CN102633819A - Preparation method of cefoxitin - Google Patents

Abstract

The invention relates to a preparation method of cefoxitin, which comprises the following steps: adding an organic solvent A into the compound aqueous solution with the structure of the formula (IV), adding N, N' -dibenzylethylenediamine diacetate or the aqueous solution thereof, and filtering to obtain an intermediate compound with the structure of the formula (III); adding a compound with an intermediate structure shown in formula (III) into acetone or tetrahydrofuran, adding chlorosulfonyl isocyanate for reaction, and hydrolyzing after the reaction is finished; then adding ethyl acetate, filtering, extracting, decoloring, salting out, and filtering to obtain an intermediate compound with a structure of formula (II); adding a compound with an intermediate structure shown in formula (II) into an organic solvent B, adding organic acid for dissolving, adding a methanol solution of sodium methoxide and tert-butyl hypochlorite for methoxylation reaction, adding sodium metabisulfite and acetic acid for neutralization after the reaction is finished, adding water for extraction, carrying out acid precipitation on a water phase, and filtering to obtain cefoxitin; the deacetylcephalothin exists in the form of sodium salt or amine salt all the time, so that condensation side reaction easily caused by low pH is avoided, and the product quality and yield can be better controlled.

Description

A kind of preparation method of cefoxitin

technical field

The invention relates to a preparation method of a compound, in particular to a preparation method of cefoxitin, and belongs to the technical field of pharmaceutical chemical synthesis.

Background technique

Cefoxitin Sodium, chemical name: (6R, 7S)-3-carbamoyloxymethyl-7α-methoxy-8-oxo-7β-[2-(2-thienyl) Sodium acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate is a semi-synthetic cephamycin antibiotic developed by Merck Company of the United States, belonging to the second Substitute cephalosporin antibiotics. Cefoxitin sodium has a strong antibacterial effect on Gram-negative bacteria, and its antibacterial spectrum includes Escherichia coli, Klebsiella pneumoniae, indole-positive Proteus and Serratia, Klebsiella, influenza bacillus, Salmonella, and Shigella wait. It also has a good effect on staphylococcus and various streptococci. Clinically, it is mainly used for respiratory tract infection, endocarditis, peritonitis, pyelonephritis, urinary tract infection, sepsis, bone, joint, skin and soft tissue infection caused by the above-mentioned sensitive bacteria.

With the widespread use and even abuse of β-lactam antibiotics, the ability of bacteria to produce β-lactamase is stimulated, which leads to the increasingly serious problem of drug resistance. Due to the presence of the methoxyl group at the 7α position of cefoxitin sodium, it has relatively strong resistance to β-lactamase compared with common cephalosporins, which is also the commonality of cefoxitin antibiotics.

Cefoxitin acid, also known as cefoxitin, is the free acid form of cefoxitin sodium, and its chemical structure is as follows:

There are many synthetic routes of cefoxitin reported in open literature at present, but there are certain problems in realizing industrialized production. For example:

1) U.S. Patent Document US 4297488: Using cephamycin C as raw material, thiopheneacetyl group is introduced through acyl exchange reaction, and then cefoxitin is obtained through deprotection group reaction. Although the method is simple, the fermentation level of raw material cefamycin C Low, it is difficult to realize industrial production like cephalosporin C, which makes the cost of this route too high. In fact, the only industrialized cephamycin core on the market is only 7-MAC, the full name is 7β-amino-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl Base]-3-cephem-4-carboxylic acid benzhydryl ester.

2) WO2004083217: using cephalothin as raw material, cefoxitin was obtained through methoxidation, hydrolysis and carbamylation. The method is highly practical and is currently the preferred method for producing cefoxitin.

3) European patent document EP 1748049: announced the method of using cephalothin as starting material to prepare cefoxitin in one step. In addition to the last step of crystallization, there is no crystallization and purification step in the process, and the product impurities are basically uncontrollable, and it is almost impossible to meet the quality standards of various pharmacopoeias.

4) Chinese patent document CN101007812: 7β-amino-7α-methoxy-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid As a raw material, the product is obtained through acylation, hydrolysis, and carbamylation reactions. The "7-MAC" described in this document is actually the recognized free acid form of 7-MAC, which can only be obtained by hydrolysis of 7-MAC, which means that the 4-position carboxyl group must be protected first and then deprotected, and the overall yield does not account for Advantage.

5) Chinese patent CN 101613361: use deacetylated 7ACA as raw material, undergo acylation, carbamylation, and finally methoxyl to obtain cefoxitin. In this method, deacetyl cephalothin is separated in the form of acid, and if the pH is too low, cephalothin lactone will be partially formed during crystallization, which will affect the quality and yield. And when reacting with CSI in the next step, the side reaction of forming cephalothin lactone under acidic and anhydrous conditions is more serious, and the product quality and yield are difficult to guarantee. The following is the reaction formula of this side reaction:

The existing reported literatures all have the problem that the raw materials or process conditions are not suitable for scale-up production, or the product quality and yield are not competitive enough.

Contents of the invention

The invention provides a preparation method of cefoxitin aiming at the deficiencies of the existing technology.

Explanation of terms:

Semi-benzathine salt: that is, the compound is composed of two molecules of deacetyl cephalothinic acid and one molecule of benzathine (i.e., N, N'-dibenzylethylenediamine);

DBED: Abbreviation for N, N'-dibenzylethylenediamine diacetate, also known as benzathine diacetate and benzathine acetate;

CSI: Abbreviation for chlorosulfonyl isocyanate;

Technical scheme of the present invention is as follows:

A preparation method of cefoxitin, the synthetic route is as follows:

In the formula, M ⁺ is Na ⁺ or Et ₃ NH ⁺ ;

Including the following steps:

(1) Add organic solvent A to the aqueous solution of the compound of formula (IV), and add N, N'-dibenzylethylenediamine diacetate (DBED) or N, N' - an aqueous solution of dibenzylethylenediamine diacetate, the compound of the intermediate formula (III) is precipitated, the temperature is lowered to 0-10° C., and the precipitate is filtered to obtain the compound of the intermediate formula (III);

Organic solvent A is: one of dichloromethane, chloroform or a combination of any ratio;

(2) Add the compound of the intermediate formula (III) obtained in step (1) into acetone or tetrahydrofuran, control the temperature at -65°C to -20°C, and add chlorosulfonyl isocyanate (CSI) for carbamylation reaction , then add water or acid and heat up to -10°C to 20°C for hydrolysis; add ethyl acetate after hydrolysis, filter to remove benzathine hydrochloride, wash the filtrate with aqueous sodium chloride, add aqueous sodium bicarbonate to the organic phase The product is extracted into the water phase, after decolorization, sodium chloride is added for salting out, and the precipitate is collected by filtration to obtain a compound of the intermediate formula (II);

(3) The compound of the intermediate formula (II) structure obtained in step (2) is added in the organic solvent B, and under the condition of -80～0°C, an organic acid is added to form demethoxycefoxitin acid Supersaturated solution, then add methanol solution of sodium methoxide and tert-butyl hypochlorite under temperature control at -95～-70°C for methoxidation reaction; after methoxidation reaction, add sodium metabisulfite and acetic acid for neutralization, add water for extraction, water After acid analysis, the precipitate is filtered to obtain the compound of formula (I), i.e. cefoxitin;

The organic solvent B is selected from one of dichloromethane, tetrahydrofuran, methanol or a combination in any ratio.

The compound of the formula (IV) in the step (1) is deacetylcefalotin sodium (M ⁺ is Na ⁺ ) or deacetylcefalotin triethylamine salt (M ⁺ is Et ₃ NH ⁺ ). Its synthesis method can be obtained by referring to the similar descriptions in the open documents in this field, for example: it is obtained by hydrolyzing cefalotin sodium with sodium hydroxide in a methanol/water mixture, and then distilling off methanol under reduced pressure (see US Patent Document US7662955); Obtained from cefalotin sodium after catalyzed hydrolysis by acetyl esterase (see Chinese patent document CN101555252); react 2-thiopheneacetyl chloride with deacetylated 7-ACA under the catalysis of triethylamine (see Chinese patent document CN101914105A), and then concentrate Remove organic solvents.

Preferably according to the present invention, the reaction molar ratio of the compound of formula (IV) and N,N'-dibenzylethylenediamine diacetate in the step (1) is 1: (0.5-1).

Preferably according to the present invention, the organic solvent A in the step (1) is dichloromethane or chloroform.

Preferably according to the present invention, the molar ratio of chlorosulfonyl isocyanate to the intermediate compound of formula (III) in the step (2) is (1-3):1.

Preferably according to the present invention, in the step (2), the acid used for the hydrolysis reaction is hydrochloric acid or sulfuric acid.

Preferably according to the present invention, the organic solvent B in the step (3) is dichloromethane or tetrahydrofuran, or a combination of dichloromethane, tetrahydrofuran and methanol in any ratio;

Preferably according to the present invention, in the step (3), the organic acid is one of formic acid, trifluoroacetic acid, fluoroboric acid, methanesulfonic acid, p-toluenesulfonic acid or a combination of any ratio; preferred organic acid For methanesulfonic acid or p-toluenesulfonic acid.

Preferably according to the present invention, in the step (3), the molar ratio of the organic acid to the compound of the intermediate formula (II) is (1-2):1.

Preferably according to the present invention, in the step (3), the methoxidation reaction temperature is -95 to -80°C, and the molar ratio of sodium methoxide to the compound of the intermediate formula (II) is (3 to 8): 1; The molar ratio of tert-butyl acid to the intermediate compound of formula (II) is (1-3):1.

According to the present invention, one of preferred schemes, a kind of preparation method of cefoxitin, comprises the steps:

(1) Add 200ml of dichloromethane (organic solvent A) to 1000ml of an aqueous solution containing 100-120g of deacetylcefalotin sodium, and then add 50-80g of N,N'-dibenzyl In a solution prepared from ethylenediamine diacetate and 800ml of water, the compound of the intermediate formula (III) is precipitated, the temperature is lowered to 0-10°C, and the precipitate is filtered to obtain the compound of the intermediate formula (III);

(2) Add the compound of intermediate formula (III) obtained in step (1) into 1000ml of acetone, cool down to -50°C to -20°C, and add 35 to 60ml of chlorosulfonyl isocyanate dropwise to carry out the carbamylation reaction ; After the carbamylation reaction was detected by HPLC, 198ml of water was added, and the temperature was raised to -10～10°C for hydrolysis; after the hydrolysis was completed, 1980ml of ethyl acetate was added, and benzathine hydrochloride was removed by filtration, and the filtrate was washed with aqueous sodium chloride solution. Layering, add aqueous sodium bicarbonate solution to the organic phase to extract the product into the water phase, then add activated carbon to the water phase for decolorization, filter, add 200g of sodium chloride to the filtrate for salting out, the compound of the intermediate formula (II) structure is precipitated, stir for 1 hour and filter , to obtain the compound of intermediate formula (II) structure;

(3) Add the compound of intermediate formula (II) obtained in step (2) into 680ml of tetrahydrofuran, cool down to -50～-10°C, add 16.0～21.4ml of methanesulfonic acid, cool down to -95～-80°C ℃, then add 160-220g of 30wt% methanol solution of sodium methoxide and 24.25-30.75g of tert-butyl hypochlorite for methoxidation reaction, after the reaction is completed, add 51g of sodium metabisulfite and 61.5ml of glacial acetic acid, then add activated carbon for decolorization, and then add 850ml of water, adjusted to pH=2 with hydrochloric acid, cooled to 0-10°C, filtered to collect the precipitate, to obtain the compound of formula (I), ie cefoxitin.

Technical characteristics of the present invention:

The preferred organic solvent in the step (1) of the present invention can effectively improve the crystallization process of the reactants. The compound of the intermediate formula (II) prepared in the step (2) of the present invention is a sodium salt, and the form of the sodium salt is conducive to low-temperature acidification and dissolution before the next step of the methoxidation reaction to form a supersaturated solution. If it is demethoxycefoxitin acid isolated as in CN 101613361, it is almost impossible to dissolve in the next step of use, and adding organic base or silanization cannot solve this problem, and the follow-up methoxylation reaction is in the heterogeneous phase basically impossible under these conditions.

The beneficial effects of the present invention are as follows:

1. In the present invention, deacetylated cephalothin exists in the form of sodium salt or amine salt, which avoids the condensation side reaction easily caused by low pH, overcomes the disadvantages of CN 101613361, can better control product quality and yield, and adapts to Industrial production.

2. The present invention adds organic solvent A to the aqueous solution of the compound of formula (IV) structure, which can effectively improve the crystallization process. It is difficult to avoid severe foaming when the compound of formula (III) structure crystallizes out using ethyl acetate or other solvents. Phenomenon;

3. The compound of formula (II) in the present invention is in the form of sodium salt, which overcomes the disadvantage of being difficult to dissolve in the next step after crystallization in the form of acid, and is beneficial to product dissolution and further reaction.

4. The raw materials of the present invention are commonly used materials in the market, and have the advantages of economy and easy disposal of three wastes, effectively reducing the cost of raw materials for the synthesis of cefoxitin acid; and the comprehensive yield is high, the product quality is easy to control, and the production safety is high. , suitable for large-scale industrial production.

Detailed ways

The present invention will be further described below in conjunction with the examples, but the protection scope of the present invention is not limited thereto.

The deacetylated cephalothin sodium described in the examples is obtained by cefalotin sodium after catalyzed hydrolysis by acetyl esterase; the preparation method of cefalotin sodium is according to the cephalothin acid obtained in Example 1 in Chinese patent document CN101555252 (application number 200910027790.1). Obtained after dissolving with sodium bicarbonate solution;

The preparation method of tert-butyl hypochlorite is synthesized with reference to the synthetic method in "Synthesis and Characterization of New Rubber Chlorinating Agent" (Li Yanli, Shi Shuxian, etc., Journal of Beijing University of Chemical Technology, 31(4):45～49);

N, N'-dibenzylethylenediamine diacetate was purchased from Shanghai Sinopharm Group Reagent Company, chlorosulfonyl isocyanate was purchased from Shanghai Bangcheng Chemical Company, and methanesulfonic acid was purchased from Shanghai Sinopharm Group Reagent Company.

Example 1

A preparation method of cefoxitin, comprising the steps of:

(1) Add 200ml of dichloromethane (organic solvent A) to the aqueous solution 1000ml of the compound of formula (IV) structure (containing deacetyl cephalothin sodium 110g), then add 56g of N,N'-dichloromethane at 30°C with temperature control A solution made of benzylethylenediamine diacetate and 800ml of water, the compound of the intermediate formula (III) is precipitated, the temperature is lowered to 0-10°C and stirred for 2 hours; the precipitate is collected by filtration, and the product is washed with water and methylene chloride in turn, Vacuum drying gave 132g of the intermediate compound of formula (III), with a yield of 95.2%;

Detected by ¹ H NMR (400MHz, CDCl ₃ ), the results are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ9.02 (d, 1H, J=8.4Hz, CONH), 7.31-7.44 (m, 6H), 6.92-6.96 (m, 2H, thiophene-H), 7.73 (br , 2H, CONH ₂ ), 5.53-5.56(dd, 1H), 4.95(d, 1H, J=4.8), 4.06-4.23(abd, 2H, J=12.8Hz), 3.92(s, 2H), 3.80( s, 2H), 3.39-3.54 (abd, 2H, J = 18.0 Hz), 2.91 (s, 2H).

(2) Add the compound of the intermediate formula (III) structure obtained in step (1) to 1000ml of acetone, drop the temperature to -40°C and add 61ml of chlorosulfonyl isocyanate dropwise to carry out carbamylation reaction; HPLC detects carbamoyl After the completion of the chemical reaction, add 198ml of water, and heat up to -10°C to carry out the hydrolysis reaction; after the completion of the hydrolysis, add 1980ml of ethyl acetate, and filter to remove benzathine hydrochloride. The filtrate was washed with aqueous sodium chloride, and the layers were separated. An aqueous solution of sodium bicarbonate was added to the organic phase to extract the product into the aqueous phase. Add active carbon to the water phase for decolorization, filter, add 200g of sodium chloride to the filtrate for salting out, the compound of the intermediate formula (II) structure is separated out, stir for 1 hour; filter to get the precipitate, then wash the product with a mixed solution of 450ml acetone and 100ml purified water, Vacuum drying gave 102.3g of the intermediate compound of formula (II), with a yield of 87.7%;

Detected by ¹ H NMR (400MHz, CDCl ₃ ), the results are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ9.02 (d, 1H, J=8.4Hz, CONH), 7.34-7.36 (m, 1H, thiophene-H), 6.92-6.96 (m, 2H, thiophene-H ), 6.53 (br, 2H, CONH ₂ ), 5.49 (dd, 1H, J=4.8, 8.4Hz, lactom ring NCOCH-), 4.95 (d, 1H, J=4.8Hz lactam ring-CHNS), 4.74-4.88 (abd, 2H, J=12.0 Hz), 3.76-3.77 (d, 2H, J=2.4 Hz), 3.20-3.46 (abd, 2H, J=17.2 Hz).

(3) Add the intermediate compound of formula (II) obtained in step (2) into 680ml of tetrahydrofuran (organic solvent B), cool down to -25°C, slowly add 17.4ml of methanesulfonic acid; continue to cool down to -80°C , then add 180g of 30wt% methanol solution of sodium methoxide and 27.95g of tert-butyl hypochlorite for methoxidation reaction, add 51g of sodium metabisulfite and 61.5ml of glacial acetic acid after the reaction is completed, then add activated carbon for decolorization, then add 850ml of water, and use hydrochloric acid Adjust the pH to 2, the compound of formula (I) is precipitated, lower the temperature to 0-10°C and stir for 1 hour; filter to collect the precipitate, and wash the product with a mixture of 175ml purified water and 34ml tetrahydrofuran. Vacuum drying obtained 85.6g of the compound of formula (I), i.e. cefoxitin, with a yield of 82.1%;

Detected by ¹ H NMR (400MHz, CDCl ₃ ), the results are as follows:

¹ H NMR (400MHz, CDCl ₃ ) δ9.44 (S, 1H, CONH), 7.36-7.37 (m, 1H, thiophene-H), 6.95-6.97 (m, 2H, thiophene-H), 6.59 (br, 2H, CONH ₂ ), 5.15(s, 1H, lactam ring-H), 4.82(abd, 1H, J=12.8Hz), 4.60(abd, 1H, J=12.8Hz), 3.80-3.86(m, 2H) , 3.54 (abd, 1H, J=18.0 Hz), 3.38 (s, 3H, OCH3), 3.30 (abd, 1H, J=18.0 Hz).

Example 2

The preparation method of cefoxitin as described in embodiment 1, difference is:

The organic solvent A described in the step (1) is chloroform, and 128.5 g of the compound of the intermediate formula (III) is obtained, with a yield of 94.9%.

The intermediate compound of formula (III) was detected by ¹ H NMR (400 MHz, CDCl ₃ ), and the result was the same as that in Example 1.

Example 3

The preparation method of cefoxitin as described in embodiment 1, difference is:

In step (2), add 80 g of the compound of the intermediate formula (III) prepared according to step (1) of Example 1 into 600 ml of tetrahydrofuran, drop the temperature to -50°C and add 39 ml of chlorosulfonyl isocyanate dropwise for carbamylation Reaction: After the carbamylation reaction was detected by HPLC, 120ml of 5wt% hydrochloric acid was added, and the temperature was raised to 10°C for a hydrolysis reaction; after the hydrolysis was completed, 1200ml of ethyl acetate was added, and then benzathine hydrochloride was removed by filtration. The filtrate was washed with aqueous sodium chloride, and the layers were separated. An aqueous solution of sodium bicarbonate was added to the organic phase to extract the product into the aqueous phase. Add active carbon to the water phase for decolorization, filter, add 120g of sodium chloride to the filtrate for salting out, the compound of the intermediate formula (II) structure is precipitated, stir for 1 hour; filter to take the precipitate, wash the product with a mixture of 300ml acetone and 50ml purified water, vacuum Dry to obtain 58.5g intermediate compound of formula (II), yield 82.7%;

The intermediate compound of formula (II) was detected by ¹ H NMR (400 MHz, CDCl ₃ ), and the result was the same as that in Example 1.

Example 4

The preparation method of cefoxitin as described in embodiment 1, difference is:

In step (3), 60 g of the compound of the intermediate formula (II) structure prepared according to step (2) of Example 1 was added to a mixed solution of 900 ml of dichloromethane and 200 ml of methanol, and the temperature was lowered to -40 °C and p-methyl 18.5ml of benzenesulfonic acid, cooled to -85°C, then added 130g of 30wt% methanol solution of sodium methoxide and 23.2g of tert-butyl hypochlorite for methoxidation reaction, added 30g of sodium pyrosulfite and 36ml of glacial acetic acid after the reaction was completed, and then added 500ml of water, adjust the pH value of the system to 6-7, and let it stand for stratification. Add 8g of activated carbon to the water phase and stir for 20 minutes to decolorize, filter, wash with 300ml of water, combine the filtrates, adjust the feed solution to pH=2 with 10wt% hydrochloric acid, the compound of the formula (I) structure is precipitated, cool to 0-5°C and stir for 1 hour Get precipitate by filtration, wash product with the mixed solution of 200ml purified water and 12ml ethyl acetate, obtain the compound of 51.7g formula (I) structure through vacuum drying, i.e. cefoxitin, yield 84.6%.

Cefoxitin was detected by ¹ H NMR (400 MHz, CDCl ₃ ), and the result was the same as that in Example 1.

Example 5

The preparation method of cefoxitin as described in embodiment 4, difference is:

Add 60 g of the compound of the intermediate formula (II) obtained according to step (2) of Example 3 to a mixed solution of 600 ml of dichloromethane, 80 ml of tetrahydrofuran and 100 ml of methanol, cool down to -15°C and add 11.0 ml of methanesulfonic acid, Cool down to -85°C, then add 140g of 30wt% methanol solution of sodium methoxide and 24.5g of tert-butyl hypochlorite for methoxidation reaction, add 30g of sodium metabisulfite and 36ml of glacial acetic acid after the reaction is completed, and then add 500ml of water to adjust the pH of the system The value is 6-7, standing for layering. Add 8g of activated carbon to the water phase and stir for 20 minutes to decolorize, filter, wash with 300ml of water, combine the filtrates, adjust the feed solution to pH=2 with 10wt% hydrochloric acid, the compound of the formula (I) structure is precipitated, cool to 0-5°C and stir for 1 hour Get precipitate by filtration, wash product with the mixed solution of 200ml purified water and 12ml ethyl acetate, obtain the compound of 50.9g formula (I) structure through vacuum drying, i.e. cefoxitin, yield 83.3%.

Cefoxitin was detected by ¹ H NMR (400 MHz, CDCl ₃ ), and the result was the same as that in Example 1.

Claims (10)

1. the preparation method of a cefoxitin is characterized in that, synthetic route is following:

In the formula, M ⁺Be Na ⁺Or Et ₃NH ⁺, DBED is N, N '-dibenzyl-ethylenediamin diacetate, CSI are Sulfuryl chloride isocyanate;

Comprise the steps:

(1) in the compound water solution of formula (IV) structure; Add organic solvent A, temperature control adds N, N '-dibenzyl-ethylenediamin diacetate or N for 10 ℃～50 ℃; The aqueous solution of N '-dibenzyl-ethylenediamin diacetate; The compound of midbody formula (III) structure is separated out, and is cooled to 0～10 ℃, filters the compound that obtains midbody formula (III) structure;

Organic solvent A is: one of methylene dichloride, chloroform or arbitrarily than combination;

The compound of midbody formula (III) structure that (2) step (1) is made joins in acetone or the THF; Temperature control-65 ℃～-20 ℃; Add Sulfuryl chloride isocyanate and carry out the carbamylation reaction, add entry or acid then and be warming up to-10 ℃～20 ℃ and be hydrolyzed; Add ETHYLE ACETATE after hydrolysis is accomplished, filter and remove benzyl star hydrochloride, filtrate with after the sodium chloride aqueous solution washing; Organic phase adds sodium bicarbonate aqueous solution product is extracted into water; Add the chlorination sodium salt after the decolouring and analyse, cross the leaching deposition, get the compound of midbody formula (II) structure;

The compound of midbody formula (II) structure that (3) step (2) is made adds in the organic solvent B; Under-80～0 ℃ condition; Add organic acid and make its supersaturated solution that forms the de-methoxy cefoxitin acid, the methanol solution and the t-butyl hypochlorate of temperature control-95～-70 ℃ adding sodium methylate carry out the methoxy reaction then; After the methoxy reaction finished, adding Sodium Pyrosulfite and acetic acid neutralization added the water extraction, and water is crossed the leaching deposition through acid out, gets formula (I) compound, i.e. cefoxitin;

Organic solvent B be selected from one of methylene dichloride, THF, methyl alcohol or arbitrarily than combination.

2. preparation method as claimed in claim 1 is characterized in that, the compound of said step (1) Chinese style (IV) structure is deacetylate Glaxo) or deacetylate cefoxitin triethylamine salt.

3. preparation method as claimed in claim 1 is characterized in that, the compound and the N of said step (1) Chinese style (IV) structure, and the reaction mol ratio of N '-dibenzyl-ethylenediamin diacetate is 1: (0.5～1); Preferably, the organic solvent A in the said step (1) is: methylene dichloride or chloroform.

4. preparation method as claimed in claim 1 is characterized in that, the compound mol ratio of Sulfuryl chloride isocyanate and midbody formula (III) structure is (1～3) in the said step (2): 1.

5. preparation method as claimed in claim 1 is characterized in that, the acid in the said step (2) is hydrochloric acid or sulfuric acid.

6. preparation method as claimed in claim 1 is characterized in that, in the said step (3), it is-80～0 ℃ that organic acid adds temperature; Preferably, organic solvent B is methylene dichloride or THF, perhaps methylene dichloride, THF and the combination of methyl alcohol with any ratio.

7. preparation method as claimed in claim 1 is characterized in that, in the said step (3), organic acid be one of formic acid, trifluoroacetic acid, fluoroboric acid, methylsulfonic acid, p-methyl benzenesulfonic acid or arbitrarily than combination; Preferred organic acid is methylsulfonic acid or p-methyl benzenesulfonic acid.

8. preparation method as claimed in claim 1 is characterized in that, in the said step (3), the mol ratio of the compound of organic acid and midbody formula (II) structure is (1～2): 1.

9. preparation method as claimed in claim 1 is characterized in that, in the said step (3), the methoxy temperature of reaction is-95～-80 ℃, and the compound mol ratio of sodium methylate and midbody formula (II) structure is (3～8): 1; The compound mol ratio of t-butyl hypochlorate and midbody formula (II) structure is (1～3): 1.

10. preparation method as claimed in claim 1 is characterized in that, comprises the steps:

(1) in the aqueous solution 1000ml that contains deacetylate Glaxo) 100～120g, adds 200ml methylene dichloride (organic solvent A); And then temperature control adds 50～80g N for 20 ℃～40 ℃; The solution that N '-dibenzyl-ethylenediamin diacetate and 800ml water are made into, the compound of midbody formula (III) structure is separated out, and is cooled to 0～10 ℃; Cross the leaching deposition, obtain the compound of midbody formula (III) structure;

The compound of midbody formula (III) structure that (2) step (1) is made joins in the 1000ml acetone, is cooled to-50 ℃～-20 ℃ and drips Sulfuryl chloride isocyanate 35～60ml, carries out the carbamylation reaction; HPLC adds 198ml water after detecting carbamylation reaction completion, is warming up to-10～10 ℃ and is hydrolyzed; Add ETHYLE ACETATE 1980ml after hydrolysis is accomplished, filter and remove benzyl star hydrochloride, filtrating is washed with sodium chloride aqueous solution; Layering, organic phase add sodium bicarbonate aqueous solution product are extracted into water, and water adds activated carbon decolorizing then; Filter, filtrating adds the sodium-chlor of 200g to be saltoutd, and the compound of midbody formula (II) structure is separated out; Stir filtration in 1 hour, obtain the compound of midbody formula (II) structure;

The compound of midbody formula (II) structure that (3) step (2) is made joins in the 680ml THF, is cooled to-50～-10 ℃, adds 16.0～21.4ml methylsulfonic acid; Be cooled to-95～-80 ℃, the methanol solution and the 24.25～30.75g t-butyl hypochlorate that add 160～220g 30wt% sodium methylate then carry out the methoxy reaction, add 51g Sodium Pyrosulfite and 61.5ml Glacial acetic acid min. 99.5 after reaction is accomplished; Add activated carbon decolorizing then, add 850ml water again, regulate pH=2 with hydrochloric acid; Be cooled to 0～10 ℃; Cross the leaching deposition, obtain the compound of formula (I) structure, i.e. cefoxitin.