-TMCA solution is prepared by mixing 7-TMCA, acetonitrile and N,O-bistrimethylsilylacetamide.

[0026] Preferably, the molar ratio of 7-TMCA to N,O-bistrimethylsilylacetamide in the 7-TMCA solution is 1:(1.1-1.5).

[0027] Further preferably, the molar ratio of 7-TMCA to N,O-bistrimethylsilylacetamide in the 7-TMCA solution is 1:(1.1-1.2).

[0028] Preferably, the mass ratio of 7-TMCA to acetonitrile in the 7-TMCA solution is 1:(4-8).

[0029] Further preferably, the mass ratio of 7-TMCA to acetonitrile in the 7-TMCA solution is 1:(4-5).

[0030] Preferably, the insulation reaction time of the HO-EPCP acyl chloride solution and the 7-TMCA solution is 1.5 to 2.5 hours.

[0031] More preferably, the insulation reaction time of the HO-EPCP acyl chloride solution and the 7-TMCA solution is 1.8 to 2.2 hours.

[0032] Preferably, the preparation method of cefoperazone further includes post-treatment, which includes: first adding purified water, activated carbon and sodium metabisulfite to the reaction solution containing cefoperazone for decolorization, then filtering, washing with a mixture of acetonitrile and purified water, adding water to the filtrate for crystallization, growing crystals, separating solids, and vacuum drying the solids to obtain cefoperazone.

[0033] Preferably, the method for preparing cefoperazone further comprises the step of reacting 1-methyl-5-mercapto-1,2,3,4-tetrazolyl and 7-ACA in boron trifluoride-acetonitrile at 25-35° C. under inert gas protection to prepare 7-TMCA.

[0034] In some embodiments, the reaction time at 25-35℃ is 1-2h, after the reaction, the temperature is lowered to 0-5℃, purified water is added and the pH is adjusted to 3.0-4.0, and the mixture is crystallized at 0-5℃ under stirring, filtered, the filter cake is washed with purified water and acetone in sequence, and dried to obtain the 7-TMCA.

[0035] Compared with the prior art, the present application has the following advantages:

[0036] The preparation method of cefoperazone of the present application can effectively reduce the content of impurity H in cefoperazone, and experiments have confirmed that the content of impurity H in cefoperazone can be reduced to below 0.15%, the yield of cefoperazone reaches above 90%, the purity reaches above 99.6%, and the content of other impurities is less than 0.15%, so that the cefoperazone prepared by the method of the present application can be used to prepare cefoperazone sodium that fully meets the quality standards of cefoperazone sodium raw material medicine. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 HPLC spectrum of cefoperazone of Example 1;

[0038] Figure 2 HPLC spectrum of cefoperazone of Example 2;

[0039] Figure 3 HPLC spectrum of cefoperazone of Example 3;

[0040] Figure 4 HPLC spectrum of cefoperazone of Example 4;

[0041] Figure 5 HPLC spectrum of cefoperazone of Comparative Example 1;

[0042] Figure 6 HPLC spectrum of cefoperazone of Comparative Example 2.

[0043] Figure 7 H-NMR spectrum of impurity H; 1 H-NMR spectrum;

[0044] Figure 8 MS spectrum of impurity H. DETAILED DESCRIPTION

[0045] The present application will be further described below in combination with examples. However, the present application is not limited to the following examples. The implementation conditions used in the examples can be further adjusted according to different requirements of specific use, and the implementation conditions not mentioned are the conventional conditions in the industry. The technical features involved in each embodiment of the present application can be combined with each other as long as there is no conflict.

[0046] The applicant prepares cefoperazone as an important intermediate of cefoperazone sodium according to the prior art, and the impurity H in the reaction product cefoperazone sodium has a structure formula of

[0047] Impurity H

[0048] The 1H-NMR spectrum of impurity H is shown in Figure 7 , and the MS spectrum is shown in Figure 8 According to the structure confirmation, impurity H is produced in the mixing reaction of HO-EPCP acyl chloride and 7-TMCA. Through a series of experimental results, it is found that the content of impurity H is reduced by about 50% when cefoperazone is converted into cefoperazone sodium. Therefore, in order to control the content of impurity H in cefoperazone sodium within 0.1%, the content of impurity H in cefoperazone must be controlled within 0.15%.

[0049] In order to reduce the content of impurity H, the applicant has conducted a large number of researches, and it is found that the content of impurity H in the product can be further reduced by adding HO-EPCP acyl chloride solution to 7-TMCA solution during the mixing reaction of HO-EPCP acyl chloride and 7-TMCA. In combination with other experimental operations, the content of impurity H in cefoperazone is successfully controlled within 0.15%.

[0050] Specifically, according to a large amount of experimental data combined with the structure of impurity H, the inventors of the present application speculate that impurity H is an amide impurity formed by the reaction of cefoperazone acyl chloride with the amino group of 7-TMCA, the reaction process is that HO-EPCP acyl chloride reacts with 7-TMCA to generate cefoperazone, cefoperazone reacts with residual phosphorus oxychloride in the reaction solution (it is difficult to ensure that HO-EPCP and phosphorus oxychloride are completely reacted when preparing the HO-EPCP acyl chloride solution, and in order to improve the yield of HO-EPCP acyl chloride, phosphorus oxychloride is usually slightly excessive) to generate cefoperazone acyl chloride, and cefoperazone acyl chloride reacts with 7-TMCA to generate impurity H. If the HO-EPCP acyl chloride solution and the 7-TMCA solution are directly mixed and reacted, the heat release of the reaction is difficult to control, and a large amount of impurities will be generated; if the method of adding 7-TMCA solution dropwise into the HO-EPCP acyl chloride solution is used, then in the early stage of the reaction, the cefoperazone and HO-EPCP generated in the reaction system can react with phosphorus oxychloride to generate the corresponding acyl chloride, which has a competitive effect, and it is inevitable to generate impurity H. When the method of adding HO-EPCP acyl chloride solution dropwise into the 7-TMCA solution is used, in the early stage of the reaction, the concentration of phosphorus oxychloride in the reaction system is significantly lower than that of directly mixing the HO-EPCP acyl chloride solution and the 7-TMCA solution or using the method of adding 7-TMCA solution dropwise into the HO-EPCP acyl chloride solution, and in the competitive reaction, the corresponding cefoperazone acyl chloride is less generated, so that the amount of impurity H continuously generated by the reaction with 7-TMCA is less. Further, in combination with other reaction operation optimization, the content of impurity H in cefoperazone is successfully reduced to less than 0.15%, the yield of cefoperazone reaches more than 90%, the purity of cefoperazone reaches more than 99.6%, the content of other impurities is less than 0.15%, and then cefoperazone is used for preparing cefoperazone sodium, so that cefoperazone sodium completely meeting the quality standard of cefoperazone sodium drug substance can be obtained.

[0051] The technical solutions and technical effects of the present application are further described below in combination with examples and comparative examples.

[0052] In the following examples and comparative examples, the raw materials and reagents used are all obtained by market purchase.

[0053] In the following examples and comparative examples, unless otherwise specified, "%" means mass percent.

[0054] In the following examples and comparative examples, the HPLC detection method is as follows:

[0055] Chromatographic column: Agilent ZORBAX Eclipse Plus C18 column, 4.6 mm x 150 mm, 5 μm or a chromatographic column with equivalent performance;

[0056] Mobile phase: triethylamine acetic acid solution (triethylamine 14 ml and glacial acetic acid 5.7 ml, dilute with water to 100 ml, shake well) - acetonitrile - water (1.2:150:850), and adjust the pH value to 3.0±0.2 with glacial acetic acid;

[0057] Detection wavelength: 254 nm;

[0058] Flow rate: 1.2 mL / min;

[0059] Column temperature: 30°C.

[0060] Example 1

[0061] 1. Preparation of 7-TMCA

[0062] In a dry 500 mL four-necked reaction flask, 1-methyl-5-mercapto-1,2,3,4- tetrazole 70.0 g and boron trifluoride acetonitrile 80 g were added and stirred to dissolve. 7-ACA 16.0 g was quickly added under nitrogen, and the temperature was controlled at 30±5°C. The reaction was carried out for 1.5 h, and then the reaction was stopped by cooling to 0-5°C. Purified water 100 g was added dropwise, and 40% sodium hydroxide solution was added to adjust the pH to 3.0-4.0. The mixture was stirred at 0-5°C for 2 h to crystallize, and then filtered. The filter cake was washed with purified water 30 g and acetone 30 g, and then dried at 50°C under vacuum to obtain 7-TMCA 18.2 g, with a molar yield of 94.3%.

[0063] 2. Preparation of cefoperazone

[0064] 2.1. Preparation of 7-TMCA solution

[0065] In a dry 250 mL four-necked reaction flask, 7-TMCA 12.0 g, acetonitrile 50 g, and N,O-bistrimethylsilylacetamide (BSA) 8.2 g were added and stirred to dissolve. The mixture was cooled to 0°C and used as prepared.

[0066] 2.2. Preparation of HO-EPCP acyl chloride solution

[0067] In a dry 250 mL four-necked reaction flask, HO-EPCP 13.0 g, N,N-dimethylacetamide 60 g, and acetonitrile 48 g were added and stirred to dissolve. The mixture was cooled to -25°C, and phosphorus oxychloride 6.3 g was added dropwise (about 10 min for dropwise addition). After the dropwise addition was completed, the mixture was further reacted at -25°C for 0.5 h and used as prepared.

[0068] 2.3. Preparation of cefoperazone

[0069] Control the temperature at -25±5℃ and add the HO-EPCP chloride solution dropwise to the 7-TMCA solution (addition is completed in about 0.5h). After the addition is complete, continue to keep the temperature and react for 2h. Add 35g of purified water, 0.2g of activated carbon and 0.1g of sodium metabisulfite, decolorize for 0.5h, filter, wash with 20g of acetonitrile / purified water (1:2), transfer the filtrate to a 1000mL reaction bottle, continue to add 100g of purified water until crystals precipitate, keep the temperature and grow the crystals for 2h, filter, and vacuum dry at 50℃ to obtain 21.8g of cefoperazone with a molar yield of 92.4%. HPLC test results are shown in Figure 1 The purity of cefoperazone is 99.708%, the impurity H content is 0.084%, and the contents of other single impurities are all less than 0.15%.

[0070] Example 2

[0071] Preparation of 7-TMCA

[0072] In a dry 500mL four-necked reaction flask, 105.0g of 1-methyl-5-mercapto-1,2,3,4-tetrazole and 120g of boron trifluoride acetonitrile were added and stirred to dissolve. 24.0g of 7-ACA was quickly added under nitrogen, the temperature was controlled at 30±5°C, the reaction was continued for 2.0h, the reaction was terminated, the temperature was lowered to 0-5°C, 150g of purified water was added dropwise, and 40% sodium hydroxide solution was added dropwise to adjust the pH to 3.0-4.0. The mixture was stirred and crystallized at 0-5°C for 2h, filtered, and the filter cake was washed with 45g of purified water and 45g of acetone in sequence. It was dried in vacuo at 50°C to obtain 27.6g of 7-TMCA with a molar yield of 95.4%.

[0073] 2. Preparation of Cefoperazone

[0074] 2.1.7-TMCA solution preparation

[0075] In a dry 1000 mL four-necked reaction flask, add 24.0 g of 7-TMCA, 100 g of acetonitrile, and 16.5 g of N,O-bistrimethylsilylacetamide (BSA), stir to dissolve, and cool to 0°C for later use.

[0076] 2.2. Preparation of HO-EPCP Acyl Chloride Solution

[0077] In a dry 500 mL four-necked reaction flask, add HO-EPCP 26.0 g, N,N-dimethylacetamide 120 g, and acetonitrile 96 g. Cool to -25°C with stirring, and add phosphorus oxychloride 12.6 g dropwise (addition takes about 10 min). After the addition is complete, continue to heat and react for 0.5 h. Set aside.

[0078] 2.3. Preparation of Cefoperazone

[0079] The temperature was controlled at 25±5°C, the HO-EPCP acyl chloride solution was added dropwise into the 7-TMCA solution (about 0.5 h for dropwise addition to end), and the reaction was continued for 2 h after dropwise addition was completed. Purified water 70 g, activated carbon 0.4 g and sodium metabisulfite 0.2 g were added, and the solution was decolorized for 0.5 h, filtered, washed with acetonitrile / purified water 40 g (1:2), and the filtrate was transferred into a 1000 mL reaction flask, and purified water 200 g was continuously added until crystals precipitated, and the solution was incubated for 2 h to crystallize, filtered, and dried at 50°C under vacuum to obtain cefoperazone 44.1 g with a molar yield of 93.5%. The HPLC detection results are shown in Table 1. Figure 2 The purity of cefoperazone was 99.645%, the content of impurity H was 0.088%, and the contents of other single impurities were less than 0.15%.

[0080] Example 3

[0081] 1. Preparation of 7-TMCA

[0082] A dry 500 L reaction kettle was charged with 1-methyl-5-mercapto-1,2,3,4-tetrazole 105.0 kg, boron trifluoride acetonitrile 120 kg, and stirred to dissolve. 7-ACA 24.0 kg was quickly added under nitrogen, the temperature was controlled at 30±5°C, and the reaction was continued for 1.5 h. The reaction was completed, the temperature was lowered to 0-5°C, purified water 150 kg was added, and 40% sodium hydroxide solution was added dropwise to adjust the pH to 3.0-4.0. The solution was incubated at 0-5°C and stirred for 2 h to crystallize, centrifuged, and the filter cake was washed with purified water 45 kg and acetone 45 kg in sequence, and dried at 50°C under vacuum to obtain 7-TMCA 27.3 kg with a molar yield of 94.3%.

[0083] 2. Preparation of cefoperazone

[0084] 2.1. Preparation of 7-TMCA solution

[0085] A dry 1000 L reaction kettle was charged with 7-TMCA 24.0 kg, acetonitrile 100 kg, and N,O-bistrimethylsilylacetamide (BSA) 16.5 kg, and stirred to dissolve. The solution was cooled to 0°C and reserved;

[0086] 2.2. Preparation of HO-EPCP acyl chloride solution

[0087] A dry 500 L reaction kettle was charged with HO-EPCP 26.0 kg, N,N-dimethylacetamide 120 kg, and acetonitrile 96 kg, and stirred to dissolve. The solution was cooled to -25°C, and phosphorus oxychloride 12.6 kg was added dropwise (about 10 min for dropwise addition to end), and the reaction was continued for 0.5 h after dropwise addition was completed. The solution was reserved;

[0088] 2.3. Preparation of cefoperazone

[0089] Control the temperature at -25±5℃ and add the HO-EPCP chloride solution dropwise to the 7-TMCA solution (addition is completed in about 0.5h). After the addition is complete, continue to keep the temperature and react for 2h. Add 70kg of purified water, 0.4kg of activated carbon and 0.2kg of sodium metabisulfite, decolorize for 0.5h, filter, wash with 40kg of acetonitrile / purified water (1:2), transfer the filtrate to a 1000L crystallization kettle, continue to add 200kg of purified water until crystals precipitate, keep the temperature and grow the crystals for 2h, centrifuge, and vacuum dry at 50℃ to obtain 43.9kg of cefoperazone with a molar yield of 93.0%. HPLC test results are shown in Figure 3 The purity of cefoperazone is 99.752%, the impurity H content is 0.05%, and the contents of other impurities are all less than 0.15%.

[0090] Example 4

[0091] Preparation of 7-TMCA

[0092] In a dry 1000L reactor, 210.0kg of 1-methyl-5-mercapto-1,2,3,4-tetrazole and 240kg of boron trifluoride acetonitrile were added and stirred to dissolve. 48.0kg of 7-ACA was quickly added under nitrogen, the temperature was controlled at 30±5°C, the reaction was continued for 2.0h, the reaction was terminated, the temperature was lowered to 0-5°C, 300kg of purified water was added, and 40% sodium hydroxide solution was added dropwise to adjust the pH to 3.0-4.0. The mixture was stirred and crystallized at 0-5°C for 2h, centrifuged, and the filter cake was washed with 90kg of purified water and 90kg of acetone in sequence. It was dried in vacuo at 50°C to obtain 55.3kg of 7-TMCA with a molar yield of 95.5%.

[0093] 2. Preparation of Cefoperazone

[0094] 2.1.7-TMCA solution preparation

[0095] In a dry 1000L reactor, add 48.0kg of 7-TMCA, 200kg of acetonitrile, and 33kg of N,O-bistrimethylsilylacetamide (BSA), stir to dissolve, and cool to 0°C for later use;

[0096] 2.2. Preparation of HO-EPCP acyl chloride

[0097] In a dry 500L reactor, add 52.0kg of HO-EPCP, 240kg of N,N-dimethylacetamide, and 192kg of acetonitrile, cool to -25°C with stirring, and add 25.2kg of phosphorus oxychloride dropwise (addition takes about 10 minutes). After the addition is complete, continue to keep the reaction warm for 0.5h and set aside;

[0098] 2.3. Preparation of Cefoperazone

[0099] The temperature was controlled at 25±5°C, the HO-EPCP acyl chloride solution was added dropwise into the 7-TMCA solution (about 0.5 h for dropwise addition to end), and the reaction was continued for 2 h after dropwise addition was completed. Purified water 140 kg, activated carbon 0.8 kg and sodium metabisulfite 0.4 kg were added, and the solution was decolorized for 0.5 h, filtered, washed with acetonitrile / purified water 80 kg (1:2), and the filtrate was transferred into a 2000 L crystallization kettle. Purified water 400 kg was continuously added until crystals precipitated, and the solution was incubated for 2 h to allow crystals to grow. The solution was centrifuged, and the crystals were dried under vacuum at 50°C to obtain 87.3 kg of cefoperazone with a molar yield of 92.5%. The HPLC detection results are shown in Table 1. Figure 4 The purity of cefoperazone was 99.610%, the content of impurity H was 0.075%, and the contents of other impurities were less than 0.15%.

[0100] Comparative Example 1

[0101] 1. Preparation of 7-TMCA

[0102] A dry 500 mL four-necked reaction flask was charged with 1-methyl-5-mercapto-1,2,3,4-tetrazole 70.0 g and boron trifluoride acetonitrile 80 g, and stirred to dissolve. 7-ACA 16.0 g was quickly added under nitrogen, and the temperature was controlled at 30±5°C. The reaction was continued for 1.5 h, and the reaction was terminated. The temperature was lowered to 0-5°C, and purified water 100 g was added dropwise while adjusting the pH to 3.0-4.0 by dropwise addition of 40% sodium hydroxide solution. The solution was incubated at 0-5°C for 2 h to allow crystals to grow, and the crystals were filtered. The filter cake was washed with purified water 30 g and acetone 30 g, and dried under vacuum at 50°C to obtain 7-TMCA 18.2 g with a molar yield of 94.3%.

[0103] 2. Preparation of cefoperazone

[0104] 2.1. Preparation of 7-TMCA solution

[0105] A dry 250 mL four-necked reaction flask was charged with 7-TMCA 12.0 g, acetonitrile 50 g and N,O-bistrimethylsilylacetamide 8.2 g, and stirred to dissolve. The solution was cooled to 0°C and reserved;

[0106] 2.2. Preparation of HO-EPCP acyl chloride solution

[0107] A dry 250 mL four-necked reaction flask was charged with HO-EPCP 13.0 g, N,N-dimethylacetamide 60 g and acetonitrile 48 g, and stirred to dissolve. The solution was cooled to -25°C, and phosphorus oxychloride 6.3 g was added dropwise (about 10 min for dropwise addition to end). The reaction was continued for 0.5 h after dropwise addition was completed, and the solution was reserved;

[0108] 2.3. Preparation of cefoperazone

[0109] Control the temperature at -25±5℃ and add the 7-TMCA solution dropwise to the HO-EPCP chloride solution (addition is completed in about 0.5h). After the addition is complete, continue to keep the temperature for 2h. Add 35g of purified water, 0.2g of activated carbon and 0.1g of sodium metabisulfite, decolorize for 0.5h, filter, wash with 20g of acetonitrile / purified water (1:2), transfer the filtrate to a 1000mL reaction bottle, continue to add 100g of purified water until crystals precipitate, keep the temperature for 2h, filter, and vacuum dry at 50℃ to obtain 21.5g of cefoperazone with a molar yield of 91.1%. HPLC test results are shown in Figure 5 The purity of cefoperazone is 99.162%, and the impurity H content is 0.535%.

[0110] Comparative Example 2

[0111] Preparation of 7-TMCA

[0112] In a dry 500mL four-necked reaction flask, 98.0g of 1-methyl-5-mercapto-1,2,3,4-tetrazole and 112g of boron trifluoride acetonitrile were added and stirred to dissolve. 22.4g of 7-ACA was quickly added under nitrogen, the temperature was controlled at 30±5°C, the reaction was continued for 2.0h, the reaction was terminated, the temperature was lowered to 0-5°C, 140g of purified water was added dropwise, and 40% sodium hydroxide solution was added dropwise to adjust the pH to 3.0-4.0. The mixture was stirred and crystallized at 0-5°C for 2h, filtered, and the filter cake was washed with 42g of purified water and 42g of acetone in sequence. It was dried in vacuo at 50°C to obtain 25.5g of 7-TMCA with a molar yield of 94.4%.

[0113] 2. Preparation of Cefoperazone

[0114] 2.1.7-TMCA solution preparation

[0115] In a dry 250 mL four-necked reaction flask, add 24.0 g of 7-TMCA, 100 g of acetonitrile, and 16.5 g of N,O-bistrimethylsilylacetamide, stir to dissolve, and cool to 0°C for later use;

[0116] 2.2. Preparation of HO-EPCP Acyl Chloride Solution

[0117] In a dry 1000 mL four-necked reaction flask, add 26.0 g of HO-EPCP, 120 g of N,N-dimethylacetamide, and 96 g of acetonitrile. Cool to -25°C with stirring, and add 12.6 g of phosphorus oxychloride dropwise (addition takes about 10 minutes). After the addition is complete, continue to keep the reaction warm for 0.5 h and set aside.

[0118] 2.3. Preparation of Cefoperazone

[0119] Control the temperature at -25±5℃, add the 7-TMCA solution dropwise to the HO-EPCP chloride solution (addition is completed in about 0.5h), and continue to keep warm for 2h after the addition is complete. Add 70g of purified water, 0.4g of activated carbon and 0.2g of sodium metabisulfite, decolorize for 0.5h, filter, wash with 40g of acetonitrile / purified water (1:2), transfer the filtrate to a 1000mL reaction bottle, continue to add 200g of purified water until crystals precipitate, keep warm for 2h, filter, and vacuum dry at 50℃ to obtain 44.1g of cefoperazone with a molar yield of 93.5%. HPLC test results are shown in Figure 6 , cefoperazone 99.427%, impurity H content 0.363%.

[0120] The above detailed description of the present invention is intended to enable persons familiar with the art to understand the contents of the present invention and implement them. It does not limit the scope of protection of the present invention. Any equivalent changes or modifications made based on the spirit of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing cefoperazone, characterized in that: The preparation method of cefoperazone comprises: Providing 7-TMCA solution; Providing HO-EPCP acyl chloride solution; The HO-EPCP acyl chloride solution was added dropwise to the 7-TMCA solution at -30 to -20°C. After the addition was complete, the mixture was kept at -30 to -20°C to obtain a reaction solution containing cefoperazone.

2. The method for preparing cefoperazone according to claim 1, wherein The molar ratio of 7-TMCA in the 7-TMCA solution to HO-EPCP in the HO-EPCP acyl chloride solution is 1:(1.05-1.15).

3. The method for preparing cefoperazone according to claim 1, wherein The HO-EPCP acyl chloride solution is prepared by dropwise adding phosphorus oxychloride to a solution consisting of HO-EPCP, N,N-dimethylacetamide, and acetonitrile at -30 to -20°C, and then continuing to heat at -30 to -20°C to react to obtain the HO-EPCP acyl chloride solution.

4. The method for preparing cefoperazone according to claim 3, wherein The molar ratio of HO-EPCP to phosphorus oxychloride is 1:(1.05-1.08); and / or, the mass ratio of the HO-EPCP to N,N-dimethylacetamide and acetonitrile is 1:(2-5):(2-5); And / or, in the method for preparing the HO-EPCP acyl chloride solution, the insulation reaction time is 0.4 to 0.6 h.

5. The method for preparing cefoperazone according to claim 1, wherein The 7-TMCA solution is prepared by mixing 7-TMCA, acetonitrile and N,O-bistrimethylsilylacetamide.

6. The method for preparing cefoperazone according to claim 1, wherein The molar ratio of 7-TMCA to N,O-bistrimethylsilylacetamide in the 7-TMCA solution is 1:(1.1-1.4), and / or the mass ratio of 7-TMCA to acetonitrile is 1:(4-8).

7. The method for preparing cefoperazone according to claim 1, wherein The insulation reaction time is 1.5 to 2.5 hours.

8. The method for preparing cefoperazone according to claim 1, wherein The preparation method of cefoperazone also includes post-treatment, which includes: first adding purified water, activated carbon and sodium metabisulfite to the reaction solution containing cefoperazone for decolorization, then filtering, washing with a mixture of acetonitrile and purified water, adding water to the filtrate for crystallization, growing crystals, separating solids, and vacuum drying the solids to obtain cefoperazone.

9. The method for preparing cefoperazone according to claim 1, wherein The preparation method of cefoperazone further comprises the step of reacting 1-methyl-5-mercapto-1,2,3,4-tetrazolyl and 7-ACA in boron trifluoride acetonitrile at 25-35° C. under inert gas protection to prepare 7-TMCA.

10. The method for preparing cefoperazone according to claim 9, characterized in that: The reaction time at 25-35° C. is 1-2 hours. After the reaction, the temperature is lowered to 0-5° C., purified water is added and the pH is adjusted to 3.0-4.0, and crystallization is carried out by stirring at 0-5° C., and the filter cake is washed with purified water and acetone in sequence and dried to obtain the 7-TMCA.

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