Process for the preparation of cefoperazone impurity A

Abstract

The present application relates to the field of cefoperazone acid, and discloses a preparation method of cefoperazone impurity A, which comprises the following steps: (1) performing acyl chloride treatment on oxypiperazine acid in the presence of an acyl chloride reagent to generate an acyl chloride compound of oxypiperazine acid; (2) performing silylation treatment on 7-aminocephalosporanic acid in the presence of a silylation reagent to generate a silylated compound of 7-aminocephalosporanic acid; (3) reacting the acyl chloride compound of oxypiperazine acid with the silylated compound of 7-aminocephalosporanic acid to generate an intermediate compound (I); (4) hydrolyzing the intermediate compound (I) under the action of penicillin acylase to generate an intermediate compound (II); and (5) performing esterification and cyclization reaction on the intermediate compound (II) in the presence of a first crystallization solvent, a first organic solvent and a cyclization reagent to obtain the cefoperazone impurity A. The method disclosed by the present application is simple in process, and can obtain the cefoperazone impurity A with high purity, which can be used as a control sample for cefoperazone detection.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of cefoperazone acid, in particular to a preparation method of cefoperazone impurity A. BACKGROUND

[0002] The chemical name of cefoperazone impurity A is (5aR,6R)-6-[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazin-1-yl)-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dione, and the English name is (5aR,6R)-6-[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazin-1-yl)-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-5a,6-dihydro-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dione, and the structural formula is shown as formula (I):

[0003]

[0004] A series of impurities will be produced during the production and storage of cefoperazone, and the production of these impurities has a serious impact on the quality of cefoperazone products, which makes it lose antibacterial activity, affects the curative effect, and even produces toxic side effects. The pharmacopoeia of each country has strictly controlled the impurities in cefoperazone, and the European Pharmacopoeia has clearly listed six organic impurities, and impurity A is one of them. SUMMARY

[0005] The purpose of the present application is to provide a preparation method of cefoperazone impurity A with simple process and high product purity, and the cefoperazone impurity A prepared by the method can be used as a control sample in the detection of cefoperazone.

[0006] In order to achieve the above purpose, the present application provides a preparation method of cefoperazone impurity A, which comprises:

[0007] (1) acyl chloride treatment is carried out on oxypiperazine acid in the presence of an acyl chloride reagent to generate an acyl chloride compound of oxypiperazine acid;

[0008] (2) silanization treatment is carried out on 7-aminocephalosporanic acid in the presence of a silanization reagent to generate a silanization compound of 7-aminocephalosporanic acid;

[0009] (3) the acyl chloride compound of oxypiperazine acid reacts with the silanization compound of 7-aminocephalosporanic acid to generate an intermediate compound (I);

[0010] intermediate compound (I) ;

[0011] (4) the intermediate compound (I) is hydrolyzed under the action of penicillin acylase to generate the intermediate compound (II) ;

[0012] intermediate compound (II) ;

[0013] (5) the intermediate compound (II) is subjected to esterification and cyclization reaction in the presence of a first crystallization solvent, a first organic solvent and a cyclization reagent to obtain the cefoperazone impurity A.

[0014] The application provides a method for preparing the cefoperazone impurity A, which has the advantages of simple process and high purity of the prepared cefoperazone impurity A, and can be used as an impurity control sample in the detection of cefoperazone.

[0015] In the application, penicillin acylase is used to prepare the intermediate compound (II), and the cyclization and esterification reaction of the cefoperazone impurity A is realized in a non-aqueous solvent by using a p-toluenesulfonic acid reagent, so that the yield of the impurity is reduced and the purity of the product is improved. DETAILED DESCRIPTION

[0016] The endpoints of the ranges and any values disclosed herein are not limited to the precise values stated. The endpoints of the ranges and any values are understood to be approximate values. The endpoints of the ranges and any values are understood to be approximate values. For ranges comprising a single numerical value, this numerical value is understood to be that numerical value and also to be the next lower and next higher numerical values. For ranges including two numerical values, this numerical value is understood to be that numerical value and also to be the next lower and next higher numerical values. The ranges and individual points within those ranges can be combined to form new ranges, and the disclosure is understood to include all possible new ranges formed by combining the individual numerical values from designated ranges.

[0017] The application provides a preparation method of the cefoperazone impurity A, which comprises the following steps:

[0018] (1) an acyl chloride treatment is performed on oxypiperazinic acid (HO-EPCP for short) in the presence of an acyl chloride reagent to generate an acyl chloride of oxypiperazinic acid;

[0019] (2) a silylation treatment is performed on 7-aminocephalosporanic acid (7-ACA for short) in the presence of a silylation reagent to generate a silylated product of 7-aminocephalosporanic acid;

[0020] (3) the acyl chloride of oxypiperazinic acid and the silylated product of 7-aminocephalosporanic acid are reacted to generate the intermediate compound (I) ;

[0021] intermediate compound (I) ;

[0022] (4) the intermediate compound (I) is hydrolyzed by penicillin acylase to generate the intermediate compound (II);

[0023] the intermediate compound (II);

[0024] (5) the intermediate compound (II) is subjected to esterification and cyclization reaction in the presence of the first crystallization solvent, the first organic solvent and the cyclization reagent to obtain the cephalosporin impurity A.

[0025] Preferably, the acyl chloride reagent is selected from at least one of phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and thionyl chloride, and more preferably phosphorus oxychloride.

[0026] Preferably, the molar ratio of the oxypiperazinic acid to the acyl chloride reagent is 1:1-2, such as 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2 and any range between any two of them.

[0027] Preferably, in step (1), the method of the acyl chloride treatment comprises adding the acyl chloride reagent to the mixture of the first organic solvent and the second organic solvent containing the oxypiperazinic acid and reacting to generate the acyl chloride of the oxypiperazinic acid. For example, the first solvent, the second solvent and the oxypiperazinic acid can be put into a reaction tank, and the acyl chloride reagent is added dropwise into the reaction tank after the oxypiperazinic acid is dissolved.

[0028] Preferably, the condition of the acyl chloride treatment comprises a temperature of -60℃ to -20℃, and more preferably -30℃ to -25℃. It should be understood that the temperature when the acyl chloride reagent is added dropwise is also within this range, and the reaction is incubated within this range after the addition is completed. The product after the reaction can be stored at a temperature of -60℃ to -40℃.

[0029] Preferably, the first organic solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, and more preferably N,N-dimethylformamide and / or N,N-dimethylacetamide.

[0030] Preferably, the second organic solvent is selected from at least one of acetonitrile, tetrahydrofuran and 1,4-dioxane. The inventors of the present application found that the use of dichloromethane as the second solvent has an adverse effect on step (3).

[0031] Preferably, the amount of the oxypiperazinic acid, the first organic solvent and the second organic solvent is 1:2-5 (such as 2, 3, 4, 5 and any range between any two of them) : 1-3 (such as 1, 1.5, 2, 2.5, 3 and any range between any two of them) by weight.

[0032] In step (2) of the present application, the silanization treatment of 7-ACA is carried out using a silanization reagent.

[0033] Preferably, the silanization reagent is selected from at least one of trimethylchlorosilane, trimethylsilyl iodide, N,O-bis(trimethylsilyl)acetamide, N-methyl tert-butyldimethylsilyl trifluoroacetamide and N-methyl trimethylsilyl trifluoroacetamide, more preferably N,O-bis(trimethylsilyl)acetamide.

[0034] Preferably, the molar ratio of 7-aminocephalosporanic acid to the silanization reagent is 1:1-1.5, such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5 and any range between any two of them.

[0035] Preferably, in step (2), the silanization treatment is carried out in the presence of a second organic solvent. The second organic solvent is the same as the second organic solvent mentioned in step (1).

[0036] Preferably, the amount of 7-aminocephalosporanic acid and the second organic solvent is 1:3-8 by weight, such as 1:3, 1:4, 1:5, 1:6, 1:7, 1:8 and any range between any two of them.

[0037] The silanization treatment can be carried out at room temperature, and the material after silanization treatment can be stored at a lower temperature, such as 0-10℃ for standby.

[0038] Preferably, in step (3), the reaction is carried out by mixing the acyl chloride of oxapiperazinic acid with the silanide of 7-aminocephalosporanic acid at a temperature of -60℃ to -20℃, and then reacting at a temperature of -40℃ to -20℃ to obtain the intermediate compound (I).

[0039] Preferably, the temperature of the mixing is -50℃ to -30℃, such as -50, -45, -40, -35, -30℃ and any range between any two of them. After the mixing is completed, the temperature is raised for reaction, preferably the temperature of the reaction is -35℃ to -25℃.

[0040] Preferably, the molar ratio of the acyl chloride of oxapiperazinic acid to the silanide of 7-aminocephalosporanic acid is 1:1-1.2, such as 1:1, 1:1.15, 1:1.2 and any range between any two of them.

[0041] Preferably, in step (3), the method further comprises: adding water to the product after the reaction to quench the reaction, to obtain a material containing intermediate compound (I) and trimethylsilanol. The material containing intermediate compound (I) further comprises water, the first solvent and the second solvent. Trimethylsilanol can be separated from the material after quenching by stirring and then layering (the upper layer material). The amount of water can be selected within a wide range, for example, the volume of water can be 0.3-2 times the volume of the product after the reaction, for example, 0.3, 0.5, 1, 1.5, 2 times and any range between any two values.

[0042] Preferably, the method further comprises: performing a crystallization treatment on the product after the reaction in step (3).

[0043] Preferably, the crystallization treatment comprises: controlling the temperature of the material containing intermediate compound (I) to be 10-30℃ (for example, 10, 15, 20, 25, 30℃ and any range between any two values), more preferably 20-25℃, adding water to the material containing intermediate compound (I) until the material becomes turbid, and performing a first crystal growth (the amount of water added is preferably 0.8-1.4 times the volume of the product after the reaction, for example, 0.8, 1, 1.2, 1.4 times and any range between any two values); continue to add water (the amount of water added is preferably 0.2-1 times the volume of the product after the reaction, for example, 0.2, 0.4, 0.6, 0.8, 1 times and any range between any two values), and then cool to 0-8℃ (for example, 0, 2, 4, 6, 8℃ and any range between any two values), and perform a second crystal growth.

[0044] In order to obtain a product with higher purity, preferably, the method further comprises: performing a decolorization treatment on the material containing intermediate compound (I) before the crystallization treatment.

[0045] The material containing intermediate compound (I) can be decolorized in a decolorizing bottle, and the decolorizing agent can be selected from sodium sulfite, activated carbon and the like, and the type and amount of the decolorizing agent can be adjusted by a person skilled in the art according to the actual situation.

[0046] The obtained crystals can be separated by solid-liquid separation (such as suction filtration), and then washed and dried to obtain intermediate compound (I). When washing, acetonitrile and water mixture (the weight ratio of acetonitrile to water can be 1:3-5) can be used first, and then water can be used. After washing, the material can be suctioned dry, and then dried in a vacuum oven to obtain intermediate compound (I).

[0047] In step (4), the intermediate compound (I) is hydrolyzed by penicillin acylase to generate the intermediate compound (II). The penicillin acylase can be in the form of immobilized enzyme, and the amount thereof can be determined according to the amount of the material to be treated, for example, can be 0.6-1.5 times the amount of the intermediate compound (I) by weight, for example, can be 0.6, 0.8, 1, 1.2, 1.5 times and any range between any two values. The immobilized penicillin acylase can be obtained by commercial purchase, for example, from Shanghai Banglin Biotechnology Co., Ltd. Preferably, the enzyme activity of the penicillin acylase is 120-300 U per 1 g of the intermediate compound (I).

[0048] Preferably, in step (4), the hydrolysis conditions include a temperature of 5-20℃, for example, can be 5, 10, 12, 14, 15, 18, 20℃ and any range between any two values, more preferably 10-15℃.

[0049] Preferably, in step (4), the hydrolysis conditions include a pH of 7-9, for example, can be 7, 7.2, 7.4, 7.6, 7.8, 8, 8.2, 8.4, 8.6, 8.8, 9 and any range between any two values. The pH of the system can be controlled by an alkali liquor, which can be ammonia, diethylamine, triethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, etc., preferably ammonia. The concentration of the alkali liquor is not particularly limited, for example, can be 5-15 wt%.

[0050] It should be understood that the hydrolysis is carried out in the presence of water, and the amount of water can be selected within a wide range, preferably, the amount of water is 8-12 times the amount of the intermediate compound (I) by weight, for example, can be 8, 9, 10, 11, 12 times and any range between any two values.

[0051] After the reaction is completed, the enzyme can be separated from the liquid by a conventional solid-liquid separation method (such as filtration with a screen), and the separated material can be subjected to crystallization treatment. Preferably, the method further comprises: subjecting the hydrolyzed product to crystallization treatment.

[0052] Preferably, the crystallization treatment conditions include a temperature of 15-30℃, for example, can be 15, 20, 25, 30℃ and any range between any two values, more preferably 20-25℃, and a pH of 4.5-5.5, for example, can be 4.5, 5, 5.5 and any range between any two values.

[0053] Before the crystallization treatment, the hydrolyzed product can also be subjected to acidification treatment, so that the pH after the acidification treatment is 4.5-5.5. The acidization can be performed using an acid conventional in the art, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc., and preferably sulfuric acid. The concentration of the acid can be selected within a wide range, such as 10-40 wt%.

[0054] In the present application, in step (5), the method of the esterification cyclization reaction comprises: performing an esterification cyclization reaction on the intermediate compound (II) in the presence of a first crystallization solvent, a first organic solvent, and a cyclization reagent, to obtain Cefoperazone impurity A.

[0055] Preferably, the first crystallization solvent is selected from at least one of dichloromethane, trichloromethane, tetrachloromethane, methanol, ethanol, and isopropanol.

[0056] Preferably, the amount of the first crystallization solvent is 7-15 parts by weight, such as 7, 8, 10, 12, 14, 15 parts by weight and any range consisting of any two of them, preferably 8-12 parts by weight, and the amount of the first organic solvent is 1-3 parts by weight, such as 1, 1.5, 2, 2.5, 3 parts by weight and any range consisting of any two of them, preferably 1.5-2.5 parts by weight, compared to 1 part by weight of the intermediate compound (II).

[0057] Preferably, in step (5), the method of the esterification cyclization reaction comprises: performing an esterification cyclization reaction on the intermediate compound (II) in the presence of dichloromethane, N,N-dimethylacetamide, and a cyclization reagent, to obtain Cefoperazone impurity A.

[0058] Preferably, the cyclization reagent is p-toluenesulfonic acid and / or p-ethylbenzenesulfonic acid.

[0059] Preferably, the temperature of the esterification cyclization reaction is -70°C to 20°C, more preferably -40°C to 10°C, further preferably -25°C to 0°C, such as -25, -20, -15, -10, -5, 0°C and any range consisting of any two of them.

[0060] Preferably, the molar ratio of the intermediate compound (II) to the cyclization reagent is 1:0.2-2, more preferably 1:0.5-1.5, further preferably 1:0.8-1.2.

[0061] Preferably, the method further comprises: performing a crystallization treatment on the product after the esterification cyclization reaction in the presence of a second crystallization solvent.

[0062] Preferably, the second crystallization solvent is selected from at least one of dichloromethane, trichloromethane, tetrachloromethane, methanol, ethanol, and isopropanol.

[0063] Preferably, the amount of the intermediate compound (II) and the second crystallization solvent is 1:8-15 by weight, such as 1:8, 1:10, 1:12, 1:15 and any range consisting of any two values between them.

[0064] The first crystallization solvent and the second crystallization solvent can be the same or different.

[0065] In the present application, the crystallization conditions such as the crystallization temperature can be consistent with the conditions of the esterification cyclization reaction. The crystallized crystals can be subjected to post-processing operations such as solid-liquid separation, washing and drying to obtain cephalosporin A.

[0066] The present application will be described in detail below by way of examples.

[0067] In the following examples, the reagents and materials used are commercially available unless otherwise specified.

[0068] The purity of cephalosporin A is detected by HPLC method according to the cephalosporin sodium related substance detection method in Chinese Pharmacopoeia 2020 edition.

[0069] The immobilized penicillin acylase is purchased from Shanghai Banglin Biotechnology Co., Ltd., and the enzyme activity is 198 U / g.

[0070] Example 1

[0071] This example is used to illustrate the preparation method of cephalosporin A according to the present application.

[0072] (1) Preparation of HO-EPCP acyl chloride

[0073]

[0074] N,N-dimethylacetamide 32 g, acetonitrile 14 g, HO-EPCP 12.5 g, and phosphorus oxychloride 7.24 g were put into the reaction tank, and after cooling, phosphorus oxychloride 7.24 g was added dropwise, and the temperature was controlled at-28±2℃. After the dropwise addition was completed, the reaction was maintained. After the reaction was completed, the temperature was lowered to-50℃ for storage.

[0075] (2) Preparation of 7-ACA silane

[0076]

[0077] At room temperature, acetonitrile 48 g and 7-ACA 9.3 g were put into the reaction bottle, and after stirring, N,O-bis(trimethylsilyl)acetamide 11.6 g was added dropwise. After the dropwise addition was completed, the mixture was stirred until the solid was completely dissolved. The solution was cooled to 0-10℃ for storage.

[0078] (3) Preparation of intermediate compound (I)

[0079]

[0080] The HO-EPCP acyl chloride material liquid is mixed with the 7-ACA silylated material liquid, and the mixing process is controlled at -40±2℃. After the mixing is completed, the reaction is warmed and controlled at -30±2℃, and the reaction is preserved. After the reaction is completed, 67.2 mL of water is slowly added dropwise, and after the dropping is completed, stirring is performed, and after the stirring is completed, the liquid is separated, and the lower water phase is transferred to a decolorizing bottle. 0.08 g of sodium bisulfite and 0.64 g of activated carbon are added, stirring and decolorizing are performed, and after the activated carbon is removed by suction filtration, the liquid is transferred to a crystallization reaction bottle. The temperature of the material liquid is controlled at 23±2℃, 168 mL of purified water is added dropwise until the material liquid is turbid, and after the crystal is grown, 101 mL of purified water is continuously added dropwise. After the dropping is completed, the temperature is lowered to 5℃, and the crystal is grown. Filtration is performed by suction, and the liquid is washed with a mixture of acetonitrile and purified water (8.96 g of acetonitrile and 33.6 g of purified water). Then, the liquid is washed with 80 mL of purified water, and after the liquid is dried by suction, the intermediate compound (I) is obtained by drying in a vacuum oven.

[0081] (4) Preparation of the intermediate compound (II)

[0082]

[0083] In the enzyme reactor, 9 g of immobilized penicillin acylase is added, and after being washed with water, the immobilized penicillin acylase is reserved.

[0084] 10 g of the intermediate compound (I) and 100 mL of water are added, and the internal temperature is controlled at 13±2℃. 9 wt% ammonia water is added to control the pH of the system to be 8, and after the reaction is completed, the enzyme and the liquid are separated through a screen in the reactor. After the separation is completed, the pH of the liquid is adjusted to 4.9 by using a 25 wt% sulfuric acid solution, and the liquid is crystallized at a temperature of 22℃.

[0085] (5) Preparation of cefoperazone impurity A

[0086]

[0087] 10 g of the intermediate compound (II) is dissolved in a mixed solvent containing 100 g of dichloromethane and 15 g of N,N-dimethylformamide, the temperature is controlled at -20℃, 3.4 g of p-toluenesulfonic acid is added, and stirring is performed; after the reaction is completed, 120 g of ethanol is added to precipitate a solid, and the solid is filtered, washed, and dried to obtain cefoperazone impurity A.

[0088] The yield, the recovery rate, and the purity of cefoperazone impurity A are shown in Table 1.

[0089] Example 2

[0090] This example is used to illustrate the preparation method of cefoperazone impurity A according to the present application.

[0091] (1) Preparation of HO-EPCP acyl chloride

[0092] Into the reaction tank, put N,N-dimethylacetamide 32 g, tetrahydrofuran 14 g, HO-EPCP 12.5 g, and after cooling, drop in phosphorus oxychloride 7.24 g, control the temperature at -28±2℃, and keep the reaction after dropping. After the reaction is completed, cool to -50℃ for storage.

[0093] (2) Preparation of 7-ACA silylated product

[0094] At room temperature, put tetrahydrofuran 48 g and 7-ACA 9.3 g into the reaction bottle, and after stirring uniformly, drop in N,O-bis(trimethylsilyl)acetamide 11.6 g. After dropping, stir and react until the solid is completely dissolved. Cool the solution to 0-10℃ for storage.

[0095] (3) Preparation of intermediate compound (I)

[0096] Mix the HO-EPCP acyl chloride solution and the 7-ACA silylated product solution, and control the temperature at -40±2℃ during mixing. After mixing, warm the solution for reaction, control the temperature at -30±2℃, and keep the reaction. After the reaction is completed, slowly drop in water 67.2 mL, stir, separate the layers after standing, and transfer the lower aqueous phase into a decolorizing bottle. Add sodium bisulfite 0.08 g and activated carbon 0.64 g, stir for decolorization, and after filtration to remove the carbon, transfer into a crystallization reaction bottle. Control the temperature of the solution at 23±2℃, drop in purified water 168 mL until the solution is turbid, and continue to drop in purified water 101 mL after crystallization. After dropping, cool to 5℃ for crystallization. Filter, and wash with a mixture of acetonitrile and purified water (acetonitrile 8.96 g + purified water 33.6 g). Further wash with 80 mL of purified water, and dry in a vacuum oven to obtain the intermediate compound (I).

[0097] (4) Preparation of intermediate compound (II)

[0098] Into the enzyme reactor, add 9 g of immobilized penicillin acylase, and after washing with water, reserve for use.

[0099] Add 10 g of intermediate compound (I) and 100 mL of water, and control the internal temperature at 13±2℃. Add 9 wt% ammonia water to control the pH of the system at 7.5, separate the enzyme from the solution through the screen in the reactor after the reaction is completed, and after separation, adjust the pH of the solution to 4.9 with 25 wt% sulfuric acid solution, and crystallize at 22℃.

[0100] (5) Preparation of cefoperazone impurity A

[0101] Dissolve 10 g of intermediate compound (II) in a mixed solvent containing 100 g of ethanol and 15 g of N,N-dimethylformamide, control the temperature at -20 °C, add 3.4 g of p-toluenesulfonic acid, and stir the reaction; after the reaction is completed, add 120 g of dichloromethane to precipitate the solid, filter, wash, and dry to obtain cefoperazone impurity A.

[0102] The results of the yield, recovery rate, and purity of cefoperazone impurity A are shown in Table 1.

[0103] Example 3

[0104] This example is used to illustrate the preparation method of cefoperazone impurity A according to the present application.

[0105] (1) Preparation of HO-EPCP acyl chloride

[0106] Put N,N-dimethylacetamide 32 g, acetonitrile 14 g, and HO-EPCP 12.5 g into a reaction tank, and after cooling, add dropwise phosphorus oxychloride 7.24 g, control the temperature at -28 ± 2 °C during the process, and after the dropwise addition is completed, keep the reaction. After the reaction is completed, cool to -50 °C for storage.

[0107] (2) Preparation of 7-ACA silyl compound

[0108] At room temperature, put acetonitrile 48 g and 7-ACA 9.3 g into a reaction bottle, stir until uniform, then add dropwise N,O-bis(trimethylsilyl)acetamide 11.6 g, after the dropwise addition is completed, stir the reaction until the solid is completely dissolved, and cool the solution to 0-10 °C for storage.

[0109] (3) Preparation of intermediate compound (I)

[0110] Mix the HO-EPCP acyl chloride solution and the 7-ACA silyl compound solution, control the temperature at -40 ± 2 °C during the mixing process. After the mixing is completed, warm the reaction, control the temperature at -30 ± 2 °C, and keep the reaction. After the reaction is completed, slowly add water 67.2 mL, stir after the addition is completed, stand to separate the layers, and transfer the lower aqueous phase to a decolorizing bottle. Add sodium bisulfite 0.08 g and activated carbon 0.64 g, stir to decolorize, remove the carbon by suction filtration, and transfer to a crystallization reaction bottle. Control the temperature of the solution at 23 ± 2 °C, add purified water 168 mL dropwise until the solution is turbid, continue to add purified water 101 mL after the crystals are grown. After the dropwise addition is completed, cool to 5 °C, and grow the crystals. Filter by suction, and wash with a mixture of acetonitrile and purified water (acetonitrile 8.96 g + purified water 33.6 g). Then wash with 80 mL of purified water, and dry in a vacuum oven to obtain the intermediate compound (I).

[0111] (4) Preparation of intermediate compound (II)

[0112] In an enzyme reactor, add 9 g of immobilized penicillin acylase, wash with water, and reserve for use.

[0113] Add 10 g of intermediate compound (I), 100 mL of water, and control the internal temperature at 13±2℃. Add 9 wt% ammonia water to control the pH of the system at 8.5, and separate the enzyme from the solution by a sieve in the reactor after the reaction is completed. Adjust the pH of the solution to 4.9 with 25 wt% sulfuric acid solution, and perform crystallization at a temperature of 22℃.

[0114] (5) Preparation of Cefoperazone Impurity A

[0115] Dissolve 10 g of intermediate compound (II) in a mixed solvent containing 100 g of dichloromethane and 15 g of N,N-dimethylformamide, control the temperature at -20℃, add 3.4 g of p-toluenesulfonic acid, and stir to react. After the reaction is completed, add 120 g of ethanol to precipitate the solid, filter, wash, and dry to obtain Cefoperazone Impurity A.

[0116] The yield, recovery rate, and purity of Cefoperazone Impurity A are shown in Table 1.

[0117] Example 4

[0118] Perform the operation according to the method described in Example 1, except that the crystallization method in step (3) is different. Specifically, control the temperature of the solution in the crystallization reaction bottle at 23±2℃, and then lower the temperature to 5℃ after 296 mL of the solution is continuously added dropwise, and then crystallize.

[0119] The yield, recovery rate, and purity of Cefoperazone Impurity A are shown in Table 1.

[0120] Example 5

[0121] Perform the operation according to the method described in Example 1, except that the amount of N,N-dimethylformamide used in step (5) is 10 g.

[0122] The yield, recovery rate, and purity of Cefoperazone Impurity A are shown in Table 1.

[0123] Example 6

[0124] Perform the operation according to the method described in Example 1, except that the amount of N,N-dimethylformamide used in step (5) is 30 g.

[0125] The yield, recovery rate, and purity of Cefoperazone Impurity A are shown in Table 1.

[0126] Example 7

[0127] Perform the operation according to the method described in Example 1, except that the reaction and crystallization temperature in step (5) is controlled at 0℃.

[0128] The yield, recovery rate, and purity of Cefoperazone Impurity A are shown in Table 1.

[0129] Table 1

[0130]

[0131]

[0132] The preferred embodiments of the present application have been described in detail, but the present application is not limited thereto. Various simple modifications can be made to the technical solutions of the present application within the technical concept of the present application, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be considered as disclosed by the present application and fall within the protection scope of the present application.

Claims

1. A process for the preparation of cefoperazone impurity A, characterized in that, The method comprises: (1) acyl chlorination treatment is performed on the oxypiperazine acid in the presence of an acyl chlorination reagent to generate an acyl chlorination compound of the oxypiperazine acid; Piperazine; Oxypiperazine acid chloride; (2) silylation treatment is performed on the 7-aminocephalosporanic acid in the presence of a silylation reagent to generate a silylation compound of the 7-aminocephalosporanic acid; (3) the acyl chlorination compound of the oxypiperazine acid reacts with the silylation compound of the 7-aminocephalosporanic acid to generate an intermediate compound (I); Intermediate compound (I); (4) the intermediate compound (I) is hydrolyzed under the action of penicillin acylase to generate an intermediate compound (II); Intermediate compound (II); (5) esterification and cyclization reaction is performed on the intermediate compound (II) in the presence of a first crystallization solvent, a first organic solvent and a cyclization reagent to obtain the cephalosporin A impurity; Cefoperazone impurity A; In step (5), the temperature of the esterification and cyclization reaction is -20 to 0°C.

2. The method of claim 1, wherein, The acyl chlorination reagent is at least one selected from phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and thionyl chloride.

3. The method of claim 2, wherein, The acyl chlorination reagent is phosphorus oxychloride.

4. The method of claim 2, wherein, The molar ratio of the oxypiperazine acid to the acyl chlorination reagent is 1:1-2.

5. The method of claim 1, wherein, In step (1), the method of the acyl chlorination treatment comprises adding the acyl chlorination reagent to a mixture of a first organic solvent and a second organic solvent containing the oxypiperazine acid and performing reaction to generate the acyl chlorination compound of the oxypiperazine acid.

6. The method of claim 5, wherein, In step (1), the conditions of the acyl chlorination treatment comprise a temperature of -60°C to -20°C; and / or The first organic solvent is at least one selected from N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; and / or The second organic solvent is at least one selected from acetonitrile, tetrahydrofuran and 1,4-dioxane; and / or The oxypiperazine acid, the first organic solvent and the second organic solvent are used in a ratio of 1:2-5:1-3 by weight.

7. The method of claim 6, wherein, In step (1), the conditions of the acyl chlorination treatment comprise a temperature of -30°C to -25°C.

8. The method of claim 1, wherein, The silylation reagent is at least one selected from trimethylchlorosilane, trimethylsilyl iodide, N,O-bis(trimethylsilyl)acetamide, N-methyl tert-butyldimethylsilyl trifluoroacetamide and N-methyltrimethylsilyl trifluoroacetamide.

9. The method of claim 8, wherein, The silylation reagent is N,O-bis(trimethylsilyl)acetamide.

10. The method of claim 8, wherein, The molar ratio of the 7-aminocephalosporanic acid to the silylation reagent is 1:1-1.

5.

11. The method of claim 1, wherein, In step (2), the silylation treatment is performed in the presence of a second organic solvent.

12. The method of claim 11, wherein, The 7-aminocephalosporanic acid and the second organic solvent are used in a ratio of 1:3-8 by weight.

13. The method of claim 1, wherein, In step (3), the reaction mode comprises mixing the acyl chlorination compound of the oxypiperazine acid with the silylation compound of the 7-aminocephalosporanic acid under the condition of -60°C to -20°C, and then performing reaction under the condition of -40°C to -20°C to obtain the intermediate compound (I).

14. The method of claim 13, wherein, The molar ratio of the acyl chlorination compound of the oxypiperazine acid to the silylation compound of the 7-aminocephalosporanic acid is 1:1-1.2; and / or In step (3), the method further comprises adding water to the product after reaction to quench the reaction and obtain a material containing the intermediate compound (I) and trimethylsilanol.

15. The method of claim 1, wherein, The method further comprises: performing a crystallization treatment on the product after the reaction in step (3).

16. The method of claim 15, wherein, The crystallization treatment comprises: controlling the temperature of the material containing the intermediate compound (I) to be 10-30℃, adding water to make the material turbid, and performing a first crystal growth; continuing to add water to crystallize, and then cooling to 0-8℃, and performing a second crystal growth.

17. The method of claim 16, wherein, The method further comprises: performing a decolorization treatment on the material containing the intermediate compound (I) before the crystallization treatment.

18. The method of claim 16, wherein, The temperature of the material containing the intermediate compound (I) is controlled to be 20-25℃.

19. The method of claim 1, wherein, In step (4), the hydrolysis conditions comprise: a temperature of 5-20℃; and a pH of 7-9.

20. The method of claim 19, wherein, In step (4), the hydrolysis conditions comprise: a temperature of 10-15℃.

21. The method of claim 19, wherein, The method further comprises: performing a crystallization treatment on the product after the hydrolysis.

22. The method of claim 21, wherein, The crystallization treatment comprises: a temperature of 15-30℃; and a pH of 4.5-5.

5.

23. The method of claim 22, wherein, The crystallization treatment comprises: a temperature of 20-25℃.

24. The method of claim 1, wherein, In step (5), the first crystallization solvent is selected from at least one of dichloromethane, trichloromethane, tetrachloromethane, methanol, ethanol, and isopropanol.

25. The method of claim 24, wherein, In step (5), the amount of the first crystallization solvent is 7-15 parts by weight, and the amount of the first organic solvent is 1-3 parts by weight, compared to 1 part by weight of the intermediate compound (II); and / or The cyclization reagent is p-toluenesulfonic acid and / or p-ethylbenzenesulfonic acid; and / or The molar ratio of the intermediate compound (II) to the cyclization reagent is 1:0.2-2.

26. The method of claim 25, wherein, The cyclization reagent is p-toluenesulfonic acid.

27. The method of claim 25, wherein, The molar ratio of the intermediate compound (II) to the cyclization reagent is 1:0.5-1.

5.

28. The method of claim 27, wherein, The molar ratio of the intermediate compound (II) to the cyclization reagent is 1:0.8-1.

2.

29. The method of claim 1, wherein, The method further comprises: performing a crystallization treatment on the product after the esterification cyclization reaction in the presence of a second crystallization solvent.

30. The method of claim 29, wherein, The second crystallization solvent is selected from at least one of dichloromethane, trichloromethane, tetrachloromethane, methanol, ethanol, and isopropanol; and / or The amount of the intermediate compound (II) and the second crystallization solvent is 1:8-15 by weight.

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