CN111471058A - Process for preparing cephapirin analogues - Google Patents

Abstract

The present invention relates to a method for preparing the cefepime analogs of formula VII.

Description

Process for the preparation of cefepime analogs

technical field

The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a cefepime analog.

Background technique

Bacterial infectious diseases are the most common clinical diseases, and severe infections can cause death. The use of cephalosporin antibiotics provides a new class of drugs with broad antibacterial spectrum, strong antibacterial activity and good therapeutic effect for clinical practice. Since the advent of the first cephalosporin antibiotics, cephalosporin antibiotics have been used for decades, with new varieties emerging one after another, and the antibacterial spectrum and activity are increasing day by day. However, bacterial resistance has made this type of antibiotics a serious challenge in terms of application scope and efficacy, and it has also brought great difficulties to the development of global cephalosporin drugs. After 2000, few new cephalosporin antibiotics have come out again. Although my country is a big country in the production and consumption of cephalosporins, the development of drugs is still dominated by imitations. Therefore, it is of great significance to study new cephalosporin antibiotics with domestic independent intellectual property rights.

)，分别用于治疗包括糖尿病足感染在内的复杂性皮肤及皮肤软组织感染(cSSSIs)。头孢吡普是广谱抗生素，对革兰阳性菌、革兰阴性菌、厌氧菌都具有抗菌活性，是第一个对耐甲氧西林金黄色葡萄球菌(MRSA)和万古霉素耐药金黄色葡葡球菌(VRSA)有效的头孢菌素类抗生素。MRSA所产的青霉素结合蛋白2a(PBP2a)位于细菌细胞表面狭窄的凹槽上，头孢吡普C-3位大的疏水吡咯酮甲叉基侧链便于使PBP2a构象发生变化，形成一个稳定的酰基酶复合物。这是其他不具有该结构的头抱菌素类抗生素所无法达到的，也是其对耐药革兰阳性球菌具有强效抗菌活性的原因。Ceftobiprole is a broad-spectrum cephalosporin antibiotic, and its water-soluble prodrug is Ceftobiprole Medocaril, both of which are produced by Basilea Pharmaceutica, Switzerland. Co-developed with Johnson & Johnson PRD. The cefepip injection applied by Basilea Pharmaceutica was approved for listing in Canada and Switzerland in 2008 (trade name

), respectively, for the treatment of complex skin and skin and soft tissue infections (cSSSIs) including diabetic foot infections. Cefepime is a broad-spectrum antibiotic with antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, and anaerobic bacteria. It is the first methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant gold Effective cephalosporin antibiotic for Staphylococcus aureus (VRSA). Penicillin-binding protein 2a (PBP2a) produced by MRSA is located in a narrow groove on the bacterial cell surface, and the large hydrophobic pyrrolidone methylidene side chain at the C-3 position of cefepime facilitates the conformational change of PBP2a to form a stable acyl group enzyme complex. This is not achieved by other cephalosporin antibiotics that do not have this structure, and is the reason for its potent antibacterial activity against drug-resistant Gram-positive cocci.

Cefepirox is the world's first cephalosporin against methicillin-resistant Staphylococcus aureus. Although the drug was not reviewed by the US FDA due to incomplete clinical data and was withdrawn from the market in 2010, the short-lived appearance of cefepirox is still a major concern. The research and development of new cephalosporin antibiotics brings new hope. Based on the pyrrolidone vinyl cephalosporin structure of cefepime, we designed and synthesized a class of pyrrolidone vinyl cephalosporin antibiotics (cefepime analogs) containing aliphatic, substituted or unsubstituted benzene rings, and substituted or unsubstituted heteroaromatic rings.

The cefepime analog of the present application is a novel cephalosporin antibiotic, so its preparation method is extremely important for providing samples for preclinical research, and can also be used as a reference route for subsequent process development.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a method for preparing cefepime analogs. Through this route, cefepime analogs of structural formula VII with various types of R substituents can be successfully obtained, and the impurity ceflactone that is easily generated during the synthesis of cephalosporins can be avoided. The process of pH to purify and obtain the intermediate; the preparation route of compound III of general formula can avoid the hydrolysis by-product of compound XI and improve the reaction yield.

The present invention provides a method for preparing a cefepime analog, as shown in the formula, comprising the following steps:

Step 1, 7-amino-3-deacetoxycephalosporanic acid (D-7ACA) is treated with a base in a suitable solvent, the base is an inorganic base or an organic base, preferably sodium bicarbonate, triethylamine or N, N-diisopropylethylamine, most preferably triethylamine. The appropriate solvent is dichloromethane, tetrahydrofuran, dioxane, N,N-dimethylformamide or the mixed solvent of the above solvent and water, the mixed solvent of water and dioxane is preferred here (volume ratio 1:1) ). The solution is cooled to between 0 °C and 10 °C, preferably 0 °C, and treated with di-tert-butyl dicarbonate to obtain the amino-protected compound I;

In step 2, compound I is treated with pyridine in a suitable solvent, and the equivalent of pyridine is 2-4 equivalents, and the optimal amount is 3 equivalents. Suitable solvents are aprotic solvents, preferably dichloromethane herein. At room temperature, compound II is obtained by oxidation with manganese dioxide, and the equivalent of manganese dioxide is 10-50 equivalents, and the optimum is 20 equivalents;

In step 3, compound II and the phosphorus salt represented by formula III (see below for the preparation method) are placed in a suitable solvent. The solution is cooled to between 0°C and 10°C, preferably 0°C, and treated with N,O-bistrimethylsilylacetamide to react to generate compound IV;

In step 4, compound IV is placed in an appropriate solvent, and the appropriate solvent is an aprotic solvent, and ethyl acetate is the best in this paper, and the tert-butoxycarbonyl protecting group is removed under the action of hydrochloric acid to obtain compound V;

In step 5, compound V and the active ester VI of the side chain of foetalin are dissolved in a suitable solvent, and the appropriate solvent is an aprotic solvent, and the optimal solvent in this paper is N,N-dimethylformamide, and treated with alkali to obtain cefepime with structural formula VII Common analogs, the base is an organic base, preferably tetramethylguanidine, triethylamine or N,N-diisopropylethylamine, most preferably tetramethylguanidine.

In the compound of formula VII of the present application, R is a C4-C6 nitrogen atom-containing cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted N atom-containing heteroaryl group, and the phenyl group or the N atom-containing Substituents for the heteroaryl groups of atoms are halogen, methyl, methoxy, nitro, hydroxy, amino, preferably phenyl, 2-chlorophenyl or 3-pyridyl.

Another aspect of the present invention provides a preparation method of compound III phosphorus salt, comprising the following steps:

Step 1,4-Bromobutyryl chloride is dissolved in a suitable solvent, suitable solvent is carbon tetrachloride, dichloromethane, 1,2-dichloroethane, most preferably 1,2-dichloroethane, with N - Treatment with bromosuccinimide (NBS) and hydrobromic acid, and the temperature is raised to 70°C to 80°C to react to generate compound VIII;

Step 2, the primary amine compound IX is placed in an appropriate solvent, treated with N,N-diisopropylethylamine (DIEA), and the appropriate solvent is tetrahydrofuran, dichloromethane, N,N-dimethylformamide , the most optimal in this paper is dichloromethane, the solution is cooled to between 0 °C and 10 °C, preferably 0 °C, and compound X is treated with compound VIII; the R is a C4-C6 nitrogen atom-containing cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted N-atom-containing heteroaryl, and the substituent of said phenyl or N-atom-containing heteroaryl is halogen, methyl, methoxy, nitro, hydroxyl, Amino, preferably phenyl, 2-chlorophenyl or 3-pyridyl.

Step 3, under the condition that N,N-dimethylformamide is used as a solvent, the compound X is cooled to between 0 °C and 10 °C, preferably 0 °C, and treated with sodium hydride (NaH) to obtain compound XI;

In step 4, compound XI is treated with triphenylphosphine in an appropriate solvent, the appropriate solvent is toluene, N,N-dimethylformamide or xylene, most preferably toluene, and the temperature is raised to 0 °C to obtain formula III Phosphorus salt shown;

Detailed ways

The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications can be made in the present invention without departing from the spirit and scope of the invention.

Example 1

(6R,7R)-tert-butyl 7-iminocarbonate-3-hydroxymethyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene- Preparation of 2-Carboxylic Acid

3-Deacetyl-7-aminocephelenic acid (D-7-ACA) (2.37g) was dispersed in 15mL of water, 3mL of triethylamine was added, then cooled to 0°C, 4.5g of di-tert-butyl dicarbonate and 15 mL dioxane. After stirring at room temperature for 16 hours, 50 mL of ethyl acetate and 50 mL of water were added to the reaction solution, followed by stirring and separation, and the aqueous layer was retained. The aqueous layer was cooled to 0°C, and the pH was adjusted to about 2.0 with dilute hydrochloric acid, and extracted with ethyl acetate three times (50 mL*3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 3.1 g of an off-white solid with a yield of 91%. ESI-MS(m/z): 353.26[M+Na] ⁺ .

Example 2

(6R,7R)-tert-butyl 7-iminocarbonate-3-formyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2 - Preparation of carboxylic acids

(6R,7R)-tert-butyl 7-iminocarbonate-3-hydroxymethyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene- 2-Carboxylic acid (0.5 g) was dissolved in 5 mL of dichloromethane, 0.38 mL of pyridine and 2.6 g of manganese dioxide were added, the mixture was stirred at room temperature for 24 hours, filtered with celite, and concentrated to dryness under reduced pressure. Column chromatography (ethyl acetate:petroleum ether=1:3) gave 0.3 g of a brown-red solid in a yield of 60%. ESI-MS(m/z): 351.16[M+Na] ⁺ .

Example 3

(6R,7R)-tert-butyl 7-iminocarbonate-3-[(E)-1-(pyridin-3-yl)-2-oxo-pyrrolidine-3-ylidenemethyl]-8- Preparation of oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Under the ice-water bath, in a 100ml single-necked flask, successively added (6R,7R)-7-imino tert-butyl carbonate-3-formyl-8-oxo-5-thia-1-aza-bicyclo and [4.2.0] Oct-2-ene-2-carboxylic acid (2 g, 6.1 mmol), [1-(pyridin-3-yl)-2-oxo-pyrrolidin-3-yl]-triphenyl- Phosphine bromide (3.39g, 6.1mmol), 50ml propylene oxide, after fully stirring for 10min, BSA (7.43g, 36.6mmol) was added dropwise, during the dropwise addition, the reaction system gradually turned brown-black, and with the reaction Proceed, the brown-black gradually becomes darker. After TLC detected the reaction was complete, the solvent was evaporated to dryness to obtain a thick slurry. Add 50ml of dichloromethane and 50ml of water, the layering is obvious at this time, and the water layer is still transparent; 5% aqueous sodium hydroxide solution is added dropwise and shaken sufficiently, with the continuous addition of sodium hydroxide aqueous solution, the color of the water layer gradually changes Deep, when the water layer PH=9, stop dripping, slowly layering; then continue to add water to the organic layer, repeat three times to completely extract the product to the water layer; add dichloromethane to the water layer for washing, then the water layer is slowly added dropwise for 5 % hydrochloric acid solution, with the continuous addition of the hydrochloric acid solution, a precipitate gradually formed, stop adding the hydrochloric acid solution dropwise when the precipitation no longer occurs, fully stir and beat, filter to obtain 2.16g of bright yellow solid, the yield is 75%. ESI-MS(m/z): 473.04[M+H] ⁺ .

Example 4

(6R,7R)-tert-butyl 7-iminocarbonate-3-[(E)-1-(2-chlorophenyl)-2-oxo-pyrrolidine-3-ylidenemethyl]-8- Preparation of oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Under the ice-water bath, in a 100ml single-necked flask, successively added (6R,7R)-7-imino tert-butyl carbonate-3-formyl-8-oxo-5-thia-1-aza-bicyclo and [4.2.0] Oct-2-ene-2-carboxylic acid (1 g, 3.05 mmol), [1-(2-chlorophenyl)-2-oxo-pyrrolidin-3-yl]-triphenyl- Phosphine bromide (1.63g, 3.05mmol), 50ml of propylene oxide, after fully stirring for 10min, BSA (3.71g, 18.3mmol) was added dropwise, during the dropwise addition, the reaction system gradually turned brown-black, and with the reaction Proceed, the brown-black gradually becomes darker. After TLC detected the reaction was complete, the solvent was evaporated to dryness to obtain a thick slurry. Add 50ml of dichloromethane and 50ml of water, the layering is obvious at this time, and the water layer is still transparent; 5% aqueous sodium hydroxide solution is added dropwise and shaken sufficiently, with the continuous addition of sodium hydroxide aqueous solution, the color of the water layer gradually changes Deep, when the water layer PH=9, stop dripping, slowly layering; then continue to add water to the organic layer, repeat three times to completely extract the product to the water layer; add dichloromethane to the water layer for washing, and then slowly dropwise add 5 to the water layer. % hydrochloric acid solution, with the continuous addition of the hydrochloric acid solution, a precipitate gradually formed, stop adding the hydrochloric acid solution dropwise when no more precipitation occurs, fully stir and beat, filter to obtain 1.11g of bright yellow solid, the yield is 72%. ESI-MS(m/z): 506.46[M+H] ⁺ .

Example 5

(6R,7R)-7-Amino-3-[(E)-1-(pyridin-3-yl)-2-oxo-pyrrolidine-3-ylidenemethyl]-8-oxo-5- Preparation of Thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

In a 100ml single-neck bottle, add (6R,7R)-7-imino tert-butyl carbonate-3-[(E)-1-(pyridin-3-yl)-2-oxo-pyrrolidine-3- Methylenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (1 g, 2.69 mmol), 50 ml ethyl acetate , stirring continuously to form a suspension. 1.67 ml of 38% hydrochloric acid solution was added dropwise, and with constant stirring, the suspension gradually precipitated. After 3 hours, the reaction was detected by TLC, filtered, and washed with ethyl acetate for several times to obtain 0.85 g of a brownish-yellow solid with a yield of 85%. ESI-MS(m/z): 473.42[M-HCl+H] ⁺ .

Example 6

(6R,7R)-7-Amino-3-[(E)-1-(2-chlorophenyl)-2-oxo-pyrrolidine-3-ylidenemethyl]-8-oxo-5- Preparation of Thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

In a 100ml single-neck bottle, add (6R,7R)-7-imino tert-butyl carbonate-3-[(E)-1-(2-chlorophenyl)-2-oxo-pyrrolidine-3- Methylenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.5 g, 0.99 mmol), 50 ml ethyl acetate ester, at which point a suspension formed with constant stirring. 1.67 ml of 38% hydrochloric acid solution was added dropwise, and with constant stirring, the suspension gradually precipitated. After 3 hours, the reaction was detected by TLC, filtered, and washed with ethyl acetate for several times to obtain 0.39 g of a brownish-yellow solid with a yield of 87%. ESI-MS(m/z): 406.46[M-HCl+H] ⁺ .

Example 7

(6R,7R)-7-[2-(5-Amino-[1,2,4]thiadiazol-3-yl)-methoxyimino-acetamido]-3-[(E)-1 -(Pyridin-3-yl)-2-oxo-pyrrolidine-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]octane- Preparation of 2-ene-2-carboxylic acid

In a 100ml single-neck bottle, add (6R,7R)-7-amino-3-[(E)-1-(pyridin-3-yl)-2-oxo-pyrrolidine-3-ylidenemethyl] successively -8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.2 g, 0.36 mmol), cefazolin active ester (0.19 g , 0.54 mmol), 10 ml of N,N-dimethylformamide, after complete dissolution, tetramethyl biguanide (0.06 g, 0.54 mmol) was added dropwise. After TLC detected the completion of the reaction, 50 ml of ethyl acetate was added, and a large amount of flocculent precipitates were precipitated in the system at this time. After thorough stirring, the flocculent precipitates turned into granular precipitates, which were filtered to obtain the crude product. Black solid 0.12 g, yield 60%. QTOF-MS(m/z): 557.1[M+H] ⁺ .

Example 8

(6R,7R)-7-[2-(5-Amino-[1,2,4]thiadiazol-3-yl)-methoxyimino-acetamido]-3-[(E)-1 -(2-Chlorophenyl)-2-oxo-pyrrolidine-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]octane- Preparation of 2-ene-2-carboxylic acid

In a 100ml single-neck bottle, add (6R,7R)-7-amino-3-[(E)-1-(2-chlorophenyl)-2-oxo-pyrrolidine-3-ylidenemethyl] in turn -8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.2 g, 0.49 mmol), cefazolam active ester (0.26 g , 0.74 mmol), 10 ml of N,N-dimethylformamide, after complete dissolution, tetramethyl biguanide (0.09 g, 0.74 mmol) was added dropwise. After TLC detected the completion of the reaction, 50 ml of ethyl acetate was added, and a large amount of flocculent precipitates were precipitated in the system at this time. After thorough stirring, the flocculent precipitates turned into granular precipitates, which were filtered to obtain the crude product. Black solid 0.19 g, yield 65%. ESI-MS(m/z): 590.44[M+H] ⁺ .

Example 9

Preparation of 2,4-dibromobutyryl chloride

12.8 g of 4-bromobutyryl chloride was dissolved in 28 mL of 1,2-dichloroethane, and 14.7 g of N-bromosuccinimide and hydrobromic acid (7 drops) were added. Heat to 80°C and stir for 1.5 hours. Cool and concentrate under reduced pressure until no liquid evaporates. Filter, wash twice with 10 mL of dichloromethane, concentrate the filtrate under reduced pressure, and then distill under reduced pressure to obtain 10.9 g of a pale yellow liquid with a yield of 60%.

Example 10

Preparation of 24-dibromo-N-(pyridin-3-yl)-butanamide

In an ice-water bath, in a 100ml double-necked flask, add 3-aminopyridine (2g, 21.28mmol), 50ml of dichloromethane and 4.1g of N,N-diisopropylethylamine successively, slowly drop in 10ml of dichloromethane to dilute 2,4-dibromobutyryl chloride (6.75 g, 25.54 mmol). After TLC detected the completion of the reaction, 30 ml of water was added, the organic layer was extracted and the solvent was evaporated to dryness to obtain 6.32 g of a white solid with a yield of 94%. ESI-MS(m/z): 322.97[M+H] ⁺ .

Example 11

Preparation of 2,4-dibromo-N-(2-chlorophenyl)-butanamide

In an ice-water bath, in a 100ml double-necked flask, add 2-chloroaniline (2g, 15.75mmol), 50ml of dichloromethane and 3.1g of N,N-diisopropylethylamine successively, slowly drop in 10ml of dichloromethane to dilute 2,4-dibromobutyryl chloride (5.0 g, 18.9 mmol). After TLC detected that the reaction was complete, 30 ml of water was added, the organic layer was extracted and the solvent was evaporated to dryness to obtain 7.9 g of a white solid with a yield of 93.2%. ESI-MS(m/z): 356.07[M+H] ⁺ .

Example 12

Preparation of 3-bromo-1-(pyridin-3-yl)-2-oxo-pyrrolidine

2,4-Dibromo-N-(pyridin-3-yl)-butanamide (1.4g) was dissolved in 20mL of N,N-dimethylformamide, cooled to 0°C, 0.20g of sodium hydrogen was added in batches, 0 After stirring at °C for 15 minutes, it was stirred at room temperature overnight. 40 mL of water and 40 mL of saturated aqueous ammonium chloride solution were added, extracted twice with ethyl acetate (80 mL*2), washed with 20 mL of saturated brine, and dried over anhydrous sodium sulfate. The organic layer was evaporated to dryness to obtain 2.23 g of pure white solid with a yield of 74.3%. ESI-MS(m/z): 240.9,242.9[M+H] ⁺ .

Example 13

Preparation of 3-bromo-1-(2-chlorophenyl)-2-oxo-pyrrolidine

2,4-Dibromo-N-(2-chlorophenyl)-butanamide (1.55g) was dissolved in 20mL of N,N-dimethylformamide, cooled to 0°C, 0.20g of sodium hydrogen was added in batches, 0 After stirring at °C for 15 minutes, it was stirred at room temperature overnight. 40 mL of water and 40 mL of saturated aqueous ammonium chloride solution were added, extracted twice with ethyl acetate (80 mL*2), washed with 20 mL of saturated brine, and dried over anhydrous sodium sulfate. The organic layer was evaporated to dryness to obtain 2.56 g of pure white solid with a yield of 82.8%. ESI-MS(m/z): 274.83[M+H] ⁺ .

Example 14

Preparation of [1-(pyridin-3-yl)-2-oxo-pyrrolidin-3-yl]-triphenyl-phosphine bromide

In a 100ml single-neck flask, add 3-bromo-1-(pyridin-3-yl)-2-oxo-pyrrolidine (1.40g, 6mmol), triphenylphosphine (7g, 26.9mmol) and 15ml toluene successively to mix Uniformly, stirring at 100°C for complete dissolution and continuing the reaction for 2 hours, TLC detected that the reaction was complete, adding 30 ml of ethyl acetate, continuing to stir and gradually cooling to room temperature to precipitate a white precipitate, filtered, and the filter cake was washed with ethyl acetate to obtain 2.60 g of white solid with a yield of 2.60 g. 86.1%. ESI-MS(m/z): 423.02[M-Br+H] ⁺ .

Example 15

Preparation of [1-(2-Chlorophenyl)-2-oxo-pyrrolidin-3-yl]-triphenyl-phosphine bromide

In a 100ml single-necked bottle, add 3-bromo-1-(2-chlorophenyl)-2-oxo-pyrrolidine (2g, 7.33mmol), triphenylphosphine (10g, 37.8mmol) and 25ml toluene to mix successively Uniformly, stirred at 100 °C for complete dissolution and continued the reaction for 2 h, TLC detected the reaction was complete, added 50 ml of ethyl acetate, continued to stir and gradually cooled to room temperature to precipitate a white precipitate, filtered, and the filter cake was washed with ethyl acetate to obtain 3.6 g of white solids with a yield of 3.6 g. 84.2%. ESI-MS (m/z): 456.20 [M-Br+H] ⁺ .

Claims (4)

1. A process for preparing a cefepime analog of formula VII, comprising the steps of:

step 1, reacting 7-amino-3-desacetoxycephalosporanic acid (D-7ACA) with di-tert-butyl dicarbonate in the presence of alkali to obtain a compound I with protected amino;

step 2, oxidizing the compound I with manganese dioxide in the presence of pyridine to obtain a compound II;

step 3, reacting the compound II with a phosphorus salt shown as a formula III to generate a compound IV;

step 4, removing the tert-butoxycarbonyl protecting group from the compound IV under the action of hydrochloric acid to obtain a compound V;

step 5, treating the compound V with an aminothiazoly loximate side chain active ester VI to obtain a ceftazidime analogue with a structural formula VII; wherein R is C4-C6 nitrogen atom-containing cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted N atom-containing heteroaryl, and the substituent of the phenyl or the N atom-containing heteroaryl is halogen, methyl, methoxy, nitro, hydroxyl or amino.

2. The process for preparing cepham analogs according to claim 1, wherein R is C4-C6 nitrogen atom-containing cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted N atom-containing heteroaryl, and the phenyl or N atom-containing heteroaryl has halogen, methyl, methoxy, nitro, hydroxy, amino, preferably phenyl, 2-chlorophenyl or 3-pyridyl as the substituent.

3. Process for the preparation of ceftobiprole analogues according to any of claims 1-2,

the base used in step 1 is an inorganic or organic base, preferably sodium bicarbonate, triethylamine or N, N-diisopropylethylamine, most preferably triethylamine.

4. A process for the preparation of a ceftobiprole analogue according to any one of claims 1 to 3, wherein the process for the preparation of the phosphorus salt of compound iii comprises the following steps:

step 1, 4-bromobutyryl chloride reacts with N-bromosuccinimide (NBS) in the presence of hydrobromic acid to generate a compound VIII;

step 2, reacting the compound VIII with a primary amine compound IX in the presence of N, N-Diisopropylethylamine (DIEA) to generate a compound X;

step 3, treating the compound X with sodium hydride (NaH) under the condition of using N, N-dimethylformamide as a solvent to obtain a compound XI;

step 4, treating the compound XI with triphenylphosphine to obtain a phosphorus salt shown in a formula III; r is C4-C6 nitrogen atom-containing cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted N atom-containing heteroaryl, and the substituent of the phenyl or the N atom-containing heteroaryl is halogen, methyl, methoxy, nitro, hydroxyl, amino, preferably phenyl, 2-chlorophenyl or 3-pyridyl.