Preparation method of cefuroxime derivatives

Abstract

This invention discloses a method for preparing cefotaxime derivatives, comprising the following steps: (1) hydroxyl protection; (2) reduction / substitution: the reduction step is: the obtained 2,3-di(methoxymethoxy)benzaldehyde reacts with sodium borohydride to obtain the corresponding 2,3-di(methoxymethoxy)benzyl alcohol (intermediate 2); or the substitution step is: the obtained 2,3-di(methoxymethoxy)benzaldehyde reacts with RMgBr to obtain the hydroxyl carbon-substituted product of 2,3-di(methoxymethoxy)benzyl alcohol (intermediate 2). (3) Mitsunobu reaction; (4) hydrazinolysis; (5) condensation; (6) amidation; (7) deprotection; (8) deprotection to obtain cefotaxime derivatives. The process is simple and can synthesize a variety of cefotaxime derivatives.

Description

Technical Field

[0001] The invention relates to a preparation method of a cefuroxime derivative and belongs to the field of organic synthesis. Background Art

[0002] Cefuroxime was first successfully synthesized by SmithKline Beecham in 1994, but the production cost was high. It was later developed into a special pet medicine by Pfizer and was first allowed to be used for the treatment of skin infections in cats and dogs in the European Union in 2006. It was not until 2008 that the United States allowed its use for the treatment of skin and soft tissue infections in cats and dogs. It is not yet available in my country.

[0003] Cefuroxime sodium is a new third-generation cephalosporin antibiotic for animals currently in use. Its structural feature is that a tetrahydrofuran heterocycle is linked to the C-position of the cephalosporin nucleus through a CC bond, which gives the product a broad-spectrum antibacterial activity and stability against β-lactamase. As an antibacterial agent, cefuroxime sodium has a broad antibacterial spectrum, and has the advantages of rapid absorption, slow elimination, high bioavailability, good safety, and high therapeutic index in dogs and cats. It is an ideal long-acting antibiotic for humans and animals (dogs and cats), and has shown unique application prospects in veterinary clinics. How to further improve its antibacterial activity and avoid drug resistance has become an issue that we urgently need to study.

[0004] Studies have shown that synthetic iron carrier-drug conjugates are effective in circumventing common antibiotic resistance mechanisms, such as outer membrane permeability barriers, inactivation of related enzymes, and efflux mechanisms. 3+ β-lactam antibiotics with side chains and siderophore-β-lactam antibiotic conjugates; the synthesized conjugates with β-lactam antibiotics have antibacterial activity. When they are taken up by bacterial cells, the siderophore-β-lactam antibiotic conjugates bind to penicillin-binding proteins located in the periplasm, thereby inhibiting the growth of Gram-negative bacteria. To this end, we hope to synthesize siderophore conjugates of cefuroxime.

[0005] CN 111620893 A discloses a C-3 tetrahydrofuran-substituted cephalosporin-siderophore coupled compound and a preparation method and application thereof. The present invention provides another C-3 tetrahydrofuran-substituted cephalosporin-siderophore coupled compound and a preparation method thereof. Summary of the invention

[0006] In view of the above problems, the object of the present invention is to provide a method for preparing a cefuroxime derivative, which has a simple preparation method.

[0007] In order to achieve the above first purpose, the technical solution of the present invention is: a method for preparing a cefuroxime derivative, comprising the following steps:

[0008] (1) Hydroxyl protection: 2,3-dihydroxybenzaldehyde reacts with chloromethyl methyl ether ((MOMOCl)) to obtain 2,3-di(methoxymethoxy)benzaldehyde (intermediate 1);

[0009] (2) Reduction / substitution: The reduction step is: the obtained 2,3-di(methoxymethoxy)benzaldehyde reacts with sodium borohydride to obtain the corresponding 2,3-di(methoxymethoxy)benzyl alcohol (intermediate 2);

[0010] Or the substitution step is: the obtained 2,3-bis(methoxymethoxy)benzaldehyde reacts with RMgBr to obtain the hydroxy carbon substitution product of 2,3-bis(methoxymethoxy)benzyl alcohol (intermediate 2)

[0011] (3) Mitsunobu reaction: the intermediate 2 obtained reacts with N-hydroxyphthalimide to obtain intermediate 3;

[0012] (4) Hydrazinolysis: The intermediate 3 obtained reacts with hydrazine hydrate to obtain intermediate 4;

[0013] (5) Condensation: The intermediate 4 obtained is reacted with 2-oxo-2-(2-(tritylamino)thiazol-4-yl)acetic acid to obtain intermediate 5.

[0014] (6) Amidation: The obtained intermediate 5 is reacted with (6R, 7R)-7-amino-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate to obtain intermediate 6.

[0015] (7) Deprotection: The obtained intermediate 6 is reacted with hydrosulfite to obtain (6R, 7R)-7-((Z)-2-(((2,3-bis(methoxymethoxy)benzyl)oxy)imino)-2-(2-(tritylamino)thiazol-4-yl)acetylamino)-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and its derivatives (Intermediate 7);

[0016] (8) Deprotection: The intermediate 7 obtained is reacted with triethylsilane to remove the MOMO protecting group to obtain a cefuroxime derivative.

[0017] In the above scheme: in step (1), 2,3-dihydroxybenzaldehyde and its aldehyde carbon-substituted derivatives are dissolved in an organic solvent, potassium carbonate is added under an ice-water bath, the temperature is controlled at about 0°C, and then chloromethyl methyl ether is slowly added dropwise; after the addition is completed, the reaction temperature is raised to room temperature and the reaction is continued to be stirred until the reaction is complete; insoluble matter is removed by suction filtration, and the mixture is washed with acetone; most of the acetone solvent is removed by vacuum from the obtained filtrate, and ethyl acetate and water are added, extracted with ethyl acetate, the organic phases are combined, the organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a silica gel column using petroleum ether / ethyl acetate to obtain intermediate 1. The ratio of the amount of 2,3-dihydroxybenzaldehyde to the volume of the organic solvent (acetone) is 1 mmol:3.75 ml.

[0018] In the above scheme: the molar ratio of the 2,3-dihydroxybenzaldehyde, chloromethyl methyl ether and potassium carbonate is 1:3:10.

[0019] In the above scheme: in step (2), the reduction step is: dissolving the intermediate 1 in methanol and cooling to 0°C, then adding sodium borohydride in batches, then heating the reaction to room temperature, after the reaction is completed, removing most of the methanol solvent under reduced pressure, adding water and ethyl acetate to the residue, extracting, washing the organic layer with saturated brine, drying over anhydrous sodium sulfate, filtering and concentrating in vacuo to obtain the intermediate 2, wherein the molar ratio of the intermediate 1 to sodium borohydride is 1:3;

[0020] The replacement steps are:

[0021] The intermediate 1 was dissolved in THF solution and cooled to -20°C under nitrogen atmosphere, then RMgBr THF solution was added dropwise to keep the reaction mixture below 10°C. After addition, the mixture was heated to room temperature, stirred for reaction, and then saturated NH4Cl aqueous solution was slowly added to quench the mixture; the solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Petroleum ether / ethyl acetate = 10 / 1 was used as the eluent and purified by silica gel column chromatography to obtain the substituted intermediate 2, wherein R is one of ethyl, methyl, benzyl, cyclohexyl and phenyl.

[0022] In the above scheme: in step (3), the intermediate 2 is dissolved in a mixed solvent of tetrahydrofuran and dimethyl sulfoxide, N-hydroxyphthalimide and triphenylphosphine are added in sequence, and then the temperature is controlled at 0°C in an ice-water bath, and diisopropyl azodicarboxylate is slowly added dropwise. After the addition, the resulting mixture is heated to 35°C and stirred for reaction. After the reaction is completed, a saturated saline solution is added for quenching, and intermediate 3 is obtained after post-treatment;

[0023] The molar ratio of the intermediate 2, N-hydroxyphthalimide, triphenylphosphine and diisopropyl azodicarboxylate is 1:1.2-1.4:1.5-2:1.5-2.

[0024] In the above scheme: step (4) is: dissolving intermediate 3 in ethanol, adding hydrazine hydrate, stirring at room temperature until the reaction is complete, filtering out the solid, adding water, and extracting with ethyl acetate to obtain intermediate 4; the molar ratio of intermediate 3 to hydrazine hydrate is 1:1.5-2.

[0025] In the above scheme: step (5) is: under a nitrogen atmosphere, the intermediate 4 is dissolved in ethanol, and then the compound 2-oxo-2-(2-(tritylamino)thiazol-4-yl)acetic acid and acetic acid are added, and the mixture is stirred at 60°C-70°C to react to obtain the intermediate 5.

[0026] The molar ratio of the intermediate 4 to 2-oxo-2-(2-(tritylamino)thiazol-4-yl)acetic acid is 1:1-1.1.

[0027] In the above scheme: step (6) is: under a nitrogen atmosphere, the intermediate 5 is dissolved in N,N-dimethylformamide, and the compounds diphenyl chlorophosphate and N,N-diisopropylethylamine are added dropwise in sequence at minus 30°C. After reacting at minus 30°C for 2 hours, a solution of the compound (6R, 7R)-7-amino-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in N,N-dimethylformamide cooled at minus 30°C is added, and the mixture is continuously stirred and reacted at minus 30°C to obtain the intermediate 6.

[0028] In the above scheme: step (7) is: dissolving intermediate 6 in a mixed solution of acetonitrile and water, then heating the resulting mixture to 40°C, adding sodium bicarbonate, and adding hydrosulfite after 5 minutes; the solution is stirred at 40°C to react to obtain intermediate 7.

[0029] In the above scheme, step (8) is as follows: intermediate 7 is dissolved in anhydrous dichloromethane, triethylsilane is added, the resulting mixture is cooled to -15°C, trifluoroacetic acid is added, the solution is stirred and reacted at -15°C for 11-13 hours, the reaction solution is gradually heated to room temperature and stirred and reacted until the reaction is complete, volatiles and solvents are removed by vacuum concentration, tert-butyl methyl ether is added to the residue to obtain a white solid, the solid is sonicated in an ultrasonic bath, centrifuged, the supernatant is removed, and the tert-butyl methyl ether-ultrasound-centrifugation step is repeated twice. The obtained solid is subjected to reduced pressure to remove the solvent to obtain the product.

[0030] The ratio of the amount of the substance of intermediate 1 to the volume of methanol was 1 mmol:2 mL.

[0031] The volume ratio of the intermediate 2 to tetrahydrofuran and dimethyl sulfoxide is 1 mmol: 1.6 mL: 0.8 mL. The reaction time is 1.5-12 h.

[0032] The ratio of the amount of the substance of intermediate 3 to the volume of ethanol was 1 mmol:5 mL.

[0033] The ratio of the amount of the substance of intermediate 4 to the volume of acetic acid is 138 mmol:1 mL.

[0034] The ratio of the amount of intermediate 5 to the volume of N,N-dimethylformamide was 1 mmol:1.2 mL, and the reaction time was about 12 h.

[0035] The ratio of the amount of the substance of intermediate 6 to the volume of acetonitrile and water was 1 mmol:3.6 mL:1.2 mL. The reaction time was 0.2 h.

[0036] The ratio of the amount of intermediate 7 to the volume of dichloromethane was 1 mmol:5 mL, and the reaction time was about 15 h.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] (1) Raw materials and reagents are cheaper and easier to obtain: the raw materials and reagents used in the reaction are all mature commercial products with low prices and stable supply, which can ensure a stable supply of raw materials for industrial production. The currently used method is to use a derivative of the aldehyde group of 2,3-dihydroxybenzaldehyde with carbon substitution, which is protected by a hydroxyl group and then reduced to prepare intermediate 2. The raw materials (derivatives of the aldehyde group of 2,3-dihydroxybenzaldehyde with carbon substitution) are uncommon and expensive. The raw materials and reagents of the present invention are cheaper and easier to obtain: the raw materials and reagents used in the reaction are all mature commercial products with low prices and stable supply, which can ensure a stable supply of raw materials for industrial production.

[0039] (2) The reaction steps for synthesizing cefuroxime derivatives are short: starting from the main raw material 2,3-dihydroxybenzaldehyde, after steps such as substitution and reduction, only eight steps are required to obtain the product. Compared with the traditional synthesis route, the reaction is more convenient and is conducive to reducing production costs.

[0040] (3) The operation process is simpler: Each step of the reaction is connected in the simplest way, making the entire reaction process smoother, which is conducive to improving the synthesis efficiency and the overall reaction yield.

[0041] (4) Better atom economy: During the entire reaction process, there are only a small number of leaving groups, and the leaving groups are all common small molecule compounds with low value, reflecting the higher atom economy of the synthetic route. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 This is the mass spectrum of the intermediate 1 of Example 1.

[0043] Figure 2 It is the mass spectrum of intermediate 4 of Example 1.

[0044] Figure 3 This is the mass spectrum of the intermediate 5 of Example 1.

[0045] Figure 4 It is the mass spectrum of intermediate 6 of Example 1.

[0046] Figure 5 Mass spectrum of intermediate 7 of Example 1.

[0047] Figure 6 It is the mass spectrum of compound 3 of Example 2.

[0048] Figure 7 It is the mass spectrum of compound 5 of Example 2.

[0049] Figure 8 This is the mass spectrum of product 6 from Example 2.

[0050] Fig. 9 It is the mass spectrum of compound 8 of Example 2.

[0051] Fig.10 This is the mass spectrum of liquid 3 of Example 3.

[0052] Fig.11 This is the mass spectrum of product 5 of Example 3.

[0053] Fig.12 This is the mass spectrum of product 6 from Example 3.

[0054] Fig.13 This is the mass spectrum of product 8 in Example 3.

[0055] Fig.14 This is the mass spectrum of liquid 9 in Example 4.

[0056] Fig.15 This is the mass spectrum of liquid 10 in Example 5.

[0057] Fig.16 This is the mass spectrum of liquid 11 in Example 6. DETAILED DESCRIPTION

[0058] The present invention will be further described below through specific embodiments and in conjunction with the accompanying drawings:

[0059] Example 1

[0060] Step 1:

[0061] Ingredients ratio

[0062]

[0063] The reaction formula is:

[0064]

[0065] 11.1 g of 2,3-dihydroxybenzaldehyde was dissolved in 300 mL of acetone, 55.2 g of potassium carbonate was added under an ice-water bath, and then 18.2 mL of chloromethyl methyl ether was slowly added dropwise. After the addition was completed, the reaction was warmed to room temperature and continued to stir for 30 minutes. After the reaction was completed, the insoluble matter was removed by suction filtration and washed with acetone. The obtained filtrate was vacuum-removed from most of the acetone solvent and then ethyl acetate and water were added, extracted with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in a vacuum. The residue was purified by chromatography on a silica gel column with petroleum ether / ethyl acetate, and the volume ratio of petroleum ether / ethyl acetate was 20 / 1 to obtain 17.45 g of colorless liquid 2,3-di(methoxymethoxy)benzaldehyde with a yield of 96%. 1 H NMR (400 MHz, Chloroform-d) δ 10.46 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.21–7.10 (m, 1H), 5.26 (s, 2H), 5.24 (s, 2H), 3.58 (s, 3H), 3.52 (s, 3H). Mass spectrum as Figure 1 shown.

[0066] Step 2:

[0067] Ingredients ratio:

[0068]

[0069] Reaction:

[0070]

[0071] 12.0 g of 2,3-bis(methoxymethoxy)benzaldehyde was dissolved in 100 mL of methanol and cooled to 0°C, and then 6.03 g of sodium borohydride was added in batches, and then the reaction was heated to room temperature. After the reaction was completed (TLC detection), most of the methanol solvent was removed under reduced pressure, and water and ethyl acetate were added to the residue. Ethyl acetate was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain 11.4 g of 2,3-bis(methoxymethoxy)benzyl alcohol as a white solid, with a yield of 94%.

[0072] Step 3:

[0073] Ingredient ratio for steps 3 and 4

[0074]

[0075] Reaction:

[0076]

[0077] 11.4 g of 2,3-bis(methoxymethoxy)benzyl alcohol was dissolved in a mixed solvent of 80 mL of tetrahydrofuran and 40 mL of dimethyl sulfoxide, and 9.79 g of N-hydroxyphthalimide and 19.7 g of triphenylphosphine were added in sequence, followed by slow dropwise addition of 14.8 mL of diisopropyl azodicarboxylate for 30 minutes under an ice-water bath. After addition, the resulting mixture was heated to 35 ° C and stirred for 1 h. After the reaction was completed, a saturated aqueous solution of common salt solution was added for quenching. The solution was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was then concentrated in vacuo to obtain a crude product of 2-((2,3-bis(methoxymethoxy)benzyloxy)isoindoline-1,3-dione intermediate 3.

[0078] Step 4

[0079] Reaction:

[0080]

[0081] The crude product of 2-((2,3-bis(methoxymethoxy)benzyloxy)isoindoline-1,3-dione was dissolved in 250 mL of ethanol, 4.55 mL of 80% hydrazine hydrate was added, and the resulting mixture was stirred at room temperature for 1 h. The solid was filtered off, and 180 mL of water was added. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The product was purified by chromatography on a silica gel column with dichloromethane / methanol, the volume ratio of dichloromethane / methanol being 2. Chloroform / methanol = 20 / 1 to obtain 8.28 g of O-(2,3-bis(methoxymethoxy)benzyl)hydroxylamine as a white solid, with a two-step yield of 68%.

[0082] Step 5:

[0083] Ingredients ratio

[0084]

[0085] Under nitrogen atmosphere, 8.28 g of compound O-(2,3-bis(methoxymethoxy)benzyl)hydroxylamine was dissolved in 100 mL of ethanol, followed by the addition of 14.1 g of compound 2-oxo-2-(2-(tritylamino)thiazol-4-yl)acetic acid and 5 drops of acetic acid. The mixture was stirred at 60°C for 6 hours. After the reaction was completed, the insoluble matter was filtered out, the solvent was evaporated from the filtrate under reduced pressure, and the product was purified by chromatography on silica gel with dichloromethane / methanol (9 / 1) to obtain 19.30 g of (Z)-2-((2,3-bis(methoxymethoxy)benzyloxy)imino)-2-(2-(tritylamino)thiazol-4-yl)acetic acid in a yield of 89%.

[0086]

[0087] Step 6:

[0088] Ingredients ratio:

[0089]

[0090] Under nitrogen atmosphere, 2.02 g of compound (Z)-2-((2,3-bis(methoxymethoxy)benzyloxy)imino)-2-(2-(tritylamino)thiazol-4-yl)acetic acid was dissolved in 8.0 mL of N,N-dimethylformamide, and 588 μL of compound diphenyl chlorophosphate and 1.04 mL of N,N-diisopropylethylamine were added dropwise at -30°C. After reacting at -30°C for 2 hours, 810.8 mg of compound (6R,7R)-7-amino-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (16) cooled at -30°C was added. 16.0mL solution, the mixture was stirred at minus 30°C for 12 hours. After the reaction was completed, saturated sodium bicarbonate was added to quench the reaction, extracted with ethyl acetate, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered to remove insoluble matter, the filtrate was evaporated under reduced pressure to remove the solvent, and the mixture was purified by chromatography on silica gel with ethyl acetate to obtain 4-nitrophenyl (6R, 7R)-7-((Z)-2-(((2,3-bis(methoxymethoxy)benzyl)oxy)imino)-2-(2-(tritylamino)thiazol-4-yl)acetamido)-8-oxo-3-(((S)-tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 1.68g, yield 82%.

[0091]

[0092] Step 7:

[0093]

[0094] Ingredients ratio:

[0095]

[0096] 1.23 g of 4-nitrophenyl (6R, 7R)-7-((Z)-2-(((2,3-bis(methoxymethoxy)benzyl)oxy)imino)-2-(2-(tritylamino)thiazol-4-yl)acetamido)-8-oxo-3-(((S)-tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate was dissolved in a mixed solution of 43.0 mL of acetonitrile and 14.0 mL of water, and then the resulting mixture was heated to 40° C., 4.46 g of sodium bicarbonate was added, and 3.08 g of hydrosulfite was added after 5 minutes. The solution was stirred at 40° C. for 10 minutes. After the reaction was completed, the reaction solution was poured into a mixture of dichloromethane and water. The mixed solution was then adjusted to pH 3 using 17% hydrochloric acid, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant and concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane / methanol, with a volume ratio of dichloromethane / methanol of 20 / 1. 1.01 g of a brownish yellow solid (6R, 7R)-7-((Z)-2-(((2,3-bis(methoxymethoxy)benzyl)oxy)imino)-2-(2-(tritylamino)thiazol-4-yl)acetylamino)-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was obtained, with a yield of 94%.

[0097] Step 8:

[0098]

[0099] Under nitrogen atmosphere, 900 mg of (6R, 7R)-7-((Z)-2-(((2,3-bis(methoxymethoxy)benzyl)oxy)imino)-2-(2-(tritylamino)thiazol-4-yl)acetylamino)-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was dissolved in 5 mL of anhydrous dichloromethane, and then 479 μL of triethylsilane was added and the resulting mixture was cooled to minus 15°C, and 7.65 mL of trifluoroacetic acid was added. After the solution was stirred at minus 15°C for 12 hours, the reaction solution was gradually heated to room temperature and stirred for 3 hours. After vacuum concentration to remove volatiles and solvents, tert-butyl methyl ether was added to the residue to obtain a white solid. The product was sonicated for 10 minutes in an ultrasonic oven and then centrifuged for 10 minutes. The supernatant was removed and the tert-butyl methyl ether-ultrasound-centrifugation steps were repeated twice. The obtained solid was decompressed by an oil pump to remove the solvent to obtain the product 540 mg of cefuroxime with a yield of 96%.

[0100] Example 2

[0101]

[0102] Step (1)

[0103] 1. Chemical reaction formula

[0104]

[0105] 2. Feeding ratio

[0106]

[0107] 11.1 g of 2,3-dihydroxybenzaldehyde was dissolved in 300 mL of acetone, 55.2 g of potassium carbonate was added under an ice-water bath, and then 18.2 mL of chloromethyl methyl ether was slowly added dropwise. After the addition was completed, the reaction was warmed to room temperature and continued to stir for 30 minutes. After the reaction was completed, the insoluble matter was removed by suction filtration and washed with acetone. After most of the acetone solvent was removed by vacuum from the obtained filtrate, ethyl acetate and water were added, extracted with ethyl acetate, the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in a vacuum. The residue was purified by chromatography on a silica gel column using petroleum ether / ethyl acetate, and the volume ratio of petroleum ether / ethyl acetate was 20 / 1 to obtain 17.45 g of a colorless liquid 2 with a yield of 96%. 1 H NMR (400 MHz, Chloroform-d) δ 10.46 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.21–7.10 (m, 1H), 5.26 (s, 2H), 5.24 (s, 2H), 3.58 (s, 3H), 3.52 (s, 3H). Mass spectrum as Figure 1 shown.

[0108] 2. Step 21, Chemical Reaction Formula

[0109]

[0110] 2. Feeding ratio

[0111]

[0112] 2 was dissolved in THF solution and cooled to -20°C under nitrogen atmosphere, then methylmagnesium bromide THF solution was added dropwise to keep the reaction mixture below 10°C. After addition, the mixture was heated to room temperature and stirred for 3 hours, then saturated NH4Cl aqueous solution was slowly added to quench the mixture. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography with petroleum ether / ethyl acetate = 10 / 1 gave liquid 3 (9.16 g, yield 91.6%).

[0113] 1H NMR(400MHz,Chloroform-d)δ7.06–6.90(m,3H),5.18–5.12(m,1H),5.10(q,J=2.4,1.9Hz,2H), 5.09–5.01(m,2H),3.50(d,J=2.6Hz,3H),3.41(d,J=2.3Hz,3H),2.82(s,1H),1.59–1.29(m,3H).

[0114] Step 31, chemical reaction formula

[0115]

[0116] 2. Feeding ratio (including the feeding ratio in step 4)

[0117]

[0118] Operation process

[0119] 3 was dissolved in a mixed solvent of 80 mL of tetrahydrofuran and 4 mL of dimethyl sulfoxide, 4 and triphenylphosphine were added in sequence, and then diisopropyl azodicarboxylate was slowly added dropwise for 30 minutes under an ice-water bath. After addition, the resulting mixture was warmed to 35 ° C and stirred for 1 h, and the reaction was monitored by TLC. After the reaction was completed, a saturated aqueous solution of common salt solution was added for quenching. The solution was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was then concentrated in vacuo. Purified by silica gel chromatography with dichloromethane / methanol = 20 / 1. 5 (1.69 g, yield 88%) was obtained.

[0120] 1H NMR(400MHz,Chloroform-d)δ7.80–7.61(m,4H),7.45(td,J=7.8,1.9Hz,1H),7.17–7.05(m,2H),6.00(p,J=6.7Hz,1H) ,5.11(d,J=7.2Hz,2H),5.04(dd,J=6.6,3.4Hz,2H),3.56–3.51(m,3H),3.45–3.36(m,3H),1.68(dd,J=8.0,6.5Hz,3H).

[0121] Step 41, chemical reaction formula

[0122]

[0123] 2. Feeding ratio

[0124]

[0125] 3. Operation process

[0126] The product 5 was dissolved in ethanol, 80% hydrazine hydrate was added, and the resulting mixture was stirred at room temperature for 1 h. The solid was filtered off, 8 ml of water was added, the mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was then concentrated in vacuo. Purification by ethyl acetate silica gel chromatography gave a white solid 6 (0.8 g, 0.0341 mol, yield 79%).

[0127] 1 H NMR(400MHz,DMSO-d6)δ7.13–6.94(m,3H),5.74(s,2H),5.26–5.14(m,2H),5.15–5 .03(m,2H),4.97(t,J=6.5Hz,1H),3.51(s,3H),3.41(s,3H),1.28(d,J=6.5Hz,3H).

[0128] Step 51, chemical reaction formula

[0129]

[0130] 2. Feeding ratio

[0131]

[0132] Operation process

[0133] Under a nitrogen atmosphere, compound 6 was dissolved in ethanol, and then compound 7 and 2 drops of acetic acid were added. The mixture was stirred at 60°C for 6 hours and the reaction was monitored by TLC. After the reaction was completed, the insoluble matter was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure. The product was purified by chromatography on silica gel with dichloromethane / methanol = 9 / 1 to obtain 8 (1.53 g, yield 90%).

[0134] 1H NMR (400MHz, DMSO-d6) δ8.88 (s, 2H), 7.40–7.17 (m, 15H), 7.10–6.98 (m, 3H), 6.69 (s, 1H), 5.52 (q, J = 6.5 Hz, 1H), 5.25–5.15 (m, 2H), 5.15–5.05 (m, 2H), 3.49 (s, 3H), 3.41 (s, 3H), 1.40 (d, J = 6.6 Hz, 2H). Step 6:

[0135] 1. Chemical reaction formula

[0136]

[0137] 2. Feeding ratio

[0138]

[0139]

[0140] Under nitrogen atmosphere, compound 34 (2.02 g, 0.00309 mol) was dissolved in N,N-dimethylformamide (8.0 mL), and diphenyl chlorophosphate (576 μL, 0.0028 mol) and N,N-diisopropylethylamine (1.04 mL, 0.0059 mol) were added dropwise at -30°C. After reacting at -30°C for 2 hours, a solution of compound 16 (794.6 mg, 0.0020 mol) in N,N-dimethylformamide (16.0 mL) cooled at -30°C was added. The mixture was stirred at -30°C for 12 hours and the reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate was added to quench the reaction, and the mixture was extracted with ethyl acetate. The mixture was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. The solvent was evaporated from the filtrate under reduced pressure, and 35 (1.64 g, yield 83%) was purified by chromatography on silica gel with ethyl acetate.

[0141] Step 7:

[0142] 1. Chemical reaction formula

[0143]

[0144] 2. Feeding ratio

[0145]

[0146] Operation process

[0147] 23 (1.23 g, 0.00120 mol) was dissolved in a mixed solution of acetonitrile (43.0 mL) and water (14.0 mL), and the resulting mixture was then heated to 40°C, sodium bicarbonate (4.46 g, 0.0520 mol) was added, and then hydrosulfite (3.08 g, 0.0194 mol) was added 5 minutes later. The solution was stirred at 40°C for 10 minutes, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into a mixed solution of dichloromethane and water, and then hydrochloric acid (2 M) was used to adjust the pH to 3, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated in vacuo. The residue was purified by silica gel chromatography with dichloromethane / methanol = 20 / 1 to obtain a brown solid 37 (999 mg, yield 92%).

[0148] Step 8:

[0149] 1. Chemical reaction formula

[0150]

[0151] 2. Feeding ratio

[0152]

[0153] Under nitrogen atmosphere, 37 (900 mg, 0.00994 mol) was dissolved in anhydrous dichloromethane (5 mL), and then triethylsilane (476 μL, 0.00298 mol) was added and the resulting mixture was cooled to minus 15°C, and trifluoroacetic acid (7.61 mL, 0.1 mol) was added. After the solution was stirred at minus 15°C for 12 hours, the reaction solution was gradually warmed to room temperature and stirred for 3 hours. After vacuum concentration to remove volatiles and solvents, tert-butyl methyl ether was added to the residue to obtain a white solid. After ultrasonication for 10 minutes, centrifugation was performed for 10 minutes using a centrifuge, and the supernatant was removed. The tert-butyl methyl ether-ultrasound-centrifugation step was repeated twice, and the resulting solid was decompressed by an oil pump to remove the solvent to obtain product D (551 mg, yield 96.5%).

[0154] Example 3

[0155]

[0156] Step 11, chemical reaction formula

[0157]

[0158] 2. Feeding ratio

[0159]

[0160]

[0161] Dissolve 11.1 g of 2,3-dihydroxybenzaldehyde in 300 mL of acetone, add 55.2 g of potassium carbonate in an ice-water bath, and then slowly drop 18.2 mL of chloromethyl methyl ether. After the addition is complete, warm the reaction to room temperature and continue stirring for 30 minutes. After the reaction is complete, remove the insoluble matter by suction filtration and wash with acetone. After most of the acetone solvent is removed from the obtained filtrate by vacuum, add ethyl acetate and water, and extract with ethyl acetate.

[0162] The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on a silica gel column with petroleum ether / ethyl acetate in a volume ratio of 20 / 1 to obtain 17.45 g of colorless liquid 2 with a yield of 96%. 1 H NMR (400 MHz, Chloroform-d) δ 10.46 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.21–7.10 (m, 1H), 5.26 (s, 2H), 5.24 (s, 2H), 3.58 (s, 3H), 3.52 (s, 3H). Mass spectrum as Figure 1 shown.

[0163] Step 21, chemical reaction formula

[0164]

[0165] 2. Feeding ratio

[0166]

[0167] Operation process

[0168] Dissolve 2 in THF solution and cool to -20°C under nitrogen atmosphere, then drop benzylmagnesium bromide in THF solution to keep the reaction mixture below 10°C. After addition, the mixture was heated to room temperature and stirred for 3 hours, then quenched by slowly adding saturated NH4Cl aqueous solution. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography with petroleum ether / ethyl acetate = 10 / 1 as eluent gave liquid 3 (10.84 g, yield 80%).

[0169] 1H NMR(400MHz,Chloroform-d)δ7.22–7.12(m,5H),7.04–6.93(m,3H),5.21–5.15(m,1H),5.11(s,2H),5. 06–5.00(m,2H),3.49(s,3H),3.41(s,3H),3.06(dd,J=13.8,4.6Hz,1H),2.95(dd,J=13.8,8.9Hz,1H).

[0170] Step 31, chemical reaction formula

[0171]

[0172] 2. Feeding ratio

[0173]

[0174]

[0175] Operation process

[0176] 3 was dissolved in a mixed solvent of tetrahydrofuran, 4 and triphenylphosphine were added in sequence, and then diisopropyl azodicarboxylate was slowly added dropwise under an ice-water bath for 30 minutes. After addition, the resulting mixture was warmed to 35 ° C and stirred for 1 h, and the reaction was monitored by TLC. After the reaction was completed, a saturated aqueous solution of common salt solution was added for quenching. The solution was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was then concentrated in vacuo. Purified by silica gel chromatography with dichloromethane / methanol = 20 / 1. 5 (1.8 g, yield 78%) was obtained. 1 H NMR(400MHz,Chloroform-d)δ7.75–7.68(m,2H),7.66–7.61(m,2H),7.51(dd,J=7.7 ,1.7Hz,1H),7.33–7.28(m,2H),7.27–7.22(m,2H),7.20–7.12(m,2H),7.08(dd,J=8 .2,1.7Hz,1H),6.19(dd,J=7.8,5.9Hz,1H),5.07(d,J=1.3Hz,2H),4.91(d,J=5.6Hz ,1H),4.82(d,J=5.6Hz,1H),3.46(s,4H),3.38(s,3H),3.27(dd,J=14.5,5.8Hz,1H).

[0177] Step 41, chemical reaction formula

[0178]

[0179] 2. Feeding ratio

[0180]

[0181] The product 5 was dissolved in ethanol, 80% hydrazine hydrate was added, and the resulting mixture was stirred at room temperature for 1 h. The solid was filtered off, water was added, the mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was then concentrated in vacuo. Purification by ethyl acetate silica gel chromatography gave a white solid 6 (0.9 g, 75% yield).

[0182] 1H NMR(400MHz, DMSO-d6)δ7.24(dd,J=8.7,6.1Hz,2H),7.17(d,J=7.2Hz,3H),7.09–6.98(m,3H),5.22–5.1 0(m,3H),5.06(d,J=5.5Hz,1H),4.98(d,J=5.4Hz,1H),3.49(s,3H),3.40(s,3H),2.90(d,J=6.5Hz,2H).

[0183] Step 51, chemical reaction formula

[0184]

[0185] 2. Feeding ratio

[0186]

[0187]

[0188] Operation process

[0189] Under nitrogen atmosphere, compound 6 was dissolved in ethanol, and then compound 7 and 2 drops of acetic acid were added. The mixture was stirred at 60°C for 6 hours and the reaction was monitored by TLC. After the reaction was completed, the insoluble matter was removed by filtration, and the solvent was evaporated from the filtrate under reduced pressure. The product was purified by chromatography on silica gel with dichloromethane / methanol = 20 / 1 to obtain 8 (1.7 g, yield 85%).

[0190] 1 H NMR(400MHz,DMSO-d6)δ7.45–6.86(m,22H),6.67(s,1H),5.60(dd,J=7.8,5.0Hz ,1H),5.27–5.13(m,2H),5.12–4.93(m,2H),3.42(d,J=13.3Hz,6H),3.02(s,2H).

[0191] Step 61, chemical reaction formula

[0192]

[0193] Feeding ratio

[0194]

[0195] Operation process

[0196] Under nitrogen atmosphere, compound 34 (2.02 g, 0.00277 mol) was dissolved in N,N-dimethylformamide (8.0 mL), and diphenyl chlorophosphate (564 μL, 0.0028 mol) and N,N-diisopropylethylamine (0.82 mL, 0.0059 mol) were added dropwise at -30°C. After reacting at -30°C for 2 hours, a solution of compound 16 (710.8 mg, 0.0020 mol) in N,N-dimethylformamide (16.0 mL) cooled at -30°C was added. The mixture was stirred at -30°C for 12 hours and the reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate was added to quench the reaction, and the mixture was extracted with ethyl acetate. The mixture was washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and the insoluble matter was removed by filtration. The solvent was evaporated from the filtrate under reduced pressure, and 35 (1.53 g, yield 79%) was purified by chromatography on silica gel with ethyl acetate.

[0197] Step 7:

[0198] 1. Chemical reaction formula

[0199]

[0200] 2. Feeding ratio

[0201]

[0202] Operation process

[0203] 36 (1.23 g, 0.00120 mol) was dissolved in a mixed solution of acetonitrile (43.0 mL) and water (14.0 mL), and the resulting mixture was then heated to 40°C, sodium bicarbonate (4.07 g, 0.0520 mol) was added, and then hydrosulfite (2.81 g, 0.0194 mol) was added 5 minutes later. The solution was stirred at 40°C for 10 minutes, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into a mixed solution of dichloromethane and water, and then the pH was adjusted to 3 using hydrochloric acid (2 M), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated in vacuo. The residue was purified by silica gel chromatography with dichloromethane / methanol = 20 / 1 to obtain a brown solid 37 (907 mg, 0.00092 mol, yield 84%).

[0204] Step 81, chemical reaction formula

[0205]

[0206] 2. Feeding ratio

[0207]

[0208] Operation process

[0209] Under nitrogen atmosphere, 37 (900 mg, 0.00994 mol) was dissolved in anhydrous dichloromethane (5 mL), and then triethylsilane (476 μL, 0.00298 mol) was added and the resulting mixture was cooled to minus 15°C, and trifluoroacetic acid (7.61 mL, 0.1 mol) was added. After the solution was stirred at minus 15°C for 12 hours, the reaction solution was gradually warmed to room temperature and stirred for 3 hours. After vacuum concentration to remove volatiles and solvents, tert-butyl methyl ether was added to the residue to obtain a white solid. After ultrasonication for 10 minutes, centrifugation was performed in a centrifuge for 10 minutes, and the supernatant was removed. The tert-butyl methyl ether-ultrasound-centrifugation step was repeated twice, and the resulting solid was decompressed by an oil pump to remove the solvent to obtain product D (573 mg, 0.0088 mol, yield 96%).

[0210] Example 4

[0211] 1. Chemical reaction formula

[0212]

[0213] 2. Feeding ratio

[0214]

[0215] Operation process

[0216] 2 was dissolved in THF, cooled to -20°C under nitrogen atmosphere, and then a THF solution of cyclohexylmagnesium bromide was added dropwise to keep the reaction mixture below 10°C. After addition, the mixture was heated to room temperature, stirred for 3 hours, and then quenched by slowly adding a saturated NH4Cl aqueous solution. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Liquid 9 (544 mg, yield 79%) was obtained by purification by silica gel column chromatography using petroleum ether / ethyl acetate = 10 / 1 as eluent.

[0217] 1H NMR(400MHz,Chloroform-d)δ7.03–6.89(m,3H),5.11(d,J=1.0Hz,2H),5.04(s,2H),4.57(d,J=8.2Hz,1H),3.51(s,3H),3.42(s,3H),2. 40(s,1H),2.03(dt,J=12.5,3.5Hz,1H),1.74–1.67(m,2H),1.59–1.52(m,2H),1.30–1.22(m,1H),1.21–1.14(m,2H),1.13–1.04(m,3H).

[0218] Example 5

[0219] 1. Chemical reaction formula

[0220]

[0221] 2. Feeding ratio

[0222]

[0223] Operation process

[0224] 2 was dissolved in THF solution and cooled to -20°C under nitrogen atmosphere, then phenylmagnesium bromide THF solution was added dropwise to keep the reaction mixture below 10°C. After addition, the mixture was heated to room temperature and stirred for 3 hours, and then saturated NH4Cl aqueous solution was slowly added to quench the mixture. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Liquid 10 (570 mg, yield 85%) was obtained by silica gel column chromatography using petroleum ether / ethyl acetate = 10 / 1 as eluent.

[0225] 1 H NMR(400MHz,Chloroform-d)δ7.38–7.29(m,2H),7.24(t,J=7.6Hz,2H),7.19–7.09(m,1H),6.99(dd,J=8.2,1.6Hz,1H),6.90(t,J=8.0Hz,1H),6.74–6 .66(m,1H),6.11(s,1H),5.09(d,J=1.0Hz,2H),5.07–5.01(m,1H),4.97(d , J=5.9Hz, 1H), 3.46 (d, J=1.3Hz, 3H), 3.40 (s, 3H), 3.33–2.88 (m, 1H). Example 6

[0226] 1. Chemical reaction formula

[0227]

[0228] 2. Feeding ratio

[0229]

[0230] 3. Operation process

[0231] 2 was dissolved in THF solution and cooled to -20°C under nitrogen atmosphere, then ethylmagnesium bromide solution in THF was added dropwise to keep the reaction mixture below 10°C. After addition, the mixture was heated to room temperature and stirred for 3 hours, then saturated NH4Cl aqueous solution was slowly added to quench the mixture. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Liquid 11 (460 mg, yield 82%) was obtained by silica gel column chromatography using petroleum ether / ethyl acetate = 10 / 1 as eluent.

[0232] 1 H NMR(400MHz,Chloroform-d)δ7.06–6.91(m,3H),5.14–5.09(m,2H),5.05(pd,J=6.0,5.2,3.6Hz,2H),4.84(ddd, J=7.6,5.9,1.5Hz,1H),3.56–3.47(m,3H),3.47–3.37(m,3H),2.54(s,1H),1.89–1.65(m,2H),0.95–0.83(m,3H).

[0233] The present invention is not limited to the above-mentioned embodiments. Those skilled in the art will appreciate that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and purpose of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims

1. A method for preparing a cefuroxime derivative, characterized in that: The following steps are involved: (1) Hydroxyl protection: 2,3-dihydroxybenzaldehyde reacts with chloromethyl methyl ether to obtain intermediate 1 2,3-di(methoxymethoxy)benzaldehyde. The reaction formula is: (2) Reduction / substitution: The reduction step is: the obtained 2,3-di(methoxymethoxy)benzaldehyde reacts with sodium borohydride to obtain the corresponding 2,3-di(methoxymethoxy)benzyl alcohol; Or the substitution step is: the obtained 2,3-bis(methoxymethoxy)benzaldehyde reacts with RMgBr to obtain a 2,3-bis(methoxymethoxy)benzyl alcohol hydroxyl carbon substitution product, wherein R is one of ethyl, methyl, benzyl, cyclohexyl, and phenyl; the reaction formula is (3) Mitsunobu reaction: The product of step (2) reacts with N-hydroxyphthalimide to obtain intermediate 3, the structural formula of intermediate 3 is: (4) Hydrazinolysis: The intermediate 3 obtained is reacted with hydrazine hydrate to obtain the intermediate 4, the structural formula of the intermediate 4 is: (5) Condensation: The intermediate 4 obtained is reacted with 2-oxo-2-(2-(tritylamino)thiazol-4-yl)acetic acid to obtain the intermediate 5, whose structural formula is: (6) Amidation: The obtained intermediate 5 is reacted with (6R, 7R)-7-amino-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate to obtain intermediate 6, the structural formula of which is: (7) Deprotection: The intermediate 6 obtained is reacted with hydrosulfite to obtain the intermediate 7 (6R, 7R)-7-((Z)-2-(((2,3-bis(methoxymethoxy)benzyl)oxy)imino)-2-(2-(tritylamino)thiazol-4-yl)acetylamino)-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid or a derivative thereof, the structural formula of which is: or (8) Deprotection: The intermediate 7 obtained is reacted with triethylsilane to remove the MOMO protecting group to obtain a cefuroxime derivative having the structural formula: 。 2. The method for preparing the cefuroxime derivative according to claim 1, characterized in that: In step (1), 2,3-dihydroxybenzaldehyde is dissolved in acetone, potassium carbonate is added in an ice-water bath, the temperature is controlled at about 0°C, and then chloromethyl methyl ether is slowly added dropwise; after the addition is completed, the reaction temperature is raised to room temperature and the reaction is continued to be stirred until the reaction is complete; insoluble matter is removed by suction filtration, and the mixture is washed with acetone; most of the acetone solvent is removed from the obtained filtrate under vacuum, and ethyl acetate and water are added thereto, and the mixture is extracted with ethyl acetate, the organic phases are combined, the organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated in vacuo, and the residue is purified by chromatography on a silica gel column using petroleum ether / ethyl acetate to obtain intermediate 1.

3. The method for preparing the cefuroxime derivative according to claim 2, characterized in that: The molar ratio of the 2,3-dihydroxybenzaldehyde, chloromethyl methyl ether and potassium carbonate is 1:3:

10.

4. The method for preparing the cefuroxime derivative according to claim 2, characterized in that: In step (2), the reduction step is as follows: dissolving the intermediate 1 in methanol and cooling to 0°C, then adding sodium borohydride in batches, then heating the reaction to room temperature, and after the reaction is completed, removing most of the methanol solvent under reduced pressure, adding water and ethyl acetate to the residue, extracting, washing the organic layer with saturated brine, drying over anhydrous sodium sulfate, filtering and concentrating in vacuo to obtain the intermediate 2, wherein the molar ratio of the intermediate 1 to sodium borohydride is 1:3; The replacement steps are: The intermediate 1 was dissolved in THF solution and cooled to -20°C under nitrogen atmosphere, and then RMgBr THF solution was added dropwise to keep the reaction mixture below 10°C. After the addition, the mixture was heated to room temperature, stirred for reaction, and then saturated NH4Cl aqueous solution was slowly added to quench the mixture; the solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by silica gel column chromatography using petroleum ether / ethyl acetate = 10 / 1 as eluent to obtain a substituted intermediate 2, wherein R is one of ethyl, methyl, benzyl, cyclohexyl and phenyl.

5. The method for preparing the cefuroxime derivative according to claim 4, characterized in that: In step (3), the intermediate 2 is dissolved in a mixed solvent of tetrahydrofuran and dimethyl sulfoxide, N-hydroxyphthalimide and triphenylphosphine are added in sequence, and then the temperature is controlled at 0°C in an ice-water bath, and diisopropyl azodicarboxylate is slowly added dropwise. After the addition is complete, the resulting mixture is heated to 35°C and stirred for reaction. After the reaction is completed, a saturated saline solution is added for quenching, and intermediate 3 is obtained after post-treatment; The molar ratio of the intermediate 2, N-hydroxyphthalimide, triphenylphosphine and diisopropyl azodicarboxylate is 1:1.2-1.4:1.5-2:1.5-2.

6. The method for preparing the cefuroxime derivative according to claim 5, characterized in that: Step (4) is: dissolving the intermediate 3 in ethanol, adding hydrazine hydrate, stirring at room temperature until the reaction is complete, filtering out the solid, adding water, and extracting with ethyl acetate to obtain the intermediate 4; the molar ratio of the intermediate 3 to the hydrazine hydrate is 1:1.5-2.

7. The method for preparing the cefuroxime derivative according to claim 6, characterized in that: Step (5) is: under a nitrogen atmosphere, the intermediate 4 is dissolved in ethanol, and then the compound 2-oxo-2-(2-(tritylamino)thiazol-4-yl)acetic acid and acetic acid are added, and the mixture is stirred at 60° C.-70° C. to react to obtain the intermediate 5. The molar ratio of the intermediate 4 to 2-oxo-2-(2-(tritylamino)thiazol-4-yl)acetic acid is 1:1-1.

1.

8. The method for preparing the cefuroxime derivative according to claim 7, characterized in that: Step (6) is as follows: under a nitrogen atmosphere, the intermediate 5 is dissolved in N,N-dimethylformamide, and compounds diphenyl chlorophosphate and N,N-diisopropylethylamine are added dropwise in sequence at minus 30°C. After reacting at minus 30°C for 2 hours, a solution of the compound (6R, 7R)-7-amino-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in N,N-dimethylformamide cooled at minus 30°C is added, and the mixture is continuously stirred and reacted at minus 30°C to obtain the intermediate 6.

9. The method for preparing the cefuroxime derivative according to claim 8, characterized in that: Step (7) is: dissolving intermediate 6 in a mixed solution of acetonitrile and water, then heating the resulting mixture to 40° C., adding sodium bicarbonate, and then adding hydrosulfite after 5 minutes; the solution is stirred at 40° C. to react to obtain intermediate 7.

10. The method for preparing the cefuroxime derivative according to claim 8, characterized in that: Step (8) is as follows: the intermediate 7 is dissolved in anhydrous dichloromethane, triethylsilane is added, the mixture is cooled to -15°C, trifluoroacetic acid is added, the solution is stirred and reacted at -15°C for 11-13 hours, the reaction solution is gradually heated to room temperature and the stirring reaction is continued until the reaction is complete, volatiles and solvents are removed by vacuum concentration, tert-butyl methyl ether is added to the residue to obtain a white solid, the solid is sonicated in an ultrasonic wave, centrifuged, the supernatant is removed, and the tert-butyl methyl ether-ultrasound-centrifugation step is repeated twice. The obtained solid is subjected to reduced pressure to remove the solvent to obtain the product.

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