CN102807573A - Method for preparing ceftizoxime - Google Patents

Abstract

The invention provides a method for preparing ceftizoxime. The method comprises the following steps of: (1) dissolving 2-(2-amino-4-thiazolyl)-2-methoxy-imine acetic acid in an organic solvent, and reacting with N-succinimide under the catalysis of dicyclohexyl carbodiimide/dimethylamino pyridine (DCC/DMAP) to obtain active ester; (2) dissolving the active ester in dichloromethane, and adding 7-amino-3-demethylation-3-cephalosporanic acid (7-ANCA) and alkali for reacting to obtain ceftizoxime acid; and (3) reacting the ceftizoxime acid with a salifying agent to obtain the ceftizoxime, wherein the salifying agent is sodium acetate, sodium ethoxide, sodium 2-ethylhexanoate, sodium isocaproate, sodium bicarbonate or sodium hydroxide.

Description

A kind of preparation method of SKF-88373

 

Technical field

The present invention relates to a kind of preparation method of SKF-88373, belong to medical technical field.

 

Background technology

SKF-88373 is developed by Japanese Fujisawa Pharmaceutical Co., Ltd the earliest; And at first go on the market in Japan in nineteen eighty-two; It is English by name: Ceftizoxime, and molecular formula is: C13H13N5O5S2, chemical name is: (6r; 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino acetamido]-assorted two ring [4.2.0] oct-2-ene-2-carboxylic acid sodium salts of 8-oxo-5-thia-1-ammonia, structural formula is:

SKF-88373 belongs to third generation cephalosporin, has broad-spectrum antibacterial action, and is stable to the wide spectrum β-Nei Xiananmei (comprising penicillinase and cephalosporinase) of multiple gram-positive microorganism and Gram-negative bacteria generation.SKF-88373 has powerful anti-microbial effect to escherichia coli, Klebsiella Pneumoniae, Proteus mirabilis, and hemophilus influenzae and neisseria gonorrhoeae are had good anti-microbial effect.SKF-88373 reaches sterilization functions through the biosynthesizing that suppresses the bacteria cell wall mucopeptide.At present; SKF-88373 is mainly used in disease such as meningitis and simple property gonorrhoea due to lower respiratory infection, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, streptococcus pneumoniae or the hemophilus influenzae of treatment due to the sensitive organism clinically, and diseases such as wound and burn are also had extraordinary result of treatment.

Compound method about SKF-88373; Two lines are disclosed in the U.S. Pat 4427674; Article one, be to be raw material to methoxybenzyl ester with 7-phenylacetylamino-3-cephalosporin-4-carboxyl acid; Side chain is introduced 2-in the C7 position suitable-methoxyimino-2-(2-formamido group) thiazolyl acetic acid is sloughed the blocking group that C4 introduces side chain afterwards, obtains SKF-88373; Another is to be that raw material and the direct condensation of cefotaxime acetate get SKF-88373 with 7-amino-3-demethyl-3-Cephalosporanic acid (7-ANCA), and this route side reaction is more, and products therefrom needs through column chromatography purification.

People such as Zhang Fengxia have carried out improving (referring to " synthesizing of SKF-88373 " to above-mentioned the 2nd route; Zhang Fengxia etc., ACAD J GCP, the 23rd the 3rd phase of volume; 2007); With 7-ANCA is raw material, makes ceftizoxime acid with 2-(2-amino-4-thiazolyl)-2-methoxy imino acetyl benzothiazole thioesters (AE-active ester) condensation, obtains SKF-88373 with the salt forming agent reaction again.This method adopts active ester method, and technology is simple, and reaction conditions is gentle, and products therefrom impurity is few, and the yield that 7-ANCA and the condensation of AE-active ester make ceftizoxime acid is 90.3%.Yet be prone to residual 2-mercaptobenzothiazole (captax) in this method product, harmful.

 

Summary of the invention

In order to overcome the defective of prior art, the invention provides a kind of preparation method of SKF-88373.The product yield that obtains according to method of the present invention significantly improves, and residual harmful substance not in the product.

For realizing the foregoing invention purpose, the present invention provides following technical scheme:

The invention provides a kind of preparation method of SKF-88373, it comprises the steps:

(1) 2-(2-amino-4-thiazolyl)-2-methoxy imino acetate is dissolved in the organic solvent, under DCC/DMAP catalysis, obtains active ester, said organic solvent alcohols kind solvent, preferred alcohol with the reaction of N-succinimide;

(2) active ester is dissolved in the methylene dichloride, adds 7-ANCA and alkali reaction and obtain ceftizoxime acid; A kind of in described buck sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate, triethylamine, the diethylamine, preferred triethylamine;

(3) ceftizoxime acid obtains SKF-88373 with the salt forming agent reaction, and said salt forming agent is sodium acetate, sodium ethylate, Sodium isooctanoate, isocaproic acid sodium, sodium hydrogencarbonate or sodium hydroxide, preferred sodium hydrogencarbonate.

The present invention has changed the lower defective of domestic and international SKF-88373 raw material production moderate purity; The active ester reactive behavior that the present invention adopts is higher; 7-ANCA and active ester condensation make the yield of ceftizoxime acid up to more than 95%; Reduce the generation of impurity, especially avoided being prone in the prior art generation of residual harmful 2-mercaptobenzothiazole (captax).

 

Embodiment

With 2-(2-amino-4-thiazolyl)-2-methoxy imino acetate (2.01g 10mmol) is dissolved in the 20ml ethanol, add DMAP (1.83g, 15mmol) and DCC (3g; 6.0mmol) stirring at room is after half a hour, add N-hydroxy-succinamide (1.2g, 10mmol), stirring at room is after half a hour; After adding saturated NH4Cl solution stirring, ethyl acetate extraction is told ethyl acetate layer; Organic phase is washed through saturated common salt, anhydrous sodium sulfate drying, and steaming desolventizes; (wash-out of ethyl acetate/methanol=10:1) obtains active ester 2.8g, yield 94% to column chromatography.

(2.8g 9.4mmol) is dissolved in the 20ml methylene dichloride, and (1.9g 9.4mmol) with triethylamine 10ml stirring at room reaction after 8 hours, with the hydrochloric acid soln acid adjustment property (PH=2.0) of 1mol/l, and reacts 2h down at-5 ℃ to add 7-ANCA with active ester.Dichloromethane extraction, activated carbon decolorizing, dry back concentrate ceftizoxime acid 3.5g, yield 97%.MS(m/z):384(M+H)+。

With ceftizoxime acid (3.5g 9.1mmol) is dissolved in the 10ml ETHYLE ACETATE, splashes into the ETHYLE ACETATE 20ml that is dissolved with the 5g sodium hydrogencarbonate, 25 ℃ of stirring and crystallizing, the white crystal 3.6g of 30 ℃ of decompression oven dry, it is 99.1% that HPLC detects purity, MS (m/z): 406 (M+H)+.

According to the foregoing description the present invention has been made detailed description.Need to prove that above embodiment explains for example.Under the prerequisite that does not depart from the present invention's spirit and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood that within protection scope of the present invention.

Claims (1)

1. the preparation method of a SKF-88373, it comprises the steps:

(1) 2-(2-amino-4-thiazolyl)-2-methoxy imino acetate is dissolved in the organic solvent, under DCC/DMAP catalysis, obtains active ester, said organic solvent alcohols kind solvent, preferred alcohol with the reaction of N-succinimide;

(2) active ester is dissolved in the methylene dichloride, adds 7-ANCA and alkali reaction and obtain ceftizoxime acid; A kind of in described buck sodium hydroxide, Pottasium Hydroxide, sodium hydrogencarbonate, triethylamine, the diethylamine, preferred triethylamine;

(3) ceftizoxime acid obtains SKF-88373 with the salt forming agent reaction, and said salt forming agent is sodium acetate, sodium ethylate, Sodium isooctanoate, isocaproic acid sodium, sodium hydrogencarbonate or sodium hydroxide, preferred sodium hydrogencarbonate.