Preparation method of cefoperazone sodium impurity H

Abstract

The invention relates to the technical field of cefoperazone sodium, and particularly discloses a preparation method of a cefoperazone sodium impurity H. The preparation method of the cefoperazone sodium impurity H provided by the invention comprises the following steps: carrying out carboxyl protection reaction on a compound shown in a formula 2 and a compound shown in a formula 3 to obtain a compound shown in a formula 4; carrying out condensation reaction on the compound shown in the formula 4 and a compound shown in a formula 5 to obtain a compound shown in a formula 6; and carrying out carboxyl deprotection reaction on the compound shown in the formula 6 to obtain the cefoperazone sodium impurity H. According to the method, a strategy of precisely controlling a synthesis path is adopted, the limitation of a traditional process is broken through, and efficient directional generation of impurity products is realized. The synthesis method provides an impurity H reference substance for quality control of a cefoperazone sodium preparation, and is beneficial to accurate identification and quantitative analysis of related impurities, so that controllable drug quality is ensured, and clinical medication safety is guaranteed.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of cefoperazone sodium, and particularly relates to a preparation method of cefoperazone sodium impurity H. BACKGROUND

[0002] Cefoperazone sodium is an organic compound, and its chemical formula is C 25 H 26 N9NaO8S2, which is a third-generation cephalosporin, has good antibacterial effects on enterobacteriaceae bacteria such as escherichia coli, klebsiella, proteus, salmonella typhi, shigella, citrobacter, and pseudomonas aeruginosa, and has poor effects on enterobacter aerogenes, enterobacter cloacae, salmonella typhimurium and acinetobacter, and is used for treating various infections caused by sensitive enzyme-producing bacteria, such as respiratory system, urogenital system, biliary tract, gastrointestinal tract, chest and abdominal cavity, skin and soft tissue infections, has good curative effects on intracranial infections caused by haemophilus influenzae and meningococcus, and can also treat infections caused by pseudomonas aeruginosa.

[0003] At present, the production process of cefoperazone sodium generally uses 7-TMCA and HO-EPCP as starting materials, 7-TMCA is subjected to silanization, HO-EPCP is subjected to acyl chloride, and then the two are subjected to condensation reaction to obtain cefoperazone acid, and then the cefoperazone acid is neutralized by sodium bicarbonate to obtain cefoperazone sodium.

[0004] Cefoperazone sodium is a clinical drug, and the requirement for impurity content is extremely strict. In production, 7-TMCA (double mother nucleus) reacts with HO-EPCP acyl chloride to generate polymer impurity H, and its chemical structure is shown in formula 1, and its chemical name is: (7aR, 7R)-7-({[(7aR, 7R)-7-{[(2R)-2-{[(4-ethyl-2,3-dioxopiperazin-1-yl) carbonyl]amino}-2-(4-hydroxyphenyl) acetyl]amino}-3-{[(1-methyl-1,2,3,4-tetrazol-5-yl) thio]methyl}-6-oxo-2,6,7,7a-tetrahydroazepino[2,1-b][1,3]thiazin-4-yl] carbonyl}amino)-3-{[(1-methyl-1,2,3,4-tetrazol-5-yl) thio]methyl}-6-oxo-2,6,7,7a-tetrahydroazepino[2,1-b][1,3]thiazine-4-carboxylic acid. It is confirmed through quality research that impurity H is a key process-related impurity generated in the synthesis process of cefoperazone acid. The impurity is generated in the synthesis stage of cefoperazone acid. A number of studies have shown that impurity H is a common polymer impurity in the production process of cefoperazone sodium, and can be detected in batches produced by many enterprises (the content is usually 0.1%~0.3%), and due to its structural characteristics, it is difficult to completely remove by conventional purification process. From the safety point of view, polymer impurities have been confirmed to cause allergic reactions or nephrotoxicity; cefoperazone sodium impurity H shows certain cytotoxicity in in vitro experiments. According to the ICH guideline (Q3A), the general impurity is ≤0.1% (reporting threshold) or ≤0.15% (identification threshold), and the quality control requirement of the impurity has exceeded the identification threshold of ICH Q3A guideline at present, which prompts to strictly monitor it, and to establish qualitative and quantitative analysis methods at the same time.

[0005]

[0006] Formula 1 In the drug consistency evaluation system, impurity research plays a core role: on the one hand, it is an important technical basis for drug quality control, and on the other hand, it plays a key role in ensuring drug safety, optimizing research and development processes, and meeting regulatory standards. It is confirmed through market research that the cefoperazone sodium impurity H reference substance has been commercialized (main suppliers include well-known enterprises such as Guangzhou Aichixi Biomedical Technology Co., Ltd., Guangdong Deyuan Biotechnology Service Co., Ltd., etc.), which provides convenient conditions for related quality research. However, the synthesis path of cefoperazone sodium impurity H has not been reported in the current public academic literature, which brings challenges to its structure confirmation. Therefore, developing a targeted synthesis method for cefoperazone sodium impurity H to provide a reference substance for its quality control has clear practicality and urgency. SUMMARY

[0007] In view of the above problems, the present application provides a preparation method of cefoperazone sodium impurity H, which adopts the strategy of accurately controlling the synthesis path, breaks through the limitation of traditional process, and realizes the efficient directional generation of impurity product.

[0008] To solve the above technical problems, the technical scheme provided by the present application is: The preparation method of cefoperazone sodium impurity H comprises the following steps: The compound shown as formula 2 is subjected to carboxyl protection reaction with the compound shown as formula 3 to obtain a compound shown as formula 4; The compound shown as formula 4 is subjected to condensation reaction with a compound shown as formula 5 to obtain a compound shown as formula 6; The compound shown as formula 6 is subjected to carboxyl deprotection reaction to obtain cefoperazone sodium impurity H shown as formula 1;

[0009] Formula 2

[0010] Formula 3

[0011] Formula 4

[0012] Formula 5

[0013] Formula 6

[0014] Formula 1.

[0015] Compared with the prior art, the preparation method of cefoperazone sodium impurity H provided by the present application (the synthesis route is shown as formula a) has the advantages of convenient raw material source, simple process flow, mild reaction condition, high synthesis efficiency and excellent product purity. The synthesis method provides a key impurity reference substance (i.e. impurity H reference substance) for quality control of cefoperazone sodium preparation, which helps to accurately identify and quantitatively analyze related impurities, so as to ensure controllable drug quality and guarantee the safety of clinical medication.

[0016]

[0017] Formula a Preferably, the preparation method of cefoperazone sodium impurity H comprises the following steps: S100, under an inert atmosphere, the compound shown as formula 2 and the compound shown as formula 3 are added to an aprotic solvent a, and subjected to carboxyl protection reaction under the action of an acidic catalyst to obtain a compound shown as formula 4; S200, the compound shown in formula 4 and the compound shown in formula 5 are added into an aprotic solvent b, and a condensation reaction is carried out under the action of a condensing agent and an acid binding agent, to obtain a compound shown in formula 6; S300, the compound shown in formula 6 is added into a solvent c, and a carboxyl deprotection reaction is carried out at 0-5°C under the action of an acidic reagent, to obtain the cefoperazone sodium impurity H.

[0018] For example, in S100, the inert atmosphere includes a nitrogen atmosphere.

[0019] Preferably, in S100, the molar ratio of the compound shown in formula 2 to the compound shown in formula 3 is 1: (1.2-1.6).

[0020] Further preferably, in S100, the aprotic solvent a includes at least one of dichloromethane, tetrahydrofuran, dimethyl sulfoxide or dimethyl formamide.

[0021] Further preferably, in S100, the mass-volume ratio of the compound shown in formula 2 to the aprotic solvent a is 1g: (7-10) mL.

[0022] Further preferably, in S100, the acidic catalyst includes at least one of boron trifluoride etherate or trifluoromethanesulfonic acid.

[0023] The preferred acidic catalyst of the present application has super strong acidity and can still maintain high catalytic activity at low temperature.

[0024] Further preferably, in S100, the molar ratio of the compound shown in formula 2 to the acidic catalyst is 1: (0.05-0.1).

[0025] Preferably, in S100, the temperature of the carboxyl protection reaction is 15-40°C, and the reaction time is 12-24h.

[0026] For example, in S100, the temperature when the materials are added is 0-5°C. This reduces the reaction activity and inhibits the occurrence of side reactions.

[0027] Preferably, in S100, after the carboxyl protection reaction is completed, the following steps are further included: Water is added to the reaction system, and the pH of the reaction system is adjusted to 7-8, the liquid is separated, the aqueous phase is extracted with the aprotic solvent a, the organic phases are combined and washed with saturated brine, the liquid is separated, the organic phase is dried and concentrated, and the obtained residue is purified to obtain the compound shown in formula 4.

[0028] In an example, in S100, the volume ratio of the aprotic solvent a used in the protection reaction of the carboxyl group, water, the aprotic solvent a used in the extraction, and the saturated brine is (210-300):(250-300):(60-80):(250-300).

[0029] In an example, in S100, the pH of the reaction system is adjusted to 7-8 by using sodium bicarbonate.

[0030] Further preferably, in S100, the purification is performed by using dry column chromatography, and the eluent comprises a mixture of dichloromethane and methanol in a volume ratio of (8-15):1.

[0031] Preferably, in S200, the molar ratio of the compound of formula 4 to the compound of formula 5 is 1:(1-1.4).

[0032] Further preferably, in S200, the aprotic solvent b comprises at least one of dichloromethane, acetonitrile, toluene, or dimethylformamide.

[0033] Further preferably, in S200, the mass-volume ratio of the compound of formula 4 to the aprotic solvent b is 1 g:(5-8) mL.

[0034] Further preferably, in S200, the condensing agent comprises at least one of a polypeptide condensing agent or a carbonyl ylide condensing agent.

[0035] More preferably, in S200, the condensing agent comprises at least one of 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-bis(dimethylamino)carbenium tetrafluoroborate (TBTU), or O-(benzotriazol-1-yl)-bis(dimethylamino)carbenium hexafluorophosphate (HBTU).

[0036] In S200 of the present application, the reaction raw materials have large steric hindrance, and the preferred condensing agent has high selective activity, which can preferentially react with the carboxyl group to generate an active ylide, and then react with the amino group, thereby improving the reactivity of the carboxyl group.

[0037] Further preferably, in S200, the molar ratio of the compound of formula 4 to the condensing agent is 1:(1-1.2).

[0038] Further preferably, in S200, the acid-binding agent comprises at least one of triethylamine, N,N-diisopropylethylamine, or pyridine.

[0039] Further preferably, in S200, the molar ratio of the compound of formula 4 to the acid-binding agent is 1:(1-1.5).

[0040] Preferably, in S200, the temperature of the condensation reaction is 15-40℃, and the reaction time is 16-24h.

[0041] Preferably, in S200, after the condensation reaction, the method further comprises: Water is added to the reaction system, and the liquid is separated; the aqueous phase is extracted with an extractant, and the organic phases are combined and washed with saturated brine, and the liquid is separated; the organic phase is dried and concentrated, and the obtained residue is purified to obtain the compound shown in formula 6.

[0042] Preferably, in S200, the volume ratio of the aprotic solvent b, water, the extractant, and the saturated brine is (175-280):(800-1200):(300-400):(250-300).

[0043] Further preferably, in S200, the extractant comprises at least one of ethyl acetate or dichloromethane.

[0044] Further preferably, in S200, the purification comprises the following steps: The obtained residue is subjected to dry column chromatography, and the eluent comprises a mixture of dichloromethane and methanol in a volume ratio of (10-30):1; the obtained enriched substance is subjected to beating, washing, and drying to obtain the compound shown in formula 6.

[0045] More preferably, in S200, the solvent used for beating comprises ethyl acetate and n-hexane in a volume ratio of 1:(4-8).

[0046] More preferably, in S200, the solvent used for beating comprises ethyl acetate and petroleum ether in a volume ratio of 1:(4-8).

[0047] More preferably, in S200, the temperature of the beating is room temperature, and the beating time is 0.8-1.2h.

[0048] Preferably, in S200, the washing liquid used for washing comprises at least one of n-hexane or petroleum ether.

[0049] Further preferably, in S300, the solvent c comprises at least one of dichloromethane, methanol, ethanol, dimethylacetamide, or acetonitrile.

[0050] Preferably, the solvent c has high solubility for the compound shown in formula 6.

[0051] Further preferably, in S300, the mass-volume ratio of the compound shown in formula 6 to the solvent c is 1g:(5-8)mL.

[0052] Further preferably, in S300, the acidic reagent comprises at least one of trifluoroacetic acid, hydrochloric acid, or sulfuric acid.

[0053] In S300 of the present application, due to the steric hindrance of the tert-butyl ester, the OH - It is difficult to attack the ester group with large steric hindrance, and the hydrolysis is difficult. Under acidic conditions, the acid (such as TFA, HCl, H2SO4) can first protonate the carbonyl oxygen of the ester (-C=O + H), enhance the electrophilicity of the carbonyl carbon, and make it easy to be attacked by water molecules.

[0054] Further preferably, in S300, the molar ratio of the compound of formula 6 to the acidic reagent is 1:(1-1.3).

[0055] Preferably, in S300, the time of the carboxyl deprotection reaction is 2h-3h.

[0056] Preferably, in S300, after the carboxyl deprotection reaction is completed, it further comprises: adding water to the reaction system to perform crystallization, solid-liquid separation and washing, beating the obtained solid with a beating liquid, solid-liquid separation and washing, freeze-drying, to obtain the cefoperazone sodium impurity H.

[0057] For example, in S300, the volume ratio of solvent c, water and beating liquid is (150-240):(350-420):(150-200).

[0058] Further preferably, in S300, the beating liquid comprises acetonitrile and water in a volume ratio of 1:(3-5).

[0059] Further preferably, in S300, the beating liquid comprises acetone and water in a volume ratio of 1:(3-5).

[0060] The present application has the following beneficial effects: The present application successfully develops a preparation method with significant advantages by systematically evaluating various synthesis paths and process parameters of cefoperazone sodium impurity H. This method breaks through the limitations of traditional processes and realizes the efficient directional generation of impurity H by using the strategy of precise control of the synthesis path. The present application is committed to improving the quality control level of cefoperazone sodium drug by developing drug impurity H reference substance, which has important value for perfecting the drug quality standard system and ensuring the safety of clinical medication, and will make a substantial contribution to public health security. BRIEF DESCRIPTION OF DRAWINGS

[0061] Figure 1 is the HPLC spectrum of impurity H (T=54.846min) in cefoperazone acid of the present application; Figure 2 is the HPLC spectrum of impurity H (T=54.530min) in cefoperazone sodium of the present application; Figure 3 HPLC chromatogram of the impurity H of cefoperazone sodium in Example 1 of the present application; Figure 4 LCMS chromatogram of the impurity H of cefoperazone sodium in Example 1 of the present application; Figure 5 HNMR chromatogram of the impurity H of cefoperazone sodium in Example 1 of the present application; DETAILED DESCRIPTION In order to make the objectives, technical solutions and advantages of the present application clearer, the present application will be further described in detail below in combination with examples. It should be understood that the specific examples described herein are only used to explain the present application and do not limit the present application.

[0062] A number of studies show that the dimer or multimer impurities are easily produced in the synthesis process of cefoperazone sodium, and the impurity H (polymer) is difficult to be completely removed by crystallization purification due to the similarity of molecular structure (see Journal of Pharmaceutical and Biomedical Analysis, 2010, 53(4): 1013-1017); the impurity H is detected in the samples of cefoperazone sodium produced by different manufacturers, and the content is between 0.1% and 0.3%, which confirms that the impurity is a process common impurity (see Drug Development and Industrial Pharmacy, 2015, 41(6): 1020-1026).

[0063] In order to verify that the impurity H is a key process-related impurity produced in the synthesis process of cefoperazone acid, the present application prepares cefoperazone acid and cefoperazone sodium by the conventional method of the prior art, and performs high performance liquid chromatography analysis on the prepared substances.

[0064] The preparation method of cefoperazone acid comprises the following steps: Step a, 7-TMCA 12 g, acetonitrile 60 mL are added to a dry 250 mL three-necked flask, N,O-bis(trimethylsilyl)acetamide (BSA) 8.2 g is added dropwise at room temperature, stirring reaction is performed for 2.5 h, the reaction solution is cooled to 0℃, and 7-TMCA solution is obtained.

[0065] Step b, HO-EPCP 13 g, N,N-dimethylacetamide 75 mL, acetonitrile 55 mL are added to a dry 250 mL three-necked flask, stirring is performed to cool to-25℃, 6.3 g of phosphorus oxychloride is added dropwise, and after the dropwise addition is completed, the reaction is continued for 1.5 h, and HO-EPCP acyl chloride solution is obtained.

[0066] The present application does not limit the order between step a and step b.

[0067] Step c, at -20℃±5℃, the HO-EPCP acyl chloride solution was added dropwise into the 7-TMCA solution, and after the dropwise addition was completed, the reaction was continued for 2h; then water 50mL, activated carbon 0.3g and sodium pyrosulfite 0.2g were added, and the mixture was decolored for 30min, then filtered, and the filter cake was washed with acetonitrile / water (1:2, by volume) 20g; the filtrate was transferred into a 1L reaction flask, and water 100mL was further added until crystals precipitated, and the mixture was stirred for 2h, then filtered, and the filter cake was dried at 45℃ under vacuum to obtain 21.8g of cefoperazone acid.

[0068] The cefoperazone acid prepared was analyzed by high performance liquid chromatography, and the results are shown in Table 1. Figure 1 As shown in Table 1, the HPLC content of the cefoperazone acid was 98.85%, and the content of impurity H (T=54.846min) was 0.68%.

[0069] The preparation method of cefoperazone sodium comprises the following steps: Step d, acetone 90mL was added into the reaction flask, and stirring was started, then cefoperazone acid 50g and purified water 50mL were added, and the pH was adjusted to 7 by dropwise adding saturated sodium bicarbonate solution at 5℃~10℃ until the cefoperazone acid particles disappeared and the pH no longer changed, indicating that the reaction was complete. Then 2g of activated carbon was added, and the mixture was decolored for 1h, then filtered with a 0.45μm filter, and the filtrate was placed in a clean bottle, and stirring was started while controlling the temperature at 15℃, then acetone 80mL, ethanol 50mL and crystal seeds 3g were added, and the mixture was stirred for 30min; the above-mentioned solution was added into the reaction flask in batches, and the mixture was stirred for 30min to crystallize, then filtered, and the filter cake was washed with water / acetone (5:95, by volume) 50mL, and dried at 40℃ to obtain 50.5g of white solid cefoperazone sodium.

[0070] The cefoperazone sodium prepared was analyzed by high performance liquid chromatography, and the results are shown in Table 2. Figure 2 As shown in Table 2, the HPLC content of the cefoperazone sodium was 99.21%, and the content of impurity H (T=54.530min) was 0.22%.

[0071] As can be seen from Table 1 and Table 2, Figures 1-2 Impurity H is a related impurity generated in the synthesis of cefoperazone acid, which is generated in the synthesis stage of cefoperazone acid, and is difficult to be effectively removed by conventional purification processes, and finally remains in the cefoperazone sodium finished product.

[0072] Studies have shown that impurity H is a polymer impurity, which may have immunogenicity or nephrotoxicity. For example, in terms of structural analogy toxicity, cefalosporin polymer impurities are prone to cause allergic reactions or renal tubular damage, and their toxicity is higher than that of monomer drugs (see Toxicology Letters, 2008, 180(2): 81-87); in terms of specific impurity toxicity, cefoperazone sodium polymer impurities show a tendency of renal tubular necrosis in animal experiments, suggesting that their content needs to be strictly controlled (see Regulatory Toxicology and Pharmacology, 2012, 64(1): 29-35); in terms of clinical adverse reactions, the adverse reactions (such as skin rash, abnormal renal function) of some cefoperazone sodium preparations are positively correlated with the content of polymer impurities (Journal of Clinical Pharmacy Case, Chinese Drug Warning, 2021, Vol. 18).

[0073] In the present application, the manufacturer not indicated is a product that can be obtained by purchase.

[0074] In order to better illustrate the present application, the following examples are further illustrated.

[0075] Example 1 The present embodiment provides a preparation method of cefoperazone sodium impurity H (see formula a), comprising the following steps: S100, the compound shown in formula 2 (30g, 0.09mol), dichloromethane (300mL, 10V) is added to a 1000mL three-necked flask, replaced by nitrogen for 3 times, cooled to 0℃, then the compound shown in formula 3 (30g, 0.14mol) and trifluoromethanesulfonic acid (1.37g, 0.01mol) are added, and the reaction is carried out at room temperature for 16h. 300mL water is added to the reaction system, the pH of the reaction system is adjusted to 7 with sodium bicarbonate, stirred for 10min, then separated, the water phase is extracted with 80mL dichloromethane, the organic phases are combined and washed with 300mL saturated brine, separated, the organic phase is dried with anhydrous sodium sulfate, filtered, the mother liquor is concentrated to dryness, the remaining residue is purified by dry column chromatography, eluted with eluent V (dichloromethane): V (methanol)=10:1, enriched product, 27.7g (0.07mol) of the compound shown in formula 4 is obtained, the yield is 78.9%, and the purity is 98.3%.

[0076] The molar ratio of the compound shown in formula 2, the compound shown in formula 3 and the acid catalyst trifluoromethanesulfonic acid is 1:1.5:0.1.

[0077] S200, the compound shown as formula 4 (35 g, 0.09 mol), dimethylformamide (280 mL, 8V) was added into a 1000 mL three-necked flask, stirred uniformly at room temperature, then the compound shown as formula 5 (64.6 g, 0.10 mol), HATU (41.5 g, 0.11 mol) and N,N-diisopropyl ethylamine (15.3 g, 0.12 mol) were added in sequence at room temperature, and the reaction was carried out for 16 h at room temperature. 1200 mL of water was added into the reaction system, stirred fully for 5 min, then separated, the aqueous phase was extracted with 400 mL of ethyl acetate, separated, and the aqueous phase was extracted with 300 mL of ethyl acetate again, the organic phases were combined and washed with 300 mL of saturated brine twice, the organic phase was dried with anhydrous sodium sulfate, filtered, the mother liquor was concentrated to dryness, the residue was purified by dry column chromatography, eluted with eluent V (dichloromethane):V (methanol)=20:1, after the product was enriched, 120 mL of V (ethyl acetate):V (n-hexane)=1:6 was used to beat the slurry at room temperature for 1 h, filtered, the filter cake was washed with n-hexane, and dried, to obtain 64.5 g (0.06 mol) of the compound shown as formula 6, the yield was 70.0% (calculated from the compound shown as formula 4), and the purity was 98.9%.

[0078] The molar ratio of the compound shown as formula 4, the compound shown as formula 5, the condensing agent HATU and the acid-binding agent N,N-diisopropyl ethylamine was 1:1.1:1.2:1.3.

[0079] It should be noted that the preparation of sufficient compound shown as formula 4 can be realized by performing step S100 twice.

[0080] S300, the compound shown as formula 6 (30 g, 0.03 mol), dimethylacetamide (150 mL, 5V) was added into a 500 mL three-necked flask, cooled to 2 ℃, and sulfuric acid (3 g, 0.03 mol) was added dropwise, and the reaction was carried out for 3 h after 5 min of dropping. 350 mL of water was slowly added into the reaction system, stirred fully, and a white solid was precipitated, filtered, the filter cake was washed with 80 mL of water, then 150 mL of V (water):V (acetonitrile)=4:1 was used to beat the slurry for 1.5 h, filtered, the filter cake was washed with 50 mL of V (water):V (acetonitrile)=4:1 (this compound is unstable at room temperature), and then freeze-dried, to obtain 14.7 g (0.02 mol) of impurity H, the yield was 51.9%, and the purity was 95.5%.

[0081] The molar ratio of the compound shown as formula 6 and the acidic reagent sulfuric acid was 1:1.03.

[0082] The impurity H prepared in Example 1 was subjected to high performance liquid chromatography analysis, liquid chromatography-mass spectrometry analysis and nuclear magnetic resonance hydrogen spectrum analysis respectively, and the results are shown as follows. Figures 3-5

[0083] Example 2​ The embodiment provides a preparation method of cefoperazone sodium impurity H (see formula a), which comprises the following steps. S100, the compound shown in formula 2 (30 g, 0.09 mol) and tetrahydrofuran (270 mL, 9V) are added into a 1000 mL three-necked flask, replaced with nitrogen for 3 times, cooled to 5 DEG C, then the compound shown in formula 3 (31.9 g, 0.15 mol) and boron trifluoride ether (1.1 g, 0.01 mol) are added, and the reaction is carried out at room temperature for 24 h. 280 mL of water is added into the reaction system, the pH value of the reaction system is adjusted to 27.5 by sodium bicarbonate, and after stirring for 10 min, the liquid is separated, the water phase is extracted with 70 mL of tetrahydrofuran, the organic phases are combined and washed with 280 mL of saturated brine, the liquid is separated, the organic phase is dried with anhydrous sodium sulfate, filtered, the mother liquor is concentrated to dryness, the concentrated residue is purified by dry column chromatography, elution is carried out with eluent V (dichloromethane): V (methanol) = 12:1, the product is enriched, and 27.6 g (0.07 mol) of the compound shown in formula 4 is obtained, the yield is 78.6%, and the purity is 98.4%.

[0084] The molar ratio of the compound shown in formula 2, the compound shown in formula 3 and the acid catalyst boron trifluoride ether is 1:1.6:0.08.

[0085] S200, the compound shown in formula 4 (35 g, 0.09 mol) and dichloromethane (245 mL, 7V) are added into a 1000 mL three-necked flask, stirred uniformly at room temperature, then the compound shown in formula 5 (58.8 g, 0.09 mol), TBTU (35.1 g, 0.11 mol) and triethylamine (12.0 g, 0.12 mol) are added in sequence, and the reaction is carried out at room temperature for 18 h. 1000 mL of water is added into the reaction system, the liquid is separated after stirring for 5 min, the water phase is extracted with 400 mL of dichloromethane, the liquid is separated, the water phase is extracted with 300 mL of dichloromethane again, the organic phases are combined and washed with 280 mL of saturated brine for 2 times, the organic phase is dried with anhydrous sodium sulfate, filtered, the mother liquor is concentrated to dryness, the concentrated residue is purified by dry column chromatography, elution is carried out with eluent V (dichloromethane): V (methanol) = 10:1, the product is enriched, then the residue is slurried with 120 mL V (ethyl acetate): V (petroleum ether) = 1:4 at room temperature for 1 h, filtered, the filter cake is washed with petroleum ether, and dried to obtain 55.0 g (0.05 mol) of the compound shown in formula 6, the yield is 59.7%, and the purity is 98.7%.

[0086] The molar ratio of the compound shown in formula 4, the compound shown in formula 5, the condensation agent TBTU and the acid-binding agent triethylamine is 1:1:1.2:1.3.

[0087] It should be noted that the present embodiment can be realized by performing two steps S100 to prepare the compound shown in formula 4.

[0088] S300, the compound shown in formula 6 (30 g, 0.03 mol), dichloromethane (180 mL, 6V) was added to a 500 mL three-necked flask, cooled to 0°C, hydrochloric acid (1.3 g, 0.04 mol) was added dropwise, 5 min dropwise, and the reaction was maintained for 2.5 h. 380 mL of water was slowly added to the reaction system, stirred thoroughly, and a white solid was precipitated. After filtration, the filter cake was washed with 80 mL of water, then 180 mL of slurry liquid V (water):V(acetonitrile)=3:1 was used to slurry for 1.5 h, and then filtered. The filter cake was washed with 50 mL of V (water):V(acetonitrile)=3:1 (this compound is unstable at room temperature), and then freeze-dried to obtain 14.4 g (0.02 mol) of impurity H, with a yield of 50.8% and a purity of 95.1%.

[0089] The molar ratio of the compound shown in formula 6 to the acidic reagent hydrochloric acid is 1:1.2.

[0090] Example 3 The present embodiment provides a method for preparing cefoperazone sodium impurity H (see formula a), comprising the following steps: S100, the compound shown in formula 2 (30 g, 0.09 mol), dimethyl sulfoxide (240 mL, 8V) was added to a 1000 mL three-necked flask, replaced with nitrogen for 3 times, cooled to 0°C, then the compound shown in formula 3 (24 g, 0.11 mol) and boron trifluoride ether (0.7 g, 0.005 mol) were added, and the reaction was maintained at room temperature for 14 h. 250 mL of water was added to the reaction system, and the pH of the reaction system was adjusted to 8 with sodium bicarbonate. After stirring for 10 min, the liquid was separated, the aqueous phase was extracted with 60 mL of dimethyl sulfoxide, and the organic phase was combined and washed with 250 mL of saturated brine. The organic phase was dried with anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to dryness. The residue was purified by dry column chromatography using eluent V(dichloromethane):V(methanol)=8:1 to enrich the product, and 27.1 g (0.07 mol) of the compound shown in formula 4 was obtained, with a yield of 77.2% and a purity of 98.1%.

[0091] The molar ratio of the compound shown in formula 2, the compound shown in formula 3, and the acidic catalyst boron trifluoride ether is 1:1.2:0.05.

[0092] S200, the compound shown in formula 4 (35 g, 0.09 mol), toluene (175 mL, 5V) was added into a 500 mL three-necked flask, stirred uniformly at room temperature, then the compound shown in formula 5 (82.3 g, 0.13 mol), HBTU (38 g, 0.10 mol) and pyridine (9.4 g, 0.12 mol) were added in turn, and reacted at room temperature for 20 h. 800 mL of water was added to the reaction system, stirred fully for 5 min, then separated, the aqueous phase was extracted with 400 mL of ethyl acetate, separated, and the aqueous phase was extracted with 300 mL of ethyl acetate again, the organic phases were combined and washed with 250 mL of saturated brine twice, the organic phase was dried with anhydrous sodium sulfate, filtered, the mother liquor was concentrated to dryness, the residue was purified by dry column chromatography, eluted with eluent V (dichloromethane):V (methanol)=30:1, after enrichment of the product, 120 mL of V (ethyl acetate):V (n-hexane)=1:8 was used to beat the slurry at room temperature for 1 h, filtered, the filter cake was washed with n-hexane, and dried to obtain 47.5 g (0.05 mol) of the compound shown in formula 6, with a yield of 51.6% and a purity of 98.0%.

[0093] The molar ratio of the compound shown in formula 4, the compound shown in formula 5, the condensing agent HBTU and the acid-binding agent pyridine was 1:1.4:1.1:1.3.

[0094] It should be noted that the preparation of the compound shown in formula 4 can be realized by performing the step S100 twice.

[0095] S300, the compound shown in formula 6 (30 g, 0.03 mol), anhydrous ethanol (210 mL, 7V) was added into a 500 mL three-necked flask, cooled to 5℃, trifluoroacetic acid (3.7 g, 0.03 mol) was added dropwise, and reacted for 2 h after 5 min of dropping. 400 mL of water was slowly added to the reaction system, stirred fully, and a white solid was precipitated, filtered, the filter cake was washed with 80 mL of water, then 180 mL of V (water):V (acetone)=5:1 was used to beat the slurry for 1.5 h, filtered, the filter cake was washed with 50 mL of V (water):V (acetone)=5:1 (this compound is unstable at room temperature), and freeze-dried to obtain 14.9 g (0.02 mol) of impurity H, with a yield of 52.6% and a purity of 95.2%.

[0096] The molar ratio of the compound shown in formula 6 and the acidic reagent trifluoroacetic acid was 1:1.09.

[0097] Example 4 The embodiment provides a preparation method of the impurity H of cefoperazone sodium (see formula a), which comprises the following steps. S100, the compound shown in formula 2 (30 g, 0.09 mol), dimethylformamide (210 mL, 7V) is added into a 1000 mL three-necked flask, replaced with nitrogen for 3 times, cooled to 3℃, then the compound shown in formula 3 (26.5 g, 0.12 mol) and trifluoromethanesulfonic acid (0.9 g, 0.01 mol) are added, and the reaction is carried out at room temperature for 20 h. 260 mL of water is added into the reaction system, and the pH of the reaction system is adjusted to 7.5 with sodium bicarbonate. After stirring for 10 min, the liquid is separated, the water phase is extracted with 70 mL of dimethylformamide, the organic phases are combined and washed with 260 mL of saturated brine, the liquid is separated, the organic phase is dried with anhydrous sodium sulfate, filtered, the mother liquor is concentrated to dryness, and the residue is purified by dry column chromatography. The eluent is V (dichloromethane): V (methanol) = 15:1, the product is enriched, and 27.3 g (0.07 mol) of the compound shown in formula 4 is obtained, with a yield of 77.7% and a purity of 98.2%.

[0098] The molar ratio of the compound shown in formula 2, the compound shown in formula 3 and the acidic catalyst trifluoromethanesulfonic acid is 1:1.33:0.07.

[0099] S200, the compound shown in formula 4 (35 g, 0.09 mol), acetonitrile (210 mL, 6V) is added into a 500 mL three-necked flask, stirred uniformly at room temperature, then the compound shown in formula 5 (70.5 g, 0.11 mol), HATU (34.6 g, 0.09 mol) and N,N-diisopropyl ethylamine (17.6 g, 0.14 mol) are added in sequence, and the reaction is carried out at room temperature for 22 h. 1000 mL of water is added into the reaction system, the liquid is separated after stirring for 5 min, the water phase is extracted with 400 mL of ethyl acetate, the liquid is separated, the water phase is extracted with 300 mL of ethyl acetate again, the organic phases are combined and washed with 270 mL of saturated brine twice, the organic phase is dried with anhydrous sodium sulfate, filtered, the mother liquor is concentrated to dryness, and the residue is purified by dry column chromatography. The eluent is V (dichloromethane): V (methanol) = 20:1, the product is enriched, then 120 mL of V (ethyl acetate): V (n-hexane) = 1:6 is used to beat the slurry at room temperature for 1 h, filtered, the filter cake is washed with n-hexane, dried, and 63.5 g (0.06 mol) of the compound shown in formula 6 is obtained, with a yield of 68.9% and a purity of 98.8%.

[0100] The molar ratio of the compound shown in formula 4, the compound shown in formula 5, the condensing agent HATU and the acid-binding agent N,N-diisopropyl ethylamine is 1:1.2:1:1.5.

[0101] It should be noted that the preparation of the compound shown in formula 4 can be realized by carrying out the step S100 twice.

[0102] S300. The compound shown in Formula 6 (30 g, 0.03 mol) and acetonitrile (240 mL, 8V) were added to a 500 mL three-necked flask. The mixture was cooled to 3 °C, and sulfuric acid (3.7 g, 0.04 mol) was added dropwise over 5 min. The mixture was kept at this temperature for 3 h. 420 mL of water was slowly added to the reaction system, and the mixture was stirred thoroughly. A white solid precipitated. The solid was filtered, and the filter cake was washed with 80 mL of water. The mixture was then slurried with 200 mL of a slurry (V(water):V(acetonitrile) = 4:1) for 1.5 h. The mixture was filtered, and the filter cake was washed with 50 mL of a slurry (V(water):V(acetonitrile) = 4:1) (this compound is unstable at room temperature). The mixture was then freeze-dried to obtain 14.5 g (0.02 mol) of impurity H, with a yield of 51.2% and a purity of 95.6%.

[0103] The molar ratio of the compound shown in Formula 6 to the acidic reagent sulfuric acid is 1:1.27.

[0104] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of Cefoperazone sodium impurity H, characterized in that, The method comprises the following steps: a carboxyl protection reaction of a compound shown in formula 2 with a compound shown in formula 3 to obtain a compound shown in formula 4; a condensation reaction of the compound shown in formula 4 with a compound shown in formula 5 to obtain a compound shown in formula 6; a carboxyl deprotection reaction of the compound shown in formula 6 to obtain the cefoperazone sodium impurity H shown in formula 1. Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 Formula 1.

2. The process for the preparation of Cefoperazone sodium impurity H as claimed in claim 1 wherein, The preparation method of the cefoperazone sodium impurity H specifically comprises the following steps: S100, under an inert atmosphere, the compound shown in formula 2 and the compound shown in formula 3 are added into an aprotic solvent a, and a carboxyl protection reaction is carried out under the action of an acidic catalyst to obtain the compound shown in formula 4; S200, the compound shown in formula 4 and the compound shown in formula 5 are added into an aprotic solvent b, and a condensation reaction is carried out under the action of a condensing agent and an acid-binding agent to obtain the compound shown in formula 6; S300, the compound shown in formula 6 is added into a solvent c, and a carboxyl deprotection reaction is carried out under the action of an acidic reagent at 0-5 DEG C to obtain the cefoperazone sodium impurity H.

3. The process for the preparation of Cefoperazone sodium impurity H according to claim 1 or 2, characterized in that, The molar ratio of the compound shown in formula 2 to the compound shown in formula 3 is 1:(1.2-1.6); The molar ratio of the compound shown in formula 4 to the compound shown in formula 5 is 1:(1-1.4).

4. The process for the preparation of Cefoperazone sodium impurity H according to claim 1 or 2, characterized in that, The carboxyl protection reaction is carried out at a temperature of 15-40 DEG C for 12-24 hours; The condensation reaction is carried out at a temperature of 15-40 DEG C for 16-24 hours; The carboxyl deprotection reaction is carried out for 2-3 hours.

5. The method for preparing cefoperazone sodium impurity H as described in claim 2, characterized in that, In S100, the aprotic solvent a comprises at least one of dichloromethane, tetrahydrofuran, dimethyl sulfoxide or dimethyl formamide; In S100, the acidic catalyst comprises at least one of boron trifluoride etherate or trifluoromethanesulfonic acid.

6. The process for the preparation of Cefoperazone sodium impurity H as claimed in claim 2 or 4 wherein, In S100, the mass-volume ratio of the compound shown in formula 2 to the aprotic solvent a is 1g:(7-10)mL; In S100, the molar ratio of the compound shown in formula 2 to the acidic catalyst is 1:(0.05-0.1).

7. The method for preparing cefoperazone sodium impurity H as described in claim 2, characterized in that, In S200, the aprotic solvent b comprises at least one of dichloromethane, acetonitrile, toluene or dimethyl formamide; In S200, the condensing agent comprises at least one of a polypeptide condensing agent or a carbonium salt condensing agent; In S200, the acid-binding agent comprises at least one of triethylamine, N,N-diisopropyl ethylamine or pyridine.

8. The process for the preparation of Cefoperazone sodium impurity H according to claim 2 or 7, characterized in that, In S200, the mass-volume ratio of the compound shown in formula 4 to the aprotic solvent b is 1g:(5-8)mL; In S200, the condensing agent comprises at least one of 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate, O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium tetrafluoroborate or O-(benzotriazol-1-yl)-bis(dimethylamino)carbonium hexafluorophosphate; the molar ratio of the compound shown in formula 4 to the condensing agent is 1:(1-1.2); In S200, the molar ratio of the compound shown in formula 4 to the acid-binding agent is 1:(1-1.5).

9. The method for preparing cefoperazone sodium impurity H as described in claim 2, characterized in that, In S300, the solvent c includes at least one of dichloromethane, methanol, ethanol, dimethylacetamide or acetonitrile. In S300, the acidic reagent includes at least one of trifluoroacetic acid, hydrochloric acid or sulfuric acid.

10. The process for the preparation of Cefoperazone sodium impurity H as claimed in claim 2 or 9 wherein, In S300, the mass-volume ratio of the compound of formula 6 to the solvent c is 1 g:(5-8) mL. In S300, the molar ratio of the compound of formula 6 to the acidic reagent is 1:(1-1.3).

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