Process for the preparation of a ceflomandole intermediate

Abstract

The application provides a preparation process of a ceflomandole intermediate, and belongs to the technical field of drug synthesis. The preparation process of the ceflomandole intermediate is as follows: under an inert atmosphere, a coupling reaction of a reaction raw material compound I and UBT occurs under the action of a catalyst and a ligand, so that the ceflomandole intermediate is obtained; wherein the catalyst comprises a copper salt and a rubidium salt; the ligand comprises any one of a nitrogen-containing heterocyclic ligand or an organic phosphorus ligand; the structure of the compound I is shown in formula (1). The catalyst system comprising the copper salt and the rubidium salt is used to form a complex by coordination and complexation with the ligand, the compound I and UBT are coupled to prepare the ceflomandole intermediate with high efficiency and high selectivity, the yield is high, the time consumption is short, the production efficiency is improved, the catalyst cost is low, the consumption of noble metals is reduced, the cost is saved, the quality is ensured, and the industrial value is extremely high, so that an economic and efficient scheme is provided for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, and particularly relates to a preparation process of a ceftolozane intermediate. BACKGROUND

[0002] Cephalosporin antibiotics as an important drug for clinical treatment of bacterial infections play a key role in the field of anti-infection treatment. As a new fifth-generation cephalosporin antibiotic, ceftolozane exhibits strong antibacterial activity against Pseudomonas aeruginosa and multiple drug-resistant bacteria such as gram-negative bacteria, and shows significant therapeutic effect in the treatment of complex intra-abdominal infection (cIAI) and complex urinary tract infection (cUTI), and has a broad clinical application prospect. The medicinal form of ceftolozane is mainly sulfate, that is, ceftolozane sulfate, and its chemical structure is shown as formula (2):

[0003]

[0004] In the synthesis process of ceftolozane sulfate, the synthesis of the key intermediate ceftolozane trifluoroacetate (TATD-QUATE) is crucial, and the purity and yield thereof directly affect the production efficiency and cost of the final product. The chemical structure of ceftolozane trifluoroacetate is shown as formula (3):

[0005]

[0006] Patent WO2016109259 discloses a preparation method of ceftolozane sulfate. In the method, compound I (structure as shown in formula (1)) is used as a starting material, and reacts with 3-side chain UBT (structure as shown in formula (4)) under the catalysis of 1,3-bis(trimethylsilyl)urea and potassium iodide, and then ceftolozane trifluoroacetate is obtained. However, in the actual application process, the reaction has the problem of too long reaction time, which leads to low production efficiency and unsatisfactory reaction effect, and it is difficult to meet the needs of large-scale industrial production. In order to solve the above problems, patent WO2016025839 proposes an improved scheme, which replaces the catalytic reaction system of 1,3-bis(trimethylsilyl)urea and potassium iodide in patent WO2016109259 with a catalytic reaction system composed of transition metal palladium and phosphine ligand coordinated therewith. This improvement improves the reaction efficiency to some extent, but new problems also come with it. Palladium as an expensive metal, its large-scale use in industrial production will increase the process cost, which is not conducive to the scale-up production of the reaction and limits the wide application of the process in the industrial field.

[0007]

[0008] In view of the problems in the prior art, it is urgent to develop a preparation process of ceftarolozane sulfate which can meet the production efficiency and effectively reduce the production cost. SUMMARY

[0009] In view of the problems in the prior art, the present application discloses a preparation process of a ceftarolozane intermediate, which has high yield and low by-product content when prepared by a catalytic system containing copper salt and rubidium salt, thereby improving the production efficiency of the ceftarolozane intermediate while reducing the process cost.

[0010] In order to achieve the above technical purposes, the present application provides a preparation process of a ceftarolozane intermediate, which comprises: under an inert atmosphere, coupling reaction of a reaction raw material compound I and UBT under the action of a catalyst and a ligand to obtain the ceftarolozane intermediate; wherein the catalyst comprises copper salt and rubidium salt; and the ligand comprises any one of nitrogen-containing heterocyclic ligand or organic phosphorus ligand.

[0011] The structure of the compound I is shown in formula (1):

[0012]

[0013] The reaction process of the above technical solution is as follows:

[0014]

[0015] In the coupling reaction of compound I and UBT, the patent WO2016025839 uses transition metal palladium and phosphine ligand coordinated therewith as a catalytic reaction system to perform the coupling reaction, which improves the reaction efficiency compared with the catalytic reaction system of 1,3-bis(trimethylsilyl)urea and potassium iodide in the patent WO2016109259, so based on WO2016025839, the research and development team of the present application attempts to use a lower-cost metal as a catalyst for experimental exploration, and finds that: using a single copper metal catalyst has a certain catalytic effect, but the effect is limited, and it is difficult to meet the needs of industrial application, and using a single rubidium metal catalyst has incomplete reaction conversion, and the catalytic effect has obvious defects; however, when the research and development team attempts to apply a catalytic system containing both copper salt and rubidium salt to the coupling reaction of compound I and UBT active substances, it is accidentally found that the two have a synergistic catalytic effect, which significantly improves the reaction rate and product yield. Based on this discovery, the reaction process of the above technical solution can prepare a high-purity, high-yield ceftarolozane intermediate through the coordination complex mechanism of copper, rubidium metal and ligand. At the same time, the catalytic system used in the present application is copper salt and rubidium salt which are low in price, and this feature makes it have a significant advantage in large-scale industrial production, can greatly reduce the process cost, and has very high application value and economic potential.

[0016] In some embodiments, the copper salt comprises one or more of cuprous chloride, cuprous iodide or cuprous bromide;

[0017] and / or, the rubidium salt comprises one or more of rubidium chloride, rubidium bromide, rubidium iodide or rubidium sulfate;

[0018] Preferably, the copper salt is cuprous iodide; and / or, the rubidium salt is one or both of rubidium iodide or rubidium bromide.

[0019] In some embodiments, the total molar amount of the copper salt and the rubidium salt is 10% to 20%, preferably 15% to 20% of the molar amount of the compound I.

[0020] In some embodiments, the molar ratio of the copper salt and the rubidium salt is (0.5 to 2): 1, preferably (1 to 2): 1, further preferably 2: 1.

[0021] In some embodiments, the ligand comprises at least one of 1,10-phenanthroline, triphenylphosphine, bipyridine.

[0022] In some embodiments, the ratio of the total molar amount of the copper salt and the rubidium salt to the molar amount of the ligand is 1:(1 to 5), preferably 1:(2 to 5).

[0023] In some embodiments, the coupling reaction is carried out in a solvent comprising one or more of N-methylpyrrolidone, N,N-dimethylformamide, tetrahydrofuran, toluene, preferably any one of N-methylpyrrolidone, N,N-dimethylformamide or tetrahydrofuran.

[0024] In some embodiments, the mass ratio of the solvent to the compound I is (1 to 10): 1, preferably (2 to 10): 1.

[0025] In some embodiments, the temperature of the coupling reaction is 20 to 90°C, preferably 20 to 50°C, further preferably 20 to 30°C.

[0026] In some embodiments, the preparation process further comprises a deprotection step: after extraction, the organic phase is obtained, and benzyl ether and trifluoroacetic acid are sequentially added to the organic phase for deprotection. Specifically, the reaction material is extracted with ethyl acetate solvent, and the obtained organic phase is concentrated, benzyl ether is added, and trifluoroacetic acid is slowly added at a temperature of 0 to 5°C, and then the temperature is raised to 15 to 25°C for deprotection. Optionally, the mass ratio of compound I to benzyl ether is 1:(0.5 to 2); the mass ratio of compound I to trifluoroacetic acid is 1:(2 to 5).

[0027] In some embodiments, the preparation process further comprises crystallization purification of the reacted material by using a poor solvent; the poor solvent is any one of diethyl ether, diisopropyl ether, cyclohexanone, isobutyl ether, cyclohexane, n-hexane, methyl tert-butyl ether, preferably any one of isobutyl ether, cyclohexane, n-hexane, methyl tert-butyl ether. Optionally, the poor solvent is added in an amount of 2-5 times the volume of anisole.

[0028] Optionally, the crystallization purification step further comprises: solid-liquid separation and drying of the crystallized material to obtain the ceftaroline fosamil intermediate.

[0029] Compared with the prior art, the present application has the following beneficial effects: the catalytic system containing copper salt and rubidium salt and the ligand are complexed to form a complex, which can efficiently catalyze the coupling reaction of compound I and active substance UBT to prepare the ceftaroline fosamil intermediate, not only with high reaction yield and reduced reaction time, but also greatly improving the production efficiency; and the catalyst used is low in cost, effectively reducing the consumption of noble metals such as palladium metal, significantly saving the production cost, ensuring the product quality, and showing high industrial application value, thereby providing an economic and efficient technical scheme for large-scale production of the ceftaroline fosamil intermediate. BRIEF DESCRIPTION OF DRAWINGS

[0030] The drawings constituting a part of the specification illustrate the present application and, together with the description, serve to explain the principles of the application. In the drawings:

[0031] Figure 1 The liquid chromatogram of the ceftaroline fosamil intermediate prepared in Example 1.4 of the present application is shown. DETAILED DESCRIPTION

[0032] In order to facilitate the understanding of the present application, the present application will be described more fully below, and preferred embodiments of the present application are given. However, it should be understood that these embodiments are only used for more detailed description, and should not be understood as limiting the present application in any form, i.e. not intended to limit the protection scope of the present application.

[0033] Unless otherwise defined, the technical terms used in the following examples have the same meaning as generally understood by those skilled in the art to which the present application belongs. The test reagents used in the following examples, unless otherwise specified, are conventional biochemical reagents; and the experimental methods, unless otherwise specified, are conventional methods.

[0034] In the present application, the inert atmosphere refers to a gaseous environment composed of a gas that does not chemically interact with the reactants, such as a nitrogen atmosphere, or an atmosphere formed by a zero group element gas (such as argon) in the periodic table.

[0035] In the present application, compound I is a commercially available product or is prepared by conventional methods in the prior art, such as amide condensation reaction of GCLE (7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxy benzyl ester) as a starting material after modification, and activated side chain TATD ((Z)-2-[(5-amino-[1,2,4]thiadiazol-3-yl)-carboxy-methyleneaminooxy]-2-methyl-propionic acid tert-butyl ester). The specific experimental method is referred to the preparation method of compound I in the related patent WO2016025813.

[0036] In the embodiments of the present application, the reaction time of "-" represents that the reaction time is too long, greater than 24 h; the purity and yield of "-" represent that the purity or yield of the ceftaroline intermediate is <40%.

[0037] In the embodiments of the present application, "copper salt / rubidium salt" represents copper salt and rubidium salt, and exemplary "cuprous chloride / rubidium iodide" represents cuprous chloride and rubidium iodide.

[0038] Exploration Example 1

[0039] The present exploration example explores the influence of a single catalyst on the preparation process of the ceftaroline intermediate. The specific steps are as follows:

[0040] (1) Preparation process: under nitrogen protection, compound I (680 g, 1.0 mol), UBT (594.6 g, 1.1 mol) and solvent DMF (the amount of DMF is 6 times the mass of compound I) are added to a reaction bottle. The temperature is controlled at 20-30°C, a certain amount of copper salt or rubidium salt is added to the reaction system, and ligand triphenylphosphine (78.72 g, 0.3 mol) is added and stirred to dissolve completely. After dissolution, the temperature of the reaction system is controlled at 20°C±5°C, and the reaction is stirred at this temperature for a certain time. The reaction progress is monitored by HPLC, and when the content of the raw material compound I is detected to be reduced to 2.0% or less, it is inferred that the reaction is completed. After the reaction is completed, the reaction material is cooled and purified.

[0041] (2) Deprotection and crystallization purification process: ethyl acetate is added to the cooled reaction material, and water is added for liquid-liquid extraction. The obtained organic phase is concentrated, 750 g of anisole is added, and the temperature is controlled at 0-5°C. Tri fluoroacetic acid (the mass ratio of compound I to tri fluoroacetic acid is 1:3) is slowly added dropwise, and after the dropwise addition is completed, the temperature is increased to 20°C for deprotection. After the deprotection reaction is completed, the temperature is decreased to 0-5°C, and a poor solvent 2.3 L of n-hexane is added dropwise for crystallization. After the dropwise addition is completed, the temperature is increased to 20°C for crystallization for 2 h. The filtered solid is dried under vacuum to obtain a white-like ceftaroline intermediate.

[0042] The purity and yield of the ceftaroline intermediate prepared by using different types of copper salt and rubidium salt are shown in Table 1.

[0043] Table 1

[0044]

[0045] As can be seen from Table 1, when a single copper salt catalyst is used, the purity of the reaction in the preparation process of the ceftaroline intermediate is between 92.3% and 95.5%, and the yield is between 50.5% and 70.2%, indicating that the single copper salt catalyst has a certain catalytic effect on the preparation of the ceftaroline intermediate, but its catalytic effect is poorer than that of the palladium acetate catalyst; when a single rubidium salt catalyst is used, it is found through experimental observation that the reaction is very slow and the impurities are more, and the purity and yield of the prepared ceftaroline intermediate are both less than 40%; when the catalytic system containing copper salt and rubidium salt (exploration example 1.8) is unexpectedly applied to the coupling reaction of compound I and UBT active substance by the research and development team of the present application, an unexpected synergistic catalytic effect is generated between the two, which not only reduces the reaction time compared with the single metal copper salt catalyst, the single metal rubidium salt catalyst and the palladium acetate, but also significantly improves the reaction yield and purity.

[0046] Example 1

[0047] A preparation process of a ceftaroline intermediate, the specific steps of which are as follows:

[0048] (1) Preparation process: under nitrogen protection, compound I (680 g, 1.0 mol), UBT (594.6 g, 1.1 mol) and a solvent DMF (the amount of DMF is 6 times the mass of compound I) are added to a reaction bottle. The temperature is controlled at 20-30°C, a certain amount of copper salt and rubidium salt are added to the reaction system, and a ligand triphenylphosphine (78.72 g, 0.3 mol) is added and stirred to dissolve completely. After dissolution, the temperature of the reaction system is controlled at 20°C±5°C, and stirring is carried out at this temperature for 4 hours. The reaction progress is monitored by HPLC, and when the content of the raw material compound I is detected to be reduced to 2.0% or less, it is inferred that the reaction is completed. After the reaction is completed, the reaction material is cooled and purified.

[0049] (2) Deprotection and crystallization purification process: ethyl acetate is added to the cooled reaction material, and water is added for liquid-liquid extraction. The obtained organic phase is concentrated, 750 g of anisole is added, and the temperature is controlled at 0-5°C. Tri fluoroacetic acid (the mass ratio of compound I to tri fluoroacetic acid is 1:4) is slowly added dropwise, and after the dropwise addition is completed, the temperature is raised to 20°C for deprotection. After the deprotection reaction is completed, the temperature is lowered to 0-5°C, and a poor solvent 2.3 L of methyl tert-butyl ether is added dropwise for crystallization. After the dropwise addition is completed, the temperature is raised to 20°C for 2 h, and the filtered solid is vacuum dried to obtain a white-like ceftaroline intermediate.

[0050] The reaction formula of the preparation process of the ceflomandole intermediate of the present embodiment is as follows:

[0051]

[0052] In the catalytic system comprising the copper salt and the rubidium salt, the molar amount of the copper salt and the rubidium salt are controlled based on the feeding molar amount of compound I. When the molar amount of the copper salt and the rubidium salt are both 10%, the purity and yield of the ceflomandole intermediate prepared by using different types of copper salt and rubidium salt are shown in Table 2.

[0053] Table 2

[0054]

[0055] As can be seen from the data in Table 2, when the molar amount of the copper salt and the rubidium salt are both 10%, the purity of the ceflomandole intermediate prepared by using different types of copper salt and rubidium salt is above 97% and the yield is in the range of 88% to 92% except for Example 1.13, and when the copper salt is cuprous iodide and the rubidium salt is rubidium iodide, the purity of the ceflomandole intermediate prepared is 99% and the yield is 92%. Therefore, in the preparation process of the ceflomandole intermediate of the present embodiment, the copper salt comprises one or more of cuprous chloride, cuprous iodide or cuprous bromide; and the rubidium salt comprises one or more of rubidium chloride, rubidium bromide, rubidium iodide or rubidium sulfate.

[0056] Example 2

[0057] Based on the preparation process of the ceflomandole intermediate of Example 1, the molar amount of the copper salt and the rubidium salt is changed in the present embodiment, and other parameters and control conditions are the same.

[0058] When the molar amount of the copper salt and the rubidium salt are both 5% and other parameters and control conditions are the same, the purity and yield of the ceflomandole intermediate prepared are shown in Table 3.

[0059] Table 3

[0060]

[0061] When the molar amount of the copper salt is 5% and the molar amount of the rubidium salt is 10% and other parameters and control conditions are the same, the purity and yield of the ceflomandole intermediate prepared are shown in Table 4.

[0062] Table 4

[0063]

[0064]

[0065] When the molar amount of copper salt is 10%, the molar amount of rubidium salt is 5%, and other parameters and control conditions are the same, the purity and yield of the cefllozane intermediate prepared are shown in Table 5.

[0066] Table 5

[0067]

[0068] As can be seen from the data in Tables 3-5, changing the molar amount of copper salt and rubidium salt has different purities and yields; except for copper sulfate / rubidium sulfate, when the molar amount of copper salt accounts for more than the molar amount of rubidium salt, the purity and yield of the cefllozane intermediate prepared (Examples 2.27-2.38) are higher than when the molar amount of rubidium salt accounts for more than the molar amount of copper salt (Examples 2.14-2.25). It is particularly noted that, compared to Example 1.11, when the amount of cuprous iodide is unchanged and the amount of rubidium iodide is reduced to 5% (Example 2.37), the purity of the cefllozane intermediate prepared is still 99% and the yield is 92%; therefore, when the amount of rubidium iodide is reduced to 5%, the original purity and yield can still be maintained.

[0069] Example 3

[0070] In this example, other parameters and control conditions are the same, and only the type of ligand is different.

[0071] A preparation process of a cefllozane intermediate, the specific steps of which are as follows:

[0072] (1) Preparation process: under nitrogen protection, compound I (680 g, 1.0 mol), UBT (594.6 g, 1.1 mol), and solvent DMF (the amount of DMF is 6 times the mass of compound I) are added to a reaction bottle. The system is controlled at 20-30°C, cuprous iodide (0.1 mol) and rubidium iodide (0.05 mol) are added to the reaction system, and 0.3 mol of different types of ligands are added, and stirred to dissolve completely. After dissolution is complete, the temperature of the reaction system is controlled at 20°C±5°C, and stirring is carried out at this temperature for a certain period of time. The reaction progress is monitored by HPLC, and when the content of the raw material compound I is detected to be reduced to 2.0% or less, it is inferred that the reaction is complete. After the reaction is complete, the reaction material is cooled and purified.

[0073] (2) Deprotection and crystallization purification process: ethyl acetate was added to the cooled reaction material, and water was added for liquid-liquid extraction, and the obtained organic phase was concentrated and 750 g of anisole was added, and trifluoroacetic acid (mass ratio of compound I to trifluoroacetic acid 1:3) was slowly added dropwise at a temperature of 0-5°C, and after the dropwise addition was completed, the temperature was increased to 20°C for deprotection; after the deprotection reaction was completed, the temperature was decreased to 0-5°C, and 2.3 L of a poor solvent cyclohexane was added dropwise for crystallization, and after the dropwise addition was completed, the temperature was increased to 20°C for crystallization for 2 h, and the filtered solid was vacuum dried to obtain a white ceflomandole intermediate.

[0074] The purity and yield of the ceflomandole intermediate prepared by using different types of ligands are shown in Table 6.

[0075] Table 6

[0076]

[0077] As can be seen from the data in Table 6, in the catalytic system containing copper salt and rubidium salt, the ligand is 1,10-phenanthroline, triphenylphosphine or bipyridine, and a ceflomandole intermediate with high purity and yield can be obtained.

[0078] Example 4

[0079] In this example, other parameters and control conditions are the same, and only the amount of ligand added is different.

[0080] A preparation process of a ceflomandole intermediate, the specific steps of which are as follows:

[0081] (1) Preparation process: under nitrogen protection, compound I (680 g, 1.0 mol), UBT (594.6 g, 1.1 mol) and solvent DMF (the amount of DMF is 6 times the mass of compound I) were added to the reaction bottle. The temperature was controlled at 20-30°C, and cuprous iodide (0.1 mol) and rubidium iodide (0.05 mol) were added to the reaction system, and different amounts of 1,10-phenanthroline were added, and stirred to dissolve completely. After the dissolution was completed, the temperature of the reaction system was controlled at 20°C±5°C, and stirred at this temperature for 4 h. The reaction progress was monitored by HPLC, and when the content of the raw material compound I was detected to be reduced to 2.0% or less, it was determined that the reaction was completed. After the reaction was completed, the reaction material was cooled and purified.

[0082] (2) Deprotection and crystallization purification process: ethyl acetate was added to the cooled reaction material, and water was added for liquid-liquid extraction, and the obtained organic phase was concentrated, then 750 g of anisole was added, and trifluoroacetic acid (the mass ratio of compound I to trifluoroacetic acid was 1:3) was slowly added dropwise at a temperature of 0-5°C, and then the temperature was increased to 20°C for deprotection; after the deprotection reaction was completed, the temperature was decreased to 0-5°C, and 2.3 L of normal hexane was added dropwise for crystallization, and then the temperature was increased to 20°C for crystallization for 2 h, and the filtered solid was dried under vacuum to obtain a white-like ceflomandole intermediate.

[0083] The purity and yield of the ceflomandole intermediate prepared by adding different amounts of ligand are shown in Table 7.

[0084] Table 7

[0085]

[0086]

[0087] The research and development team of the present application found that when the molar ratio of 1,10-phenanthroline to cuprous iodide and rubidium iodide was in the range of (1-5):1, the purity and yield of the ceflomandole intermediate could be maintained at a reasonable level. Further, as can be seen from the data in Table 7, when the molar ratio of 1,10-phenanthroline to cuprous iodide and rubidium iodide was in the range of (2-5):1, the purity of the ceflomandole intermediate prepared was greater than 99%, and the yield was in the range of 91%-93%. Therefore, the ratio of the total molar amount of copper salt and rubidium salt to the molar amount of ligand is 1:(1-5), preferably 1:(2-5).

[0088] Example 5

[0089] In this example, other parameters and control conditions are the same, only the type of solvent is different.

[0090] A preparation process of a ceflomandole intermediate, the specific steps of which are as follows:

[0091] (1) Preparation process: under nitrogen protection, compound I (680 g, 1.0 mol), UBT (594.6 g, 1.1 mol), and different types of solvents (the amount of solvent was 6 times the mass of compound I) were added to a reaction bottle. The temperature of the system was controlled at 20-30°C, and cuprous iodide (0.1 mol) and rubidium iodide (0.05 mol) were added to the reaction system, and 0.3 mol of bipyridine was added and stirred to dissolve completely. After dissolution, the temperature of the reaction system was controlled at 20°C±5°C, and stirring was carried out under this condition for a certain period of time. The reaction progress was monitored by HPLC, and when the content of the raw material compound I was detected to be reduced to 2.0% or less, it was inferred that the reaction was completed. After the reaction was completed, the reaction material was cooled and purified.

[0092] (2) Deprotection and crystallization purification process: ethyl acetate was added to the cooled reaction material, and water was added for liquid-liquid extraction, and the obtained organic phase was concentrated and 750 g of anisole was added, and trifluoroacetic acid (mass ratio of compound I to trifluoroacetic acid 1:5) was slowly added dropwise at a temperature of 0-5°C, and after the dropwise addition was completed, the temperature was increased to 20°C for deprotection; after the deprotection reaction was completed, the temperature was decreased to 0-5°C, and a poor solvent 2.3 L of diisopropyl ether was added dropwise for crystallization, and after the dropwise addition was completed, the temperature was increased to 20°C for crystallization for 2 h, and the filtered solid was vacuum dried to obtain a white-like ceflomandole intermediate.

[0093] The purity and yield of the ceflomandole intermediate prepared by using different types of solvents are shown in Table 8.

[0094] Table 8

[0095] Examples Solvent Reaction time (h) Purity (%) Yield (%) 5.1 DMF 4h 99.2 92.0 5.2 NMP 5h 99.3 91.2 5.3 THF 7h 99.3 90.5 5.4 Toluene 14h 99.1 88.4

[0096] As can be seen from the data in Table 8, when the reaction solvent used is DMF, NMP, THF or toluene, the purity of the ceflomandole intermediate is greater than 99%, and the yield is in the range of 88%-92%.

[0097] Example 6

[0098] In this example, other parameters and control conditions are the same, and only the amount of solvent is different.

[0099] A preparation process for a ceflomandole intermediate, the specific steps of which are as follows:

[0100] (1) Preparation process: under nitrogen protection, compound I (680 g, 1.0 mol), UBT (594.6 g, 1.1 mol) and DMF in a proportion were added to the reaction bottle. The temperature was controlled at 20-30°C, and cuprous iodide (0.1 mol) and rubidium iodide (0.05 mol) were added to the reaction system, and 0.3 mol of bipyridine was added and stirred to dissolve completely. After dissolution was completed, the temperature of the reaction system was controlled at 20°C±5°C, and the reaction was stirred at this temperature for a certain period of time. The reaction progress was monitored by HPLC, and when the content of the raw material compound I was detected to be reduced to 2.0% or less, it was inferred that the reaction was completed. After the reaction was completed, the reaction material was cooled and purified.

[0101] (2) Deprotection and crystallization purification process: ethyl acetate was added to the cooled reaction material, and water was added for liquid-liquid extraction, and the obtained organic phase was concentrated and 750 g of anisole was added, and trifluoroacetic acid (mass ratio of compound I to trifluoroacetic acid 1:3) was slowly added dropwise at a temperature of 0-5°C, and after the dropwise addition was completed, the temperature was increased to 20°C for deprotection; after the deprotection reaction was completed, the temperature was decreased to 0-5°C, and 2.3 L of normal hexane was added dropwise as a poor solvent for crystallization, and after the dropwise addition was completed, the temperature was increased to 20°C for crystallization for 2 h, and the filtered solid was vacuum dried to obtain a white cefllobipera intermediate.

[0102] The purity and yield of the cefllobipera intermediate prepared by different mass ratios of DMF to compound I are shown in Table 9.

[0103] Table 9

[0104] Examples Mass ratio of DMF to compound I Reaction time (h) Purity (%) Yield (%) 6.1 1：1 24h 95.0 78 6.2 2：1 9h 99.1 89 6.3 4：1 5h 99.3 91 6.4 6：1 4h 99.5 92 6.5 8：1 4h 99.5 92 6.6 10：1 5h 99.4 90

[0105] As can be seen from the data in Table 9, when the mass ratio of DMF to compound I is in the range of (2-10):1, the purity of the cefllobipera intermediate prepared is greater than 99%, and the yield is in the range of 89%-92%.

[0106] Example 7

[0107] In this example, other parameters and control conditions are the same, and only the reaction temperature is different.

[0108] A preparation process for a cefllobipera intermediate, the specific steps of which are as follows:

[0109] (1) Preparation process: under nitrogen protection, compound I (680 g, 1.0 mol), UBT (594.6 g, 1.1 mol), and DMF (the amount of DMF is 6 times the mass of compound I) were added to a reaction bottle. The temperature was controlled at 20-90°C, and cuprous iodide (0.1 mol) and rubidium iodide (0.05 mol) were added to the reaction system, and 0.3 mol of bipyridine was added and stirred to dissolve completely. After dissolution was completed, the reaction system was controlled at different temperatures, and stirred at the temperature for a certain period of time. The reaction progress was monitored by HPLC, and when the content of the raw material compound I was detected to be reduced to 2.0% or less, it was determined that the reaction was completed. After the reaction was completed, the reaction material was cooled and purified.

[0110] (2) Deprotection and crystallization purification process: ethyl acetate was added to the cooled reaction material, and water was added for liquid-liquid extraction, and the obtained organic phase was concentrated and 750 g of anisole was added, and trifluoroacetic acid (mass ratio of compound I to trifluoroacetic acid 1:3) was slowly added dropwise at a temperature of 0-5°C, and after the dropwise addition was completed, the temperature was increased to 20°C for deprotection; after the deprotection reaction was completed, the temperature was decreased to 0-5°C, and 2.3 L of n-hexane, a poor solvent, was added dropwise for crystallization, and after the dropwise addition was completed, the temperature was increased to 20°C for crystallization for 2 h, and the filtered solid was vacuum dried to obtain a white cefllobozane intermediate.

[0111] The purity and yield of the cefllobozane intermediate prepared at different reaction temperatures are shown in Table 10.

[0112] Table 10

[0113] Examples Reaction temperature (°C) Reaction time (h) Purity (%) Yield (%) 7.1 20 4.5h 99.2 91 7.2 30 4h 99.3 92 7.3 40 5h 97.5 80 7.4 50 6h 94.6 73 7.5 60 7h 89 50 7.6 60～90 ＞7h ＜80 ＜30

[0114] As can be seen from the data in Table 10, when the reaction temperature is in the range of 20-50°C, the purity of the cefllobozane intermediate prepared is above 99%, and the yield is in the range of 73-92%.

[0115] Example 8

[0116] In this example, other parameters and control conditions are the same, and only the used crystallization poor solvent is different.

[0117] A preparation process for a cefllobozane intermediate, the specific steps of which are as follows:

[0118] (1) Preparation process: under nitrogen protection, compound I (680 g, 1.0 mol), UBT (594.6 g, 1.1 mol), and DMF (the amount of DMF is 6 times the mass of compound I) were added to a reaction bottle. The temperature of the system was controlled at 20-30°C, and cuprous iodide (0.1 mol) and rubidium iodide (0.05 mol) were added to the reaction system, and 0.5 mol of 1,10-phenanthroline was added and stirred to dissolve completely. After the dissolution was completed, the temperature of the reaction system was controlled at 20°C±5°C, and the reaction was stirred under this condition for 3.5 h. The reaction progress was monitored by HPLC, and when the content of the raw material compound I was detected to be reduced to 2.0% or less, it was determined that the reaction was completed. After the reaction was completed, the reaction material was cooled and purified.

[0119] (2) Deprotection and crystallization purification process: ethyl acetate was added to the cooled reaction material, and then water was added for phase separation extraction. The obtained organic phase was concentrated, 750 g of anisole was added, and trifluoroacetic acid (mass ratio of compound I to trifluoroacetic acid was 1:3) was slowly added dropwise at a temperature of 0-5°C. After the dropwise addition was completed, the temperature was increased to 20°C for deprotection. After the deprotection reaction was completed, the temperature was decreased to 0-5°C, different poor solvents (the amount of addition was 3 times the volume of anisole) were added dropwise for crystallization, and after the dropwise addition was completed, the temperature was increased to 20°C for crystallization for 2 h. The filtered solid was dried under vacuum to obtain a white-like ceflomandole intermediate.

[0120] The purity and yield of the ceflomandole intermediate prepared by using different poor solvents are shown in Table 11.

[0121] Table 11

[0122]

[0123] As can be seen from the data in Table 11, when the poor solvents used are isobutyl ether, cyclohexane, n-hexane and methyl tert-butyl ether, the purity of the ceflomandole intermediate is greater than 99.2%, and the yield is in the range of 91%-94%.

[0124] It should be noted that the above content is a further detailed description of the present application in combination with specific embodiments, and the specific implementation of the present application cannot be limited to these descriptions; the size data in the present embodiment does not limit the technical solution, but only shows one specific working condition. For ordinary skilled persons in the technical field to which the present application belongs, some simple improvements and refinements can be made without departing from the concept of the present application, and all of them should be regarded as falling within the scope of protection of the present application.

Claims

1. A process for the preparation of an intermediate of ceftaroline, characterized in that, Under an inert atmosphere, reactant compound I and UBT undergo a coupling reaction in the presence of a catalyst and a ligand to obtain the cefoloza intermediate; wherein the catalyst is a copper salt and a rubidium salt; the copper salt is selected from one or more of cuprous chloride, cuprous iodide, or cuprous bromide, and the rubidium salt is selected from one or more of rubidium chloride, rubidium bromide, rubidium iodide, or rubidium sulfate; the ligand is selected from at least one of 1,10-phenanthroline and triphenylphosphine; the molar ratio of the copper salt to the rubidium salt is (0.5~2):1, and the temperature of the coupling reaction is 20~50℃; The structure of compound I is shown in formula (1): Formula (1).

2. The process for the preparation of Ceflozane intermediate as claimed in claim 1, wherein, The copper salt is cuprous iodide; and / or, the rubidium salt is one or both of rubidium iodide and rubidium bromide.

3. The process for the preparation of Ceflomandole intermediate as claimed in claim 1, wherein, The total molar amount of the copper salt and the rubidium salt is 10% to 20% of the molar amount of compound I.

4. The process for the preparation of Ceflozane intermediate as claimed in claim 3, wherein, The total molar amount of the copper salt and the rubidium salt is 15% to 20% of the molar amount of compound I.

5. The process for the preparation of Ceflomandole intermediate as claimed in claim 1, wherein, The molar ratio of the copper salt to the rubidium salt is (1~2):

1.

6. The process for the preparation of Ceflomandole intermediate as claimed in claim 1, wherein, The ratio of the total molar amount of the copper salt and the rubidium salt to the molar amount of the ligand is 1:(1~5).

7. The process for the preparation of Ceflozane intermediate as claimed in claim 6, wherein, The ratio of the total molar amount of the copper salt and the rubidium salt to the molar amount of the ligand is 1:(2~5).

8. The process of preparation of Ceflozane intermediate as claimed in claim 1 wherein, The coupling reaction is carried out in a solvent selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, tetrahydrofuran, and toluene.

9. The process for the preparation of Ceflozane intermediate as claimed in claim 8, wherein, The solvent is selected from any one of N-methylpyrrolidone, N,N-dimethylformamide, or tetrahydrofuran.

10. The process of preparation of Ceflozane intermediate as claimed in claim 8 wherein, The mass ratio of the solvent to compound I is (1~10):

1.

11. The process of preparation of Ceflozane intermediate as claimed in claim 10 wherein, The mass ratio of the solvent to compound I is (2~10):

1.

12. The process of preparation of Ceflomandole intermediate as claimed in claim 1, wherein, The preparation process further includes purifying the reacted material by crystallization using a poor solvent; the poor solvent is any one of diethyl ether, diisopropyl ether, cyclohexanone, isobutyl ether, cyclohexane, n-hexane, and methyl tert-butyl ether.

13. The process for the preparation of Ceflozane intermediate as claimed in claim 12, wherein, The undesirable solvent is any one of isobutyl ether, cyclohexane, n-hexane, and methyl tert-butyl ether.

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