CN116731039A - Process for the preparation of cephalosporin derivatives - Google Patents

Abstract

The invention discloses a preparation method of a cefvicin derivative, which comprises the following steps of (1) protecting hydroxyl; (2), reduction/substitution: the reduction steps are as follows: the obtained 2, 3-di (methoxymethoxy) benzaldehyde reacts with sodium borohydride to obtain corresponding 2, 3-di (methoxymethoxy) benzyl alcohol (intermediate 2); or the substitution steps are as follows: the resulting 2, 3-bis (methoxymethoxy) benzaldehyde was reacted with RMgBr to give a hydroxy carbon substituted product of 2, 3-bis (methoxymethoxy) benzyl alcohol (intermediate 2). (3), mitsunobu reaction: (4), hydrazinolysis (5), condensation, (6), amidation: (7) deprotection; (8) deprotection to obtain the cefvicin derivative. The process is simple, and various cephalosporin derivatives can be synthesized.

Description

Preparation method of cefovecin derivatives

Technical field

The invention relates to a preparation method of cefovecin derivatives and belongs to the field of organic synthesis.

Background technique

Ceftavicin was successfully synthesized for the first time by SmithKline Beecham in 1994, but the production cost was high. It was later developed by Pfizer as a pet drug. It was first allowed in the EU in 2006 for the treatment of skin infections in cats and dogs. It was not until 2008 in the United States. It is only allowed to be used for the treatment of skin and soft tissue infections in cats and dogs. It is not currently on the market in my country.

Cefovecin sodium is a new third-generation cephalosporin animal-specific antibiotic currently in use. Its structural feature is that a tetrahydrofuran heterocycle is linked through a C-C bond at the C-position of the cephalosporin core, thus giving the product a broad spectrum. Antibacterial activity and stability against β-lactamase. As an antibacterial agent, cefovecin sodium has a broad antibacterial spectrum. It has the advantages of fast 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). , currently has shown unique application prospects in veterinary clinical practice. How to further improve its antibacterial activity and avoid the development of drug resistance has become an urgent issue that we need to study.

Studies have shown that synthetic siderophore-drug conjugates are effective in circumventing common antibiotic resistance mechanisms, such as outer membrane permeability barriers, inactivation of related enzymes, and efflux mechanisms. So far, there have been many literature reports on β-lactam antibiotics with side chains capable of binding Fe ³⁺ and siderophore-β-lactam antibiotic couplings; synthetic β-lactam antibiotics Antibiotic-like conjugates possess antibacterial activity. When they are taken up by bacterial cells, siderophore-β-lactam antibiotic conjugates bind to penicillin-binding proteins located in the peripheral cytoplasm, thereby inhibiting the growth of Gram-negative bacteria. To this end, we hoped to synthesize siderophore conjugates of cefavicin.

CN 111620893 A discloses a C-3 tetrahydrofuran-substituted cephalosporin-siderophore couple and its preparation method and application. The invention provides another C-3 tetrahydrofuran-substituted cephalosporin-siderophore couple and Its preparation method.

Contents of the invention

In view of the above problems, the object of the present invention is to provide a preparation method of a cefavicin derivative, which is simple.

In order to achieve the above-mentioned first object, the technical solution of the present invention is: a preparation method of cefovecin derivatives, including the following steps:

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

(2) Reduction/substitution: The reduction step is: react the obtained 2,3-bis(methoxymethoxy)benzaldehyde with sodium borohydride to obtain the corresponding 2,3-bis(methoxymethoxy)benzaldehyde. base) benzyl alcohol (intermediate 2);

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

(3) Mitsunobu reaction: The obtained intermediate 2 reacts with N-hydroxyphthalimide to obtain intermediate 3;

(4) Hydrazine solution: The obtained intermediate 3 reacts with hydrazine hydrate to obtain intermediate 4;

(5) Condensation: The obtained intermediate 4 reacts with 2-oxo-2-(2-(tributylamino)thiazol-4-yl)acetic acid to obtain intermediate 5,

(6) Amidation: the obtained intermediate 5 and (6R, 7R)-7-amino-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thi-1-aza Reaction of bicyclo[4.2.0]oct-2-ene-2-carboxylate gives intermediate 6,

(7) Deprotection: The obtained intermediate 6 reacts with insurance powder to obtain (6R, 7R)-7-((Z)-2-(((2,3-bis(methoxymethoxy)benzyl) base)oxy)imino)-2-(2-(triylamino)thiazol-4-yl)acetamido)-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5- Thi-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and its derivatives (Intermediate 7);

(8) Deprotection: The obtained intermediate 7 reacts with triethylsilane to remove the MOMO protecting group to obtain a cefavicin derivative.

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 in an ice-water bath, the temperature is controlled to about 0°C, and then slowly added dropwise Chloromethyl methyl ether; after the dropwise addition is completed, warm the reaction to room temperature and continue stirring until the reaction is complete; remove the insoluble matter by suction filtration and wash with acetone; remove most of the acetone solvent from the filtrate in a vacuum and add ethyl acetate and water , extracted with ethyl acetate, combined the organic phases, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated in vacuum, and the residue was purified by silica gel column chromatography with 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 1mmol:3.75ml.

In the above solution: the ratio of the amounts of 2,3-dihydroxybenzaldehyde, chloromethyl methyl ether and potassium carbonate is 1:3:10.

In the above scheme: in step (2), the reduction step is: dissolve intermediate 1 in methanol and cool to 0°C, then add sodium borohydride in batches, and then warm the reaction to room temperature. After the reaction is completed, reduce Remove most of the methanol solvent under pressure, add water and ethyl acetate to the residue, extract, wash the organic layer with saturated brine, dry it over anhydrous sodium sulfate, filter and concentrate in vacuum to obtain intermediate 2, said intermediate 1 and sodium borohydride The ratio of the amount of substances is 1:3;

The replacement steps are:

Intermediate 1 was dissolved in a THF solution and cooled to minus 20°C under a nitrogen atmosphere. Then a THF solution of RMgBr was added dropwise to keep the reaction mixture below 10°C. After addition, the mixture was heated to room temperature, stirred, and then added with saturated NH4Cl. The 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. Using petroleum methane/ethyl acetate = 10/1 as the eluent, purify using silica gel column chromatography to obtain substituted intermediate 2, where R is ethyl, methyl, benzyl, cyclohexyl, or phenyl. A sort of.

In the above scheme: in step (3), dissolve intermediate 2 in a mixed solvent of tetrahydrofuran and dimethyl sulfoxide, add N-hydroxyphthalimide and triphenylphosphine in sequence, and then add it in an ice-water bath. Control the temperature to 0°C and slowly add diisopropyl azodicarboxylate dropwise. After the addition is completed, heat the resulting mixture to 35°C and stir the reaction. After the reaction is completed, add saturated aqueous sodium chloride solution for quenching. After post-processing, the intermediate is obtained. 3;

The ratio of the amounts of intermediate 2, N-hydroxyphthalimide, triphenylphosphine and azobisisopropyl ester is 1:1.2-1.4:1.5-2:1.5-2.

In the above scheme: step (4) is: dissolve intermediate 3 in ethanol, add hydrazine hydrate, stir the reaction at room temperature until the reaction is complete, filter out the solid, then add water, and extract with ethyl acetate to obtain intermediate 4. ; The ratio of the amounts of intermediate 3 and hydrazine hydrate is 1:1.5-2.

In the above scheme: step (5) is: dissolve intermediate 4 in ethanol under nitrogen atmosphere, and then add compound 2-oxo-2-(2-(tributylamino)thiazol-4-yl)acetic acid. and acetic acid, the mixture is stirred at 60°C-70°C to react to obtain intermediate 5,

The material amount ratio of intermediate 4 and 2-oxo-2-(2-(tributylamino)thiazol-4-yl)acetic acid is 1:1-1.1.

In the above scheme: step (6) is: dissolve intermediate 5 in N,N-dimethylformamide under a nitrogen atmosphere, and add the compounds diphenyl chlorophosphate and N,N in sequence at minus 30°C. -Diisopropylethylamine, after reacting at minus 30°C for 2 hours, add compound (6R, 7R)-7-amino-8-oxo-3-((S)-tetrahydrofuran-) that has been cooled at minus 30°C. A solution of 2-yl)-5-thi-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in N,N-dimethylformamide, the mixture was stirred at minus 30°C. The reaction yields intermediate 6.

In the above scheme: step (7) is: dissolve intermediate 6 in a mixed solution of acetonitrile and water, then heat the resulting mixture to 40°C, add sodium bicarbonate, and add insurance powder after 5 minutes; the solution is heated at 40°C. The reaction was stirred to obtain intermediate 7.

In the above scheme: step (8) is: dissolve intermediate 7 in anhydrous dichloromethane, then add triethylsilane and cool the resulting mixture to minus 15°C, add trifluoroacetic acid, and keep the solution at minus 15°C. After stirring for 11-13 hours, gradually raise the temperature of the reaction solution to room temperature and continue to stir the reaction until the reaction is complete. After vacuum concentration to remove volatile matter and solvent, add tert-butyl methyl ether to the residue to obtain a white solid. Ultrasonicate in ultrasonic waves, centrifuge, and The supernatant liquid is removed, and the tert-butyl methyl ether-ultrasonic-centrifugation steps are repeated twice. The solid obtained is the product after removing the solvent under reduced pressure.

The ratio of the amount of intermediate 1 to the volume of methanol is 1 mmol:2 mL.

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

The ratio of the amount of intermediate 3 to the volume of ethanol is 1 mmol: 5 mL.

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

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

The ratio of the amount of intermediate 6 to the volume of acetonitrile and water is 1 mmol: 3.6 mL: 1.2 mL. The reaction time is 0.2h.

The ratio of the amount of intermediate 7 to the volume of methylene chloride is 1mmol:5mL, and the reaction time is about 15h.

Compared with the prior art, the beneficial effects of the present invention are:

(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 carbon-substituted derivative of the aldehyde group of 2,3-dihydroxybenzaldehyde, protect the hydroxyl group, and then reduce the aldehyde group to prepare intermediate 2. The raw material (2,3-dihydroxybenzaldehyde Derivatives substituted by carbon on the aldehyde group) 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 mature commercial products with low prices and stable supply, which can ensure industrialization. Produce a stable supply of raw materials.

(2) The reaction steps for synthesizing cefavicin derivatives are short: starting from the main raw material 2,3-dihydroxybenzaldehyde, through substitution and reduction steps, the product can be obtained in only eight steps, which is different from traditional synthesis. Compared with other routes, the response is more convenient and helps reduce production costs.

(3) The operation process is simpler: The simplest way is used to connect each reaction step, making the entire reaction process smoother, which is beneficial to improving the synthesis efficiency and increasing the overall reaction yield.

(4) Better atom economy: There are only a small number of leaving groups in the entire reaction process, and the leaving groups are common small molecule compounds with low value, reflecting the high atom economy of the synthesis route.

Description of drawings

Figure 1 is a mass spectrum of Intermediate 1 of Example 1.

Figure 2 is a mass spectrum of Intermediate 4 of Example 1.

Figure 3 is a mass spectrum of intermediate 5 in Example 1.

Figure 4 is a mass spectrum of intermediate 6 in Example 1.

Figure 5 is a mass spectrum of intermediate 7 of Example 1.

Figure 6 is a mass spectrum of compound 3 in Example 2.

Figure 7 is a mass spectrum of compound 5 in Example 2.

Figure 8 is the mass spectrum of product 6 in Example 2.

Figure 9 is the mass spectrum of compound 8 in Example 2.

Figure 10 is a mass spectrum of Liquid 3 in Example 3.

Figure 11 is the mass spectrum of product 5 in Example 3.

Figure 12 is the mass spectrum of product 6 in Example 3.

Figure 13 is the mass spectrum of product 8 of Example 3.

Figure 14 is a mass spectrum of Liquid 9 in Example 4.

Figure 15 is a mass spectrum of the liquid 10 of Example 5.

Figure 16 is a mass spectrum of Liquid 11 of Example 6.

Detailed ways

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

Example 1

step 1:

Ingredient ratio

The reaction formula is:

Dissolve 11.1g of 2,3-dihydroxybenzaldehyde in 300mL of acetone, add 55.2g of potassium carbonate in an ice-water bath, and then slowly add 18.2mL of chloromethyl methyl ether dropwise. After the addition was complete, the reaction was warmed to room temperature and stirring continued for 30 minutes. After the reaction was completed, the insoluble matter was removed by suction filtration and washed with acetone. The obtained filtrate was vacuumed to remove most of the acetone solvent, then added ethyl acetate and water, extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated in vacuum, and the residue was Petroleum ether/ethyl acetate was purified by silica gel column chromatography. The volume ratio of petroleum ether/ethyl acetate was 20/1 to obtain 17.45g of colorless liquid 2,3-bis(methoxymethoxy)benzaldehyde. The yield is 96%. ¹ H NMR (400MHz, Chloroform-d) δ10.46 (s, 1H), 7.51 (d, J = 7.8Hz, 1H), 7.41 (d, J = 8.2Hz, 1H), 7.21–7.10 (m, 1H ), 5.26(s,2H), 5.24(s,2H), 3.58(s,3H), 3.52(s,3H). The mass spectrum is shown in Figure 1.

Step 2:

Ingredients ratio:

Reaction formula:

Dissolve 12.0g of 2,3-bis(methoxymethoxy)benzaldehyde in 100mL of methanol and cool to 0°C, then add 6.03g of sodium borohydride in batches, and then warm the reaction to room temperature until the reaction is completed. (TLC detection), remove most of the methanol solvent under reduced pressure, add water and ethyl acetate to the residue, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate in vacuum to obtain a white solid 2,3 -Bis(methoxymethoxy)benzyl alcohol 11.4g, yield 94%

Step 3:

Ingredients ratio for steps 3 and 4

Reaction formula:

Dissolve 11.4g of 2,3-bis(methoxymethoxy)benzyl alcohol in a mixed solvent of 80mL of tetrahydrofuran and 40mL of dimethyl sulfoxide, and add 9.79g of N-hydroxyphthalimide and triphenyl in sequence. 19.7g of base phosphine was added, and then 14.8mL of diisopropyl azodicarboxylate was slowly added dropwise in an ice-water bath for 30 minutes. After the addition, the resulting mixture was heated to 35°C and stirred for 1 hour. After the reaction was completed, saturated saline solution was added for quenching. The solution was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain 2-((2,3-bis(methoxymethoxy) Base) benzyloxy) isoindoline-1,3-dione intermediate 3 crude product.

Step 4

Reaction formula:

Dissolve the crude product of 2-((2,3-di(methoxymethoxy)benzyloxy)isoindoline-1,3-dione in 250 mL of ethanol, add 4.55 mL of 80% hydrazine hydrate, 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 solution and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. Purified by silica gel column chromatography with methylene chloride/methanol, the volume ratio of methylene chloride/methanol is 2. Methyl chloride/methanol = 20/1, and a white solid O-(2,3-bis(methoxymethoxy) is obtained. Benzyl)hydroxylamine 8.28g, two-step yield 68%

Step 5:

Ingredient ratio

Under a nitrogen atmosphere, 8.28g of compound O-(2,3-di(methoxymethoxy)benzyl)hydroxylamine was dissolved in 100 mL of ethanol, and then compound 2-oxo-2-(2-(tris Butylamino)thiazol-4-yl)acetic acid 14.1g 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 removed by filtration, the solvent was evaporated from the filtrate under reduced pressure, and the mixture was heated with dichloromethane/methanol ( 9/1) Purify by silica gel chromatography to obtain (Z)-2-((2,3-bis(methoxymethoxy)benzyloxy)imino)-2-(2-(tributylamino) )thiazol-4-yl)acetic acid 19.30g, yield 89%.

Step 6:

Ingredients ratio:

Under a nitrogen atmosphere, compound (Z)-2-((2,3-bis(methoxymethoxy)benzyloxy)imino)-2-(2-(tributylamino)thiazole-4 2.02g of -ethyl)acetic acid was dissolved in 8.0mL of N,N-dimethylformamide, and 588μL of the compound diphenyl chlorophosphate and 1.04mL of N,N-diisopropylethylamine were added dropwise at minus 30°C. , after reacting at minus 30°C for 2 hours, add the compound (6R, 7R)-7-amino-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thi which has been cooled at minus 30°C. -1-Azabicyclo[4.2.0]oct-2-ene-2-carboxylate (16) 810.8 mg, a solution of 16.0 mL of N,N-dimethylformamide, the mixture was stirred at minus 30°C for 12 hours, after the reaction is completed, add saturated sodium bicarbonate to quench the reaction, extract with ethyl acetate, wash with water and saturated brine in sequence, dry with anhydrous sodium sulfate, filter to remove insoluble matter, evaporate the solvent from the filtrate under reduced pressure, and use ethyl acetate to The ester was purified by silica gel chromatography to obtain 4-nitrophenyl (6R, 7R)-7-((Z)-2-(((2,3-bis(methoxymethoxy)benzyl)oxy) )imino)-2-(2-(triylamino)thiazol-4-yl)acetamido)-8-oxo-3-(((S)-tetrahydrofuran-2-yl)-5-thi- 1.68 g of 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, yield 82%.

Step 7:

Ingredients ratio:

4-Nitrophenyl(6R,7R)-7-((Z)-2-(((2,3-bis(methoxymethoxy)benzyl)oxy)imino)-2- (2-(Triylamino)thiazol-4-yl)acetamido)-8-oxo-3-(((S)-tetrahydrofuran-2-yl)-5-thi-1-azabicyclo[4.2 .0] 1.23g of oct-2-ene-2-carboxylate was dissolved in a mixed solution of 43.0mL of acetonitrile and 14.0mL of water, then the resulting mixture was heated to 40°C, 4.46g of sodium bicarbonate was added, and added after 5 minutes. 3.08g insurance powder. Stir the solution for 10 minutes at 40°C. After the reaction is completed, pour the reaction solution into a mixed solution of methylene chloride and water, then use 17% hydrochloric acid to adjust the pH to 3, extract with methylene chloride, and saturate Wash with brine, dry over anhydrous sodium sulfate, filter to remove the desiccant and concentrate in vacuum. The residue is purified by silica gel column chromatography with dichloromethane/methanol. The volume ratio of dichloromethane/methanol is 20/1. A brown color is obtained Solid (6R, 7R)-7-((Z)-2-(((2,3-bis(methoxymethoxy)benzyl)oxy)imino)-2-(2-(triyl) Amino)thiazol-4-yl)acetamido)-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thi-1-azabicyclo[4.2.0]oct-2-ene -2-carboxylic acid 1.01g, yield 94%.

Step 8:

Under a nitrogen atmosphere, (6R, 7R)-7-((Z)-2-(((2,3-bis(methoxymethoxy)benzyl)oxy)imino)-2-(2 -(Triylamino)thiazol-4-yl)acetamido)-8-oxo-3-((S)-tetrahydrofuran-2-yl)-5-thi-1-azabicyclo[4.2.0]octane Dissolve 900 mg of -2-ene-2-carboxylic acid in 5 mL of anhydrous dichloromethane, then add 479 μL of triethylsilane, cool the resulting mixture to minus 15°C, and add 7.65 mL of trifluoroacetic acid. After the solution was stirred at minus 15°C for 12 hours, the reaction solution was gradually warmed to room temperature and continued to stir for 3 hours. After vacuum concentration to remove volatile matter and solvent, tert-butyl methyl ether was added to the residue to obtain a white solid. After ultrasonic for 10 minutes, centrifuge for 10 minutes using a centrifuge to remove the supernatant and continue to repeat tert-butyl methyl ether - ultrasonic - After centrifugation step twice, the solid obtained was decompressed by an oil pump to remove the solvent, and the product cefavicin was 540 mg, with a yield of 96%.

Example 2

step 1)

1. Chemical reaction formula

2. Feeding ratio

Dissolve 11.1g of 2,3-dihydroxybenzaldehyde in 300mL of acetone, add 55.2g of potassium carbonate in an ice-water bath, and then slowly add 18.2mL of chloromethyl methyl ether dropwise. After the addition was complete, the reaction was warmed to room temperature and stirring continued for 30 minutes. After the reaction was completed, the insoluble matter was removed by suction filtration and washed with acetone. The obtained filtrate was vacuumed to remove most of the acetone solvent, then added ethyl acetate and water, extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated in vacuum, and the residue was Petroleum ether/ethyl acetate was purified by silica gel column chromatography. The volume ratio of petroleum ether/ethyl acetate was 20/1 to obtain 17.45g of colorless liquid 2 with a yield of 96%. ¹ H NMR (400MHz, Chloroform-d) δ10.46 (s, 1H), 7.51 (d, J = 7.8Hz, 1H), 7.41 (d, J = 8.2Hz, 1H), 7.21–7.10 (m, 1H ), 5.26(s,2H), 5.24(s,2H), 3.58(s,3H), 3.52(s,3H). The mass spectrum is shown in Figure 1.

2. Step 21. Chemical reaction formula

2. Feeding ratio

A solution of 2 dissolved in THF was cooled to minus 20°C under a nitrogen atmosphere, and then a THF solution of methylmagnesium bromide was added dropwise to keep the reaction mixture below 10°C. After addition, the mixture was warmed to room temperature, stirred for 3 hours, and then quenched with saturated aqueous _NH4Cl solution added slowly. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purify by silica gel column chromatography using petroleum ethyl acetate = 10/1 to obtain liquid 3 (9.16 g, yield 91.6%).

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).

Step 31. Chemical reaction formula

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

Operation process

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

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＝6.7 Hz,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).

Step 41. Chemical reaction formula

2. Feeding ratio

3. Operation process

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, and 8 ml of water was added. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. Purified by silica gel chromatography with ethyl acetate, a white solid 6 (0.8 g, 0.0341 mol, yield 79%) was obtained.

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).

Step 51. Chemical reaction formula

2. Feeding ratio

Operation process

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. The reaction was monitored by TLC. After the reaction, the insoluble matter was filtered to remove the insoluble matter, and the filtrate was evaporated under reduced pressure to remove the solvent. , purified by silica gel chromatography using dichloromethane/methanol = 9/1 to obtain 8 (1.53 g, yield 90%).

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＝6.6Hz,2H). Steps 6:

1. Chemical reaction formula

2. Feeding ratio

Under a nitrogen atmosphere, compound 34 (2.02g, 0.00309mol) was dissolved in N,N-dimethylformamide (8.0mL), and compound diphenyl chlorophosphate (576μL, 0.0028) was added dropwise at minus 30°C. mol) and N,N-diisopropylethylamine (1.04mL, 0.0059mol), after reacting at minus 30°C for 2 hours, add the N of compound 16 (794.6mg, 0.0020mol) that has been cooled at minus 30°C. N-dimethylformamide (16.0 mL) solution, the mixture was stirred at minus 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 ethyl acetate was extracted. Water and saturated sodium bicarbonate were used in sequence. Wash with brine, dry over anhydrous sodium sulfate, filter to remove insoluble matter, evaporate the solvent from the filtrate under reduced pressure, and purify by silica gel chromatography with ethyl acetate to obtain 35 (1.64 g, yield 83%).

Step 7:

1. Chemical reaction formula

2. Feeding ratio

Operation process

Dissolve 23 (1.23g, 0.00120mol) in a mixed solution of acetonitrile (43.0mL) and water (14.0mL), then heat the resulting mixture to 40°C, add sodium bicarbonate (4.46g, 0.0520mol), and wait for 5 minutes. Then add insurance powder (3.08g, 0.0194mol). 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 methylene chloride and water, and then the pH was adjusted to 3 using hydrochloric acid (2M), extracted with methylene chloride, and saturated. Wash with brine, dry over anhydrous sodium sulfate, filter to remove the desiccant and concentrate in vacuum. The residue was purified by silica gel chromatography with dichloromethane/methanol = 20/1 to obtain a brown solid 37 (999 mg, yield 92%).

Step 8:

1. Chemical reaction formula

2. Feeding ratio

Under nitrogen atmosphere, dissolve 37 (900 mg, 0.00994 mol) in anhydrous dichloromethane (5 mL), then add triethylsilane (476 μL, 0.00298 mol) and cool the resulting mixture to minus 15°C, and add trifluoroacetic acid (7.61mL, 0.1mol). After the solution was stirred at minus 15°C for 12 hours, the reaction solution was gradually warmed to room temperature and continued to stir for 3 hours. After vacuum concentration to remove volatile matter and solvent, tert-butyl methyl ether was added to the residue to obtain a white solid. After ultrasonic for 10 minutes, centrifuge for 10 minutes using a centrifuge to remove the supernatant and continue to repeat tert-butyl methyl ether - ultrasonic - The solid was centrifuged twice and the solvent was removed under reduced pressure using an oil pump to obtain product D (551 mg, yield 96.5%).

Example 3

Step 11. Chemical reaction formula

2. Feeding ratio

Dissolve 11.1g of 2,3-dihydroxybenzaldehyde in 300mL of acetone, add 55.2g of potassium carbonate in an ice-water bath, and then slowly add 18.2mL of chloromethyl methyl ether dropwise. After the addition was complete, the reaction was warmed to room temperature and stirring continued for 30 minutes. After the reaction was completed, the insoluble matter was removed by suction filtration and washed with acetone. Most of the acetone solvent was removed from the obtained filtrate under vacuum, then ethyl acetate and water were added, and extracted with ethyl acetate.

Combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate in a vacuum. The residue is purified by silica gel column chromatography with petroleum ether/ethyl acetate. The volume ratio was 20/1, and 17.45g of colorless liquid 2 was obtained, with a yield of 96%. ¹ H NMR (400MHz, Chloroform-d) δ10.46 (s, 1H), 7.51 (d, J = 7.8Hz, 1H), 7.41 (d, J = 8.2Hz, 1H), 7.21–7.10 (m, 1H ), 5.26(s,2H), 5.24(s,2H), 3.58(s,3H), 3.52(s,3H). The mass spectrum is shown in Figure 1.

Step 21. Chemical reaction formula

2. Feeding ratio

Operation process

A solution of 2 dissolved in THF was cooled to minus 20°C under a nitrogen atmosphere, and then a THF solution of ethyl magnesium bromide was added dropwise to keep the reaction mixture below 10°C. After addition, the mixture was warmed to room temperature, stirred for 3 hours, and then quenched with saturated aqueous NH4Cl solution added slowly. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Using petroleum methane/ethyl acetate = 10/1 as the eluent, the product was purified by silica gel column chromatography to obtain liquid 3 (10.84 g, yield 80%).

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).

Step 31. Chemical reaction formula

2. Feeding ratio

Operation process

Dissolve 3 in a mixed solvent of tetrahydrofuran, add 4 and triphenylphosphine in sequence, and then slowly add azodiisopropyl ester dropwise in an ice-water bath for 30 minutes. After the addition, the resulting mixture was heated to 35°C and stirred for 1 h. The reaction was monitored by TLC. After the reaction was completed, saturated saline solution was added for quenching. The solution was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. Purified by silica gel chromatography with dichloromethane/methanol=20/1. 5 was obtained (1.8 g, 78% yield).

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).

Step 41. Chemical reaction formula

2. Feeding ratio

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 aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. Purification by ethyl acetate silica gel chromatography gave a white solid 6 (0.9 g, yield 75%).

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),5.22–5.10( 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＝6.5 Hz,2H).

Step 51. Chemical reaction formula

2. Feeding ratio

Operation process

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. The reaction was monitored by TLC. After the reaction, the insoluble matter was filtered to remove the insoluble matter, and the filtrate was evaporated under reduced pressure to remove the solvent. , purified by silica gel chromatography using dichloromethane/methanol = 20/1 to obtain 8 (1.7 g, yield 85%).

¹ H NMR (400MHz, DMSO-d ₆ ) 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).

Step 61. Chemical reaction formula

Feeding ratio

Operation process

Under a nitrogen atmosphere, compound 34 (2.02g, 0.00277mol) was dissolved in N,N-dimethylformamide (8.0mL), and the compound diphenyl chlorophosphate (564μL, 0.0028) was added dropwise at minus 30°C. mol) and N,N-diisopropylethylamine (0.82mL, 0.0059mol), after reacting at minus 30°C for 2 hours, add the N of compound 16 (710.8mg, 0.0020mol) that has been cooled at minus 30°C. N-dimethylformamide (16.0 mL) solution, the mixture was stirred at minus 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 extracted with ethyl acetate, using water and saturated Wash with brine, dry over anhydrous sodium sulfate, filter to remove insoluble matter, evaporate the solvent from the filtrate under reduced pressure, and purify by silica gel chromatography with ethyl acetate to obtain 35 (1.53 g, yield 79%).

Step 7:

1. Chemical reaction formula

2. Feeding ratio

Operation process

Dissolve 36 (1.23g, 0.00120mol) in a mixed solution of acetonitrile (43.0mL) and water (14.0mL), then heat the resulting mixture to 40°C, add sodium bicarbonate (4.07g, 0.0520mol), and wait for 5 minutes. Then add insurance powder (2.81g, 0.0194mol). 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 methylene chloride and water, and then the pH was adjusted to 3 using hydrochloric acid (2M), extracted with methylene chloride, and saturated. Wash with brine, dry over anhydrous sodium sulfate, filter to remove the desiccant and concentrate in vacuum. The residue was purified by silica gel chromatography with dichloromethane/methanol = 20/1 to obtain brown solid 37 (907 mg, 0.00092 mol, yield 84%).

Step 81. Chemical reaction formula

2. Feeding ratio

Operation process

Under nitrogen atmosphere, dissolve 37 (900 mg, 0.00994 mol) in anhydrous dichloromethane (5 mL), then add triethylsilane (476 μL, 0.00298 mol) and cool the resulting mixture to minus 15°C, and add trifluoroacetic acid (7.61mL, 0.1mol). After the solution was stirred at minus 15°C for 12 hours, the reaction solution was gradually warmed to room temperature and continued to stir for 3 hours. After vacuum concentration to remove volatile matter and solvent, tert-butyl methyl ether was added to the residue to obtain a white solid. After ultrasonic for 10 minutes, centrifuge for 10 minutes using a centrifuge to remove the supernatant and continue to repeat tert-butyl methyl ether - ultrasonic - The solid was centrifuged twice and the solvent was removed under reduced pressure by an oil pump to obtain product D (573 mg, 0.0088 mol, yield 96%).

Example 4

1. Chemical reaction formula

2. Feeding ratio

Operation process

Dissolve 2 in THF, cool to minus 20°C under a nitrogen atmosphere, and then add a THF solution of cyclohexylmagnesium bromide dropwise to keep the reaction mixture below 10°C. After addition, the mixture was warmed to room temperature, stirred for 3 hours, and then quenched with saturated aqueous _NH4Cl solution added slowly. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purify by silica gel column chromatography using petroleum methane/ethyl acetate = 10/1 as the eluent to obtain liquid 9 (544 mg, yield 79%).

¹ H 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).

Example 5

1. Chemical reaction formula

2. Feeding ratio

Operation process

A solution of 2 dissolved in THF was cooled to minus 20°C under a nitrogen atmosphere, and then a THF solution of phenylmagnesium bromide was added dropwise to keep the reaction mixture below 10°C. After addition, the mixture was warmed to room temperature, stirred for 3 hours, and then quenched with saturated aqueous _NH4Cl solution added slowly. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Using petroleum methane/ethyl acetate = 10/1 as the eluent, the product was purified by silica gel column chromatography to obtain liquid 10 (570 mg, yield 85%).

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

1. Chemical reaction formula

2. Feeding ratio

3. Operation process

A solution of 2 dissolved in THF was cooled to minus 20°C under a nitrogen atmosphere, and then a THF solution of ethyl magnesium bromide was added dropwise to keep the reaction mixture below 10°C. After addition, the mixture was warmed to room temperature, stirred for 3 hours, and then quenched with saturated aqueous _NH4Cl solution added slowly. The solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Using petroleum methane/ethyl acetate = 10/1 as the eluent, the product was purified by silica gel column chromatography to obtain liquid 11 (460 mg, yield 82%).

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).

The present invention is not limited to the above-described embodiments. Those of ordinary skill in the art can understand that various changes, modifications, substitutions and modifications can be made to these embodiments without departing from the principles and purposes of the present invention. The scope of the present invention Defined by the claims and their equivalents.

Claims (10)

1. A preparation method of a cefvicin derivative, which is characterized in that: the method comprises the following steps:

(1) Hydroxyl protection: 2, 3-dihydroxybenzaldehyde reacts with chloromethyl methyl ether ((MOMOCl)) to give 2, 3-bis (methoxymethoxy) benzaldehyde (intermediate 1);

(2) Reduction/substitution: the reduction steps are as follows: the obtained 2, 3-di (methoxymethoxy) benzaldehyde reacts with sodium borohydride to obtain corresponding 2, 3-di (methoxymethoxy) benzyl alcohol (intermediate 2);

or the substitution steps are as follows: the resulting 2, 3-bis (methoxymethoxy) benzaldehyde was reacted with RMgBr to give a hydroxy carbon substituted product of 2, 3-bis (methoxymethoxy) benzyl alcohol (intermediate 2)

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

(4) Hydrazinolysis: the obtained intermediate 3 reacts with hydrazine hydrate to obtain an intermediate 4;

(5) Condensation: the intermediate 4 obtained is reacted with 2-oxo-2- (2- (tributylamino) thiazol-4-yl) acetic acid to give intermediate 5,

(6) Amidation: the resulting 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 afford intermediate 6,

(7) Deprotection: reacting the intermediate 6 obtained with sodium hydrosulfite to obtain (6R, 7R) -7- ((Z) -2- (((2, 3-bis (methoxymethoxy) benzyl) oxy) imino) -2- (2- (trisylamino) thiazol-4-yl) acetamido) -8-oxo-3- ((S) -tetrahydrofuran-2-yl) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and its derivative (intermediate 7);

(8) Deprotection: and (3) reacting the obtained intermediate 7 with triethylsilane to remove the MOMO protecting group, thereby obtaining the cefavermectin derivative.

2. The process for the preparation of a ceftazidime derivative according to claim 1, wherein: in the step (1), 2, 3-dihydroxybenzaldehyde is dissolved in an organic solvent, potassium carbonate is added under ice water bath, the temperature is controlled to be about 0 ℃, and chloromethyl methyl ether is slowly added dropwise; after the dripping is completed, the reaction is warmed up to room temperature and stirred continuously until the reaction is complete; removing insoluble substances by suction filtration, and washing by using acetone; the filtrate obtained was freed from most of the acetone solvent in vacuo, ethyl acetate and water were added, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated in vacuo, and the residue was purified by petroleum ether/ethyl acetate chromatography on a silica gel column to give intermediate 1.

3. A process for the preparation of a cefvicin derivative according to claim 2, characterized in that: the ratio of the amounts of the substances of the 2, 3-dihydroxybenzaldehyde, chloromethyl methyl ether and potassium carbonate is 1:3:10.

4. a process for the preparation of a cefvicin derivative according to claim 2, characterized in that: in the step (2), the step of reduction is as follows: dissolving the intermediate 1 in methanol and cooling to 0 ℃, then adding sodium borohydride in batches, subsequently heating the reaction to room temperature, removing most of methanol solvent under reduced pressure after the reaction is completed, adding water and ethyl acetate into residues, extracting, washing an organic layer with saturated saline water, drying with anhydrous sodium sulfate, filtering, and concentrating in vacuum to obtain an intermediate 2, wherein the ratio of the amounts of the intermediate 1 to the sodium borohydride is 1:3, a step of;

the substitution steps are as follows:

dissolving intermediate 1 in THF solution, cooling to 20deg.C under nitrogen atmosphere, then dropwise adding THF solution of RMgBr to keep the reaction mixture below 10deg.C, heating the mixture to room temperature, stirring for reaction, and then using saturated NH ₄ The mixture was quenched by slow addition of aqueous Cl; extracting the solution with ethyl acetate, and extracting with saltWashed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purifying by silica gel column chromatography with petroleum riddle/ethyl acetate=10/1 as eluent to obtain substituted intermediate 2, wherein R is one of ethyl, methyl, benzyl, cyclohexyl and phenyl.

5. The process for preparing a cephalosporin derivative according to claim 4, wherein: in the step (3), the intermediate 2 is dissolved in a mixed solvent of tetrahydrofuran and dimethyl sulfoxide, N-hydroxyphthalimide and triphenylphosphine are sequentially added, then diisopropyl azodicarboxylate is slowly added dropwise under the ice water bath at the temperature of 0 ℃, after the addition, the obtained mixture is heated to 35 ℃ and stirred for reaction, saturated saline solution is added for quenching after the reaction is completed, and the intermediate 3 is obtained through post treatment;

the ratio of the amounts of the substances of intermediate 2, N-hydroxyphthalimide, triphenylphosphine and azobisisopropylester is 1:1.2-1.4:1.5-2:1.5-2.

6. The process for preparing a cephalosporin derivative according to claim 5, characterized in that: the step (4) is as follows: dissolving the intermediate 3 in ethanol, adding hydrazine hydrate, stirring at room temperature to react completely, filtering out solid, adding water, and extracting with ethyl acetate to obtain an intermediate 4; the ratio of the amounts of intermediate 3 and hydrazine hydrate is 1:1.5-2.

7. The process for preparing a cephalosporin derivative according to claim 6, characterized in that: the step (5) is as follows: dissolving the intermediate 4 in ethanol under nitrogen atmosphere, then adding the compound 2-oxo-2- (2- (tributylamino) thiazol-4-yl) acetic acid and acetic acid, stirring the mixture at 60-70 ℃ for reaction to obtain an intermediate 5,

the ratio of the amounts of the substances of intermediate 4 and 2-oxo-2- (2- (tributylamino) thiazol-4-yl) acetic acid was 1:1-1.1.

8. The method for producing a cephalosporin derivative according to claim 7, wherein the step (6) is: dissolving the intermediate 5 in N, N-dimethylformamide under nitrogen atmosphere, dropwise adding diphenyl chlorophosphate and N, N-diisopropylethylamine at minus 30 ℃ in sequence, reacting for 2 hours at minus 30 ℃, adding N, N-dimethylformamide 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 cooled at minus 30 ℃, and continuously stirring the mixture at minus 30 ℃ to react to obtain the intermediate 6.

9. The method for producing a cephalosporin derivative as defined in claim 8, wherein the step (7) is: dissolving the intermediate 6 in a mixed solution of acetonitrile and water, heating the obtained mixture to 40 ℃, adding sodium bicarbonate, and adding sodium hydrosulfite after 5 minutes; the solution was stirred at 40 ℃ to afford intermediate 7.

10. The method for producing a cephalosporin derivative as defined in claim 8, wherein the step (8) is: dissolving the intermediate 7 in anhydrous dichloromethane, adding triethylsilane, cooling the obtained mixture to minus 15 ℃, adding trifluoroacetic acid, stirring the solution at minus 15 ℃ for reaction for 11-13 hours, gradually heating the reaction solution to room temperature, continuously stirring for reaction until the reaction is complete, vacuum concentrating to remove volatile matters and solvent, adding tert-butyl methyl ether into the residue to obtain white solid, performing ultrasonic treatment in ultrasonic waves, centrifuging, removing supernatant, continuously repeating the tert-butyl methyl ether-ultrasonic-centrifuging step twice, and removing the solvent from the obtained solid under reduced pressure to obtain the product.